The most widely used treatment for patients with obstructive sleep apnea (OSA) is positive airway pressure (PAP) therapy. Improved quality of life and cardiovascular outcomes for patients with OSA using PAP have been demonstrated. However, for some patients with OSA, PAP therapy is difficult to use or tolerate. Fortunately, there are other available treatment interventions for patients with OSA such as lifestyle interventions, surgical interventions, hypoglossal nerve stimulation (HNS), oral appliance therapy (OAT), and expiratory PAP (EPAP) devices. These alternative treatments can also improve symptoms of OSA though data regarding cardiovascular outcomes are lacking.

LIFESTYLE INTERVENTIONS

Weight loss

Because a higher body mass index (BMI) increases the risk for OSA, weight loss should be recommended for patients with OSA who are overweight. Much of the research evaluating the effect of weight loss on OSA has methodologic limitations such as lack of randomization or controls, potential confounding variables, and limited follow-up. A randomized controlled trial of 72 overweight patients with mild OSA (apnea–hypopnea index [AHI] of 5 to 15) compared a group assigned to a very low calorie diet and lifestyle counseling with a control group.¹ At 1 year, weight loss of 15 kg or more resulted in a statistically significant reduction in their AHI to normal, resolving their OSA. A 15 kg weight loss in this study was associated with an overall reduction in the AHI of at least 2 units.

Exercise

Exercise is also recommended for patients with OSA, and it can lessen the severity of symptoms even without weight loss. A meta-analysis of 5 randomized trials of 129 patients reported a reduction in the AHI of as much as 6 events per hour in individuals assigned to a strict exercise regimen.² The reduction in the AHI occurred despite a slight reduction in BMI (1.37 kg/m²).

Sleep position

For some patients, sleeping in the supine position may worsen their OSA, in which case avoiding the supine sleep position is recommended. A sleep study such as polysomnography should be performed to confirm the resolution of OSA in the nonsupine position.³ Products such as pillows or vibratory feedback devices can help the patient avoid sleeping on the back. The ability to monitor patient adherence to sleep position therapy alone is very limited.

Alcohol avoidance

Alcohol consumption depresses the central nervous system, promotes waking, and increases daytime sleepiness, thus exacerbating OSA. Patients with untreated OSA should avoid alcohol because it worsens the duration and frequency of obstructive respiratory events during sleep, and it can worsen the degree of oxygen desaturation that occurs during abnormal respiratory events.⁴

Concomitant medications

A review of medications in patients with OSA is warranted. Use of benzodiazepines, benzodiazepine-receptor agonists, barbiturates, and opiates in patients with OSA should be avoided especially if OSA is untreated. If these medications are necessary, careful monitoring is recommended. Medications that can cause weight gain such as some antidepressants should also be avoided.

SURGICAL INTERVENTIONS

Surgical interventions for OSA target the location of the obstruction in the upper airway. The upper airway consists of 3 regions: the palate, oropharynx, and larynx.⁵ More than 30 surgical soft-tissue and skeletal interventions for OSA are reported in the literature.⁶

Evaluating the outcomes of various surgical interventions for OSA is hindered by differences in the definition of surgical success or cure. As such, surgical interventions for OSA remain controversial. The practice parameters from 2010 reviewed surgical modifications of the upper airway for adults with OSA.^7,8 Success is defined as a greater than 50% reduction in the AHI to fewer than 20 events per hour, whereas surgical cure is defined as a reduction in the AHI to fewer than 5 events per hour.⁷

Uvulopalatopharyngoplasty

Uvulopalatopharyngoplasty (UPPP) is a surgical procedure that remodels the throat via removal of the tonsils and the posterior surface of the soft palate and uvula and closure of the tonsillar pillars, and thus addresses retropalatal collapse. UPPP rarely achieves a surgical cure (ie, AHI < 5) and has been shown to have a 33% reduction in the AHI, with a postoperative average AHI remaining elevated at 29.⁸ (ie, moderate to severe OSA).8 In general, 50% of patients have a 50% reduction in AHI.⁹ The 4-year responder rate for UPPP is 44% to 50%.¹⁰ Factors limiting the long-term success of this procedure include weight gain, assessment of surgical candidates,¹¹ and decreased adherence to PAP therapy after the procedure.

The use of UPPP in combination with other surgical procedures has also been evaluated.⁸ The AHI in patients with OSA improved postoperatively when UPPP was done simultaneously or in a multiphase approach with radiofrequency ablation, midline glossectomy, tongue advancement, hyoid suspension, or maxillomandibular advancement, though greater improvement was noted with the multiphase approach.

Maxillomandibular advancement

Maxillomandibular advancement is a surgical procedure that moves the maxilla and mandible forward and expands the facial skeletal framework via LeFort I maxillary and sagittal split mandibular osteotomies. Maxillomandibular advancement achieves enlargement of the nasopharyngeal, retropalatal, and hypopharyngeal airway. This increases tension on the pharyngeal soft tissue, which enlarges the medial-lateral and anteroposterior dimensions of the upper airway.¹⁴

A meta-analysis of 45 studies evaluated the change in the AHI after maxillomandibular advancement in 518 patients.¹⁵ Secondary outcomes were surgical success (> 50% reduction in AHI to < 20 events per hour) and surgical cure (AHI < 5). Patients with a higher preoperative AHI achieved the greatest magnitude reduction in AHI but were less likely to achieve surgical success or cure. Patients with a lower preoperative AHI had a greater likelihood of surgical success and cure.

Bariatric surgery

Bariatric surgery is increasingly used for treatment of OSA in individuals with morbid obesity. A systematic review of bariatric surgery including the roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy, and biliopancreatic diversion evaluated 69 studies with 13,900 patients with OSA.¹⁶ OSA was found to be improved or eliminated in 75% of patients for all bariatric surgery procedures.

Used with permission from Inspire Medical Systems, Inc.

Indications and contraindications

The indications and contraindications for HNS are shown in Table 2.

Efficacy and outcomes

Stimulation of the hypoglossal nerve results in a multilevel mechanism of action: activation and protrusion of the tongue opens the oropharyngeal airway directly but also affects the retropalatal airway by a palatoglossal coupling action.¹⁹ Sleep lab testing with polysomnography is used to titrate the voltage of HNS to achieve an open airway that resolves apneic events and normalizes airflow, breathing patterns, and oxygen saturation levels.

Approval of HNS for OSA by the US Food and Drug Administration was based on findings in the Stimulation Therapy for Apnea Reduction (STAR) trial,¹⁷ a prospective trial of 126 patients at 22 centers in the United States and Europe with the primary outcomes of AHI and oxygen desaturation index. Secondary outcomes included quality of life as measured by the Functional Outcomes of Sleep Questionnaire and Epworth Sleepiness Scale (ESS). Patient demographics included mean age 54.5, 83% men, mean BMI of 28 kg/m², and mean baseline AHI of 34 (ie, severe OSA).

Data at 5 years for 97 of the 126 patients on HNS in the STAR trial is available.²⁰ The AHI was reduced an average of 70% to levels in the mild OSA range.^20,21 Overall, 85% of the patients had improved quality-of-life measures after HNS implantation, with increased Functional Outcomes of Sleep Questionnaire scores and ESS scores in the normal range over time. Consistent HNS therapy demonstrated sustained benefits at 5 years. The AHI improved by 50% or to less than 20 in 75% of patients, with 44% having resolved OSA and 78% improved to mild OSA (AHI < 15). Device-related adverse events occurred in 6% (9 of 126) of patients requiring replacement or repositioning of the stimulator or leads.²⁰

Moderate to severe snoring was prevalent at baseline in the STAR trial, but over the course of 5 years, 85% of bed partners of patients on HNS reported no or soft snoring.^17,21 Nightly use averaged 80% over 60 months based on patient reporting, with 87% reporting use at least 5 nights per week at 36 weeks.²⁰

In terms of predictors of response to HNS therapy, the oxygen desaturation index is the only characteristic that reached a level of statistical significance; patients with higher levels of oxygen desaturation tended to improve and tolerate therapy better long-term.²⁰ A randomized controlled trial of withdrawal of HNS therapy demonstrated increased AHI and oxygen desaturation index when therapy was withdrawn, followed by improvement when therapy resumed.²²

A clinical trial of 20 patients implanted with HNS after its approval in 2014 reported that the mean AHI decreased from 33 before implant to 5.1 after implant.²³ The ESS also improved from 10.3 before implant to 6 after implant. Mean adherence to device use was 7 (± 2) hours per night. The average stimulation amplitude was 1.89 (± 0.5) volts after the titration sleep study was completed. Similar reductions in AHI were reported by Huntley et al²⁴ for patients receiving HNS implant at 2 academic centers, with no differences between the 2 cohorts in postoperative AHI.

Adverse events

The adverse events reported with HNS are related to the implant procedure or the device.²¹ Procedure-related adverse events are incision discomfort, temporary tongue weakness, headache, and mild infection of incisions. The most common device-related adverse event is discomfort from the electrical stimulation. Tongue abrasion can also occur if the tongue protrudes and rubs against a sharp tooth. Dry mouth is also commonly reported.

HNS compared with UPPP

Outcomes in patients with moderate to severe OSA matched for BMI, demographics, and preoperative AHI were evaluated comparing patients undergoing HNS (n = 20) with patients receiving UPPP (n = 20).²⁵ The AHI decreased 29% postoperatively in patients with UPPP compared with 88% in patients with HNS, 65% of which had normalization of their AHI. Surgical success was achieved in 40% of patients in the UPPP group compared with 100% in the HNS group. Greater improvement in daytime sleepiness was noted in patients in the HNS group compared with the UPPP group.

OAT devices help protrude the mandible forward and stabilize it to maintain a more patent airway during sleep. Oral appliances can be custom-made or prefabricated. Oral appliances can be titratable or nontitratable: titration provides a mechanism to adjust mandibular protrusion analogous to PAP titration, whereas the absence of titration holds the mandible in a single position. The most effective oral appliances are custom-made and titratable.

Types of OAT devices

Custom oral appliances. Custom oral appliances are fabricated using digital or physical impressions of the patient’s oral structures. Custom oral appliances are made of biocompatible materials and engage both the maxillary and mandibular arches.

Custom oral appliances are made by a qualified dentist who takes maxillary and mandibular impressions with a bite registration using the George Gauge with 40% to 50% of maximum protrusion. The appliance is fabricated in a laboratory and then fitted to the patient, who is instructed to titrate the device 0.5 mm to 1 mm per week and follow-up with the dentist at 2-week intervals. Once the patient has titrated the device to the point of comfort or improved sleep quality or snoring, polysomnography should be done with the device in place and titrated to improve the AHI as much as possible. Follow-up is recommended at 6 months and annually thereafter.

Prefabricated oral appliances. Prefabricated oral appliances are of the boil-and-bite type, only partially modified to the patient’s oral structures.

Tongue-retaining devices. Another type of oral appliance is a tongue-retaining device, which is designed to hold the tongue forward and can be custom-made or prefabricated.

Patient considerations for OAT

Practice recommendations

• Prescribed OAT should be done by a qualified dentist, and a custom, titratable appliance is preferred
• OAT is preferred over no therapy for adults with OSA who are intolerant to PAP or prefer alternative therapies
• A qualified dentist should provide oversight for dental-related side effects or occlusal changes
• Follow-up sleep testing should be conducted to confirm efficacy or titrate treatment
• Periodic office visits with the sleep physician and qualified dentist are recommended.²⁶

The quality of evidence for these recommendations is low, with the exception of use of OAT rather than no therapy, which is considered of moderate quality.

Effects of OAT

Anatomic and physiologic effects. With OAT in place in the mouth, the airway caliber in the lateral dimension are increased, and the airway size at the retropalatal level is increased.^27–30 With respect to the tongue, increased genioglossus muscle activity has been reported with OAT.

Side effects. Side effects of OAT include excess salivation, dry mouth, tooth tenderness, soft-tissue changes, jaw discomfort, tooth movement, and occlusal changes such as difficulty chewing in the morning. Feelings of suffocation, vivid dreams, and anxiety have also been reported with OAT.^31–33

Efficacy and outcomes

Review of the data on the efficacy of OAT did not illuminate factors that predict treatment success.²⁶ Data indicate that in patients with mild OSA using OAT or PAP therapy, there was no significant difference in the percentage achieving their target AHI; however, patients with moderate to severe OSA had a statistically significant greater odds of achieving their target AHI using PAP therapy compared with OAT. Therefore, OAT should be reserved for patients with severe OSA who cannot use or are intolerant to PAP.

Moderate-grade quality of evidence was reviewed for the established OAT practice recommendations for OSA outcomes before and after use of custom, titratable OAT devices.²⁶ Use of a custom OAT device reduced the mean AHI, increased mean oxygen saturation, decreased the mean oxygen desaturation, decreased the arousal index, decreased the ESS, and increased quality of life compared with values prior to use of OAT.

With respect to adherence and discontinuation, patients using OAT had higher mean adherence and lower discontinuation because of side effects compared with patients using continuous PAP.²⁶

Nasal EPAP is a new treatment for OSA that consists of a mechanical valve worn in each naris at night. The valves have a low inspiratory resistance and a high expiratory resistance thus increased pressure occurs at exhalation.

Pressure at exhalation may counter the airway collapse in OSA. With the mouth closed and use of the nasal valves, the positive pressure during the normal respiratory cycle is utilized to maintain an open airway.³⁴ At the onset and throughout inspiration, the activity of the airway dilator muscles increases. At maximum expiration, right before the end of the expiratory pause, the dilator muscle stops abruptly and the airway is of its smallest caliber. The presence of the nasal valve at this point is thought to act as a pneumatic splint to the airway, and the nasal EPAP helps keep the airway patent during the next inspiratory phase.

Nasal EPAP valves are available in a 30-day starter kit. Intended for single-night use, the kit includes valves of increasing levels of expiration resistance: low (nights 1 and 2), medium (nights 3 and 4), and normal (nights 5–30).

Outcomes of nasal EPAP therapy

A multicenter 30-day in-home trial evaluated efficacy and compliance of nasal EPAP therapy.³⁵ The AHI was reduced by 50% or more in 14 of 34 (41%) patients using nasal EPAP compared with the control group at the 30-day follow-up. The patient-reported compliance with nasal EPAP was 94%. Patients in this study had mild to moderate OSA and did not have obesity or other comorbidities such as pulmonary hypertension or cardiovascular disease.

A randomized controlled trial compared nasal EPAP with a sham device in patients with newly diagnosed or untreated OSA (N = 250) for 3 months.³⁶ A median reduction of 52% in the AHI was noted in the intention-to-treat group (N = 229) during rapid eye movement (REM) and non-REM sleep, though it was statistically significant only during REM sleep and supine sleep. At 3 months, improved OSA was maintained in 42% of the patients using nasal EPAP compared with 10% of patients using a sham device. Improvements in daytime sleepiness and adherence with 88% using EPAP the entire night were also noted.

In a 12-month study of nasal EPAP, 67% of patients (34 of 51) used nasal EPAP for the full trial duration.³⁷ Of patients using nasal EPAP for 12 months, the median AHI was reduced by 71%, the ESS improved, and adherence to full-night use was 89%.

Patient considerations for nasal EPAP

In clinical practice, nasal EPAP therapy requires nasal patency and use of a chin strap in patients with mouth leakage. Nasal EPAP may be recommended for patients who travel frequently and can go without continuous PAP or bilevel PAP for short periods of time, and for patients who do not have significant medical comorbidities.

Side effects and limitations of nasal EPAP

Reported side effects of nasal EPAP include difficulty with exhalation, nasal discomfort, dry mouth, and headache. Nasal EPAP therapy is of limited use in patients with severe OSA and severe oxygen desaturation. The efficacy of nasal EPAP beyond 12 months is unknown. Use of nasal EPAP in patients with prior upper-airway surgery and in combination with other therapies is yet to be evaluated.

The most widely used treatment for patients with obstructive sleep apnea (OSA) is positive airway pressure (PAP) therapy. Improved quality of life and cardiovascular outcomes for patients with OSA using PAP have been demonstrated. However, for some patients with OSA, PAP therapy is difficult to use or tolerate. Fortunately, there are other available treatment interventions for patients with OSA such as lifestyle interventions, surgical interventions, hypoglossal nerve stimulation (HNS), oral appliance therapy (OAT), and expiratory PAP (EPAP) devices. These alternative treatments can also improve symptoms of OSA though data regarding cardiovascular outcomes are lacking.

LIFESTYLE INTERVENTIONS

Weight loss

Because a higher body mass index (BMI) increases the risk for OSA, weight loss should be recommended for patients with OSA who are overweight. Much of the research evaluating the effect of weight loss on OSA has methodologic limitations such as lack of randomization or controls, potential confounding variables, and limited follow-up. A randomized controlled trial of 72 overweight patients with mild OSA (apnea–hypopnea index [AHI] of 5 to 15) compared a group assigned to a very low calorie diet and lifestyle counseling with a control group.¹ At 1 year, weight loss of 15 kg or more resulted in a statistically significant reduction in their AHI to normal, resolving their OSA. A 15 kg weight loss in this study was associated with an overall reduction in the AHI of at least 2 units.

Exercise

Exercise is also recommended for patients with OSA, and it can lessen the severity of symptoms even without weight loss. A meta-analysis of 5 randomized trials of 129 patients reported a reduction in the AHI of as much as 6 events per hour in individuals assigned to a strict exercise regimen.² The reduction in the AHI occurred despite a slight reduction in BMI (1.37 kg/m²).

Sleep position

For some patients, sleeping in the supine position may worsen their OSA, in which case avoiding the supine sleep position is recommended. A sleep study such as polysomnography should be performed to confirm the resolution of OSA in the nonsupine position.³ Products such as pillows or vibratory feedback devices can help the patient avoid sleeping on the back. The ability to monitor patient adherence to sleep position therapy alone is very limited.

Alcohol avoidance

Alcohol consumption depresses the central nervous system, promotes waking, and increases daytime sleepiness, thus exacerbating OSA. Patients with untreated OSA should avoid alcohol because it worsens the duration and frequency of obstructive respiratory events during sleep, and it can worsen the degree of oxygen desaturation that occurs during abnormal respiratory events.⁴

Concomitant medications

A review of medications in patients with OSA is warranted. Use of benzodiazepines, benzodiazepine-receptor agonists, barbiturates, and opiates in patients with OSA should be avoided especially if OSA is untreated. If these medications are necessary, careful monitoring is recommended. Medications that can cause weight gain such as some antidepressants should also be avoided.

SURGICAL INTERVENTIONS

Surgical interventions for OSA target the location of the obstruction in the upper airway. The upper airway consists of 3 regions: the palate, oropharynx, and larynx.⁵ More than 30 surgical soft-tissue and skeletal interventions for OSA are reported in the literature.⁶

Evaluating the outcomes of various surgical interventions for OSA is hindered by differences in the definition of surgical success or cure. As such, surgical interventions for OSA remain controversial. The practice parameters from 2010 reviewed surgical modifications of the upper airway for adults with OSA.^7,8 Success is defined as a greater than 50% reduction in the AHI to fewer than 20 events per hour, whereas surgical cure is defined as a reduction in the AHI to fewer than 5 events per hour.⁷

Uvulopalatopharyngoplasty

Uvulopalatopharyngoplasty (UPPP) is a surgical procedure that remodels the throat via removal of the tonsils and the posterior surface of the soft palate and uvula and closure of the tonsillar pillars, and thus addresses retropalatal collapse. UPPP rarely achieves a surgical cure (ie, AHI < 5) and has been shown to have a 33% reduction in the AHI, with a postoperative average AHI remaining elevated at 29.⁸ (ie, moderate to severe OSA).8 In general, 50% of patients have a 50% reduction in AHI.⁹ The 4-year responder rate for UPPP is 44% to 50%.¹⁰ Factors limiting the long-term success of this procedure include weight gain, assessment of surgical candidates,¹¹ and decreased adherence to PAP therapy after the procedure.

The use of UPPP in combination with other surgical procedures has also been evaluated.⁸ The AHI in patients with OSA improved postoperatively when UPPP was done simultaneously or in a multiphase approach with radiofrequency ablation, midline glossectomy, tongue advancement, hyoid suspension, or maxillomandibular advancement, though greater improvement was noted with the multiphase approach.

Maxillomandibular advancement

Maxillomandibular advancement is a surgical procedure that moves the maxilla and mandible forward and expands the facial skeletal framework via LeFort I maxillary and sagittal split mandibular osteotomies. Maxillomandibular advancement achieves enlargement of the nasopharyngeal, retropalatal, and hypopharyngeal airway. This increases tension on the pharyngeal soft tissue, which enlarges the medial-lateral and anteroposterior dimensions of the upper airway.¹⁴

A meta-analysis of 45 studies evaluated the change in the AHI after maxillomandibular advancement in 518 patients.¹⁵ Secondary outcomes were surgical success (> 50% reduction in AHI to < 20 events per hour) and surgical cure (AHI < 5). Patients with a higher preoperative AHI achieved the greatest magnitude reduction in AHI but were less likely to achieve surgical success or cure. Patients with a lower preoperative AHI had a greater likelihood of surgical success and cure.

Bariatric surgery

Bariatric surgery is increasingly used for treatment of OSA in individuals with morbid obesity. A systematic review of bariatric surgery including the roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy, and biliopancreatic diversion evaluated 69 studies with 13,900 patients with OSA.¹⁶ OSA was found to be improved or eliminated in 75% of patients for all bariatric surgery procedures.

Used with permission from Inspire Medical Systems, Inc.

Indications and contraindications

The indications and contraindications for HNS are shown in Table 2.

Efficacy and outcomes

Stimulation of the hypoglossal nerve results in a multilevel mechanism of action: activation and protrusion of the tongue opens the oropharyngeal airway directly but also affects the retropalatal airway by a palatoglossal coupling action.¹⁹ Sleep lab testing with polysomnography is used to titrate the voltage of HNS to achieve an open airway that resolves apneic events and normalizes airflow, breathing patterns, and oxygen saturation levels.

Approval of HNS for OSA by the US Food and Drug Administration was based on findings in the Stimulation Therapy for Apnea Reduction (STAR) trial,¹⁷ a prospective trial of 126 patients at 22 centers in the United States and Europe with the primary outcomes of AHI and oxygen desaturation index. Secondary outcomes included quality of life as measured by the Functional Outcomes of Sleep Questionnaire and Epworth Sleepiness Scale (ESS). Patient demographics included mean age 54.5, 83% men, mean BMI of 28 kg/m², and mean baseline AHI of 34 (ie, severe OSA).

Data at 5 years for 97 of the 126 patients on HNS in the STAR trial is available.²⁰ The AHI was reduced an average of 70% to levels in the mild OSA range.^20,21 Overall, 85% of the patients had improved quality-of-life measures after HNS implantation, with increased Functional Outcomes of Sleep Questionnaire scores and ESS scores in the normal range over time. Consistent HNS therapy demonstrated sustained benefits at 5 years. The AHI improved by 50% or to less than 20 in 75% of patients, with 44% having resolved OSA and 78% improved to mild OSA (AHI < 15). Device-related adverse events occurred in 6% (9 of 126) of patients requiring replacement or repositioning of the stimulator or leads.²⁰

Moderate to severe snoring was prevalent at baseline in the STAR trial, but over the course of 5 years, 85% of bed partners of patients on HNS reported no or soft snoring.^17,21 Nightly use averaged 80% over 60 months based on patient reporting, with 87% reporting use at least 5 nights per week at 36 weeks.²⁰

In terms of predictors of response to HNS therapy, the oxygen desaturation index is the only characteristic that reached a level of statistical significance; patients with higher levels of oxygen desaturation tended to improve and tolerate therapy better long-term.²⁰ A randomized controlled trial of withdrawal of HNS therapy demonstrated increased AHI and oxygen desaturation index when therapy was withdrawn, followed by improvement when therapy resumed.²²

A clinical trial of 20 patients implanted with HNS after its approval in 2014 reported that the mean AHI decreased from 33 before implant to 5.1 after implant.²³ The ESS also improved from 10.3 before implant to 6 after implant. Mean adherence to device use was 7 (± 2) hours per night. The average stimulation amplitude was 1.89 (± 0.5) volts after the titration sleep study was completed. Similar reductions in AHI were reported by Huntley et al²⁴ for patients receiving HNS implant at 2 academic centers, with no differences between the 2 cohorts in postoperative AHI.

Adverse events

The adverse events reported with HNS are related to the implant procedure or the device.²¹ Procedure-related adverse events are incision discomfort, temporary tongue weakness, headache, and mild infection of incisions. The most common device-related adverse event is discomfort from the electrical stimulation. Tongue abrasion can also occur if the tongue protrudes and rubs against a sharp tooth. Dry mouth is also commonly reported.

HNS compared with UPPP

Outcomes in patients with moderate to severe OSA matched for BMI, demographics, and preoperative AHI were evaluated comparing patients undergoing HNS (n = 20) with patients receiving UPPP (n = 20).²⁵ The AHI decreased 29% postoperatively in patients with UPPP compared with 88% in patients with HNS, 65% of which had normalization of their AHI. Surgical success was achieved in 40% of patients in the UPPP group compared with 100% in the HNS group. Greater improvement in daytime sleepiness was noted in patients in the HNS group compared with the UPPP group.

OAT devices help protrude the mandible forward and stabilize it to maintain a more patent airway during sleep. Oral appliances can be custom-made or prefabricated. Oral appliances can be titratable or nontitratable: titration provides a mechanism to adjust mandibular protrusion analogous to PAP titration, whereas the absence of titration holds the mandible in a single position. The most effective oral appliances are custom-made and titratable.

Types of OAT devices

Custom oral appliances. Custom oral appliances are fabricated using digital or physical impressions of the patient’s oral structures. Custom oral appliances are made of biocompatible materials and engage both the maxillary and mandibular arches.

Custom oral appliances are made by a qualified dentist who takes maxillary and mandibular impressions with a bite registration using the George Gauge with 40% to 50% of maximum protrusion. The appliance is fabricated in a laboratory and then fitted to the patient, who is instructed to titrate the device 0.5 mm to 1 mm per week and follow-up with the dentist at 2-week intervals. Once the patient has titrated the device to the point of comfort or improved sleep quality or snoring, polysomnography should be done with the device in place and titrated to improve the AHI as much as possible. Follow-up is recommended at 6 months and annually thereafter.

Prefabricated oral appliances. Prefabricated oral appliances are of the boil-and-bite type, only partially modified to the patient’s oral structures.

Tongue-retaining devices. Another type of oral appliance is a tongue-retaining device, which is designed to hold the tongue forward and can be custom-made or prefabricated.

Patient considerations for OAT

Practice recommendations

• Prescribed OAT should be done by a qualified dentist, and a custom, titratable appliance is preferred
• OAT is preferred over no therapy for adults with OSA who are intolerant to PAP or prefer alternative therapies
• A qualified dentist should provide oversight for dental-related side effects or occlusal changes
• Follow-up sleep testing should be conducted to confirm efficacy or titrate treatment
• Periodic office visits with the sleep physician and qualified dentist are recommended.²⁶

The quality of evidence for these recommendations is low, with the exception of use of OAT rather than no therapy, which is considered of moderate quality.

Effects of OAT

Anatomic and physiologic effects. With OAT in place in the mouth, the airway caliber in the lateral dimension are increased, and the airway size at the retropalatal level is increased.^27–30 With respect to the tongue, increased genioglossus muscle activity has been reported with OAT.

Side effects. Side effects of OAT include excess salivation, dry mouth, tooth tenderness, soft-tissue changes, jaw discomfort, tooth movement, and occlusal changes such as difficulty chewing in the morning. Feelings of suffocation, vivid dreams, and anxiety have also been reported with OAT.^31–33

Efficacy and outcomes

Review of the data on the efficacy of OAT did not illuminate factors that predict treatment success.²⁶ Data indicate that in patients with mild OSA using OAT or PAP therapy, there was no significant difference in the percentage achieving their target AHI; however, patients with moderate to severe OSA had a statistically significant greater odds of achieving their target AHI using PAP therapy compared with OAT. Therefore, OAT should be reserved for patients with severe OSA who cannot use or are intolerant to PAP.

Moderate-grade quality of evidence was reviewed for the established OAT practice recommendations for OSA outcomes before and after use of custom, titratable OAT devices.²⁶ Use of a custom OAT device reduced the mean AHI, increased mean oxygen saturation, decreased the mean oxygen desaturation, decreased the arousal index, decreased the ESS, and increased quality of life compared with values prior to use of OAT.

With respect to adherence and discontinuation, patients using OAT had higher mean adherence and lower discontinuation because of side effects compared with patients using continuous PAP.²⁶

Nasal EPAP is a new treatment for OSA that consists of a mechanical valve worn in each naris at night. The valves have a low inspiratory resistance and a high expiratory resistance thus increased pressure occurs at exhalation.

Pressure at exhalation may counter the airway collapse in OSA. With the mouth closed and use of the nasal valves, the positive pressure during the normal respiratory cycle is utilized to maintain an open airway.³⁴ At the onset and throughout inspiration, the activity of the airway dilator muscles increases. At maximum expiration, right before the end of the expiratory pause, the dilator muscle stops abruptly and the airway is of its smallest caliber. The presence of the nasal valve at this point is thought to act as a pneumatic splint to the airway, and the nasal EPAP helps keep the airway patent during the next inspiratory phase.

Nasal EPAP valves are available in a 30-day starter kit. Intended for single-night use, the kit includes valves of increasing levels of expiration resistance: low (nights 1 and 2), medium (nights 3 and 4), and normal (nights 5–30).

Outcomes of nasal EPAP therapy

A multicenter 30-day in-home trial evaluated efficacy and compliance of nasal EPAP therapy.³⁵ The AHI was reduced by 50% or more in 14 of 34 (41%) patients using nasal EPAP compared with the control group at the 30-day follow-up. The patient-reported compliance with nasal EPAP was 94%. Patients in this study had mild to moderate OSA and did not have obesity or other comorbidities such as pulmonary hypertension or cardiovascular disease.

A randomized controlled trial compared nasal EPAP with a sham device in patients with newly diagnosed or untreated OSA (N = 250) for 3 months.³⁶ A median reduction of 52% in the AHI was noted in the intention-to-treat group (N = 229) during rapid eye movement (REM) and non-REM sleep, though it was statistically significant only during REM sleep and supine sleep. At 3 months, improved OSA was maintained in 42% of the patients using nasal EPAP compared with 10% of patients using a sham device. Improvements in daytime sleepiness and adherence with 88% using EPAP the entire night were also noted.

In a 12-month study of nasal EPAP, 67% of patients (34 of 51) used nasal EPAP for the full trial duration.³⁷ Of patients using nasal EPAP for 12 months, the median AHI was reduced by 71%, the ESS improved, and adherence to full-night use was 89%.

Patient considerations for nasal EPAP

In clinical practice, nasal EPAP therapy requires nasal patency and use of a chin strap in patients with mouth leakage. Nasal EPAP may be recommended for patients who travel frequently and can go without continuous PAP or bilevel PAP for short periods of time, and for patients who do not have significant medical comorbidities.

Side effects and limitations of nasal EPAP

Reported side effects of nasal EPAP include difficulty with exhalation, nasal discomfort, dry mouth, and headache. Nasal EPAP therapy is of limited use in patients with severe OSA and severe oxygen desaturation. The efficacy of nasal EPAP beyond 12 months is unknown. Use of nasal EPAP in patients with prior upper-airway surgery and in combination with other therapies is yet to be evaluated.

The most widely used treatment for patients with obstructive sleep apnea (OSA) is positive airway pressure (PAP) therapy. Improved quality of life and cardiovascular outcomes for patients with OSA using PAP have been demonstrated. However, for some patients with OSA, PAP therapy is difficult to use or tolerate. Fortunately, there are other available treatment interventions for patients with OSA such as lifestyle interventions, surgical interventions, hypoglossal nerve stimulation (HNS), oral appliance therapy (OAT), and expiratory PAP (EPAP) devices. These alternative treatments can also improve symptoms of OSA though data regarding cardiovascular outcomes are lacking.

LIFESTYLE INTERVENTIONS

Weight loss

Because a higher body mass index (BMI) increases the risk for OSA, weight loss should be recommended for patients with OSA who are overweight. Much of the research evaluating the effect of weight loss on OSA has methodologic limitations such as lack of randomization or controls, potential confounding variables, and limited follow-up. A randomized controlled trial of 72 overweight patients with mild OSA (apnea–hypopnea index [AHI] of 5 to 15) compared a group assigned to a very low calorie diet and lifestyle counseling with a control group.¹ At 1 year, weight loss of 15 kg or more resulted in a statistically significant reduction in their AHI to normal, resolving their OSA. A 15 kg weight loss in this study was associated with an overall reduction in the AHI of at least 2 units.

Exercise

Exercise is also recommended for patients with OSA, and it can lessen the severity of symptoms even without weight loss. A meta-analysis of 5 randomized trials of 129 patients reported a reduction in the AHI of as much as 6 events per hour in individuals assigned to a strict exercise regimen.² The reduction in the AHI occurred despite a slight reduction in BMI (1.37 kg/m²).

Sleep position

For some patients, sleeping in the supine position may worsen their OSA, in which case avoiding the supine sleep position is recommended. A sleep study such as polysomnography should be performed to confirm the resolution of OSA in the nonsupine position.³ Products such as pillows or vibratory feedback devices can help the patient avoid sleeping on the back. The ability to monitor patient adherence to sleep position therapy alone is very limited.

Alcohol avoidance

Alcohol consumption depresses the central nervous system, promotes waking, and increases daytime sleepiness, thus exacerbating OSA. Patients with untreated OSA should avoid alcohol because it worsens the duration and frequency of obstructive respiratory events during sleep, and it can worsen the degree of oxygen desaturation that occurs during abnormal respiratory events.⁴

Concomitant medications

A review of medications in patients with OSA is warranted. Use of benzodiazepines, benzodiazepine-receptor agonists, barbiturates, and opiates in patients with OSA should be avoided especially if OSA is untreated. If these medications are necessary, careful monitoring is recommended. Medications that can cause weight gain such as some antidepressants should also be avoided.

SURGICAL INTERVENTIONS

Surgical interventions for OSA target the location of the obstruction in the upper airway. The upper airway consists of 3 regions: the palate, oropharynx, and larynx.⁵ More than 30 surgical soft-tissue and skeletal interventions for OSA are reported in the literature.⁶

Evaluating the outcomes of various surgical interventions for OSA is hindered by differences in the definition of surgical success or cure. As such, surgical interventions for OSA remain controversial. The practice parameters from 2010 reviewed surgical modifications of the upper airway for adults with OSA.^7,8 Success is defined as a greater than 50% reduction in the AHI to fewer than 20 events per hour, whereas surgical cure is defined as a reduction in the AHI to fewer than 5 events per hour.⁷

Uvulopalatopharyngoplasty

Uvulopalatopharyngoplasty (UPPP) is a surgical procedure that remodels the throat via removal of the tonsils and the posterior surface of the soft palate and uvula and closure of the tonsillar pillars, and thus addresses retropalatal collapse. UPPP rarely achieves a surgical cure (ie, AHI < 5) and has been shown to have a 33% reduction in the AHI, with a postoperative average AHI remaining elevated at 29.⁸ (ie, moderate to severe OSA).8 In general, 50% of patients have a 50% reduction in AHI.⁹ The 4-year responder rate for UPPP is 44% to 50%.¹⁰ Factors limiting the long-term success of this procedure include weight gain, assessment of surgical candidates,¹¹ and decreased adherence to PAP therapy after the procedure.

The use of UPPP in combination with other surgical procedures has also been evaluated.⁸ The AHI in patients with OSA improved postoperatively when UPPP was done simultaneously or in a multiphase approach with radiofrequency ablation, midline glossectomy, tongue advancement, hyoid suspension, or maxillomandibular advancement, though greater improvement was noted with the multiphase approach.

Maxillomandibular advancement

Maxillomandibular advancement is a surgical procedure that moves the maxilla and mandible forward and expands the facial skeletal framework via LeFort I maxillary and sagittal split mandibular osteotomies. Maxillomandibular advancement achieves enlargement of the nasopharyngeal, retropalatal, and hypopharyngeal airway. This increases tension on the pharyngeal soft tissue, which enlarges the medial-lateral and anteroposterior dimensions of the upper airway.¹⁴

A meta-analysis of 45 studies evaluated the change in the AHI after maxillomandibular advancement in 518 patients.¹⁵ Secondary outcomes were surgical success (> 50% reduction in AHI to < 20 events per hour) and surgical cure (AHI < 5). Patients with a higher preoperative AHI achieved the greatest magnitude reduction in AHI but were less likely to achieve surgical success or cure. Patients with a lower preoperative AHI had a greater likelihood of surgical success and cure.

Bariatric surgery

Bariatric surgery is increasingly used for treatment of OSA in individuals with morbid obesity. A systematic review of bariatric surgery including the roux-en-Y gastric bypass, laparoscopic sleeve gastrectomy, and biliopancreatic diversion evaluated 69 studies with 13,900 patients with OSA.¹⁶ OSA was found to be improved or eliminated in 75% of patients for all bariatric surgery procedures.

Used with permission from Inspire Medical Systems, Inc.

Indications and contraindications

The indications and contraindications for HNS are shown in Table 2.

Efficacy and outcomes

Stimulation of the hypoglossal nerve results in a multilevel mechanism of action: activation and protrusion of the tongue opens the oropharyngeal airway directly but also affects the retropalatal airway by a palatoglossal coupling action.¹⁹ Sleep lab testing with polysomnography is used to titrate the voltage of HNS to achieve an open airway that resolves apneic events and normalizes airflow, breathing patterns, and oxygen saturation levels.

Approval of HNS for OSA by the US Food and Drug Administration was based on findings in the Stimulation Therapy for Apnea Reduction (STAR) trial,¹⁷ a prospective trial of 126 patients at 22 centers in the United States and Europe with the primary outcomes of AHI and oxygen desaturation index. Secondary outcomes included quality of life as measured by the Functional Outcomes of Sleep Questionnaire and Epworth Sleepiness Scale (ESS). Patient demographics included mean age 54.5, 83% men, mean BMI of 28 kg/m², and mean baseline AHI of 34 (ie, severe OSA).

Data at 5 years for 97 of the 126 patients on HNS in the STAR trial is available.²⁰ The AHI was reduced an average of 70% to levels in the mild OSA range.^20,21 Overall, 85% of the patients had improved quality-of-life measures after HNS implantation, with increased Functional Outcomes of Sleep Questionnaire scores and ESS scores in the normal range over time. Consistent HNS therapy demonstrated sustained benefits at 5 years. The AHI improved by 50% or to less than 20 in 75% of patients, with 44% having resolved OSA and 78% improved to mild OSA (AHI < 15). Device-related adverse events occurred in 6% (9 of 126) of patients requiring replacement or repositioning of the stimulator or leads.²⁰

Moderate to severe snoring was prevalent at baseline in the STAR trial, but over the course of 5 years, 85% of bed partners of patients on HNS reported no or soft snoring.^17,21 Nightly use averaged 80% over 60 months based on patient reporting, with 87% reporting use at least 5 nights per week at 36 weeks.²⁰

In terms of predictors of response to HNS therapy, the oxygen desaturation index is the only characteristic that reached a level of statistical significance; patients with higher levels of oxygen desaturation tended to improve and tolerate therapy better long-term.²⁰ A randomized controlled trial of withdrawal of HNS therapy demonstrated increased AHI and oxygen desaturation index when therapy was withdrawn, followed by improvement when therapy resumed.²²

A clinical trial of 20 patients implanted with HNS after its approval in 2014 reported that the mean AHI decreased from 33 before implant to 5.1 after implant.²³ The ESS also improved from 10.3 before implant to 6 after implant. Mean adherence to device use was 7 (± 2) hours per night. The average stimulation amplitude was 1.89 (± 0.5) volts after the titration sleep study was completed. Similar reductions in AHI were reported by Huntley et al²⁴ for patients receiving HNS implant at 2 academic centers, with no differences between the 2 cohorts in postoperative AHI.

Adverse events

The adverse events reported with HNS are related to the implant procedure or the device.²¹ Procedure-related adverse events are incision discomfort, temporary tongue weakness, headache, and mild infection of incisions. The most common device-related adverse event is discomfort from the electrical stimulation. Tongue abrasion can also occur if the tongue protrudes and rubs against a sharp tooth. Dry mouth is also commonly reported.

HNS compared with UPPP

Outcomes in patients with moderate to severe OSA matched for BMI, demographics, and preoperative AHI were evaluated comparing patients undergoing HNS (n = 20) with patients receiving UPPP (n = 20).²⁵ The AHI decreased 29% postoperatively in patients with UPPP compared with 88% in patients with HNS, 65% of which had normalization of their AHI. Surgical success was achieved in 40% of patients in the UPPP group compared with 100% in the HNS group. Greater improvement in daytime sleepiness was noted in patients in the HNS group compared with the UPPP group.

OAT devices help protrude the mandible forward and stabilize it to maintain a more patent airway during sleep. Oral appliances can be custom-made or prefabricated. Oral appliances can be titratable or nontitratable: titration provides a mechanism to adjust mandibular protrusion analogous to PAP titration, whereas the absence of titration holds the mandible in a single position. The most effective oral appliances are custom-made and titratable.

Types of OAT devices

Custom oral appliances. Custom oral appliances are fabricated using digital or physical impressions of the patient’s oral structures. Custom oral appliances are made of biocompatible materials and engage both the maxillary and mandibular arches.

Custom oral appliances are made by a qualified dentist who takes maxillary and mandibular impressions with a bite registration using the George Gauge with 40% to 50% of maximum protrusion. The appliance is fabricated in a laboratory and then fitted to the patient, who is instructed to titrate the device 0.5 mm to 1 mm per week and follow-up with the dentist at 2-week intervals. Once the patient has titrated the device to the point of comfort or improved sleep quality or snoring, polysomnography should be done with the device in place and titrated to improve the AHI as much as possible. Follow-up is recommended at 6 months and annually thereafter.

Prefabricated oral appliances. Prefabricated oral appliances are of the boil-and-bite type, only partially modified to the patient’s oral structures.

Tongue-retaining devices. Another type of oral appliance is a tongue-retaining device, which is designed to hold the tongue forward and can be custom-made or prefabricated.

Patient considerations for OAT

Practice recommendations

• Prescribed OAT should be done by a qualified dentist, and a custom, titratable appliance is preferred
• OAT is preferred over no therapy for adults with OSA who are intolerant to PAP or prefer alternative therapies
• A qualified dentist should provide oversight for dental-related side effects or occlusal changes
• Follow-up sleep testing should be conducted to confirm efficacy or titrate treatment
• Periodic office visits with the sleep physician and qualified dentist are recommended.²⁶

The quality of evidence for these recommendations is low, with the exception of use of OAT rather than no therapy, which is considered of moderate quality.

Effects of OAT

Anatomic and physiologic effects. With OAT in place in the mouth, the airway caliber in the lateral dimension are increased, and the airway size at the retropalatal level is increased.^27–30 With respect to the tongue, increased genioglossus muscle activity has been reported with OAT.

Side effects. Side effects of OAT include excess salivation, dry mouth, tooth tenderness, soft-tissue changes, jaw discomfort, tooth movement, and occlusal changes such as difficulty chewing in the morning. Feelings of suffocation, vivid dreams, and anxiety have also been reported with OAT.^31–33

Efficacy and outcomes

Review of the data on the efficacy of OAT did not illuminate factors that predict treatment success.²⁶ Data indicate that in patients with mild OSA using OAT or PAP therapy, there was no significant difference in the percentage achieving their target AHI; however, patients with moderate to severe OSA had a statistically significant greater odds of achieving their target AHI using PAP therapy compared with OAT. Therefore, OAT should be reserved for patients with severe OSA who cannot use or are intolerant to PAP.

Moderate-grade quality of evidence was reviewed for the established OAT practice recommendations for OSA outcomes before and after use of custom, titratable OAT devices.²⁶ Use of a custom OAT device reduced the mean AHI, increased mean oxygen saturation, decreased the mean oxygen desaturation, decreased the arousal index, decreased the ESS, and increased quality of life compared with values prior to use of OAT.

With respect to adherence and discontinuation, patients using OAT had higher mean adherence and lower discontinuation because of side effects compared with patients using continuous PAP.²⁶

Nasal EPAP is a new treatment for OSA that consists of a mechanical valve worn in each naris at night. The valves have a low inspiratory resistance and a high expiratory resistance thus increased pressure occurs at exhalation.

Pressure at exhalation may counter the airway collapse in OSA. With the mouth closed and use of the nasal valves, the positive pressure during the normal respiratory cycle is utilized to maintain an open airway.³⁴ At the onset and throughout inspiration, the activity of the airway dilator muscles increases. At maximum expiration, right before the end of the expiratory pause, the dilator muscle stops abruptly and the airway is of its smallest caliber. The presence of the nasal valve at this point is thought to act as a pneumatic splint to the airway, and the nasal EPAP helps keep the airway patent during the next inspiratory phase.

Nasal EPAP valves are available in a 30-day starter kit. Intended for single-night use, the kit includes valves of increasing levels of expiration resistance: low (nights 1 and 2), medium (nights 3 and 4), and normal (nights 5–30).

Outcomes of nasal EPAP therapy

A multicenter 30-day in-home trial evaluated efficacy and compliance of nasal EPAP therapy.³⁵ The AHI was reduced by 50% or more in 14 of 34 (41%) patients using nasal EPAP compared with the control group at the 30-day follow-up. The patient-reported compliance with nasal EPAP was 94%. Patients in this study had mild to moderate OSA and did not have obesity or other comorbidities such as pulmonary hypertension or cardiovascular disease.

A randomized controlled trial compared nasal EPAP with a sham device in patients with newly diagnosed or untreated OSA (N = 250) for 3 months.³⁶ A median reduction of 52% in the AHI was noted in the intention-to-treat group (N = 229) during rapid eye movement (REM) and non-REM sleep, though it was statistically significant only during REM sleep and supine sleep. At 3 months, improved OSA was maintained in 42% of the patients using nasal EPAP compared with 10% of patients using a sham device. Improvements in daytime sleepiness and adherence with 88% using EPAP the entire night were also noted.

In a 12-month study of nasal EPAP, 67% of patients (34 of 51) used nasal EPAP for the full trial duration.³⁷ Of patients using nasal EPAP for 12 months, the median AHI was reduced by 71%, the ESS improved, and adherence to full-night use was 89%.

Patient considerations for nasal EPAP

In clinical practice, nasal EPAP therapy requires nasal patency and use of a chin strap in patients with mouth leakage. Nasal EPAP may be recommended for patients who travel frequently and can go without continuous PAP or bilevel PAP for short periods of time, and for patients who do not have significant medical comorbidities.

Side effects and limitations of nasal EPAP

Reported side effects of nasal EPAP include difficulty with exhalation, nasal discomfort, dry mouth, and headache. Nasal EPAP therapy is of limited use in patients with severe OSA and severe oxygen desaturation. The efficacy of nasal EPAP beyond 12 months is unknown. Use of nasal EPAP in patients with prior upper-airway surgery and in combination with other therapies is yet to be evaluated.

Supplement Editor:
Nancy Foldvary-Schaefer

Contents

Introduction—Obstructive sleep apnea: A wake-up call for better outcomes
Nancy Foldvary-Schaefer

Obstructive sleep apnea basics
Jessica Vensel Rundo

Sleep apnea and the heart
Reena Mehra

Beyond heart health: Consequences of obstructive sleep apnea
Harneet K. Walia

Positive airway pressure: Making an impact on sleep apnea
Colleen G. Lance

Alternative interventions for obstructive sleep apnea
Tina Waters

Click for related Cleveland Clinic CME activities.

Supplement Editor:
Nancy Foldvary-Schaefer

Contents

Introduction—Obstructive sleep apnea: A wake-up call for better outcomes
Nancy Foldvary-Schaefer

Obstructive sleep apnea basics
Jessica Vensel Rundo

Sleep apnea and the heart
Reena Mehra

Beyond heart health: Consequences of obstructive sleep apnea
Harneet K. Walia

Positive airway pressure: Making an impact on sleep apnea
Colleen G. Lance

Alternative interventions for obstructive sleep apnea
Tina Waters

Click for related Cleveland Clinic CME activities.

Supplement Editor:
Nancy Foldvary-Schaefer

Contents

Introduction—Obstructive sleep apnea: A wake-up call for better outcomes
Nancy Foldvary-Schaefer

Obstructive sleep apnea basics
Jessica Vensel Rundo

Sleep apnea and the heart
Reena Mehra

Beyond heart health: Consequences of obstructive sleep apnea
Harneet K. Walia

Positive airway pressure: Making an impact on sleep apnea
Colleen G. Lance

Alternative interventions for obstructive sleep apnea
Tina Waters

Click for related Cleveland Clinic CME activities.

Cardiovascular disease became the leading cause of death in the United States in the early 20th century, and it accounts for nearly half of all deaths in industrialized nations.¹ The mortality it inflicts was thought to be shared equally between both sexes and among all age groups and races.² The cardiology community implemented innovative epidemiologic research, through which risk factors for cardiovascular disease were established.¹ The development of coronary care units reduced in-hospital mortality from acute myocardial infarction from 30% to 15%.^2–5 Further advances in pharmacology, revascularization, and imaging have aided in the detection and treatment of cardiovascular disease.⁶ Though cardiovascular disease remains the number-one cause of death worldwide, rates are on the decline.⁷

For several decades, health disparities have been recognized as a source of pathology in cardiovascular medicine, resulting in inequity of care administration among select populations. In this review, we examine whether the same forward thinking that has resulted in a decline in cardiovascular disease has had an impact on the pervasive disparities in cardiovascular medicine.

DISPARITIES DEFINED

Compared with whites, members of minority groups have a higher burden of chronic diseases, receive lower quality care, and have less access to medical care. Recognizing the potential public health ramifications, in 1999 the US Congress tasked the Institute of Medicine to study and assess the extent of healthcare disparities. This led to the landmark publication, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.⁸

The Institute of Medicine defines disparities in healthcare as racial or ethnic differences in the quality of healthcare that are not due to access-related factors, clinical needs, preferences, and appropriateness of intervention.⁸ Disparities can also exist according to socioeconomic status and sex.⁹

In an early study documenting the concept of disparities in cardiovascular disease, Stone and Vanzant¹⁰ concluded that heart disease was more common in African Americans than in whites, and that hypertension was the principal cause of cardiovascular disease mortality in African Americans.

Data from US Centers for Disease Control and Prevention, reference 11

Although avoidable deaths from heart disease, stroke, and hypertensive disease declined between 2001 and 2010, African Americans still have a higher mortality rate than other racial and ethnic groups (Figure 1).¹¹

DISPARITIES AND CARDIOVASCULAR HEALTH

The concept of cardiovascular health was established by the American Heart Association (AHA) in efforts to achieve an additional 20% reduction in cardiovascular disease-related mortality by 2020.⁷ Cardiovascular health is defined as the absence of clinically manifest cardiovascular disease and is measured by 7 components:

• Not smoking or abstaining from smoking for at least 1 year
• A normal body weight, defined as a body mass index less than 25 kg/m²
• Optimal physical activity, defined as 75 minutes of vigorous physical activity or 150 minutes of moderate-intensity physical activity per week
• Regular consumption of a healthy diet
• Total cholesterol below 200 mg/dL
• Blood pressure less than 120/80 mm Hg
• Fasting blood sugar below 100 mg/dL.

Nearly 70% of the US population can claim 2, 3, or 4 of these components, but differences exist according to race,¹² and 60% of adult white Americans are limited to achieving no more than 3 of these healthy metrics, compared with 70% of adult African Americans and Hispanic Americans.

Smoking

Smoking is a major risk factor for cardiovascular disease.^12–14

Data from National Health Interview Surgery, Jamal et al, reference 16

During adolescence, white males are more likely to smoke than African American and Hispanic males,¹² but this trend reverses in adulthood, when African American men have a higher prevalence of smoking than white men (21.4% vs 19%).⁷ Rates of lifetime use are highest among American Indian or Alaskan natives and whites (75.9%), followed by African Americans (58.4%), native Hawaiians (56.8%), and Hispanics (56.7%).¹⁵ Trends for current smoking are similar (Figure 2).¹⁶ Moreover, households with lower socioeconomic status have a higher prevalence of smoking.⁷

Physical activity

People with a sedentary lifestyle are more likely to die of cardiovascular disease. As many as 250,000 deaths annually in the United States are attributed to lack of regular physical activity.¹⁷

Recognizing the potential public health ramifications, the AHA and the 2018 Federal Guidelines on Physical Activity recommend that children engage in 60 minutes of daily physical activity and that adults participate in 150 minutes of moderate-intensity or 75 minutes of vigorous physical activity weekly.^18,19

Data from Behavioral Risk Factor Surveillance System, Omura et al, reference 20

In the United States, 15.2% of adolescents reported being physically inactive, according to data published in 2016.⁷ Similar to most cardiovascular risk factors, minority populations and those of lower socioeconomic status had the worst profiles. The prevalence of physical inactivity was highest in African Americans and Hispanics (Figure 3).²⁰

Studies have shown an association between screen-based sedentary behavior (computers, television, and video games) and cardiovascular disease.^21–23 In the United States, 41% of adolescents used computers for activities other than homework for more than 3 hours per day on a school day.⁷ The pattern of use was highest in African American boys and African American girls, followed by Hispanic girls and Hispanic boys.¹⁸ Trends were similar with regard to watching television for more than 3 hours per day.

Sedentary behavior persists into adulthood, with rates of inactivity of 38.3% in African Americans, 40.1% in Hispanics, and 26.3% in white adults.⁷

Nutrition plays a major role in cardiovascular disease, specifically in the pathogenesis of atherosclerotic disease and hypertension.²⁴ Most Americans do not meet dietary recommendations, with minority communities performing worse in specific metrics.⁷

Dietary patterns are reflected in the rate of obesity in this nation. Studies have shown a direct correlation between obesity and cardiovascular disease such as coronary artery disease, heart failure, and atrial fibrillation.^25–28 According to data from the National Health and Nutrition Examination Survey (NHANES), 31% of children between the ages of 2 and 19 years are classified as obese or overweight. The highest rates of obesity are seen in Hispanic and African American boys and girls. The obesity epidemic is disproportionately rampant in children living in households with low income, low education, and high unemployment rates.^7,29–31

Despite the risks associated with obesity, only 64.8% of obese adults report being informed by a doctor or health professional that they were overweight. The proportion of obese adults informed that they were overweight was significantly lower for African Americans and Hispanics compared with whites. Similar differences are seen based on socioeconomic status, as middle-income patients were less likely to be informed than those in the higher income strata (62.4% vs 70.6%).^7,31

Blood pressure

Hypertension is a well-established risk factor for cardiovascular disease and stroke, and a blood pressure of 120/80 mm Hg or lower is identified as a component of ideal cardiovascular health.

In the United States the prevalence of hypertension in adults older than 20 is 32%.⁷ The prevalence of hypertension in African Americans is among the highest in the world.^32,33 African Americans develop high blood pressure at earlier ages, and their average resting blood pressures are higher than in whites.^34,35 For a 45-year-old without hypertension, the 40-year risk of developing hypertension is 92.7% for African Americans and 86% for whites.³⁵ Hypertension is a major risk factor for stroke, and African Americans have a 1.8 times greater rate of fatal stroke than whites.⁷

In 2013 there were 71,942 deaths attributable to high blood pressure, and the 2011 death rate associated with hypertension was 18.9 per 100,000. By race, the death rate was 17.6 per 100,000 for white males and an alarming 47.1 per 100,000 for African American males; rates were 15.2 per 100,000 for white females and 35.1 per 100,000 for African American females.⁷

It is unclear what accounts for the racial difference in prevalence in hypertension. Studies have shown that African Americans are more likely than whites to have been told on more than 2 occasions that they have hypertension. And 85.7% of African Americans are aware that they have high blood pressure, compared with 82.7% of whites.¹⁴

African Americans and Hispanics have poorer hypertension control compared with whites.^36,37 These observed differences cannot be attributed to access alone, as African Americans were more likely to be on higher-intensity blood pressure therapy, whereas Hispanics were more likely to be undertreated.^36,38 In a meta-analysis of 13 trials, Peck et al³⁹ showed that African Americans showed a lesser reduction in systolic and diastolic blood pressure when treated with angiotensin-converting enzyme (ACE) inhibitors.

The 2017 American College of Cardiology (ACC) and AHA guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults⁴⁰ identifies 4 drug classes as reducing cardiovascular disease morbidity and mortality: thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers. Of these 4 classes, thiazide diuretics and calcium channel blockers have been shown to lower blood pressure more effectively in African Americans than renin-angiotensin-aldosterone inhibition with ACE inhibitors or ARBs.

Glycemic control

Type 2 diabetes mellitus secondary to insulin resistance disproportionately affects minority groups, as the prevalence of diabetes mellitus in African Americans is almost twice as high as that in whites, and 35% higher in Hispanics compared with whites.^7,41 Based on NHANES data between 1984 and 2004, the prevalence of diabetes mellitus is expected to increase by 99% in whites, 107% in African Americans, and 127% in Hispanics by 2050. Alarmingly, African Americans over age 75 are expected to experience a 606% increase by 2050.⁴²

With regard to mortality, 21.7 deaths per 100,000 population were attributable to diabetes mellitus according to reports by the AHA in 2016. The death rate in white males was 24.3 per 100,000 compared with 44.9 per 100,000 for African Americans males. The associated mortality rate for white women was 16.2 per 100,000, and 35.8 per 100,000 for African American females.⁷

The management of coronary artery disease has evolved from prolonged bed rest to surgical, pharmacologic, and percutaneous revascularization.^2,5 Coronary revascularization procedures are now relatively common: 950,000 percutaneous coronary interventions and 397,000 coronary artery bypass procedures were performed in 2010.⁷

Nevertheless, despite similar clinical presentations, African Americans with acute myocardial infarction were less likely to be referred for coronary artery bypass grafting than whites.^43–46 They were also less likely to be given thrombolytics⁴⁷ and less likely to undergo coronary angiography with percutaneous coronary intervention.⁴⁸ Similar differences have been reported when comparing Hispanics with whites.⁴⁹

Some suggest that healthcare access is a key mediator of health disparities.⁵⁰ In 2009, Hispanics and African Americans accounted for more than 50% of those without health insurance.⁵¹ Improved access to healthcare might mitigate the disparity in revascularizations.

Massachusetts was one of the first states to mandate that all residents obtain health insurance. As a result, the uninsured rates declined in African Americans and Hispanics in Massachusetts, but a disparity in revascularization persisted. African Americans and Hispanics were 27% and 16% less likely to undergo revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) than whites,⁵¹ suggesting that disparities in revascularization are not solely secondary to healthcare access.

These findings are consistent with a 2004 Veterans Administration study,⁵² in which healthcare access was equal among races. The study showed that African Americans received fewer cardiac procedures after an acute myocardial infarction compared with whites.

Have we made progress? The largest disparity between African Americans and whites in coronary artery disease mortality existed in 1990. The disparity persisted to 2012, and although decreased, it is projected to persist to 2030.⁵³

DISPARITIES IN HEART FAILURE

An estimated 5.7 million Americans have heart failure, and 915,000 new cases are diagnosed annually.⁷ Unlike coronary artery disease, heart failure is expected to increase in prevalence by 46%, to 8 million Americans with heart failure by 2030.^7,54

Our knowledge of disparities in the area of heart failure is derived primarily from epidemiologic studies. The Multi-Ethnic Study of Atherosclerosis⁵⁵ showed that African Americans (4.6 per 1,000), followed by Hispanics (3.5 per 1,000) had a higher risk of developing heart failure compared with whites (2.4 per 1,000).The higher risk is in part due to disparities in socioeconomic status and prevalence of hypertension, as African Americans accounted for 75% of cases of nonischemic-related heart failure.⁵⁵ African Americans also have a higher 5-year mortality rate than whites.⁵⁵

Even though the 5-year mortality rate in heart failure is still 50%, the past 30 years have seen innovations in pharmacologic and device therapy and thus improved outcomes in heart failure patients. Still, significant gaps in the use of guideline-recommended therapies, quality of care, and clinical outcomes persist in contemporary practice for racial minorities with heart failure.

Disparities in inpatient care for heart failure

Patients admitted for heart failure and cared for by a cardiologist are more likely to be discharged on guideline-directed medical therapy, have fewer heart failure readmissions, and lower mortality.^56,57 Breathett et al,⁵⁸ in a study of 104,835 patients hospitalized in an intensive care unit for heart failure, found that primary intensive care by a cardiologist was associated with higher survival in both races. However, in the same study, white patients had a higher odds of receiving care from a cardiologist than African American patients.

Disparities and cardiac resynchronization therapy devices

In one-third of patients with heart failure, conduction delays result in dyssynchronous left ventricular contraction.⁵⁹ Dyssynchrony leads to reduced cardiac performance, left ventricular remodeling, and increased mortality.⁵⁶

Cardiac resynchronization therapy (CRT) was approved for clinical use in 2001, and studies have shown that it improves quality of life, exercise tolerance, cardiac performance, and morbidity and mortality rates.^59–66 The 2013 ACC/AHA guidelines for the management of heart failure give a class IA recommendation (the highest) for its use in patients with a left ventricular ejection fraction of 35% or less, sinus rhythm, left bundle branch block and a QRS duration of 150 ms or greater, and New York Heart Association class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy.⁶⁷

Despite these recommendations, racial differences are observed. A study using the Nationwide Inpatient Sample database⁵⁹ showed that between 2002 and 2010, a total of 374,202 CRT devices were implanted, averaging 41,578 annually. After adjusting for heart failure admissions, the study showed that CRT use was favored in men and in whites.

Another study, using the National Cardiovascular Data Registry,⁶⁸ looked at patients who received implantable cardiac defibrillators (ICDs) and were eligible to receive CRT. It found that African Americans and Hispanics were less likely than whites to receive CRT, even though they were more likely to meet established criteria.

Disparities and left ventricular assist devices

The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial and Heart Mate II trial demonstrated that left ventricular assist devices (LVADs) were durable options for long-term support for patients with end-stage heart failure.^69,70 Studies that examined the role of race and clinical outcomes after LVAD implantation have reported mixed findings.^71,72 Few studies have looked at the role racial differences play in accessing LVAD therapy.

Joyce et al⁷³ reviewed data from the Nationwide Inpatient Sample from 2002 to 2003 on patients admitted to the hospital with a primary diagnosis of heart failure or cardiogenic shock. A total of 297,866 patients were included in the study, of whom only 291 underwent LVAD implantation. A multivariate analysis found that factors such as age over 65, female sex, admission to a nonacademic center, geographic region, and African American race adversely influenced access to LVAD therapy.

Breathett et al⁷⁴ evaluated racial differences in LVAD implantations from 2012 to 2015, a period that corresponds to increased health insurance expansion, and found LVAD implantations increased among African American patients with advanced heart failure, but no other racial or ethnic group.

For patients with end-stage heart failure, orthotopic heart transplant is the most definitive and durable option for long-term survival. According to data from the United Network for Organ Sharing, 62,508 heart transplants were performed from January 1, 1988 to December 31, 2015. Compared with transplants of other solid organs, heart transplant occurs in significantly infrequent rates.

Barriers to transplant include lack of health insurance, considered a surrogate for low socioeconomic status. Hispanics and African Americans are less likely to have private health insurance than non-Hispanic whites, and this difference is magnified among the working poor.

Despite these perceived barriers, Kilic et al⁷⁵ found that African Americans comprised 16.4% of heart transplant recipients, although they make up only approximately 13% of the US population. They also had significantly shorter wait-list times than whites. On the negative side, African Americans had a higher unadjusted mortality rate than whites (15% vs 12% P = .002). African Americans also tended to receive their transplants at centers with lower transplant volumes and higher transplant mortality rates.

Several other studies also showed that African Americans compared to whites have significantly worse outcomes after transplant.^76–79 What accounts for this difference? Kilic et al⁷⁵ showed that African Americans had the lowest proportion of blood type matching and lowest human leukocyte antigen matching, were younger (because African Americans develop more advanced heart failure at younger ages), had higher serum creatinine levels, and were more often bridged to transplant with an LVAD.

DISPARITIES IN CARDIOVASCULAR RESEARCH

Although the United States has the most sophisticated and robust medical system in the world, select groups have significant differences in delivery and healthcare outcomes. There are many explanations for these differences, but a contributing factor may be the paucity of research dedicated to understand racial and ethnic differences.⁸⁰

Differences observed in epidemiologic studies may be secondary to pathophysiology, genetic differences, environment, and lifestyle choices. Historically, clinical trials were conducted in homogeneous populations with respect to age (middle-aged), sex (male), and race (white), and the results were generalized to heterogeneous populations.⁸⁰

Disparities in research have implications in clinical practice. Overall, the primary cause of heart failure is ischemia; however, in African Americans, the primary cause is hypertensive heart disease.⁸¹ Studies in hypertension have shown that African Americans have less of a response to neurohormonal blockade with ACE inhibitors and beta-blockers than non-African Americans.⁸² Nevertheless, neurohormonal blockade has become the cornerstone of heart failure treatment.

Retrospective analysis of the Vasodilator-Heart Failure trials⁸³ showed that treatment with isosorbide dinitrate plus hydralazine, compared with placebo, conferred a survival benefit for African Americans but not whites.⁸⁰ No survival advantage was noted when isosorbide dinitrate/hydralazine was compared to enalapril in African Americans, although enalapril was superior to isosorbide dinitrate in whites.⁴⁵ These observations were recognized 10 to 15 years after trial completion, and were only possible because the trials included sufficient numbers of African American patients to complete analysis.

In 1993, the US Congress passed the National Institutes of Health (NIH) Revitalization Act, which established guidelines requiring NIH grant applicants to include minorities in human subject research, as they were historically underrepresented in clinical research trials.^84,85

In 2001, the Beta-Blocker Evaluation of Survival Trial⁸⁶ reported its results investigating whether bucindolol, a nonselective beta-blocker, would reduce mortality in patients with advanced heart failure (New York Heart Association class III or IV). This was one of the first trials to prospectively investigate racial and ethnic differences in response to treatment. Though it showed no overall benefit in the use of bucindolol in the treatment of advanced heart failure, subgroup analysis showed that whites did enjoy a benefit in terms of lower mortality, whereas African Americans did not.

Results of the Vasodilator-Heart Failure trials led to further population-directed research, most notably the African American Heart Failure Trial,⁸⁷ a double-blind, placebo-controlled, randomized trial in patients who identified as African American. Patients who were randomized to receive a fixed dose of hydralazine and isosorbide dinitrate had a 43% lower mortality rate, a 33% lower hospitalization rate for heart failure, and better quality of life than patients in the placebo group, leading to early termination of the trial. The outcomes suggested that the combination of isosorbide dinitrate and hydralazine treats heart failure in a manner independent of pure neurohormonal blockade.

CHALLENGES IN STUDY PARTICIPATION

Recruitment of minority participants in biomedical research is a challenging task for clinical investigators.^88,89 Some of the factors thought to pose potential barriers for racial and ethnic minority participation in health research include poor access to primary medical care, failure of researchers to recruit minority populations actively, and language and cultural barriers.⁹⁰

Further, it is widely claimed that African Americans are less willing than nonminority individuals to participate in clinical research trials due to general distrust of the medical community as a result of the Tuskegee Syphilis Experiment.⁹¹ That infamous study, conducted by the US Public Health Service between 1932 and 1972, sought to record the natural progression of untreated syphilis in poor African American men in Alabama. The participants were not informed of the true purpose of the study, and they were under the impression that they were simply receiving free healthcare from the US government. Further, they were denied appropriate treatment even after it became readily available, in order for researchers to observe the progression of the disease.

While the 1993 mandate did in fact increase pressure on researchers to develop strategies to overcome participation barriers, the issue of underrepresentation of racial minorities in clinical research, including cardiovascular research, has not been resolved and continues to be a problem today.

The overall goal of clinical research is to determine the best strategies to prevent and treat disease. But if the study population is not representative of the affected population at large, the results cannot be generalized to underrepresented subgroups. The implications of underrepresentation in research are far-reaching, and can further contribute to disparate care of minority patients such as African Americans, who have a higher prevalence of cardiovascular risk factors and greater burden of heart failure.

Between 1986 and 2018, according to a PUBMED search, 10,462 articles highlighted the presence of a health-related disparity. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.

Eliminating bias

Implicit bias refers to attitudes, thoughts, and feelings that exist outside of the conscious awareness.⁹² These biases can be triggered by race, gender, or socioeconomic status. They have manifested in society as stereotypes that men are more competent than women, women are more verbal than men, and African Americans are more athletic than whites.⁹³

The concept of implicit bias is important, in that the populations that experience the greatest health disparities also suffer from negative cultural stereotypes.⁹⁴ Healthcare professionals are not inoculated against implicit bias.⁹⁵ Studies have shown that most healthcare providers have implicit biases that reflect positive attitudes toward whites and negative attitudes toward people of color.^{92,94,96–98}

The Implicit Association Test, introduced in 1998, is widely used to measure implicit bias. It measures response time of subjects to match particular social groups to particular attributes.⁹⁹ Green et al,⁹⁹ using this test, showed that although physicians reported no explicit preference for white vs African American patients or differences in perceived cooperativeness, the test revealed implicit preference favoring white Americans and implicit stereotypes of African Americans as less cooperative for medical procedures and in general. This also manifested in clinical decision-making, as white Americans were more likely, and African Americans less likely, to be treated with thrombolysis.⁹⁹

Sabin et al¹⁰⁰ showed that implicit bias was present among pediatricians, although less than in society as a whole and in other healthcare professionals.

But how does one change feelings that exist outside of the conscious awareness? Green et al⁹⁹ showed that making physicians aware of their susceptibility to bias changed their behavior. A subset of physicians who were made aware that bias was a focus of the study were more likely to refer African Americans for thrombolysis even if they had a high degree of implicit pro-white bias.^94,100 Perhaps mandating that all healthcare providers take a self-administered and confidentially reported Implicit Association Test will lead to awareness of implicit bias and minimize healthcare behaviors that contribute to the current state of disparities.

Improving access

Common indicators of access to healthcare include health insurance status, having a usual source of healthcare, and having a regular physician.¹⁰¹ Health insurance does offer protection from the costs associated with illness and health maintenance.¹⁰¹ It is also a major contributing factor in racial and ethnic disparities.

Chen et al¹⁰² examined the effects of the Affordable Care Act and found that it was associated with reduction in the probability of being uninsured, delaying necessary care, and forgoing necessary care, and increased probability of having a physician. However, earlier studies showed that access to health insurance by itself does not equate to equitable care.^103,104

Diversifying the work force

African Americans comprise 4% of physicians and Hispanic Americans 5%, despite accounting for 13% and 16% of the US population.¹⁰⁵ This underrepresentation has led to African American and Hispanic American patients being more likely than white patients to be treated by a physician from a dissimilar racial or ethnic background.¹⁰⁶ Studies have shown that minority patients in a race- or ethnic-concordant relationship are more likely to use needed health services, less likely to postpone seeking care, and report greater satisfaction.^106,107 Minority physicians often locate and practice in neighborhoods with high minority populations, and they disproportionately care for disadvantaged patients of lower socioeconomic status and poorer health.^106,108

WE ARE STILL IN THE TUNNEL, BUT THERE IS LIGHT AT THE END

The cardiovascular community has faced tremendous challenges in the past and responded with innovative research that has led to imaging that aids in the diagnosis of subclinical cardiovascular disease and invasive and pharmacologic strategies that have improved cardiovascular outcomes. One may say that there is light at the end of the tunnel; however, the existence of disparate care reminds us that we are still in the tunnel.

Disparities in cardiovascular disease management present a unique challenge for the community. There is no drug, device, or invasive procedure to eliminate this pathology. However, by acknowledging the problem and implementing changes at the system, provider, and patient level, the cardiovascular community can achieve yet another momentous achievement: the end of cardiovascular health disparities. Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.

Cardiovascular disease became the leading cause of death in the United States in the early 20th century, and it accounts for nearly half of all deaths in industrialized nations.¹ The mortality it inflicts was thought to be shared equally between both sexes and among all age groups and races.² The cardiology community implemented innovative epidemiologic research, through which risk factors for cardiovascular disease were established.¹ The development of coronary care units reduced in-hospital mortality from acute myocardial infarction from 30% to 15%.^2–5 Further advances in pharmacology, revascularization, and imaging have aided in the detection and treatment of cardiovascular disease.⁶ Though cardiovascular disease remains the number-one cause of death worldwide, rates are on the decline.⁷

For several decades, health disparities have been recognized as a source of pathology in cardiovascular medicine, resulting in inequity of care administration among select populations. In this review, we examine whether the same forward thinking that has resulted in a decline in cardiovascular disease has had an impact on the pervasive disparities in cardiovascular medicine.

DISPARITIES DEFINED

Compared with whites, members of minority groups have a higher burden of chronic diseases, receive lower quality care, and have less access to medical care. Recognizing the potential public health ramifications, in 1999 the US Congress tasked the Institute of Medicine to study and assess the extent of healthcare disparities. This led to the landmark publication, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.⁸

The Institute of Medicine defines disparities in healthcare as racial or ethnic differences in the quality of healthcare that are not due to access-related factors, clinical needs, preferences, and appropriateness of intervention.⁸ Disparities can also exist according to socioeconomic status and sex.⁹

In an early study documenting the concept of disparities in cardiovascular disease, Stone and Vanzant¹⁰ concluded that heart disease was more common in African Americans than in whites, and that hypertension was the principal cause of cardiovascular disease mortality in African Americans.

Data from US Centers for Disease Control and Prevention, reference 11

Although avoidable deaths from heart disease, stroke, and hypertensive disease declined between 2001 and 2010, African Americans still have a higher mortality rate than other racial and ethnic groups (Figure 1).¹¹

DISPARITIES AND CARDIOVASCULAR HEALTH

The concept of cardiovascular health was established by the American Heart Association (AHA) in efforts to achieve an additional 20% reduction in cardiovascular disease-related mortality by 2020.⁷ Cardiovascular health is defined as the absence of clinically manifest cardiovascular disease and is measured by 7 components:

• Not smoking or abstaining from smoking for at least 1 year
• A normal body weight, defined as a body mass index less than 25 kg/m²
• Optimal physical activity, defined as 75 minutes of vigorous physical activity or 150 minutes of moderate-intensity physical activity per week
• Regular consumption of a healthy diet
• Total cholesterol below 200 mg/dL
• Blood pressure less than 120/80 mm Hg
• Fasting blood sugar below 100 mg/dL.

Nearly 70% of the US population can claim 2, 3, or 4 of these components, but differences exist according to race,¹² and 60% of adult white Americans are limited to achieving no more than 3 of these healthy metrics, compared with 70% of adult African Americans and Hispanic Americans.

Smoking

Smoking is a major risk factor for cardiovascular disease.^12–14

Data from National Health Interview Surgery, Jamal et al, reference 16

During adolescence, white males are more likely to smoke than African American and Hispanic males,¹² but this trend reverses in adulthood, when African American men have a higher prevalence of smoking than white men (21.4% vs 19%).⁷ Rates of lifetime use are highest among American Indian or Alaskan natives and whites (75.9%), followed by African Americans (58.4%), native Hawaiians (56.8%), and Hispanics (56.7%).¹⁵ Trends for current smoking are similar (Figure 2).¹⁶ Moreover, households with lower socioeconomic status have a higher prevalence of smoking.⁷

Physical activity

People with a sedentary lifestyle are more likely to die of cardiovascular disease. As many as 250,000 deaths annually in the United States are attributed to lack of regular physical activity.¹⁷

Recognizing the potential public health ramifications, the AHA and the 2018 Federal Guidelines on Physical Activity recommend that children engage in 60 minutes of daily physical activity and that adults participate in 150 minutes of moderate-intensity or 75 minutes of vigorous physical activity weekly.^18,19

Data from Behavioral Risk Factor Surveillance System, Omura et al, reference 20

In the United States, 15.2% of adolescents reported being physically inactive, according to data published in 2016.⁷ Similar to most cardiovascular risk factors, minority populations and those of lower socioeconomic status had the worst profiles. The prevalence of physical inactivity was highest in African Americans and Hispanics (Figure 3).²⁰

Studies have shown an association between screen-based sedentary behavior (computers, television, and video games) and cardiovascular disease.^21–23 In the United States, 41% of adolescents used computers for activities other than homework for more than 3 hours per day on a school day.⁷ The pattern of use was highest in African American boys and African American girls, followed by Hispanic girls and Hispanic boys.¹⁸ Trends were similar with regard to watching television for more than 3 hours per day.

Sedentary behavior persists into adulthood, with rates of inactivity of 38.3% in African Americans, 40.1% in Hispanics, and 26.3% in white adults.⁷

Nutrition plays a major role in cardiovascular disease, specifically in the pathogenesis of atherosclerotic disease and hypertension.²⁴ Most Americans do not meet dietary recommendations, with minority communities performing worse in specific metrics.⁷

Dietary patterns are reflected in the rate of obesity in this nation. Studies have shown a direct correlation between obesity and cardiovascular disease such as coronary artery disease, heart failure, and atrial fibrillation.^25–28 According to data from the National Health and Nutrition Examination Survey (NHANES), 31% of children between the ages of 2 and 19 years are classified as obese or overweight. The highest rates of obesity are seen in Hispanic and African American boys and girls. The obesity epidemic is disproportionately rampant in children living in households with low income, low education, and high unemployment rates.^7,29–31

Despite the risks associated with obesity, only 64.8% of obese adults report being informed by a doctor or health professional that they were overweight. The proportion of obese adults informed that they were overweight was significantly lower for African Americans and Hispanics compared with whites. Similar differences are seen based on socioeconomic status, as middle-income patients were less likely to be informed than those in the higher income strata (62.4% vs 70.6%).^7,31

Blood pressure

Hypertension is a well-established risk factor for cardiovascular disease and stroke, and a blood pressure of 120/80 mm Hg or lower is identified as a component of ideal cardiovascular health.

In the United States the prevalence of hypertension in adults older than 20 is 32%.⁷ The prevalence of hypertension in African Americans is among the highest in the world.^32,33 African Americans develop high blood pressure at earlier ages, and their average resting blood pressures are higher than in whites.^34,35 For a 45-year-old without hypertension, the 40-year risk of developing hypertension is 92.7% for African Americans and 86% for whites.³⁵ Hypertension is a major risk factor for stroke, and African Americans have a 1.8 times greater rate of fatal stroke than whites.⁷

In 2013 there were 71,942 deaths attributable to high blood pressure, and the 2011 death rate associated with hypertension was 18.9 per 100,000. By race, the death rate was 17.6 per 100,000 for white males and an alarming 47.1 per 100,000 for African American males; rates were 15.2 per 100,000 for white females and 35.1 per 100,000 for African American females.⁷

It is unclear what accounts for the racial difference in prevalence in hypertension. Studies have shown that African Americans are more likely than whites to have been told on more than 2 occasions that they have hypertension. And 85.7% of African Americans are aware that they have high blood pressure, compared with 82.7% of whites.¹⁴

African Americans and Hispanics have poorer hypertension control compared with whites.^36,37 These observed differences cannot be attributed to access alone, as African Americans were more likely to be on higher-intensity blood pressure therapy, whereas Hispanics were more likely to be undertreated.^36,38 In a meta-analysis of 13 trials, Peck et al³⁹ showed that African Americans showed a lesser reduction in systolic and diastolic blood pressure when treated with angiotensin-converting enzyme (ACE) inhibitors.

The 2017 American College of Cardiology (ACC) and AHA guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults⁴⁰ identifies 4 drug classes as reducing cardiovascular disease morbidity and mortality: thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers. Of these 4 classes, thiazide diuretics and calcium channel blockers have been shown to lower blood pressure more effectively in African Americans than renin-angiotensin-aldosterone inhibition with ACE inhibitors or ARBs.

Glycemic control

Type 2 diabetes mellitus secondary to insulin resistance disproportionately affects minority groups, as the prevalence of diabetes mellitus in African Americans is almost twice as high as that in whites, and 35% higher in Hispanics compared with whites.^7,41 Based on NHANES data between 1984 and 2004, the prevalence of diabetes mellitus is expected to increase by 99% in whites, 107% in African Americans, and 127% in Hispanics by 2050. Alarmingly, African Americans over age 75 are expected to experience a 606% increase by 2050.⁴²

With regard to mortality, 21.7 deaths per 100,000 population were attributable to diabetes mellitus according to reports by the AHA in 2016. The death rate in white males was 24.3 per 100,000 compared with 44.9 per 100,000 for African Americans males. The associated mortality rate for white women was 16.2 per 100,000, and 35.8 per 100,000 for African American females.⁷

The management of coronary artery disease has evolved from prolonged bed rest to surgical, pharmacologic, and percutaneous revascularization.^2,5 Coronary revascularization procedures are now relatively common: 950,000 percutaneous coronary interventions and 397,000 coronary artery bypass procedures were performed in 2010.⁷

Nevertheless, despite similar clinical presentations, African Americans with acute myocardial infarction were less likely to be referred for coronary artery bypass grafting than whites.^43–46 They were also less likely to be given thrombolytics⁴⁷ and less likely to undergo coronary angiography with percutaneous coronary intervention.⁴⁸ Similar differences have been reported when comparing Hispanics with whites.⁴⁹

Some suggest that healthcare access is a key mediator of health disparities.⁵⁰ In 2009, Hispanics and African Americans accounted for more than 50% of those without health insurance.⁵¹ Improved access to healthcare might mitigate the disparity in revascularizations.

Massachusetts was one of the first states to mandate that all residents obtain health insurance. As a result, the uninsured rates declined in African Americans and Hispanics in Massachusetts, but a disparity in revascularization persisted. African Americans and Hispanics were 27% and 16% less likely to undergo revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) than whites,⁵¹ suggesting that disparities in revascularization are not solely secondary to healthcare access.

These findings are consistent with a 2004 Veterans Administration study,⁵² in which healthcare access was equal among races. The study showed that African Americans received fewer cardiac procedures after an acute myocardial infarction compared with whites.

Have we made progress? The largest disparity between African Americans and whites in coronary artery disease mortality existed in 1990. The disparity persisted to 2012, and although decreased, it is projected to persist to 2030.⁵³

DISPARITIES IN HEART FAILURE

An estimated 5.7 million Americans have heart failure, and 915,000 new cases are diagnosed annually.⁷ Unlike coronary artery disease, heart failure is expected to increase in prevalence by 46%, to 8 million Americans with heart failure by 2030.^7,54

Our knowledge of disparities in the area of heart failure is derived primarily from epidemiologic studies. The Multi-Ethnic Study of Atherosclerosis⁵⁵ showed that African Americans (4.6 per 1,000), followed by Hispanics (3.5 per 1,000) had a higher risk of developing heart failure compared with whites (2.4 per 1,000).The higher risk is in part due to disparities in socioeconomic status and prevalence of hypertension, as African Americans accounted for 75% of cases of nonischemic-related heart failure.⁵⁵ African Americans also have a higher 5-year mortality rate than whites.⁵⁵

Even though the 5-year mortality rate in heart failure is still 50%, the past 30 years have seen innovations in pharmacologic and device therapy and thus improved outcomes in heart failure patients. Still, significant gaps in the use of guideline-recommended therapies, quality of care, and clinical outcomes persist in contemporary practice for racial minorities with heart failure.

Disparities in inpatient care for heart failure

Patients admitted for heart failure and cared for by a cardiologist are more likely to be discharged on guideline-directed medical therapy, have fewer heart failure readmissions, and lower mortality.^56,57 Breathett et al,⁵⁸ in a study of 104,835 patients hospitalized in an intensive care unit for heart failure, found that primary intensive care by a cardiologist was associated with higher survival in both races. However, in the same study, white patients had a higher odds of receiving care from a cardiologist than African American patients.

Disparities and cardiac resynchronization therapy devices

In one-third of patients with heart failure, conduction delays result in dyssynchronous left ventricular contraction.⁵⁹ Dyssynchrony leads to reduced cardiac performance, left ventricular remodeling, and increased mortality.⁵⁶

Cardiac resynchronization therapy (CRT) was approved for clinical use in 2001, and studies have shown that it improves quality of life, exercise tolerance, cardiac performance, and morbidity and mortality rates.^59–66 The 2013 ACC/AHA guidelines for the management of heart failure give a class IA recommendation (the highest) for its use in patients with a left ventricular ejection fraction of 35% or less, sinus rhythm, left bundle branch block and a QRS duration of 150 ms or greater, and New York Heart Association class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy.⁶⁷

Despite these recommendations, racial differences are observed. A study using the Nationwide Inpatient Sample database⁵⁹ showed that between 2002 and 2010, a total of 374,202 CRT devices were implanted, averaging 41,578 annually. After adjusting for heart failure admissions, the study showed that CRT use was favored in men and in whites.

Another study, using the National Cardiovascular Data Registry,⁶⁸ looked at patients who received implantable cardiac defibrillators (ICDs) and were eligible to receive CRT. It found that African Americans and Hispanics were less likely than whites to receive CRT, even though they were more likely to meet established criteria.

Disparities and left ventricular assist devices

The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial and Heart Mate II trial demonstrated that left ventricular assist devices (LVADs) were durable options for long-term support for patients with end-stage heart failure.^69,70 Studies that examined the role of race and clinical outcomes after LVAD implantation have reported mixed findings.^71,72 Few studies have looked at the role racial differences play in accessing LVAD therapy.

Joyce et al⁷³ reviewed data from the Nationwide Inpatient Sample from 2002 to 2003 on patients admitted to the hospital with a primary diagnosis of heart failure or cardiogenic shock. A total of 297,866 patients were included in the study, of whom only 291 underwent LVAD implantation. A multivariate analysis found that factors such as age over 65, female sex, admission to a nonacademic center, geographic region, and African American race adversely influenced access to LVAD therapy.

Breathett et al⁷⁴ evaluated racial differences in LVAD implantations from 2012 to 2015, a period that corresponds to increased health insurance expansion, and found LVAD implantations increased among African American patients with advanced heart failure, but no other racial or ethnic group.

For patients with end-stage heart failure, orthotopic heart transplant is the most definitive and durable option for long-term survival. According to data from the United Network for Organ Sharing, 62,508 heart transplants were performed from January 1, 1988 to December 31, 2015. Compared with transplants of other solid organs, heart transplant occurs in significantly infrequent rates.

Barriers to transplant include lack of health insurance, considered a surrogate for low socioeconomic status. Hispanics and African Americans are less likely to have private health insurance than non-Hispanic whites, and this difference is magnified among the working poor.

Despite these perceived barriers, Kilic et al⁷⁵ found that African Americans comprised 16.4% of heart transplant recipients, although they make up only approximately 13% of the US population. They also had significantly shorter wait-list times than whites. On the negative side, African Americans had a higher unadjusted mortality rate than whites (15% vs 12% P = .002). African Americans also tended to receive their transplants at centers with lower transplant volumes and higher transplant mortality rates.

Several other studies also showed that African Americans compared to whites have significantly worse outcomes after transplant.^76–79 What accounts for this difference? Kilic et al⁷⁵ showed that African Americans had the lowest proportion of blood type matching and lowest human leukocyte antigen matching, were younger (because African Americans develop more advanced heart failure at younger ages), had higher serum creatinine levels, and were more often bridged to transplant with an LVAD.

DISPARITIES IN CARDIOVASCULAR RESEARCH

Although the United States has the most sophisticated and robust medical system in the world, select groups have significant differences in delivery and healthcare outcomes. There are many explanations for these differences, but a contributing factor may be the paucity of research dedicated to understand racial and ethnic differences.⁸⁰

Differences observed in epidemiologic studies may be secondary to pathophysiology, genetic differences, environment, and lifestyle choices. Historically, clinical trials were conducted in homogeneous populations with respect to age (middle-aged), sex (male), and race (white), and the results were generalized to heterogeneous populations.⁸⁰

Disparities in research have implications in clinical practice. Overall, the primary cause of heart failure is ischemia; however, in African Americans, the primary cause is hypertensive heart disease.⁸¹ Studies in hypertension have shown that African Americans have less of a response to neurohormonal blockade with ACE inhibitors and beta-blockers than non-African Americans.⁸² Nevertheless, neurohormonal blockade has become the cornerstone of heart failure treatment.

Retrospective analysis of the Vasodilator-Heart Failure trials⁸³ showed that treatment with isosorbide dinitrate plus hydralazine, compared with placebo, conferred a survival benefit for African Americans but not whites.⁸⁰ No survival advantage was noted when isosorbide dinitrate/hydralazine was compared to enalapril in African Americans, although enalapril was superior to isosorbide dinitrate in whites.⁴⁵ These observations were recognized 10 to 15 years after trial completion, and were only possible because the trials included sufficient numbers of African American patients to complete analysis.

In 1993, the US Congress passed the National Institutes of Health (NIH) Revitalization Act, which established guidelines requiring NIH grant applicants to include minorities in human subject research, as they were historically underrepresented in clinical research trials.^84,85

In 2001, the Beta-Blocker Evaluation of Survival Trial⁸⁶ reported its results investigating whether bucindolol, a nonselective beta-blocker, would reduce mortality in patients with advanced heart failure (New York Heart Association class III or IV). This was one of the first trials to prospectively investigate racial and ethnic differences in response to treatment. Though it showed no overall benefit in the use of bucindolol in the treatment of advanced heart failure, subgroup analysis showed that whites did enjoy a benefit in terms of lower mortality, whereas African Americans did not.

Results of the Vasodilator-Heart Failure trials led to further population-directed research, most notably the African American Heart Failure Trial,⁸⁷ a double-blind, placebo-controlled, randomized trial in patients who identified as African American. Patients who were randomized to receive a fixed dose of hydralazine and isosorbide dinitrate had a 43% lower mortality rate, a 33% lower hospitalization rate for heart failure, and better quality of life than patients in the placebo group, leading to early termination of the trial. The outcomes suggested that the combination of isosorbide dinitrate and hydralazine treats heart failure in a manner independent of pure neurohormonal blockade.

CHALLENGES IN STUDY PARTICIPATION

Recruitment of minority participants in biomedical research is a challenging task for clinical investigators.^88,89 Some of the factors thought to pose potential barriers for racial and ethnic minority participation in health research include poor access to primary medical care, failure of researchers to recruit minority populations actively, and language and cultural barriers.⁹⁰

Further, it is widely claimed that African Americans are less willing than nonminority individuals to participate in clinical research trials due to general distrust of the medical community as a result of the Tuskegee Syphilis Experiment.⁹¹ That infamous study, conducted by the US Public Health Service between 1932 and 1972, sought to record the natural progression of untreated syphilis in poor African American men in Alabama. The participants were not informed of the true purpose of the study, and they were under the impression that they were simply receiving free healthcare from the US government. Further, they were denied appropriate treatment even after it became readily available, in order for researchers to observe the progression of the disease.

While the 1993 mandate did in fact increase pressure on researchers to develop strategies to overcome participation barriers, the issue of underrepresentation of racial minorities in clinical research, including cardiovascular research, has not been resolved and continues to be a problem today.

The overall goal of clinical research is to determine the best strategies to prevent and treat disease. But if the study population is not representative of the affected population at large, the results cannot be generalized to underrepresented subgroups. The implications of underrepresentation in research are far-reaching, and can further contribute to disparate care of minority patients such as African Americans, who have a higher prevalence of cardiovascular risk factors and greater burden of heart failure.

Between 1986 and 2018, according to a PUBMED search, 10,462 articles highlighted the presence of a health-related disparity. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.

Eliminating bias

Implicit bias refers to attitudes, thoughts, and feelings that exist outside of the conscious awareness.⁹² These biases can be triggered by race, gender, or socioeconomic status. They have manifested in society as stereotypes that men are more competent than women, women are more verbal than men, and African Americans are more athletic than whites.⁹³

The concept of implicit bias is important, in that the populations that experience the greatest health disparities also suffer from negative cultural stereotypes.⁹⁴ Healthcare professionals are not inoculated against implicit bias.⁹⁵ Studies have shown that most healthcare providers have implicit biases that reflect positive attitudes toward whites and negative attitudes toward people of color.^{92,94,96–98}

The Implicit Association Test, introduced in 1998, is widely used to measure implicit bias. It measures response time of subjects to match particular social groups to particular attributes.⁹⁹ Green et al,⁹⁹ using this test, showed that although physicians reported no explicit preference for white vs African American patients or differences in perceived cooperativeness, the test revealed implicit preference favoring white Americans and implicit stereotypes of African Americans as less cooperative for medical procedures and in general. This also manifested in clinical decision-making, as white Americans were more likely, and African Americans less likely, to be treated with thrombolysis.⁹⁹

Sabin et al¹⁰⁰ showed that implicit bias was present among pediatricians, although less than in society as a whole and in other healthcare professionals.

But how does one change feelings that exist outside of the conscious awareness? Green et al⁹⁹ showed that making physicians aware of their susceptibility to bias changed their behavior. A subset of physicians who were made aware that bias was a focus of the study were more likely to refer African Americans for thrombolysis even if they had a high degree of implicit pro-white bias.^94,100 Perhaps mandating that all healthcare providers take a self-administered and confidentially reported Implicit Association Test will lead to awareness of implicit bias and minimize healthcare behaviors that contribute to the current state of disparities.

Improving access

Common indicators of access to healthcare include health insurance status, having a usual source of healthcare, and having a regular physician.¹⁰¹ Health insurance does offer protection from the costs associated with illness and health maintenance.¹⁰¹ It is also a major contributing factor in racial and ethnic disparities.

Chen et al¹⁰² examined the effects of the Affordable Care Act and found that it was associated with reduction in the probability of being uninsured, delaying necessary care, and forgoing necessary care, and increased probability of having a physician. However, earlier studies showed that access to health insurance by itself does not equate to equitable care.^103,104

Diversifying the work force

African Americans comprise 4% of physicians and Hispanic Americans 5%, despite accounting for 13% and 16% of the US population.¹⁰⁵ This underrepresentation has led to African American and Hispanic American patients being more likely than white patients to be treated by a physician from a dissimilar racial or ethnic background.¹⁰⁶ Studies have shown that minority patients in a race- or ethnic-concordant relationship are more likely to use needed health services, less likely to postpone seeking care, and report greater satisfaction.^106,107 Minority physicians often locate and practice in neighborhoods with high minority populations, and they disproportionately care for disadvantaged patients of lower socioeconomic status and poorer health.^106,108

WE ARE STILL IN THE TUNNEL, BUT THERE IS LIGHT AT THE END

The cardiovascular community has faced tremendous challenges in the past and responded with innovative research that has led to imaging that aids in the diagnosis of subclinical cardiovascular disease and invasive and pharmacologic strategies that have improved cardiovascular outcomes. One may say that there is light at the end of the tunnel; however, the existence of disparate care reminds us that we are still in the tunnel.

Disparities in cardiovascular disease management present a unique challenge for the community. There is no drug, device, or invasive procedure to eliminate this pathology. However, by acknowledging the problem and implementing changes at the system, provider, and patient level, the cardiovascular community can achieve yet another momentous achievement: the end of cardiovascular health disparities. Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.

Cardiovascular disease became the leading cause of death in the United States in the early 20th century, and it accounts for nearly half of all deaths in industrialized nations.¹ The mortality it inflicts was thought to be shared equally between both sexes and among all age groups and races.² The cardiology community implemented innovative epidemiologic research, through which risk factors for cardiovascular disease were established.¹ The development of coronary care units reduced in-hospital mortality from acute myocardial infarction from 30% to 15%.^2–5 Further advances in pharmacology, revascularization, and imaging have aided in the detection and treatment of cardiovascular disease.⁶ Though cardiovascular disease remains the number-one cause of death worldwide, rates are on the decline.⁷

For several decades, health disparities have been recognized as a source of pathology in cardiovascular medicine, resulting in inequity of care administration among select populations. In this review, we examine whether the same forward thinking that has resulted in a decline in cardiovascular disease has had an impact on the pervasive disparities in cardiovascular medicine.

DISPARITIES DEFINED

Compared with whites, members of minority groups have a higher burden of chronic diseases, receive lower quality care, and have less access to medical care. Recognizing the potential public health ramifications, in 1999 the US Congress tasked the Institute of Medicine to study and assess the extent of healthcare disparities. This led to the landmark publication, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care.⁸

The Institute of Medicine defines disparities in healthcare as racial or ethnic differences in the quality of healthcare that are not due to access-related factors, clinical needs, preferences, and appropriateness of intervention.⁸ Disparities can also exist according to socioeconomic status and sex.⁹

In an early study documenting the concept of disparities in cardiovascular disease, Stone and Vanzant¹⁰ concluded that heart disease was more common in African Americans than in whites, and that hypertension was the principal cause of cardiovascular disease mortality in African Americans.

Data from US Centers for Disease Control and Prevention, reference 11

Although avoidable deaths from heart disease, stroke, and hypertensive disease declined between 2001 and 2010, African Americans still have a higher mortality rate than other racial and ethnic groups (Figure 1).¹¹

DISPARITIES AND CARDIOVASCULAR HEALTH

The concept of cardiovascular health was established by the American Heart Association (AHA) in efforts to achieve an additional 20% reduction in cardiovascular disease-related mortality by 2020.⁷ Cardiovascular health is defined as the absence of clinically manifest cardiovascular disease and is measured by 7 components:

• Not smoking or abstaining from smoking for at least 1 year
• A normal body weight, defined as a body mass index less than 25 kg/m²
• Optimal physical activity, defined as 75 minutes of vigorous physical activity or 150 minutes of moderate-intensity physical activity per week
• Regular consumption of a healthy diet
• Total cholesterol below 200 mg/dL
• Blood pressure less than 120/80 mm Hg
• Fasting blood sugar below 100 mg/dL.

Nearly 70% of the US population can claim 2, 3, or 4 of these components, but differences exist according to race,¹² and 60% of adult white Americans are limited to achieving no more than 3 of these healthy metrics, compared with 70% of adult African Americans and Hispanic Americans.

Smoking

Smoking is a major risk factor for cardiovascular disease.^12–14

Data from National Health Interview Surgery, Jamal et al, reference 16

During adolescence, white males are more likely to smoke than African American and Hispanic males,¹² but this trend reverses in adulthood, when African American men have a higher prevalence of smoking than white men (21.4% vs 19%).⁷ Rates of lifetime use are highest among American Indian or Alaskan natives and whites (75.9%), followed by African Americans (58.4%), native Hawaiians (56.8%), and Hispanics (56.7%).¹⁵ Trends for current smoking are similar (Figure 2).¹⁶ Moreover, households with lower socioeconomic status have a higher prevalence of smoking.⁷

Physical activity

People with a sedentary lifestyle are more likely to die of cardiovascular disease. As many as 250,000 deaths annually in the United States are attributed to lack of regular physical activity.¹⁷

Recognizing the potential public health ramifications, the AHA and the 2018 Federal Guidelines on Physical Activity recommend that children engage in 60 minutes of daily physical activity and that adults participate in 150 minutes of moderate-intensity or 75 minutes of vigorous physical activity weekly.^18,19

Data from Behavioral Risk Factor Surveillance System, Omura et al, reference 20

In the United States, 15.2% of adolescents reported being physically inactive, according to data published in 2016.⁷ Similar to most cardiovascular risk factors, minority populations and those of lower socioeconomic status had the worst profiles. The prevalence of physical inactivity was highest in African Americans and Hispanics (Figure 3).²⁰

Studies have shown an association between screen-based sedentary behavior (computers, television, and video games) and cardiovascular disease.^21–23 In the United States, 41% of adolescents used computers for activities other than homework for more than 3 hours per day on a school day.⁷ The pattern of use was highest in African American boys and African American girls, followed by Hispanic girls and Hispanic boys.¹⁸ Trends were similar with regard to watching television for more than 3 hours per day.

Sedentary behavior persists into adulthood, with rates of inactivity of 38.3% in African Americans, 40.1% in Hispanics, and 26.3% in white adults.⁷

Nutrition plays a major role in cardiovascular disease, specifically in the pathogenesis of atherosclerotic disease and hypertension.²⁴ Most Americans do not meet dietary recommendations, with minority communities performing worse in specific metrics.⁷

Dietary patterns are reflected in the rate of obesity in this nation. Studies have shown a direct correlation between obesity and cardiovascular disease such as coronary artery disease, heart failure, and atrial fibrillation.^25–28 According to data from the National Health and Nutrition Examination Survey (NHANES), 31% of children between the ages of 2 and 19 years are classified as obese or overweight. The highest rates of obesity are seen in Hispanic and African American boys and girls. The obesity epidemic is disproportionately rampant in children living in households with low income, low education, and high unemployment rates.^7,29–31

Despite the risks associated with obesity, only 64.8% of obese adults report being informed by a doctor or health professional that they were overweight. The proportion of obese adults informed that they were overweight was significantly lower for African Americans and Hispanics compared with whites. Similar differences are seen based on socioeconomic status, as middle-income patients were less likely to be informed than those in the higher income strata (62.4% vs 70.6%).^7,31

Blood pressure

Hypertension is a well-established risk factor for cardiovascular disease and stroke, and a blood pressure of 120/80 mm Hg or lower is identified as a component of ideal cardiovascular health.

In the United States the prevalence of hypertension in adults older than 20 is 32%.⁷ The prevalence of hypertension in African Americans is among the highest in the world.^32,33 African Americans develop high blood pressure at earlier ages, and their average resting blood pressures are higher than in whites.^34,35 For a 45-year-old without hypertension, the 40-year risk of developing hypertension is 92.7% for African Americans and 86% for whites.³⁵ Hypertension is a major risk factor for stroke, and African Americans have a 1.8 times greater rate of fatal stroke than whites.⁷

In 2013 there were 71,942 deaths attributable to high blood pressure, and the 2011 death rate associated with hypertension was 18.9 per 100,000. By race, the death rate was 17.6 per 100,000 for white males and an alarming 47.1 per 100,000 for African American males; rates were 15.2 per 100,000 for white females and 35.1 per 100,000 for African American females.⁷

It is unclear what accounts for the racial difference in prevalence in hypertension. Studies have shown that African Americans are more likely than whites to have been told on more than 2 occasions that they have hypertension. And 85.7% of African Americans are aware that they have high blood pressure, compared with 82.7% of whites.¹⁴

African Americans and Hispanics have poorer hypertension control compared with whites.^36,37 These observed differences cannot be attributed to access alone, as African Americans were more likely to be on higher-intensity blood pressure therapy, whereas Hispanics were more likely to be undertreated.^36,38 In a meta-analysis of 13 trials, Peck et al³⁹ showed that African Americans showed a lesser reduction in systolic and diastolic blood pressure when treated with angiotensin-converting enzyme (ACE) inhibitors.

The 2017 American College of Cardiology (ACC) and AHA guidelines for the prevention, detection, evaluation, and management of high blood pressure in adults⁴⁰ identifies 4 drug classes as reducing cardiovascular disease morbidity and mortality: thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers. Of these 4 classes, thiazide diuretics and calcium channel blockers have been shown to lower blood pressure more effectively in African Americans than renin-angiotensin-aldosterone inhibition with ACE inhibitors or ARBs.

Glycemic control

Type 2 diabetes mellitus secondary to insulin resistance disproportionately affects minority groups, as the prevalence of diabetes mellitus in African Americans is almost twice as high as that in whites, and 35% higher in Hispanics compared with whites.^7,41 Based on NHANES data between 1984 and 2004, the prevalence of diabetes mellitus is expected to increase by 99% in whites, 107% in African Americans, and 127% in Hispanics by 2050. Alarmingly, African Americans over age 75 are expected to experience a 606% increase by 2050.⁴²

With regard to mortality, 21.7 deaths per 100,000 population were attributable to diabetes mellitus according to reports by the AHA in 2016. The death rate in white males was 24.3 per 100,000 compared with 44.9 per 100,000 for African Americans males. The associated mortality rate for white women was 16.2 per 100,000, and 35.8 per 100,000 for African American females.⁷

The management of coronary artery disease has evolved from prolonged bed rest to surgical, pharmacologic, and percutaneous revascularization.^2,5 Coronary revascularization procedures are now relatively common: 950,000 percutaneous coronary interventions and 397,000 coronary artery bypass procedures were performed in 2010.⁷

Nevertheless, despite similar clinical presentations, African Americans with acute myocardial infarction were less likely to be referred for coronary artery bypass grafting than whites.^43–46 They were also less likely to be given thrombolytics⁴⁷ and less likely to undergo coronary angiography with percutaneous coronary intervention.⁴⁸ Similar differences have been reported when comparing Hispanics with whites.⁴⁹

Some suggest that healthcare access is a key mediator of health disparities.⁵⁰ In 2009, Hispanics and African Americans accounted for more than 50% of those without health insurance.⁵¹ Improved access to healthcare might mitigate the disparity in revascularizations.

Massachusetts was one of the first states to mandate that all residents obtain health insurance. As a result, the uninsured rates declined in African Americans and Hispanics in Massachusetts, but a disparity in revascularization persisted. African Americans and Hispanics were 27% and 16% less likely to undergo revascularization procedures (coronary artery bypass grafting or percutaneous coronary intervention) than whites,⁵¹ suggesting that disparities in revascularization are not solely secondary to healthcare access.

These findings are consistent with a 2004 Veterans Administration study,⁵² in which healthcare access was equal among races. The study showed that African Americans received fewer cardiac procedures after an acute myocardial infarction compared with whites.

Have we made progress? The largest disparity between African Americans and whites in coronary artery disease mortality existed in 1990. The disparity persisted to 2012, and although decreased, it is projected to persist to 2030.⁵³

DISPARITIES IN HEART FAILURE

An estimated 5.7 million Americans have heart failure, and 915,000 new cases are diagnosed annually.⁷ Unlike coronary artery disease, heart failure is expected to increase in prevalence by 46%, to 8 million Americans with heart failure by 2030.^7,54

Our knowledge of disparities in the area of heart failure is derived primarily from epidemiologic studies. The Multi-Ethnic Study of Atherosclerosis⁵⁵ showed that African Americans (4.6 per 1,000), followed by Hispanics (3.5 per 1,000) had a higher risk of developing heart failure compared with whites (2.4 per 1,000).The higher risk is in part due to disparities in socioeconomic status and prevalence of hypertension, as African Americans accounted for 75% of cases of nonischemic-related heart failure.⁵⁵ African Americans also have a higher 5-year mortality rate than whites.⁵⁵

Even though the 5-year mortality rate in heart failure is still 50%, the past 30 years have seen innovations in pharmacologic and device therapy and thus improved outcomes in heart failure patients. Still, significant gaps in the use of guideline-recommended therapies, quality of care, and clinical outcomes persist in contemporary practice for racial minorities with heart failure.

Disparities in inpatient care for heart failure

Patients admitted for heart failure and cared for by a cardiologist are more likely to be discharged on guideline-directed medical therapy, have fewer heart failure readmissions, and lower mortality.^56,57 Breathett et al,⁵⁸ in a study of 104,835 patients hospitalized in an intensive care unit for heart failure, found that primary intensive care by a cardiologist was associated with higher survival in both races. However, in the same study, white patients had a higher odds of receiving care from a cardiologist than African American patients.

Disparities and cardiac resynchronization therapy devices

In one-third of patients with heart failure, conduction delays result in dyssynchronous left ventricular contraction.⁵⁹ Dyssynchrony leads to reduced cardiac performance, left ventricular remodeling, and increased mortality.⁵⁶

Cardiac resynchronization therapy (CRT) was approved for clinical use in 2001, and studies have shown that it improves quality of life, exercise tolerance, cardiac performance, and morbidity and mortality rates.^59–66 The 2013 ACC/AHA guidelines for the management of heart failure give a class IA recommendation (the highest) for its use in patients with a left ventricular ejection fraction of 35% or less, sinus rhythm, left bundle branch block and a QRS duration of 150 ms or greater, and New York Heart Association class II, III, or ambulatory IV symptoms while on guideline-directed medical therapy.⁶⁷

Despite these recommendations, racial differences are observed. A study using the Nationwide Inpatient Sample database⁵⁹ showed that between 2002 and 2010, a total of 374,202 CRT devices were implanted, averaging 41,578 annually. After adjusting for heart failure admissions, the study showed that CRT use was favored in men and in whites.

Another study, using the National Cardiovascular Data Registry,⁶⁸ looked at patients who received implantable cardiac defibrillators (ICDs) and were eligible to receive CRT. It found that African Americans and Hispanics were less likely than whites to receive CRT, even though they were more likely to meet established criteria.

Disparities and left ventricular assist devices

The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial and Heart Mate II trial demonstrated that left ventricular assist devices (LVADs) were durable options for long-term support for patients with end-stage heart failure.^69,70 Studies that examined the role of race and clinical outcomes after LVAD implantation have reported mixed findings.^71,72 Few studies have looked at the role racial differences play in accessing LVAD therapy.

Joyce et al⁷³ reviewed data from the Nationwide Inpatient Sample from 2002 to 2003 on patients admitted to the hospital with a primary diagnosis of heart failure or cardiogenic shock. A total of 297,866 patients were included in the study, of whom only 291 underwent LVAD implantation. A multivariate analysis found that factors such as age over 65, female sex, admission to a nonacademic center, geographic region, and African American race adversely influenced access to LVAD therapy.

Breathett et al⁷⁴ evaluated racial differences in LVAD implantations from 2012 to 2015, a period that corresponds to increased health insurance expansion, and found LVAD implantations increased among African American patients with advanced heart failure, but no other racial or ethnic group.

For patients with end-stage heart failure, orthotopic heart transplant is the most definitive and durable option for long-term survival. According to data from the United Network for Organ Sharing, 62,508 heart transplants were performed from January 1, 1988 to December 31, 2015. Compared with transplants of other solid organs, heart transplant occurs in significantly infrequent rates.

Barriers to transplant include lack of health insurance, considered a surrogate for low socioeconomic status. Hispanics and African Americans are less likely to have private health insurance than non-Hispanic whites, and this difference is magnified among the working poor.

Despite these perceived barriers, Kilic et al⁷⁵ found that African Americans comprised 16.4% of heart transplant recipients, although they make up only approximately 13% of the US population. They also had significantly shorter wait-list times than whites. On the negative side, African Americans had a higher unadjusted mortality rate than whites (15% vs 12% P = .002). African Americans also tended to receive their transplants at centers with lower transplant volumes and higher transplant mortality rates.

Several other studies also showed that African Americans compared to whites have significantly worse outcomes after transplant.^76–79 What accounts for this difference? Kilic et al⁷⁵ showed that African Americans had the lowest proportion of blood type matching and lowest human leukocyte antigen matching, were younger (because African Americans develop more advanced heart failure at younger ages), had higher serum creatinine levels, and were more often bridged to transplant with an LVAD.

DISPARITIES IN CARDIOVASCULAR RESEARCH

Although the United States has the most sophisticated and robust medical system in the world, select groups have significant differences in delivery and healthcare outcomes. There are many explanations for these differences, but a contributing factor may be the paucity of research dedicated to understand racial and ethnic differences.⁸⁰

Differences observed in epidemiologic studies may be secondary to pathophysiology, genetic differences, environment, and lifestyle choices. Historically, clinical trials were conducted in homogeneous populations with respect to age (middle-aged), sex (male), and race (white), and the results were generalized to heterogeneous populations.⁸⁰

Disparities in research have implications in clinical practice. Overall, the primary cause of heart failure is ischemia; however, in African Americans, the primary cause is hypertensive heart disease.⁸¹ Studies in hypertension have shown that African Americans have less of a response to neurohormonal blockade with ACE inhibitors and beta-blockers than non-African Americans.⁸² Nevertheless, neurohormonal blockade has become the cornerstone of heart failure treatment.

Retrospective analysis of the Vasodilator-Heart Failure trials⁸³ showed that treatment with isosorbide dinitrate plus hydralazine, compared with placebo, conferred a survival benefit for African Americans but not whites.⁸⁰ No survival advantage was noted when isosorbide dinitrate/hydralazine was compared to enalapril in African Americans, although enalapril was superior to isosorbide dinitrate in whites.⁴⁵ These observations were recognized 10 to 15 years after trial completion, and were only possible because the trials included sufficient numbers of African American patients to complete analysis.

In 1993, the US Congress passed the National Institutes of Health (NIH) Revitalization Act, which established guidelines requiring NIH grant applicants to include minorities in human subject research, as they were historically underrepresented in clinical research trials.^84,85

In 2001, the Beta-Blocker Evaluation of Survival Trial⁸⁶ reported its results investigating whether bucindolol, a nonselective beta-blocker, would reduce mortality in patients with advanced heart failure (New York Heart Association class III or IV). This was one of the first trials to prospectively investigate racial and ethnic differences in response to treatment. Though it showed no overall benefit in the use of bucindolol in the treatment of advanced heart failure, subgroup analysis showed that whites did enjoy a benefit in terms of lower mortality, whereas African Americans did not.

Results of the Vasodilator-Heart Failure trials led to further population-directed research, most notably the African American Heart Failure Trial,⁸⁷ a double-blind, placebo-controlled, randomized trial in patients who identified as African American. Patients who were randomized to receive a fixed dose of hydralazine and isosorbide dinitrate had a 43% lower mortality rate, a 33% lower hospitalization rate for heart failure, and better quality of life than patients in the placebo group, leading to early termination of the trial. The outcomes suggested that the combination of isosorbide dinitrate and hydralazine treats heart failure in a manner independent of pure neurohormonal blockade.

CHALLENGES IN STUDY PARTICIPATION

Recruitment of minority participants in biomedical research is a challenging task for clinical investigators.^88,89 Some of the factors thought to pose potential barriers for racial and ethnic minority participation in health research include poor access to primary medical care, failure of researchers to recruit minority populations actively, and language and cultural barriers.⁹⁰

Further, it is widely claimed that African Americans are less willing than nonminority individuals to participate in clinical research trials due to general distrust of the medical community as a result of the Tuskegee Syphilis Experiment.⁹¹ That infamous study, conducted by the US Public Health Service between 1932 and 1972, sought to record the natural progression of untreated syphilis in poor African American men in Alabama. The participants were not informed of the true purpose of the study, and they were under the impression that they were simply receiving free healthcare from the US government. Further, they were denied appropriate treatment even after it became readily available, in order for researchers to observe the progression of the disease.

While the 1993 mandate did in fact increase pressure on researchers to develop strategies to overcome participation barriers, the issue of underrepresentation of racial minorities in clinical research, including cardiovascular research, has not been resolved and continues to be a problem today.

The overall goal of clinical research is to determine the best strategies to prevent and treat disease. But if the study population is not representative of the affected population at large, the results cannot be generalized to underrepresented subgroups. The implications of underrepresentation in research are far-reaching, and can further contribute to disparate care of minority patients such as African Americans, who have a higher prevalence of cardiovascular risk factors and greater burden of heart failure.

Between 1986 and 2018, according to a PUBMED search, 10,462 articles highlighted the presence of a health-related disparity. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in the physician work force.

Eliminating bias

Implicit bias refers to attitudes, thoughts, and feelings that exist outside of the conscious awareness.⁹² These biases can be triggered by race, gender, or socioeconomic status. They have manifested in society as stereotypes that men are more competent than women, women are more verbal than men, and African Americans are more athletic than whites.⁹³

The concept of implicit bias is important, in that the populations that experience the greatest health disparities also suffer from negative cultural stereotypes.⁹⁴ Healthcare professionals are not inoculated against implicit bias.⁹⁵ Studies have shown that most healthcare providers have implicit biases that reflect positive attitudes toward whites and negative attitudes toward people of color.^{92,94,96–98}

The Implicit Association Test, introduced in 1998, is widely used to measure implicit bias. It measures response time of subjects to match particular social groups to particular attributes.⁹⁹ Green et al,⁹⁹ using this test, showed that although physicians reported no explicit preference for white vs African American patients or differences in perceived cooperativeness, the test revealed implicit preference favoring white Americans and implicit stereotypes of African Americans as less cooperative for medical procedures and in general. This also manifested in clinical decision-making, as white Americans were more likely, and African Americans less likely, to be treated with thrombolysis.⁹⁹

Sabin et al¹⁰⁰ showed that implicit bias was present among pediatricians, although less than in society as a whole and in other healthcare professionals.

But how does one change feelings that exist outside of the conscious awareness? Green et al⁹⁹ showed that making physicians aware of their susceptibility to bias changed their behavior. A subset of physicians who were made aware that bias was a focus of the study were more likely to refer African Americans for thrombolysis even if they had a high degree of implicit pro-white bias.^94,100 Perhaps mandating that all healthcare providers take a self-administered and confidentially reported Implicit Association Test will lead to awareness of implicit bias and minimize healthcare behaviors that contribute to the current state of disparities.

Improving access

Common indicators of access to healthcare include health insurance status, having a usual source of healthcare, and having a regular physician.¹⁰¹ Health insurance does offer protection from the costs associated with illness and health maintenance.¹⁰¹ It is also a major contributing factor in racial and ethnic disparities.

Chen et al¹⁰² examined the effects of the Affordable Care Act and found that it was associated with reduction in the probability of being uninsured, delaying necessary care, and forgoing necessary care, and increased probability of having a physician. However, earlier studies showed that access to health insurance by itself does not equate to equitable care.^103,104

Diversifying the work force

African Americans comprise 4% of physicians and Hispanic Americans 5%, despite accounting for 13% and 16% of the US population.¹⁰⁵ This underrepresentation has led to African American and Hispanic American patients being more likely than white patients to be treated by a physician from a dissimilar racial or ethnic background.¹⁰⁶ Studies have shown that minority patients in a race- or ethnic-concordant relationship are more likely to use needed health services, less likely to postpone seeking care, and report greater satisfaction.^106,107 Minority physicians often locate and practice in neighborhoods with high minority populations, and they disproportionately care for disadvantaged patients of lower socioeconomic status and poorer health.^106,108

WE ARE STILL IN THE TUNNEL, BUT THERE IS LIGHT AT THE END

The cardiovascular community has faced tremendous challenges in the past and responded with innovative research that has led to imaging that aids in the diagnosis of subclinical cardiovascular disease and invasive and pharmacologic strategies that have improved cardiovascular outcomes. One may say that there is light at the end of the tunnel; however, the existence of disparate care reminds us that we are still in the tunnel.

Disparities in cardiovascular disease management present a unique challenge for the community. There is no drug, device, or invasive procedure to eliminate this pathology. However, by acknowledging the problem and implementing changes at the system, provider, and patient level, the cardiovascular community can achieve yet another momentous achievement: the end of cardiovascular health disparities. Cardiovascular disease makes no distinction in race, sex, age, or socioeconomic status, and neither should the medical community.

Aspects of modern life that may promote hemorrhoids include increased consumption of processed foods, a sedentary lifestyle, and using cell phones while defecating, which translates to much more time spent on the toilet.

Hemorrhoids accounted for more than 3.5 million US outpatient visits in 2010, and they were the third leading cause of hospital admissions related to gastrointestinal disease.¹

Here, we review the process for diagnosing and grading hemorrhoids, as well as for selecting the appropriate medical or surgical treatment based on the most recent clinical evidence.

DIAGNOSING AND CLASSIFYING HEMORRHOIDS

Hemorrhoids are the distal prolapse of the arteriovenous bundle, muscle fibers, and surrounding connective tissue as an envelope below the dentate line in the anal canal. They usually present with painless rectal bleeding.²

The diagnosis of hemorrhoids relies on the history and physical examination rather than on laboratory testing or imaging studies. Typically, the presenting symptom is painless rectal bleeding associated with bowel movements, usually appearing as bright red blood on the toilet paper or coating the stool. Severe itching and anal discomfort are also common, especially with chronic hemorrhoids.

Detailed patient history

A detailed patient history is important. It should include the extent, severity, and duration of symptoms, frequency of bowel movements, associated symptoms (eg, constipation, fecal incontinence), daily dietary habits, and details of bowel movements (eg, time spent during each bowel movement and concomitant cell phone use).³

Regarding bowel habits, some patients experience lifelong constipation or diarrhea. Therefore, what a patient considers a normal bowel habit may not be normal and should be investigated.⁴ Also, it is important to exclude external thrombosed hemorrhoids, anal fissure, anal abscess, and Crohn disease.⁵

Physical examination

A digital rectal examination is the second step. During the examination, look for skin tags, sphincter tone, perianal hygiene, and synchronous anal lesions.³ Of note, the Valsalva maneuver can be performed during the digital rectal examination.

Red flags for colorectal cancer on the digital rectal examination include a mass with or without presence of hemorrhoidal sacs and a bleeding source above the level of internal hemorrhoids.

Endoscopy

Since rectal bleeding can be a sign of several diseases, including colorectal cancer, it is important to review any previous endoscopic results. Patients at high risk of colon cancer should undergo rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy.^3,4 In our practice, we recommend endoscopic evaluation for patients over age 40 with rectal bleeding, especially if they have a family history of colorectal cancer.

External or internal (grades I–IV)

Hemorrhoids can be categorized as either external or internal.

External hemorrhoids are distinguished by their outer covering with perianal skin and anoderm and their location inferior to the dentate line. They are painful if the hemorrhoidal sac is occluded by a thrombotic clot.

Internal hemorrhoids are above the dentate line and covered with rectal columnar and transitional mucosa. They are further graded on a 4-point scale³:

• Grade I—Visible hemorrhoids that do not prolapse
• Grade II—Hemorrhoids that prolapse during the Valsalva maneuver but spontaneously reduce
• Grade III—Hemorrhoids that prolapse during the Valsalva maneuver and need manual reduction
• Grade IV—Nonreducible hemorrhoids.

A RANGE OF TREATMENTS

In choosing the treatment for hemorrhoids, one should consider the disease grade and severity, its impact on the quality of life, the degree of pain it causes, the patient’s likelihood of adhering to treatment, and the patient’s personal preference.

Regardless of severity, treatment almost always starts with a high-fiber diet and other lifestyle modifications that include bowel movement behaviors. This requires practitioners to spend significant time on patient education regardless of the type or the severity of the disease.

Treatments can be grouped in 3 categories: conservative, office-based, and surgical. Practitioners should thoroughly discuss the options with the patient, emphasizing the pros and cons of each.

Conservative measures are aimed at softening the stool, relieving pain, and correcting bad toileting habits. In most cases, the primary precipitating factor is lifestyle, and unless patients change it, they are more likely to have recurrent symptoms in the long term.

No phone in the bathroom

People take their phones into the bathroom, and this habit is blamed for increasing the time on the toilet and leading to increased pressure on the anal region and straining during defecation. Some research points to a direct correlation between the time spent on the toilet and hemorrhoidal disease, although the exact cause-and-effect relationship with cell phone use has not been determined. In general, spending excessive time on the commode, including reading, should be discouraged.

Less time in the bathroom

Johannsson et al⁶ reported that patients with hemorrhoids spent more time on the toilet and had to strain harder and more often than controls in the community and hospital.

Garg and Singh⁷ and Garg⁸ use the mnemonic “TONE” for appropriate defecation habits:

• Three minutes during defecation
• Once-daily defecation
• No straining and no cell phone use during defecation
• Enough fiber.

More fiber

Fiber draws water into the lumen of the colon, increasing the water content of the stool. Recommended daily fiber intake is about 28 g for women and 38 g for men.⁹ This high level of intake is hard to achieve without supplements for someone who consumes a classic American diet with a lot of fast food.

Fiber supplements are strongly recommended in the American Society of Colon and Rectal Surgeons (ASCRS) practice guidelines³ based on a Cochrane review.¹⁰ In this meta-analysis, with fiber supplements, the relative risk of persisting or nonimproving symptoms was 0.53 (95% confidence interval [CI] 0.38–0.73) and the relative risk of bleeding was 0.50 (95% CI 028–0.89). Psyllium husk is an inexpensive bulk-forming fiber supplement; the optimal daily dosage is not known.

We recommend at least 28 g of daily fiber intake for women and 38 g for men, for which psyllium husk can be used to complement the diet.

Laxatives for some

Laxatives such as docusate are used to change the stool consistency when there is an organic bowel problem rather than a dietary issue. They can be used as a complementary treatment to enhance the effect of the fiber treatment.

Other measures

Topical anesthesia (eg, 5% lidocaine) is commonly used to treat pain from low-grade lesions, but no reliable data have been published. As most cases of hemorrhoids tend to progress over time, one should not expect long-term improvement with topical anesthesia. Nevertheless, it can be used as an ancillary treatment in select cases when short-term improvement is the main goal, and we recommend it based on our own experience.

Hygiene. Bidet use or cleaning the perianal area with water is recommended.

Phlebotonics contain a variety of ingredients including natural plant extracts such as flavonoids and synthetic products. Even though the exact mechanism of action is not known, phlebotonics are thought to increase venous and lymphatic drainage, normalize capillary permeability, and decrease inflammation in the hemorrhoidal cushions.^4,11–13

In a Cochrane review of 24 randomized controlled trials, Perera et al¹⁴ found that phlebotonics improved the outcomes of:

• Bleeding (odds ratio [OR] 0.21, number needed to treat [NNT] 4.8, P = .0002)
• Pruritus (OR 0.23, NNT 9.1, P = .02)
• Discharge or leakage (OR 0.12, NNT 5, P = .0008)
• Overall symptoms (OR 15.99, NNT 2.7, P < .00001). Overall symptoms were also improved in the subgroup of pregnant patients.

Although phlebotonics give better results than placebo in the short-term management of hemorrhoids, there is a paucity of long-term data. Thus, the ASCRS clinical practice guidelines gives the regular use of these agents only a weak recommendation.³

Flavonoids (diosmin, hesperidin, rutoside), in a meta-analysis vs placebo in 1,514 patients, showed a beneficial response in terms of bleeding (relative risk [RR] 0.33), pruritus (relative risk [RR] 0.65), and recurrences (RR 0.53).¹⁵

Although Preparation H is commonly used as an over-the-counter medication, there are no good data on it, and it is not considered a phlebotonic.

Office-based treatments—rubber band ligation, infrared photocoagulation, and sclerotherapy—are commonly used for grade I, II, and III hemorrhoids that have not responded to conservative management. The primary goal of these treatments is to decrease blood flow into the hemorrhoidal sac.

Even though office-based treatments are highly effective and major complications are uncommon, recurrence rates can be high, requiring patients to undergo additional treatments. Moreover, septic complications can occur, so patients should be closely observed for fever and urinary problems. Pain is a common symptom after office-based treatments, and bleeding may also occur.

The ASCRS guidelines strongly recommend office-based treatments for patients with grade I and II hemorrhoids, and for some with grade III hemorrhoids.³

Rubber band ligation

Iyer et al¹⁸ reported that patients on warfarin therapy had up to a 9 times higher risk of postprocedural bleeding, and patients on aspirin had a risk up to 3 times higher. Therefore, whether patients on anticoagulant therapy should undergo this procedure is unclear.

A Cochrane database review¹⁹ found this technique effective for hemorrhoid grades I through III, although some patients with grade III hemorrhoids may benefit more from excisional hemorrhoidectomy, which is associated with a lower recurrence rate than rubber band ligation.

Brown et al²⁰ performed a randomized controlled trial comparing hemorrhoidal artery ligation and rubber band ligation for symptomatic hemorrhoids in 372 patients with grade II and III hemorrhoids. Postprocedural pain scores on days 1 and 7 were significantly lower with rubber band ligation, but recurrences were more common (49% vs 30%, P = .0005, respectively).

Overall, rubber band ligation is an excellent option for grade II hemorrhoids, as it is easy to perform, is associated with low pain scores, and can be used to treat recurrences.

Infrared photocoagulation

In this procedure, an infrared probe produces heat to induce coagulation, fibrosis, and ultimately necrosis of the protruding tissue in the hemorrhoidal cushions.²¹ Even though its use was initially directed at grade I and II hemorrhoids, recent reports showed acceptable results for grades III and IV.^22,23 A randomized controlled trial comparing infrared photocoagulation and rubber band ligation in 94 patients found that both procedures were well accepted and highly effective; however, patients had better pain scores with photocoagulation in the first 24 hours after the procedure (P < .05).²⁴

Sclerotherapy

The injection can cause prostatic abscess and sepsis, although this is rare.25 Nevertheless, high fever and postprocedural pain should be carefully evaluated.

There have been few randomized trials of sclerotherapy, but success rates so far have been higher for grade I hemorrhoids than for grades II and III.^26–28 It is the preferred method for patients who have bleeding abnormalities caused by medications or other diseases (eg, cirrhosis).

Although nonsurgical treatments have substantially improved, surgery is the most effective and strongly recommended treatment for patients with high-grade internal hemorrhoids (grades III and IV), external and mixed hemorrhoids, and recurrent hemorrhoids.

The most popular surgical options are open or closed hemorrhoidectomy, stapled hemorrhoidopexy, and Doppler-guided hemorrhoidal artery ligation. Each has different success rates and different complication profiles, which need to be discussed with the patient.

Overall, surgery is associated with more adverse effects than office-based treatments or medical management. Postoperative pain is the most common complaint, but anal stricture (rare) or incontinence may occur due to excessive tissue excision and damage to the sphincter muscles. These can be avoided by maintaining the normal anoderm between excisions, by not excising all hemorrhoid sacs at once if the patient has extensive lesions, and by performing a careful dissection in the submucosal plane.

Patients with profuse bleeding or an underlying bleeding abnormality are best managed with surgical approaches performed in an operating room.

Excisional surgical hemorrhoidectomy

Excision of the hemorrhoidal sac, the most conventional surgical technique, is generally reserved for prolapsing disease. The recurrence rate after excisional hemorrhoidectomy is significantly lower than with any other approach.²⁹

Excisional hemorrhoidectomy can be performed using either an open approach, in which the edges of the mucosal defect are not reapproximated, or a closed approach, in which they are. In a systematic review, Bhatti et al³⁰ compared open vs closed techniques and found that the closed technique resulted in less postoperative pain, better wound healing, and less bleeding. Rates of recurrence, postoperative complications, and surgical site infection and lengths of stay were comparable with either procedure.

Overall, excisional hemorrhoidectomy is associated with higher pain scores than any other surgical method.²⁹ Recently, the use of electrodiathermy energy devices, also described as electrosurgical vessel-sealing devices, have further improved overall patient satisfaction.³¹

Multiple painful hemorrhoidal sacs require a careful surgical approach, as extensive resection may cause widespread fibrosis and stricture. As with anal stricture, fecal incontinence can be prevented by careful dissection. However, already existing incontinence is not a contraindication for the surgery.

Doppler-guided hemorrhoidal artery ligation

Doppler-guided hemorrhoidal artery ligation involves using a Doppler probe to find and ligate individual hemorrhoidal arteries. Additionally, mucopexy (transanal rectoanal repair) is performed to relocate the prolapsing tissue. Avital et al³² reported that at 1 year after this procedure, recurrence rates were 5.3% for grade II hemorrhoids and 13% for grade III hemorrhoids. At 5 years, recurrence rates were 12% for grade II and 31% for grade III.

To date, this procedure appears to be suitable for grade I, II, and III hemorrhoids, especially for grade II, but more studies are needed to prove its efficacy and recurrence rates for more advanced lesions. Although this technique has a high morbidity rate (18%), primarily pain or tenesmus, it causes less postoperative pain than other surgical methods.³³ Overall, it has the potential to become a favored treatment.

Stapled hemorrhoidopexy

Although pain scores are lower with stapled hemorrhoidopexy than with excisional hemorrhoidectomy, this procedure is not superior in terms of recurrences.^34,35 Also, practitioners should be careful about specific complications of stapled hemorrhoidopexy, such as rectovaginal fistula, anal stenosis, or sphincter injuries. These specific complications should be clearly explained to patients, and necessary information should be given to patients upon discharge. The primary care physician should also be careful about fistulas and stenoses in this particular patient population.

There is no best treatment for hemorrhoids. Every patient is different, and the physician and patient need to understand each other’s expectations, weigh the risks and benefits, and arrive at a mutual decision. A good patient-doctor relationship is essential.

Given the variety of available treatments, head-to-head comparisons are difficult. Moreover, the efficacy and applicability of each technique changes with the grade of the lesion or lesions and the skill of the practitioner. Lacking comprehensive studies comparing conservative, office-based, and surgical management, no decisive statements can be made based on current evidence.

Patients with compounding conditions

Pregnant patients often develop hemorrhoids as intra-abdominal pressure increases, particularly during the third trimester.³⁶ Also, acute episodes of pain and bleeding are common in pregnant women with preexisting hemorrhoids.

Conservative treatment is the main approach in pregnant patients because most hemorrhoids regress after childbirth. This includes increased dietary fiber, stool softeners, and sitz baths, which are safe to use for external hemorrhoids. Any office-based or surgical intervention should be postponed until after childbirth, if possible. Kegel exercises and lying on the left side are also recommended to relieve symptoms. In cases of severe bleeding, anal packing appears to be useful.

Immunosuppressed patients and those on anticoagulant therapy are more prone to serious complications such as sepsis and profuse bleeding. Thus, conservative management should be used in these patients as well. Injection sclerotherapy may be beneficial, as it has been shown to decrease bleeding. Of note, patients on immunosuppressive agents should stop taking them and start taking an antibiotic, and patients on anticoagulant or antiplatelet medications should be instructed to stop them 1 week before any intervention.

Crohn disease. Some patients with Crohn disease may have hemorrhoids, though this is rare. Eglinton et al,³⁷ in a series of 715 patients with Crohn disease, reported that 190 (26.6%) had symptomatic perianal disease. Of these, only 3 (1.6%) had hemorrhoids. Treatment is always conservative and directed at the Crohn disease rather than the hemorrhoids.

Patients with portal hypertension (eg, due to cirrhosis) are prone to have anorectal varices that may resemble hemorrhoids. Anorectal varices can be treated with vascular ligation, whereas sclerotherapy is the preferred method for hemorrhoids in this group, in whom coagulopathy is common.

TAKE-HOME MESSAGES

Hemorrhoidal disease is common in the United States, and with our diet and lifestyle, the incidence is likely to increase. (A national survey found that overall dietary quality improved modestly in children and adolescents in the United States from 1999 to 2012 but remained far below optimal.³⁸) Practitioners need to carefully assess hemorrhoidal symptoms and complete any necessary screening tests before establishing a diagnosis. This helps to avoid missing any underlying disease.

Fiber supplements along with dietary and lifestyle changes constitute the baseline of the management regardless of the disease grade. Office-based interventions are beneficial for grade I and II hemorrhoids and for some grade III hemorrhoids. Repeated interventions can increase the success rate. In patients with high-grade, symptomatic hemorrhoids, surgical hemorrhoidectomy is the most effective modality with the lowest recurrence rates, although it causes more pain than conservative methods.

Aspects of modern life that may promote hemorrhoids include increased consumption of processed foods, a sedentary lifestyle, and using cell phones while defecating, which translates to much more time spent on the toilet.

Hemorrhoids accounted for more than 3.5 million US outpatient visits in 2010, and they were the third leading cause of hospital admissions related to gastrointestinal disease.¹

Here, we review the process for diagnosing and grading hemorrhoids, as well as for selecting the appropriate medical or surgical treatment based on the most recent clinical evidence.

DIAGNOSING AND CLASSIFYING HEMORRHOIDS

Hemorrhoids are the distal prolapse of the arteriovenous bundle, muscle fibers, and surrounding connective tissue as an envelope below the dentate line in the anal canal. They usually present with painless rectal bleeding.²

The diagnosis of hemorrhoids relies on the history and physical examination rather than on laboratory testing or imaging studies. Typically, the presenting symptom is painless rectal bleeding associated with bowel movements, usually appearing as bright red blood on the toilet paper or coating the stool. Severe itching and anal discomfort are also common, especially with chronic hemorrhoids.

Detailed patient history

A detailed patient history is important. It should include the extent, severity, and duration of symptoms, frequency of bowel movements, associated symptoms (eg, constipation, fecal incontinence), daily dietary habits, and details of bowel movements (eg, time spent during each bowel movement and concomitant cell phone use).³

Regarding bowel habits, some patients experience lifelong constipation or diarrhea. Therefore, what a patient considers a normal bowel habit may not be normal and should be investigated.⁴ Also, it is important to exclude external thrombosed hemorrhoids, anal fissure, anal abscess, and Crohn disease.⁵

Physical examination

A digital rectal examination is the second step. During the examination, look for skin tags, sphincter tone, perianal hygiene, and synchronous anal lesions.³ Of note, the Valsalva maneuver can be performed during the digital rectal examination.

Red flags for colorectal cancer on the digital rectal examination include a mass with or without presence of hemorrhoidal sacs and a bleeding source above the level of internal hemorrhoids.

Endoscopy

Since rectal bleeding can be a sign of several diseases, including colorectal cancer, it is important to review any previous endoscopic results. Patients at high risk of colon cancer should undergo rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy.^3,4 In our practice, we recommend endoscopic evaluation for patients over age 40 with rectal bleeding, especially if they have a family history of colorectal cancer.

External or internal (grades I–IV)

Hemorrhoids can be categorized as either external or internal.

External hemorrhoids are distinguished by their outer covering with perianal skin and anoderm and their location inferior to the dentate line. They are painful if the hemorrhoidal sac is occluded by a thrombotic clot.

Internal hemorrhoids are above the dentate line and covered with rectal columnar and transitional mucosa. They are further graded on a 4-point scale³:

• Grade I—Visible hemorrhoids that do not prolapse
• Grade II—Hemorrhoids that prolapse during the Valsalva maneuver but spontaneously reduce
• Grade III—Hemorrhoids that prolapse during the Valsalva maneuver and need manual reduction
• Grade IV—Nonreducible hemorrhoids.

A RANGE OF TREATMENTS

In choosing the treatment for hemorrhoids, one should consider the disease grade and severity, its impact on the quality of life, the degree of pain it causes, the patient’s likelihood of adhering to treatment, and the patient’s personal preference.

Regardless of severity, treatment almost always starts with a high-fiber diet and other lifestyle modifications that include bowel movement behaviors. This requires practitioners to spend significant time on patient education regardless of the type or the severity of the disease.

Treatments can be grouped in 3 categories: conservative, office-based, and surgical. Practitioners should thoroughly discuss the options with the patient, emphasizing the pros and cons of each.

Conservative measures are aimed at softening the stool, relieving pain, and correcting bad toileting habits. In most cases, the primary precipitating factor is lifestyle, and unless patients change it, they are more likely to have recurrent symptoms in the long term.

No phone in the bathroom

People take their phones into the bathroom, and this habit is blamed for increasing the time on the toilet and leading to increased pressure on the anal region and straining during defecation. Some research points to a direct correlation between the time spent on the toilet and hemorrhoidal disease, although the exact cause-and-effect relationship with cell phone use has not been determined. In general, spending excessive time on the commode, including reading, should be discouraged.

Less time in the bathroom

Johannsson et al⁶ reported that patients with hemorrhoids spent more time on the toilet and had to strain harder and more often than controls in the community and hospital.

Garg and Singh⁷ and Garg⁸ use the mnemonic “TONE” for appropriate defecation habits:

• Three minutes during defecation
• Once-daily defecation
• No straining and no cell phone use during defecation
• Enough fiber.

More fiber

Fiber draws water into the lumen of the colon, increasing the water content of the stool. Recommended daily fiber intake is about 28 g for women and 38 g for men.⁹ This high level of intake is hard to achieve without supplements for someone who consumes a classic American diet with a lot of fast food.

Fiber supplements are strongly recommended in the American Society of Colon and Rectal Surgeons (ASCRS) practice guidelines³ based on a Cochrane review.¹⁰ In this meta-analysis, with fiber supplements, the relative risk of persisting or nonimproving symptoms was 0.53 (95% confidence interval [CI] 0.38–0.73) and the relative risk of bleeding was 0.50 (95% CI 028–0.89). Psyllium husk is an inexpensive bulk-forming fiber supplement; the optimal daily dosage is not known.

We recommend at least 28 g of daily fiber intake for women and 38 g for men, for which psyllium husk can be used to complement the diet.

Laxatives for some

Laxatives such as docusate are used to change the stool consistency when there is an organic bowel problem rather than a dietary issue. They can be used as a complementary treatment to enhance the effect of the fiber treatment.

Other measures

Topical anesthesia (eg, 5% lidocaine) is commonly used to treat pain from low-grade lesions, but no reliable data have been published. As most cases of hemorrhoids tend to progress over time, one should not expect long-term improvement with topical anesthesia. Nevertheless, it can be used as an ancillary treatment in select cases when short-term improvement is the main goal, and we recommend it based on our own experience.

Hygiene. Bidet use or cleaning the perianal area with water is recommended.

Phlebotonics contain a variety of ingredients including natural plant extracts such as flavonoids and synthetic products. Even though the exact mechanism of action is not known, phlebotonics are thought to increase venous and lymphatic drainage, normalize capillary permeability, and decrease inflammation in the hemorrhoidal cushions.^4,11–13

In a Cochrane review of 24 randomized controlled trials, Perera et al¹⁴ found that phlebotonics improved the outcomes of:

• Bleeding (odds ratio [OR] 0.21, number needed to treat [NNT] 4.8, P = .0002)
• Pruritus (OR 0.23, NNT 9.1, P = .02)
• Discharge or leakage (OR 0.12, NNT 5, P = .0008)
• Overall symptoms (OR 15.99, NNT 2.7, P < .00001). Overall symptoms were also improved in the subgroup of pregnant patients.

Although phlebotonics give better results than placebo in the short-term management of hemorrhoids, there is a paucity of long-term data. Thus, the ASCRS clinical practice guidelines gives the regular use of these agents only a weak recommendation.³

Flavonoids (diosmin, hesperidin, rutoside), in a meta-analysis vs placebo in 1,514 patients, showed a beneficial response in terms of bleeding (relative risk [RR] 0.33), pruritus (relative risk [RR] 0.65), and recurrences (RR 0.53).¹⁵

Although Preparation H is commonly used as an over-the-counter medication, there are no good data on it, and it is not considered a phlebotonic.

Office-based treatments—rubber band ligation, infrared photocoagulation, and sclerotherapy—are commonly used for grade I, II, and III hemorrhoids that have not responded to conservative management. The primary goal of these treatments is to decrease blood flow into the hemorrhoidal sac.

Even though office-based treatments are highly effective and major complications are uncommon, recurrence rates can be high, requiring patients to undergo additional treatments. Moreover, septic complications can occur, so patients should be closely observed for fever and urinary problems. Pain is a common symptom after office-based treatments, and bleeding may also occur.

The ASCRS guidelines strongly recommend office-based treatments for patients with grade I and II hemorrhoids, and for some with grade III hemorrhoids.³

Rubber band ligation

Iyer et al¹⁸ reported that patients on warfarin therapy had up to a 9 times higher risk of postprocedural bleeding, and patients on aspirin had a risk up to 3 times higher. Therefore, whether patients on anticoagulant therapy should undergo this procedure is unclear.

A Cochrane database review¹⁹ found this technique effective for hemorrhoid grades I through III, although some patients with grade III hemorrhoids may benefit more from excisional hemorrhoidectomy, which is associated with a lower recurrence rate than rubber band ligation.

Brown et al²⁰ performed a randomized controlled trial comparing hemorrhoidal artery ligation and rubber band ligation for symptomatic hemorrhoids in 372 patients with grade II and III hemorrhoids. Postprocedural pain scores on days 1 and 7 were significantly lower with rubber band ligation, but recurrences were more common (49% vs 30%, P = .0005, respectively).

Overall, rubber band ligation is an excellent option for grade II hemorrhoids, as it is easy to perform, is associated with low pain scores, and can be used to treat recurrences.

Infrared photocoagulation

In this procedure, an infrared probe produces heat to induce coagulation, fibrosis, and ultimately necrosis of the protruding tissue in the hemorrhoidal cushions.²¹ Even though its use was initially directed at grade I and II hemorrhoids, recent reports showed acceptable results for grades III and IV.^22,23 A randomized controlled trial comparing infrared photocoagulation and rubber band ligation in 94 patients found that both procedures were well accepted and highly effective; however, patients had better pain scores with photocoagulation in the first 24 hours after the procedure (P < .05).²⁴

Sclerotherapy

The injection can cause prostatic abscess and sepsis, although this is rare.25 Nevertheless, high fever and postprocedural pain should be carefully evaluated.

There have been few randomized trials of sclerotherapy, but success rates so far have been higher for grade I hemorrhoids than for grades II and III.^26–28 It is the preferred method for patients who have bleeding abnormalities caused by medications or other diseases (eg, cirrhosis).

Although nonsurgical treatments have substantially improved, surgery is the most effective and strongly recommended treatment for patients with high-grade internal hemorrhoids (grades III and IV), external and mixed hemorrhoids, and recurrent hemorrhoids.

The most popular surgical options are open or closed hemorrhoidectomy, stapled hemorrhoidopexy, and Doppler-guided hemorrhoidal artery ligation. Each has different success rates and different complication profiles, which need to be discussed with the patient.

Overall, surgery is associated with more adverse effects than office-based treatments or medical management. Postoperative pain is the most common complaint, but anal stricture (rare) or incontinence may occur due to excessive tissue excision and damage to the sphincter muscles. These can be avoided by maintaining the normal anoderm between excisions, by not excising all hemorrhoid sacs at once if the patient has extensive lesions, and by performing a careful dissection in the submucosal plane.

Patients with profuse bleeding or an underlying bleeding abnormality are best managed with surgical approaches performed in an operating room.

Excisional surgical hemorrhoidectomy

Excision of the hemorrhoidal sac, the most conventional surgical technique, is generally reserved for prolapsing disease. The recurrence rate after excisional hemorrhoidectomy is significantly lower than with any other approach.²⁹

Excisional hemorrhoidectomy can be performed using either an open approach, in which the edges of the mucosal defect are not reapproximated, or a closed approach, in which they are. In a systematic review, Bhatti et al³⁰ compared open vs closed techniques and found that the closed technique resulted in less postoperative pain, better wound healing, and less bleeding. Rates of recurrence, postoperative complications, and surgical site infection and lengths of stay were comparable with either procedure.

Overall, excisional hemorrhoidectomy is associated with higher pain scores than any other surgical method.²⁹ Recently, the use of electrodiathermy energy devices, also described as electrosurgical vessel-sealing devices, have further improved overall patient satisfaction.³¹

Multiple painful hemorrhoidal sacs require a careful surgical approach, as extensive resection may cause widespread fibrosis and stricture. As with anal stricture, fecal incontinence can be prevented by careful dissection. However, already existing incontinence is not a contraindication for the surgery.

Doppler-guided hemorrhoidal artery ligation

Doppler-guided hemorrhoidal artery ligation involves using a Doppler probe to find and ligate individual hemorrhoidal arteries. Additionally, mucopexy (transanal rectoanal repair) is performed to relocate the prolapsing tissue. Avital et al³² reported that at 1 year after this procedure, recurrence rates were 5.3% for grade II hemorrhoids and 13% for grade III hemorrhoids. At 5 years, recurrence rates were 12% for grade II and 31% for grade III.

To date, this procedure appears to be suitable for grade I, II, and III hemorrhoids, especially for grade II, but more studies are needed to prove its efficacy and recurrence rates for more advanced lesions. Although this technique has a high morbidity rate (18%), primarily pain or tenesmus, it causes less postoperative pain than other surgical methods.³³ Overall, it has the potential to become a favored treatment.

Stapled hemorrhoidopexy

Although pain scores are lower with stapled hemorrhoidopexy than with excisional hemorrhoidectomy, this procedure is not superior in terms of recurrences.^34,35 Also, practitioners should be careful about specific complications of stapled hemorrhoidopexy, such as rectovaginal fistula, anal stenosis, or sphincter injuries. These specific complications should be clearly explained to patients, and necessary information should be given to patients upon discharge. The primary care physician should also be careful about fistulas and stenoses in this particular patient population.

There is no best treatment for hemorrhoids. Every patient is different, and the physician and patient need to understand each other’s expectations, weigh the risks and benefits, and arrive at a mutual decision. A good patient-doctor relationship is essential.

Given the variety of available treatments, head-to-head comparisons are difficult. Moreover, the efficacy and applicability of each technique changes with the grade of the lesion or lesions and the skill of the practitioner. Lacking comprehensive studies comparing conservative, office-based, and surgical management, no decisive statements can be made based on current evidence.

Patients with compounding conditions

Pregnant patients often develop hemorrhoids as intra-abdominal pressure increases, particularly during the third trimester.³⁶ Also, acute episodes of pain and bleeding are common in pregnant women with preexisting hemorrhoids.

Conservative treatment is the main approach in pregnant patients because most hemorrhoids regress after childbirth. This includes increased dietary fiber, stool softeners, and sitz baths, which are safe to use for external hemorrhoids. Any office-based or surgical intervention should be postponed until after childbirth, if possible. Kegel exercises and lying on the left side are also recommended to relieve symptoms. In cases of severe bleeding, anal packing appears to be useful.

Immunosuppressed patients and those on anticoagulant therapy are more prone to serious complications such as sepsis and profuse bleeding. Thus, conservative management should be used in these patients as well. Injection sclerotherapy may be beneficial, as it has been shown to decrease bleeding. Of note, patients on immunosuppressive agents should stop taking them and start taking an antibiotic, and patients on anticoagulant or antiplatelet medications should be instructed to stop them 1 week before any intervention.

Crohn disease. Some patients with Crohn disease may have hemorrhoids, though this is rare. Eglinton et al,³⁷ in a series of 715 patients with Crohn disease, reported that 190 (26.6%) had symptomatic perianal disease. Of these, only 3 (1.6%) had hemorrhoids. Treatment is always conservative and directed at the Crohn disease rather than the hemorrhoids.

Patients with portal hypertension (eg, due to cirrhosis) are prone to have anorectal varices that may resemble hemorrhoids. Anorectal varices can be treated with vascular ligation, whereas sclerotherapy is the preferred method for hemorrhoids in this group, in whom coagulopathy is common.

TAKE-HOME MESSAGES

Hemorrhoidal disease is common in the United States, and with our diet and lifestyle, the incidence is likely to increase. (A national survey found that overall dietary quality improved modestly in children and adolescents in the United States from 1999 to 2012 but remained far below optimal.³⁸) Practitioners need to carefully assess hemorrhoidal symptoms and complete any necessary screening tests before establishing a diagnosis. This helps to avoid missing any underlying disease.

Fiber supplements along with dietary and lifestyle changes constitute the baseline of the management regardless of the disease grade. Office-based interventions are beneficial for grade I and II hemorrhoids and for some grade III hemorrhoids. Repeated interventions can increase the success rate. In patients with high-grade, symptomatic hemorrhoids, surgical hemorrhoidectomy is the most effective modality with the lowest recurrence rates, although it causes more pain than conservative methods.

Aspects of modern life that may promote hemorrhoids include increased consumption of processed foods, a sedentary lifestyle, and using cell phones while defecating, which translates to much more time spent on the toilet.

Hemorrhoids accounted for more than 3.5 million US outpatient visits in 2010, and they were the third leading cause of hospital admissions related to gastrointestinal disease.¹

Here, we review the process for diagnosing and grading hemorrhoids, as well as for selecting the appropriate medical or surgical treatment based on the most recent clinical evidence.

DIAGNOSING AND CLASSIFYING HEMORRHOIDS

Hemorrhoids are the distal prolapse of the arteriovenous bundle, muscle fibers, and surrounding connective tissue as an envelope below the dentate line in the anal canal. They usually present with painless rectal bleeding.²

The diagnosis of hemorrhoids relies on the history and physical examination rather than on laboratory testing or imaging studies. Typically, the presenting symptom is painless rectal bleeding associated with bowel movements, usually appearing as bright red blood on the toilet paper or coating the stool. Severe itching and anal discomfort are also common, especially with chronic hemorrhoids.

Detailed patient history

A detailed patient history is important. It should include the extent, severity, and duration of symptoms, frequency of bowel movements, associated symptoms (eg, constipation, fecal incontinence), daily dietary habits, and details of bowel movements (eg, time spent during each bowel movement and concomitant cell phone use).³

Regarding bowel habits, some patients experience lifelong constipation or diarrhea. Therefore, what a patient considers a normal bowel habit may not be normal and should be investigated.⁴ Also, it is important to exclude external thrombosed hemorrhoids, anal fissure, anal abscess, and Crohn disease.⁵

Physical examination

A digital rectal examination is the second step. During the examination, look for skin tags, sphincter tone, perianal hygiene, and synchronous anal lesions.³ Of note, the Valsalva maneuver can be performed during the digital rectal examination.

Red flags for colorectal cancer on the digital rectal examination include a mass with or without presence of hemorrhoidal sacs and a bleeding source above the level of internal hemorrhoids.

Endoscopy

Since rectal bleeding can be a sign of several diseases, including colorectal cancer, it is important to review any previous endoscopic results. Patients at high risk of colon cancer should undergo rigid proctoscopy, flexible sigmoidoscopy, or colonoscopy.^3,4 In our practice, we recommend endoscopic evaluation for patients over age 40 with rectal bleeding, especially if they have a family history of colorectal cancer.

External or internal (grades I–IV)

Hemorrhoids can be categorized as either external or internal.

External hemorrhoids are distinguished by their outer covering with perianal skin and anoderm and their location inferior to the dentate line. They are painful if the hemorrhoidal sac is occluded by a thrombotic clot.

Internal hemorrhoids are above the dentate line and covered with rectal columnar and transitional mucosa. They are further graded on a 4-point scale³:

• Grade I—Visible hemorrhoids that do not prolapse
• Grade II—Hemorrhoids that prolapse during the Valsalva maneuver but spontaneously reduce
• Grade III—Hemorrhoids that prolapse during the Valsalva maneuver and need manual reduction
• Grade IV—Nonreducible hemorrhoids.

A RANGE OF TREATMENTS

In choosing the treatment for hemorrhoids, one should consider the disease grade and severity, its impact on the quality of life, the degree of pain it causes, the patient’s likelihood of adhering to treatment, and the patient’s personal preference.

Regardless of severity, treatment almost always starts with a high-fiber diet and other lifestyle modifications that include bowel movement behaviors. This requires practitioners to spend significant time on patient education regardless of the type or the severity of the disease.

Treatments can be grouped in 3 categories: conservative, office-based, and surgical. Practitioners should thoroughly discuss the options with the patient, emphasizing the pros and cons of each.

Conservative measures are aimed at softening the stool, relieving pain, and correcting bad toileting habits. In most cases, the primary precipitating factor is lifestyle, and unless patients change it, they are more likely to have recurrent symptoms in the long term.

No phone in the bathroom

People take their phones into the bathroom, and this habit is blamed for increasing the time on the toilet and leading to increased pressure on the anal region and straining during defecation. Some research points to a direct correlation between the time spent on the toilet and hemorrhoidal disease, although the exact cause-and-effect relationship with cell phone use has not been determined. In general, spending excessive time on the commode, including reading, should be discouraged.

Less time in the bathroom

Johannsson et al⁶ reported that patients with hemorrhoids spent more time on the toilet and had to strain harder and more often than controls in the community and hospital.

Garg and Singh⁷ and Garg⁸ use the mnemonic “TONE” for appropriate defecation habits:

• Three minutes during defecation
• Once-daily defecation
• No straining and no cell phone use during defecation
• Enough fiber.

More fiber

Fiber draws water into the lumen of the colon, increasing the water content of the stool. Recommended daily fiber intake is about 28 g for women and 38 g for men.⁹ This high level of intake is hard to achieve without supplements for someone who consumes a classic American diet with a lot of fast food.

Fiber supplements are strongly recommended in the American Society of Colon and Rectal Surgeons (ASCRS) practice guidelines³ based on a Cochrane review.¹⁰ In this meta-analysis, with fiber supplements, the relative risk of persisting or nonimproving symptoms was 0.53 (95% confidence interval [CI] 0.38–0.73) and the relative risk of bleeding was 0.50 (95% CI 028–0.89). Psyllium husk is an inexpensive bulk-forming fiber supplement; the optimal daily dosage is not known.

We recommend at least 28 g of daily fiber intake for women and 38 g for men, for which psyllium husk can be used to complement the diet.

Laxatives for some

Laxatives such as docusate are used to change the stool consistency when there is an organic bowel problem rather than a dietary issue. They can be used as a complementary treatment to enhance the effect of the fiber treatment.

Other measures

Topical anesthesia (eg, 5% lidocaine) is commonly used to treat pain from low-grade lesions, but no reliable data have been published. As most cases of hemorrhoids tend to progress over time, one should not expect long-term improvement with topical anesthesia. Nevertheless, it can be used as an ancillary treatment in select cases when short-term improvement is the main goal, and we recommend it based on our own experience.

Hygiene. Bidet use or cleaning the perianal area with water is recommended.

Phlebotonics contain a variety of ingredients including natural plant extracts such as flavonoids and synthetic products. Even though the exact mechanism of action is not known, phlebotonics are thought to increase venous and lymphatic drainage, normalize capillary permeability, and decrease inflammation in the hemorrhoidal cushions.^4,11–13

In a Cochrane review of 24 randomized controlled trials, Perera et al¹⁴ found that phlebotonics improved the outcomes of:

• Bleeding (odds ratio [OR] 0.21, number needed to treat [NNT] 4.8, P = .0002)
• Pruritus (OR 0.23, NNT 9.1, P = .02)
• Discharge or leakage (OR 0.12, NNT 5, P = .0008)
• Overall symptoms (OR 15.99, NNT 2.7, P < .00001). Overall symptoms were also improved in the subgroup of pregnant patients.

Although phlebotonics give better results than placebo in the short-term management of hemorrhoids, there is a paucity of long-term data. Thus, the ASCRS clinical practice guidelines gives the regular use of these agents only a weak recommendation.³

Flavonoids (diosmin, hesperidin, rutoside), in a meta-analysis vs placebo in 1,514 patients, showed a beneficial response in terms of bleeding (relative risk [RR] 0.33), pruritus (relative risk [RR] 0.65), and recurrences (RR 0.53).¹⁵

Although Preparation H is commonly used as an over-the-counter medication, there are no good data on it, and it is not considered a phlebotonic.

Office-based treatments—rubber band ligation, infrared photocoagulation, and sclerotherapy—are commonly used for grade I, II, and III hemorrhoids that have not responded to conservative management. The primary goal of these treatments is to decrease blood flow into the hemorrhoidal sac.

Even though office-based treatments are highly effective and major complications are uncommon, recurrence rates can be high, requiring patients to undergo additional treatments. Moreover, septic complications can occur, so patients should be closely observed for fever and urinary problems. Pain is a common symptom after office-based treatments, and bleeding may also occur.

The ASCRS guidelines strongly recommend office-based treatments for patients with grade I and II hemorrhoids, and for some with grade III hemorrhoids.³

Rubber band ligation

Iyer et al¹⁸ reported that patients on warfarin therapy had up to a 9 times higher risk of postprocedural bleeding, and patients on aspirin had a risk up to 3 times higher. Therefore, whether patients on anticoagulant therapy should undergo this procedure is unclear.

A Cochrane database review¹⁹ found this technique effective for hemorrhoid grades I through III, although some patients with grade III hemorrhoids may benefit more from excisional hemorrhoidectomy, which is associated with a lower recurrence rate than rubber band ligation.

Brown et al²⁰ performed a randomized controlled trial comparing hemorrhoidal artery ligation and rubber band ligation for symptomatic hemorrhoids in 372 patients with grade II and III hemorrhoids. Postprocedural pain scores on days 1 and 7 were significantly lower with rubber band ligation, but recurrences were more common (49% vs 30%, P = .0005, respectively).

Overall, rubber band ligation is an excellent option for grade II hemorrhoids, as it is easy to perform, is associated with low pain scores, and can be used to treat recurrences.

Infrared photocoagulation

In this procedure, an infrared probe produces heat to induce coagulation, fibrosis, and ultimately necrosis of the protruding tissue in the hemorrhoidal cushions.²¹ Even though its use was initially directed at grade I and II hemorrhoids, recent reports showed acceptable results for grades III and IV.^22,23 A randomized controlled trial comparing infrared photocoagulation and rubber band ligation in 94 patients found that both procedures were well accepted and highly effective; however, patients had better pain scores with photocoagulation in the first 24 hours after the procedure (P < .05).²⁴

Sclerotherapy

The injection can cause prostatic abscess and sepsis, although this is rare.25 Nevertheless, high fever and postprocedural pain should be carefully evaluated.

There have been few randomized trials of sclerotherapy, but success rates so far have been higher for grade I hemorrhoids than for grades II and III.^26–28 It is the preferred method for patients who have bleeding abnormalities caused by medications or other diseases (eg, cirrhosis).

Although nonsurgical treatments have substantially improved, surgery is the most effective and strongly recommended treatment for patients with high-grade internal hemorrhoids (grades III and IV), external and mixed hemorrhoids, and recurrent hemorrhoids.

The most popular surgical options are open or closed hemorrhoidectomy, stapled hemorrhoidopexy, and Doppler-guided hemorrhoidal artery ligation. Each has different success rates and different complication profiles, which need to be discussed with the patient.

Overall, surgery is associated with more adverse effects than office-based treatments or medical management. Postoperative pain is the most common complaint, but anal stricture (rare) or incontinence may occur due to excessive tissue excision and damage to the sphincter muscles. These can be avoided by maintaining the normal anoderm between excisions, by not excising all hemorrhoid sacs at once if the patient has extensive lesions, and by performing a careful dissection in the submucosal plane.

Patients with profuse bleeding or an underlying bleeding abnormality are best managed with surgical approaches performed in an operating room.

Excisional surgical hemorrhoidectomy

Excision of the hemorrhoidal sac, the most conventional surgical technique, is generally reserved for prolapsing disease. The recurrence rate after excisional hemorrhoidectomy is significantly lower than with any other approach.²⁹

Excisional hemorrhoidectomy can be performed using either an open approach, in which the edges of the mucosal defect are not reapproximated, or a closed approach, in which they are. In a systematic review, Bhatti et al³⁰ compared open vs closed techniques and found that the closed technique resulted in less postoperative pain, better wound healing, and less bleeding. Rates of recurrence, postoperative complications, and surgical site infection and lengths of stay were comparable with either procedure.

Overall, excisional hemorrhoidectomy is associated with higher pain scores than any other surgical method.²⁹ Recently, the use of electrodiathermy energy devices, also described as electrosurgical vessel-sealing devices, have further improved overall patient satisfaction.³¹

Multiple painful hemorrhoidal sacs require a careful surgical approach, as extensive resection may cause widespread fibrosis and stricture. As with anal stricture, fecal incontinence can be prevented by careful dissection. However, already existing incontinence is not a contraindication for the surgery.

Doppler-guided hemorrhoidal artery ligation

Doppler-guided hemorrhoidal artery ligation involves using a Doppler probe to find and ligate individual hemorrhoidal arteries. Additionally, mucopexy (transanal rectoanal repair) is performed to relocate the prolapsing tissue. Avital et al³² reported that at 1 year after this procedure, recurrence rates were 5.3% for grade II hemorrhoids and 13% for grade III hemorrhoids. At 5 years, recurrence rates were 12% for grade II and 31% for grade III.

To date, this procedure appears to be suitable for grade I, II, and III hemorrhoids, especially for grade II, but more studies are needed to prove its efficacy and recurrence rates for more advanced lesions. Although this technique has a high morbidity rate (18%), primarily pain or tenesmus, it causes less postoperative pain than other surgical methods.³³ Overall, it has the potential to become a favored treatment.

Stapled hemorrhoidopexy

Although pain scores are lower with stapled hemorrhoidopexy than with excisional hemorrhoidectomy, this procedure is not superior in terms of recurrences.^34,35 Also, practitioners should be careful about specific complications of stapled hemorrhoidopexy, such as rectovaginal fistula, anal stenosis, or sphincter injuries. These specific complications should be clearly explained to patients, and necessary information should be given to patients upon discharge. The primary care physician should also be careful about fistulas and stenoses in this particular patient population.

There is no best treatment for hemorrhoids. Every patient is different, and the physician and patient need to understand each other’s expectations, weigh the risks and benefits, and arrive at a mutual decision. A good patient-doctor relationship is essential.

Given the variety of available treatments, head-to-head comparisons are difficult. Moreover, the efficacy and applicability of each technique changes with the grade of the lesion or lesions and the skill of the practitioner. Lacking comprehensive studies comparing conservative, office-based, and surgical management, no decisive statements can be made based on current evidence.

Patients with compounding conditions

Pregnant patients often develop hemorrhoids as intra-abdominal pressure increases, particularly during the third trimester.³⁶ Also, acute episodes of pain and bleeding are common in pregnant women with preexisting hemorrhoids.

Conservative treatment is the main approach in pregnant patients because most hemorrhoids regress after childbirth. This includes increased dietary fiber, stool softeners, and sitz baths, which are safe to use for external hemorrhoids. Any office-based or surgical intervention should be postponed until after childbirth, if possible. Kegel exercises and lying on the left side are also recommended to relieve symptoms. In cases of severe bleeding, anal packing appears to be useful.

Immunosuppressed patients and those on anticoagulant therapy are more prone to serious complications such as sepsis and profuse bleeding. Thus, conservative management should be used in these patients as well. Injection sclerotherapy may be beneficial, as it has been shown to decrease bleeding. Of note, patients on immunosuppressive agents should stop taking them and start taking an antibiotic, and patients on anticoagulant or antiplatelet medications should be instructed to stop them 1 week before any intervention.

Crohn disease. Some patients with Crohn disease may have hemorrhoids, though this is rare. Eglinton et al,³⁷ in a series of 715 patients with Crohn disease, reported that 190 (26.6%) had symptomatic perianal disease. Of these, only 3 (1.6%) had hemorrhoids. Treatment is always conservative and directed at the Crohn disease rather than the hemorrhoids.

Patients with portal hypertension (eg, due to cirrhosis) are prone to have anorectal varices that may resemble hemorrhoids. Anorectal varices can be treated with vascular ligation, whereas sclerotherapy is the preferred method for hemorrhoids in this group, in whom coagulopathy is common.

TAKE-HOME MESSAGES

Hemorrhoidal disease is common in the United States, and with our diet and lifestyle, the incidence is likely to increase. (A national survey found that overall dietary quality improved modestly in children and adolescents in the United States from 1999 to 2012 but remained far below optimal.³⁸) Practitioners need to carefully assess hemorrhoidal symptoms and complete any necessary screening tests before establishing a diagnosis. This helps to avoid missing any underlying disease.

Fiber supplements along with dietary and lifestyle changes constitute the baseline of the management regardless of the disease grade. Office-based interventions are beneficial for grade I and II hemorrhoids and for some grade III hemorrhoids. Repeated interventions can increase the success rate. In patients with high-grade, symptomatic hemorrhoids, surgical hemorrhoidectomy is the most effective modality with the lowest recurrence rates, although it causes more pain than conservative methods.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

A workup for secondary causes of hypertriglyceridemia was negative for hypothyroidism and nephrotic syndrome. She was currently taking no medications. She had no family history of dyslipidemia, and she denied alcohol consumption.

Based on the patient’s presentation, history, and the results of laboratory testing and skin biopsy, the diagnosis was eruptive xanthoma.

A RESULT OF ELEVATED TRIGLYCERIDES

Eruptive xanthoma is associated with elevation of chylomicrons and triglycerides.¹ Hyperlipidemia that causes eruptive xanthoma may be familial (ie, due to a primary genetic defect) or secondary to another disease, or both.

Types of primary hypertriglyceridemia include elevated chylomicrons (Frederickson classification type I), elevated very-low-density lipoprotein (VLDL) (Frederickson type IV), and elevation of both chylomicrons and VLDL (Frederickson type V).^2,3 Hypertriglyceridemia may also be secondary to obesity, diabetes mellitus, hypothyroidism, nephrotic syndrome, liver cirrhosis, excess ethanol ingestion, and medicines such as retinoids and estrogens.^2,3

Lesions of eruptive xanthoma are yellowish papules 2 to 5 mm in diameter surrounded by an erythematous border. They are formed by clusters of foamy cells caused by phagocytosis of macrophages as a consequence of increased accumulations of intracellular lipids. The most common sites are the buttocks, extensor surfaces of the arms, and the back.⁴

Eruptive xanthoma occurs with markedly elevated triglyceride levels (ie, > 1,000 mg/dL),⁵ with an estimated prevalence of 18 cases per 100,000 people (< 0.02%).⁶ Diagnosis is usually established through the clinical history, physical examination, and prompt laboratory confirmation of hypertriglyceridemia. Skin biopsy is rarely if ever needed.

RECOGNIZE AND TREAT PROMPTLY TO AVOID FURTHER COMPLICATIONS

Severe hypertriglyceridemia poses an increased risk of acute pancreatitis. Early recognition and medical treatment in our patient prevented serious complications.

Treatment of eruptive xanthoma includes identifying the underlying cause of hypertriglyceridemia and commencing lifestyle modifications that include weight reduction, aerobic exercise, a strict low-fat diet with avoidance of simple carbohydrates and alcohol,⁷ and drug therapy.

The patient’s treatment plan

Although HMG-CoA reductase inhibitors (statins) have a modest triglyceride-lowering effect and are useful to modify cardiovascular risk, fibric acid derivatives (eg, gemfibrozil, fenofibrate) are the first-line therapy.⁸ Omega-3 fatty acids, statins, or niacin may be added if necessary.⁸

Our patient’s uncontrolled glycemia caused marked hypertriglyceridemia, perhaps from a decrease in lipoprotein lipase activity in adipose tissue and muscle. Lifestyle modifications, glucose-lowering agents (metformin, glimepiride), and fenofibrate were prescribed. She was also advised to seek medical attention if she developed upper-abdominal pain, which could be a symptom of pancreatitis.

An 83-year-old woman with hypertension, hypothyroidism, and a history of depression presented to the emergency department with acute shortness of breath and hypoxia. She was found to have submassive pulmonary embolism, and a heparin infusion was started immediately.

Urgent nasopharyngeal laryngoscopy revealed a hematoma at the base of her tongue that extended into the vallecula, piriform sinuses, and aryepiglottic fold, causing acute airway obstruction. These features combined with the supratherapeutic aPTT led to the diagnosis of pseudo-Ludwig angina.

DANGER OF RAPID AIRWAY COMPROMISE

Pseudo-Ludwig angina is a rare condition in which over-anticoagulation causes sublingual swelling leading to airway obstruction, whereas true Ludwig angina is an infectious regional suppuration of the neck.

Most reported cases of pseudo-Ludwig angina have resulted from overanticogulation with warfarin or warfarin-like substances (rodenticides), or from coagulopathy due to liver disease.^1–3 Early recognition is essential to avoid airway compromise.

In our patient, all anticoagulation was discontinued, and she was intubated until the hematoma began to resolve, the aPTT returned to normal, and respiratory compromise improved. At follow-up 2 months later, the sublingual hematoma had completely resolved (Figure 1). And at a 6-month follow-up visit, the pulmonary embolism had resolved, and pulmonary pressures by 2-dimensional echocardiography were normal.

An 83-year-old woman with hypertension, hypothyroidism, and a history of depression presented to the emergency department with acute shortness of breath and hypoxia. She was found to have submassive pulmonary embolism, and a heparin infusion was started immediately.

Urgent nasopharyngeal laryngoscopy revealed a hematoma at the base of her tongue that extended into the vallecula, piriform sinuses, and aryepiglottic fold, causing acute airway obstruction. These features combined with the supratherapeutic aPTT led to the diagnosis of pseudo-Ludwig angina.

DANGER OF RAPID AIRWAY COMPROMISE

Pseudo-Ludwig angina is a rare condition in which over-anticoagulation causes sublingual swelling leading to airway obstruction, whereas true Ludwig angina is an infectious regional suppuration of the neck.

Most reported cases of pseudo-Ludwig angina have resulted from overanticogulation with warfarin or warfarin-like substances (rodenticides), or from coagulopathy due to liver disease.^1–3 Early recognition is essential to avoid airway compromise.

In our patient, all anticoagulation was discontinued, and she was intubated until the hematoma began to resolve, the aPTT returned to normal, and respiratory compromise improved. At follow-up 2 months later, the sublingual hematoma had completely resolved (Figure 1). And at a 6-month follow-up visit, the pulmonary embolism had resolved, and pulmonary pressures by 2-dimensional echocardiography were normal.

An 83-year-old woman with hypertension, hypothyroidism, and a history of depression presented to the emergency department with acute shortness of breath and hypoxia. She was found to have submassive pulmonary embolism, and a heparin infusion was started immediately.

Urgent nasopharyngeal laryngoscopy revealed a hematoma at the base of her tongue that extended into the vallecula, piriform sinuses, and aryepiglottic fold, causing acute airway obstruction. These features combined with the supratherapeutic aPTT led to the diagnosis of pseudo-Ludwig angina.

DANGER OF RAPID AIRWAY COMPROMISE

Pseudo-Ludwig angina is a rare condition in which over-anticoagulation causes sublingual swelling leading to airway obstruction, whereas true Ludwig angina is an infectious regional suppuration of the neck.

Most reported cases of pseudo-Ludwig angina have resulted from overanticogulation with warfarin or warfarin-like substances (rodenticides), or from coagulopathy due to liver disease.^1–3 Early recognition is essential to avoid airway compromise.

In our patient, all anticoagulation was discontinued, and she was intubated until the hematoma began to resolve, the aPTT returned to normal, and respiratory compromise improved. At follow-up 2 months later, the sublingual hematoma had completely resolved (Figure 1). And at a 6-month follow-up visit, the pulmonary embolism had resolved, and pulmonary pressures by 2-dimensional echocardiography were normal.

A 50-year-old man with Crohn disease and psoriatic arthritis treated with infliximab and methotrexate presented to a tertiary care hospital with fever, cough, and chest discomfort. The symptoms had first appeared 2 weeks earlier, and he had gone to an urgent care center, where he was prescribed a 5-day course of azithromycin and a corticosteroid, but this had not relieved his symptoms.

Bronchoscopy revealed edematous mucosa throughout, with minimal secretion. Specimens for bacterial, acid-fast bacillus, and fungal cultures were obtained from bronchoalveolar lavage. Endobronchial lymph node biopsy with ultrasonographic guidance revealed nonnecrotizing granuloma.

Bronchoalveolar lavage cultures showed no growth, but the patient’s serum histoplasma antigen was positive at 5.99 ng/dL (reference range: none detected), leading to the diagnosis of mediastinal granuloma due to histoplasmosis with possible dissemination. His immunosuppressant drugs were stopped, and oral itraconazole was started.

At a follow-up visit 2 months later, his serum antigen level had decreased to 0.68 ng/dL, and he had no symptoms whatsoever. At a visit 1 month after that, infliximab and methotrexate were restarted because of an exacerbation of Crohn disease. His oral itraconazole treatment was to be continued for at least 12 months, given the high suspicion for disseminated histoplasmosis while on immunosuppressant therapy.

DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LUNG DISEASE AND LYMPHADENOPATHY

The differential diagnosis of granulomatous lung disease and lymphadenopathy is broad and includes noninfectious and infectious conditions.¹

Noninfectious causes include lymphoma, sarcoidosis, inflammatory bowel disease, hypersensitivity pneumonia, side effects of drugs (eg, methotrexate, etanercept), rheumatoid nodules, vasculitis (eg, Churg-Strauss syndrome, granulomatosis with polyangiitis, primary amyloidosis, pneumoconiosis (eg, beryllium, cobalt), and Castleman disease.

There is concern that tumor necrosis factor antagonists may increase the risk of lymphoma, but a 2017 study found no evidence of this.²

Infectious conditions associated with granulomatous lung disease include tuberculosis, nontuberculous mycobacterial infection, fungal infection (eg, Cryptococcus, Coccidioides, Histoplasma, Blastomyces), brucellosis, tularemia (respiratory type B), parasitic infection (eg, Toxocara, Leishmania, Echinococcus, Schistosoma), and Whipple disease.

HISTOPLASMOSIS

Histoplasmosis, caused by infection with Histoplasma capsulatum, is the most prevalent endemic mycotic disease in the United States.³ The fungus is commonly found in the Ohio and Mississippi River valleys in the United States, and also in Central and South America and Asia.

Risk factors for histoplasmosis include living in or traveling to an endemic area, exposure to aerosolized soil that contains spores, and exposure to bats or birds and their droppings.⁴

Fewer than 5% of exposed individuals develop symptoms, which include fever, chills, headache, myalgia, anorexia, cough, and chest pain.⁵ Patients may experience symptoms shortly after exposure or may remain free of symptoms for years, with intermittent relapses of symptoms.⁶ Hilar or mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis.⁷

The risk of disseminated histoplasmosis is greater in patients with reduced cell-mediated immunity, such as in human immunodeficiency virus infection, acquired immunodeficiency syndrome, solid-organ or bone marrow transplant, hematologic malignancies, immunosuppression (corticosteroids, disease-modifying antirheumatic drugs, and tumor necrosis factor antagonists), and congenital T-cell deficiencies.⁸

In a retrospective study, infliximab was the tumor necrosis factor antagonist most commonly associated with histoplasmosis.⁹ In a study of patients with rheumatoid arthritis, the disease-modifying drug most commonly associated was methotrexate.¹⁰

Isolation of H capsulatum from clinical specimens remains the gold standard for confirmation of histoplasmosis. The sensitivity of culture to detect H capsulatum depends on the clinical manifestations: it is 74% in patients with disseminated histoplasmosis, but only 42% in patients with acute pulmonary histoplasmosis.¹¹ The serum histoplasma antigen test has a sensitivity of 91.8% in disseminated histoplasmosis, 87.5% in chronic pulmonary histoplasmosis, and 83% in acute pulmonary histoplasmosis.¹²

Urine testing for histoplasma antigen has generally proven to be slightly more sensitive than serum testing in all manifestations of histoplasmosis.¹³ Combining urine and serum testing increases the likelihood of antigen detection.

TREATMENT

Asymptomatic patients with mediastinal histoplasmosis do not require treatment. (Note: in some cases, lymphadenopathy is found incidentally, and biopsy is done to rule out malignancy.)

Standard treatment of symptomatic mediastinal histoplasmosis is oral itraconazole 200 mg, 3 times daily for 3 days, followed by 200 mg orally once or twice daily for 6 to 12 weeks.¹⁴

Although stopping immunosuppressant drugs is considered the standard of care in treating histoplasmosis in immunocompromised patients, there are no guidelines on when to resume them. However, a retrospective study of 98 cases of histoplasmosis in patients on tumor necrosis factor antagonists found that resuming immunosuppressants might be safe with close monitoring during the course of antifungal therapy.⁹ The role of long-term suppressive therapy with antifungal agents in patients on chronic immunosuppressive therapy is still unknown and needs further study.

TAKE-HOME MESSAGES

• Histoplasmosis is the most prevalent endemic mycotic disease in the United States, and mediastinal lymphadenopathy is commonly seen in acute pulmonary histoplasmosis.
• Histoplasmosis should be included in the differential diagnosis of granulomatous lung disease in patients from an endemic area or with a history of travel to an endemic area.
• Immunosuppressive agents such as tumor necrosis factor antagonists and disease-modifying antirheumatic drugs can predispose to invasive fungal infection, including histoplasmosis.
• While isolation of H capsulatum from culture remains the gold standard for the diagnosis of histoplasmosis, the histoplasma antigen tests (serum and urine) is more sensitive than culture.

A 50-year-old man with Crohn disease and psoriatic arthritis treated with infliximab and methotrexate presented to a tertiary care hospital with fever, cough, and chest discomfort. The symptoms had first appeared 2 weeks earlier, and he had gone to an urgent care center, where he was prescribed a 5-day course of azithromycin and a corticosteroid, but this had not relieved his symptoms.

Bronchoscopy revealed edematous mucosa throughout, with minimal secretion. Specimens for bacterial, acid-fast bacillus, and fungal cultures were obtained from bronchoalveolar lavage. Endobronchial lymph node biopsy with ultrasonographic guidance revealed nonnecrotizing granuloma.

Bronchoalveolar lavage cultures showed no growth, but the patient’s serum histoplasma antigen was positive at 5.99 ng/dL (reference range: none detected), leading to the diagnosis of mediastinal granuloma due to histoplasmosis with possible dissemination. His immunosuppressant drugs were stopped, and oral itraconazole was started.

At a follow-up visit 2 months later, his serum antigen level had decreased to 0.68 ng/dL, and he had no symptoms whatsoever. At a visit 1 month after that, infliximab and methotrexate were restarted because of an exacerbation of Crohn disease. His oral itraconazole treatment was to be continued for at least 12 months, given the high suspicion for disseminated histoplasmosis while on immunosuppressant therapy.

DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LUNG DISEASE AND LYMPHADENOPATHY

The differential diagnosis of granulomatous lung disease and lymphadenopathy is broad and includes noninfectious and infectious conditions.¹

Noninfectious causes include lymphoma, sarcoidosis, inflammatory bowel disease, hypersensitivity pneumonia, side effects of drugs (eg, methotrexate, etanercept), rheumatoid nodules, vasculitis (eg, Churg-Strauss syndrome, granulomatosis with polyangiitis, primary amyloidosis, pneumoconiosis (eg, beryllium, cobalt), and Castleman disease.

There is concern that tumor necrosis factor antagonists may increase the risk of lymphoma, but a 2017 study found no evidence of this.²

Infectious conditions associated with granulomatous lung disease include tuberculosis, nontuberculous mycobacterial infection, fungal infection (eg, Cryptococcus, Coccidioides, Histoplasma, Blastomyces), brucellosis, tularemia (respiratory type B), parasitic infection (eg, Toxocara, Leishmania, Echinococcus, Schistosoma), and Whipple disease.

HISTOPLASMOSIS

Histoplasmosis, caused by infection with Histoplasma capsulatum, is the most prevalent endemic mycotic disease in the United States.³ The fungus is commonly found in the Ohio and Mississippi River valleys in the United States, and also in Central and South America and Asia.

Risk factors for histoplasmosis include living in or traveling to an endemic area, exposure to aerosolized soil that contains spores, and exposure to bats or birds and their droppings.⁴

Fewer than 5% of exposed individuals develop symptoms, which include fever, chills, headache, myalgia, anorexia, cough, and chest pain.⁵ Patients may experience symptoms shortly after exposure or may remain free of symptoms for years, with intermittent relapses of symptoms.⁶ Hilar or mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis.⁷

The risk of disseminated histoplasmosis is greater in patients with reduced cell-mediated immunity, such as in human immunodeficiency virus infection, acquired immunodeficiency syndrome, solid-organ or bone marrow transplant, hematologic malignancies, immunosuppression (corticosteroids, disease-modifying antirheumatic drugs, and tumor necrosis factor antagonists), and congenital T-cell deficiencies.⁸

In a retrospective study, infliximab was the tumor necrosis factor antagonist most commonly associated with histoplasmosis.⁹ In a study of patients with rheumatoid arthritis, the disease-modifying drug most commonly associated was methotrexate.¹⁰

Isolation of H capsulatum from clinical specimens remains the gold standard for confirmation of histoplasmosis. The sensitivity of culture to detect H capsulatum depends on the clinical manifestations: it is 74% in patients with disseminated histoplasmosis, but only 42% in patients with acute pulmonary histoplasmosis.¹¹ The serum histoplasma antigen test has a sensitivity of 91.8% in disseminated histoplasmosis, 87.5% in chronic pulmonary histoplasmosis, and 83% in acute pulmonary histoplasmosis.¹²

Urine testing for histoplasma antigen has generally proven to be slightly more sensitive than serum testing in all manifestations of histoplasmosis.¹³ Combining urine and serum testing increases the likelihood of antigen detection.

TREATMENT

Asymptomatic patients with mediastinal histoplasmosis do not require treatment. (Note: in some cases, lymphadenopathy is found incidentally, and biopsy is done to rule out malignancy.)

Standard treatment of symptomatic mediastinal histoplasmosis is oral itraconazole 200 mg, 3 times daily for 3 days, followed by 200 mg orally once or twice daily for 6 to 12 weeks.¹⁴

Although stopping immunosuppressant drugs is considered the standard of care in treating histoplasmosis in immunocompromised patients, there are no guidelines on when to resume them. However, a retrospective study of 98 cases of histoplasmosis in patients on tumor necrosis factor antagonists found that resuming immunosuppressants might be safe with close monitoring during the course of antifungal therapy.⁹ The role of long-term suppressive therapy with antifungal agents in patients on chronic immunosuppressive therapy is still unknown and needs further study.

TAKE-HOME MESSAGES

• Histoplasmosis is the most prevalent endemic mycotic disease in the United States, and mediastinal lymphadenopathy is commonly seen in acute pulmonary histoplasmosis.
• Histoplasmosis should be included in the differential diagnosis of granulomatous lung disease in patients from an endemic area or with a history of travel to an endemic area.
• Immunosuppressive agents such as tumor necrosis factor antagonists and disease-modifying antirheumatic drugs can predispose to invasive fungal infection, including histoplasmosis.
• While isolation of H capsulatum from culture remains the gold standard for the diagnosis of histoplasmosis, the histoplasma antigen tests (serum and urine) is more sensitive than culture.

A 50-year-old man with Crohn disease and psoriatic arthritis treated with infliximab and methotrexate presented to a tertiary care hospital with fever, cough, and chest discomfort. The symptoms had first appeared 2 weeks earlier, and he had gone to an urgent care center, where he was prescribed a 5-day course of azithromycin and a corticosteroid, but this had not relieved his symptoms.

Bronchoscopy revealed edematous mucosa throughout, with minimal secretion. Specimens for bacterial, acid-fast bacillus, and fungal cultures were obtained from bronchoalveolar lavage. Endobronchial lymph node biopsy with ultrasonographic guidance revealed nonnecrotizing granuloma.

Bronchoalveolar lavage cultures showed no growth, but the patient’s serum histoplasma antigen was positive at 5.99 ng/dL (reference range: none detected), leading to the diagnosis of mediastinal granuloma due to histoplasmosis with possible dissemination. His immunosuppressant drugs were stopped, and oral itraconazole was started.

At a follow-up visit 2 months later, his serum antigen level had decreased to 0.68 ng/dL, and he had no symptoms whatsoever. At a visit 1 month after that, infliximab and methotrexate were restarted because of an exacerbation of Crohn disease. His oral itraconazole treatment was to be continued for at least 12 months, given the high suspicion for disseminated histoplasmosis while on immunosuppressant therapy.

DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS LUNG DISEASE AND LYMPHADENOPATHY

The differential diagnosis of granulomatous lung disease and lymphadenopathy is broad and includes noninfectious and infectious conditions.¹

Noninfectious causes include lymphoma, sarcoidosis, inflammatory bowel disease, hypersensitivity pneumonia, side effects of drugs (eg, methotrexate, etanercept), rheumatoid nodules, vasculitis (eg, Churg-Strauss syndrome, granulomatosis with polyangiitis, primary amyloidosis, pneumoconiosis (eg, beryllium, cobalt), and Castleman disease.

There is concern that tumor necrosis factor antagonists may increase the risk of lymphoma, but a 2017 study found no evidence of this.²

Infectious conditions associated with granulomatous lung disease include tuberculosis, nontuberculous mycobacterial infection, fungal infection (eg, Cryptococcus, Coccidioides, Histoplasma, Blastomyces), brucellosis, tularemia (respiratory type B), parasitic infection (eg, Toxocara, Leishmania, Echinococcus, Schistosoma), and Whipple disease.

HISTOPLASMOSIS

Histoplasmosis, caused by infection with Histoplasma capsulatum, is the most prevalent endemic mycotic disease in the United States.³ The fungus is commonly found in the Ohio and Mississippi River valleys in the United States, and also in Central and South America and Asia.

Risk factors for histoplasmosis include living in or traveling to an endemic area, exposure to aerosolized soil that contains spores, and exposure to bats or birds and their droppings.⁴

Fewer than 5% of exposed individuals develop symptoms, which include fever, chills, headache, myalgia, anorexia, cough, and chest pain.⁵ Patients may experience symptoms shortly after exposure or may remain free of symptoms for years, with intermittent relapses of symptoms.⁶ Hilar or mediastinal lymphadenopathy is common in acute pulmonary histoplasmosis.⁷

The risk of disseminated histoplasmosis is greater in patients with reduced cell-mediated immunity, such as in human immunodeficiency virus infection, acquired immunodeficiency syndrome, solid-organ or bone marrow transplant, hematologic malignancies, immunosuppression (corticosteroids, disease-modifying antirheumatic drugs, and tumor necrosis factor antagonists), and congenital T-cell deficiencies.⁸

In a retrospective study, infliximab was the tumor necrosis factor antagonist most commonly associated with histoplasmosis.⁹ In a study of patients with rheumatoid arthritis, the disease-modifying drug most commonly associated was methotrexate.¹⁰

Isolation of H capsulatum from clinical specimens remains the gold standard for confirmation of histoplasmosis. The sensitivity of culture to detect H capsulatum depends on the clinical manifestations: it is 74% in patients with disseminated histoplasmosis, but only 42% in patients with acute pulmonary histoplasmosis.¹¹ The serum histoplasma antigen test has a sensitivity of 91.8% in disseminated histoplasmosis, 87.5% in chronic pulmonary histoplasmosis, and 83% in acute pulmonary histoplasmosis.¹²

Urine testing for histoplasma antigen has generally proven to be slightly more sensitive than serum testing in all manifestations of histoplasmosis.¹³ Combining urine and serum testing increases the likelihood of antigen detection.

TREATMENT

Asymptomatic patients with mediastinal histoplasmosis do not require treatment. (Note: in some cases, lymphadenopathy is found incidentally, and biopsy is done to rule out malignancy.)

Standard treatment of symptomatic mediastinal histoplasmosis is oral itraconazole 200 mg, 3 times daily for 3 days, followed by 200 mg orally once or twice daily for 6 to 12 weeks.¹⁴

Although stopping immunosuppressant drugs is considered the standard of care in treating histoplasmosis in immunocompromised patients, there are no guidelines on when to resume them. However, a retrospective study of 98 cases of histoplasmosis in patients on tumor necrosis factor antagonists found that resuming immunosuppressants might be safe with close monitoring during the course of antifungal therapy.⁹ The role of long-term suppressive therapy with antifungal agents in patients on chronic immunosuppressive therapy is still unknown and needs further study.

TAKE-HOME MESSAGES

• Histoplasmosis is the most prevalent endemic mycotic disease in the United States, and mediastinal lymphadenopathy is commonly seen in acute pulmonary histoplasmosis.
• Histoplasmosis should be included in the differential diagnosis of granulomatous lung disease in patients from an endemic area or with a history of travel to an endemic area.
• Immunosuppressive agents such as tumor necrosis factor antagonists and disease-modifying antirheumatic drugs can predispose to invasive fungal infection, including histoplasmosis.
• While isolation of H capsulatum from culture remains the gold standard for the diagnosis of histoplasmosis, the histoplasma antigen tests (serum and urine) is more sensitive than culture.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

No, they are not required or needed, but daily radiography and arterial blood gas testing are common practice: eg, 60% of intensive care unit (ICU) patients get daily radiographs,¹ even though results provide low diagnostic yield and are unlikely to alter patient management compared with testing only when indicated.

The Choosing Wisely campaign,² a collaborative effort of a number of professional societies, advises against ordering these diagnostic tests daily because routine testing increases risks to patients and burdens the healthcare system. Instead, testing is recommended only in response to a specific clinical question, or when the test results will affect the patient’s treatment.

CHEST RADIOGRAPHS: DAILY VS CLINICALLY INDICATED

Chest radiographs enable practitioners to monitor the position of endotracheal tubes and central venous catheters, evaluate fluid status, follow up on abnormal findings, detect complications of procedures (such as a pneumothorax), and identify otherwise undetected conditions.

And daily chest radiographs often detect abnormalities. A 1991 study by Hall et al³ of 538 chest radiographs in 74 patients on mechanical ventilation reported that 30% of daily routine chest radiographs disclosed a new but minor finding (eg, a small change in endotracheal tube position or a small infiltrate). The new findings were major in 13 (17.6%) of the 74 patients (95% confidence interval [CI] 9%–26%). These included findings that required an immediate diagnostic or therapeutic intervention (eg, endotracheal tube below the tracheal carina, malposition of a catheter, pneumothorax, large pleural effusion).

But most studies say daily radiographs are not needed. In a large prospective study published in 2006, Graat et al⁴ evaluated the clinical value of 2,457 routine chest radiographs in 754 patients in a combined surgical and medical ICU. Daily chest radiographs revealed new or unexpected findings in 5.8% of cases, but only 2.2% warranted a change in therapy. No differences were found between the medical and surgical patients. The authors concluded that daily routine radiographs in ICU patients seldom reveal unexpected, clinically relevant abnormalities, and those findings rarely require urgent intervention.

A 2010 meta-analysis of 8 studies (7,078 patients) by Oba and Zaza⁵ compared on-demand and daily routine strategies of performing chest radiographs. They estimated that eliminating daily routine chest radiographs would not affect death rates in the hospital (odds ratio [OR] 1.02, 95% CI 0.89–1.17, P = .78) or the ICU (OR 0.92, 95% CI 0.76–1.11, P = .4). They also found no significant differences in length of stay or duration of mechanical ventilation. This meta-analysis suggests that routine radiographs can be eliminated without adversely affecting outcomes in ICU patients.

A larger meta-analysis (9 trials, 39,358 radiographs, 9,611 patients) published in 2012 by Ganapathy et al⁶ also found no harm associated with restrictive radiography protocols. These investigators compared a daily chest radiography protocol against a protocol based on clinical indications. The primary outcome was the mortality rate in the ICU; secondary outcomes were the mortality rate in the hospital, the length of stay in the ICU, and duration of mechanical ventilation. They found no differences between routine and restrictive strategies in terms of ICU mortality (risk ratio [RR] 1.04, 95% CI 0.84–1.28, P = .72), hospital mortality (RR 0.98, 95% CI 0.68–1.41, P = .91), or other secondary outcomes.

Clinically indicated testing is better

The conclusion from these studies is that routine chest radiographs in patients undergoing mechanical ventilation does not improve patient outcomes, and thus, a clinically indicated protocol is preferred.

Furthermore, routine daily radiographs have adverse effects such as more cumulative radiation exposure to the patient⁷ and greater risk of accidental removal of devices (eg, catheters, tubes).⁸ Another concern is a higher risk of hospital-associated infections from bacterial spread from caregivers’ hands.⁹

Finally, daily radiographs increase the use of healthcare resources and expenditures. In a 2011 study, Gershengorn et al¹ estimated that adopting a clinically indicated radiography strategy could save more than $144 million annually in the United States.

The ACR agrees. Appropriateness criteria published by the American College of Radiology (ACR) in 2015¹⁰ recommend against routine daily chest radiographs in the ICU, in keeping with the findings of the critical care community. The ACR recommends an initial radiograph at admission to the ICU. However, follow-up radiographs should be obtained only for specific clinical indications, including a change in the patient’s clinical condition or to check for proper placement of endotracheal or nasogastric or orogastric tubes, pulmonary arterial catheters, central venous catheters, chest tubes, and other life-support devices.

Ultrasonography as an alternative

Ultrasonography is widely available and provides an alternative to chest radiography for detecting significant abnormalities in patients on mechanical ventilation without exposing them to radiation and using relatively fewer resources.

A 2012 meta-analysis (8 studies, 1,048 patients) found that bedside ultrasonography reliably detects pneumothorax.¹¹ It can also provide a rapid diagnosis of the cause of acute respiratory failure such as pneumonia or pulmonary edema.¹² Ultrasonography, with the appropriate expertise, can also confirm the position of an endotracheal tube¹³ or central venous catheter.¹⁴

Arterial blood gas testing has value for managing patients undergoing mechanical ventilation, and it is one of the most commonly performed diagnostic tests in the ICU. It provides reliable information about the patient’s oxygenation and acid-base status. It is commonly requested when changing ventilator settings.

Downsides. Arterial blood gas measurements account for 10% to 20% of the cost incurred during ICU stay.¹⁵ In addition, they require an arterial puncture—an invasive procedure associated with potentially serious complications such as occlusion of the artery, digital embolization leading to digital ischemia, local infection, pseudoaneurysm, hematoma, bleeding, and skin necrosis.

Is daily testing needed?

Guidelines say no. The 2013 American Association for Respiratory Care¹⁶ guidelines suggest that arterial blood gas testing should be based on the clinical assessment of the patient. They recommend blood gas analysis to evaluate the patient’s ventilatory status (reflected by the partial pressure of arterial carbon dioxide [PaCO₂], acid-base status (reflected by pH), arterial oxygenation (partial pressure of arterial oxygen [PaO₂] and oxyhemoglobin saturation), oxygen-carrying capacity, and whether the patient likely has an intrapulmonary shunt. They state that testing is useful to quantify the response to therapeutic or diagnostic interventions such as cardiopulmonary exercise testing, to monitor severity and progression of documented disease, and to assess the adequacy of circulatory response.

Studies agree

The ACR recommendation to test “as clinically indicated” is supported by studies showing that patient outcomes are not inferior for arterial blood gas testing when clinically indicated instead of daily, and that this practice is associated with fewer complications, less resource use, and reduced overall patient care costs.

A 2015 study compared the efficacy and safety of obtaining arterial blood gases based on clinical assessment vs daily in 300 critically ill patients.¹⁷ Overall, fewer samples were obtained per patient in the clinical assessment group than in the daily group (all patients 3.7 vs 5.5; ventilated patients 2.03 vs 6.12; P < .001 for both). In ventilated patients, there was a 60% decrease in arterial blood gas orders without affecting patient outcomes and safety, including a lower risk of complications and overall cost of care.

In another study, Martinez-Balzano et al¹⁸ evaluated the effect of guidelines they developed to optimize the use of arterial blood gas testing in their ICUs. These guidelines encouraged testing of arterial blood gases after an acute respiratory event or for a rational clinical concern, and discouraged testing for routine surveillance, after planned changes of positive end-expiratory pressure or inspired oxygen fraction on mechanical ventilation, for spontaneous breathing trials, or when a disorder was not suspected.

Compared with data collected before implementation, these guidelines reduced the number of arterial blood gas tests by 821.5 per month (41.5%), or approximately 1 test per patient per mechanical-ventilation day for each month (43.1%; P < .001). Appropriately indicated testing rose to 83.4% from a baseline of 67.5% (P = .002). Additionally, this approach was associated with saving 49 liters of blood, reducing ICU costs by $39,432, and freeing up 1,643 staff work hours for other tasks. There were no significant differences in days on mechanical ventilation, severity of illness, or mortality between the 2 periods.¹⁸

Extubation effects. Routine arterial blood gas testing has not been shown to affect extubation decisions in patients on mechanical ventilation. In a study of 83 patients who completed a spontaneous breathing trial (total of 100 trials), Salam et al¹⁹ found arterial blood gas values obtained during the trial did not change the extubation decision in 93% of the cases.

In a study of 54 extubations in 52 patients,²⁰ 65% of the extubations were performed without obtaining an arterial blood gas test after the patient completed a trial of spontaneous breathing. The extubation success rate was 94% for the entire group, and it was the same regardless of whether testing was done (94.7% vs 94.3%, respectively).

Alternatives to arterial blood gases

There are less-invasive means to obtain the information that comes from an arterial blood gas test.

Pulse oximetry is a rapid noninvasive tool that provides continuous assessment of peripheral arterial oxygen saturation as a surrogate marker for tissue arterial oxygenation. However, it cannot measure PaO₂ or PaCO₂.²¹

Transcutaneous carbon dioxide (PTCO₂) monitoring is another continuous noninvasive alternative. The newer PTCO₂ devices are useful in patients with acute respiratory failure and in critically ill patients on vasopressors or vasodilators. Studies have shown good correlation between PTCO₂ and PaCO₂.^22,23

End-tidal carbon dioxide (PetCO₂) is another alternative to estimate PaCO₂. It can also be used to confirm endotracheal tube placement, during transportation, during procedures in which the patient is under conscious sedation, and to monitor the effectiveness of cardiopulmonary resuscitation and return of circulation after cardiac arrest. PetCO₂ measurements are not as accurate as arterial blood gas testing owing to a difference of approximately 2 to 5 mm Hg between PaCO₂ and PetCO₂ in normal lungs due to alveolar dead space. This difference may be much higher depending on the clinical condition and the degree of alveolar dead space.^21,24,25

Venous blood gases, which can be obtained from a peripheral or central venous catheter, are adequate to assess pH and partial pressure of carbon dioxide (PCO₂) in hemodynamically stable patients. Walkey et al²⁶ found that the accuracy of venous blood gas measurement to predict arterial blood gases was 90%. They recommended adjusting the venous pH up by 0.05 and the PCO₂ down by 5 mm Hg to account for the positive bias of venous blood gases. A limitation of this method is that the values are not reliable in patients who are in shock.

These alternatives can be used as a substitute for daily arterial blood gases. However, in certain clinical scenarios, arterial blood gas measurement remains a necessary and useful clinical tool.

TAKE-HOME MESSAGE

Most scientific evidence suggests that chest radiographs and arterial blood gas measurement in patients undergoing mechanical ventilation—and critically ill, in general—are best done when clinically indicated rather than routinely on a daily basis. This will reduce cost and harm to patients that may result from these unnecessary tests and not adversely affect outcomes.

An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.

On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.

On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.

Further blood testing revealed the following:

• Troponin I (3 hours after the first level) 15.5 ng/mL
• B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
• C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
• Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).

Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.

A chest radiograph showed no acute cardiopulmonary processes.

Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰

Causes of myocarditis are numerous (Table 1),^3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.²³

• Parvovirus B19
• Coxsackievirus B
• Adenovirus species
• Human herpesvirus 6
• Staphylococcus aureus
• Corynebacterium diphtheria
• Trypanosoma cruzi
• Influenza H1/N1

INFECTIOUS CAUSES OF MYOCARDITIS

Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,^11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders^.21

S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.^24,25

Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.^3,26

TREATMENT FOR MYOCARDITIS

3. Which treatment is the most appropriate at this time?

• Intravenous immunoglobulin
• Interferon beta
• Acyclovir
• Prednisone
• Colchicine

Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.

Supportive care

In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.¹⁶

Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.^3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.³

Intravenous immunoglobulin

Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,²¹ but limited supportive data are available in adults.³ As such, recent ESC guidelines do not provide recommendations regarding its use in adults.³

Interferon beta

Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.³ This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.³ Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.²⁸

Nucleoside analogues

Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.³ Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.³

Immunosuppressive agents

Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,²⁹ the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.

Colchicine

Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.^3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.^21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.

Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.³⁰ The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.³¹

The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.

DISCHARGE INSTRUCTIONS

4. Before discharge, this patient should be instructed to do which of the following?

• Take over-the-counter NSAIDs to supplement the effects of colchicine
• Avoid competitive sports and athletics for at least 6 months
• Call to schedule repeat cardiac MRI
• No further instruction is needed

NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.^3,21 Thus, their use is not recommended in most cases.³

Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.³ Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.^3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.

Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.³ Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.^3,9 Repeat cardiac MRI was not performed for our patient.

CASE CONCLUDED

The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.

At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.

During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.

At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.

KEY POINTS

• 

  Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
• Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
• Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
• If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.

Our suggested strategy for approaching myocarditis is shown in Figure 3.

An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.

On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.

On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.

Further blood testing revealed the following:

• Troponin I (3 hours after the first level) 15.5 ng/mL
• B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
• C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
• Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).

Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.

A chest radiograph showed no acute cardiopulmonary processes.

Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰

Causes of myocarditis are numerous (Table 1),^3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.²³

• Parvovirus B19
• Coxsackievirus B
• Adenovirus species
• Human herpesvirus 6
• Staphylococcus aureus
• Corynebacterium diphtheria
• Trypanosoma cruzi
• Influenza H1/N1

INFECTIOUS CAUSES OF MYOCARDITIS

Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,^11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders^.21

S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.^24,25

Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.^3,26

TREATMENT FOR MYOCARDITIS

3. Which treatment is the most appropriate at this time?

• Intravenous immunoglobulin
• Interferon beta
• Acyclovir
• Prednisone
• Colchicine

Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.

Supportive care

In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.¹⁶

Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.^3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.³

Intravenous immunoglobulin

Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,²¹ but limited supportive data are available in adults.³ As such, recent ESC guidelines do not provide recommendations regarding its use in adults.³

Interferon beta

Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.³ This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.³ Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.²⁸

Nucleoside analogues

Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.³ Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.³

Immunosuppressive agents

Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,²⁹ the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.

Colchicine

Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.^3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.^21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.

Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.³⁰ The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.³¹

The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.

DISCHARGE INSTRUCTIONS

4. Before discharge, this patient should be instructed to do which of the following?

• Take over-the-counter NSAIDs to supplement the effects of colchicine
• Avoid competitive sports and athletics for at least 6 months
• Call to schedule repeat cardiac MRI
• No further instruction is needed

NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.^3,21 Thus, their use is not recommended in most cases.³

Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.³ Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.^3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.

Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.³ Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.^3,9 Repeat cardiac MRI was not performed for our patient.

CASE CONCLUDED

The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.

At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.

During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.

At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.

KEY POINTS

• 

  Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
• Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
• Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
• If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.

Our suggested strategy for approaching myocarditis is shown in Figure 3.

An 18-year-old man without any significant medical history was transferred from another hospital for higher-level care after presenting with unremitting chest pain. He had been in his usual state of good health until 7 days before presentation, when he developed mild rhinorrhea and a sore throat, but not a cough. He went to an outpatient clinic, where a rapid test for group A streptococci was done; the result was negative, and he was sent home on supportive measures.

On the day of admission, he awoke with severe, pressure-like, midsternal, nonradiating pain, which he rated 10 on a scale of 10. The pain intensified in the supine position and improved with sitting. A complete review of systems was otherwise negative. He denied having had similar symptoms in the past, as well as sick contacts, recent travel, toxin exposure, illicit substance abuse, pets at home, or tick bites. His family history was negative for cardiac arrhythmias, premature coronary artery disease, thoracic aneurysms or dissection, and infiltrative disorders. His surgical and social histories were unremarkable. He said he had no drug allergies.

On examination, his temperature was 38.1°C (100.6°F), heart rate 101 beats per minute, blood pressure 142/78 mm Hg, respiratory rate 16 breaths per minute, and oxygen saturation 98% on room air. He appeared anxious but was in no acute distress. Neck examination showed no elevation in jugular venous pulsation, bruits, thyromegaly, or lymphadenopathy. Cardiac examination revealed tachycardia without murmurs, rubs, or gallops. Lungs were clear to auscultation. Examination of all 4 extremities found 2+ pulses (on a scale of 0 to 4+) throughout and no cyanosis, clubbing, or edema. Abdominal, neurologic, and dermatologic examinations were unremarkable.

Further blood testing revealed the following:

• Troponin I (3 hours after the first level) 15.5 ng/mL
• B-type natriuretic peptide 200 mg/dL (reference range 0–100 mg/dL)
• C-reactive protein 0.9 mg/dL (reference range 0.0–0.8 mg/dL)
• Erythrocyte sedimentation rate 10 mm/h (reference range < 15 mm/h).

Metabolic and hematologic assessments were unremarkable. A toxicology screen for drugs of abuse was negative. Viral serologic testing was not done.

A chest radiograph showed no acute cardiopulmonary processes.

Given his presenting symptoms, persistent tachycardia, rapidly rising troponin I level, and electrocardiogram showing diffuse ST elevation, he was taken for urgent cardiac catheterization. Coronary angiography revealed no evidence of atherosclerotic disease, acute thrombosis, dissection, or aneurysm. Echocardiography 2 hours after the procedure showed a normal ejection fraction and no regional wall-motion abnormalities or valvular heart disease.

1. Which test should be done next to further evaluate this patient’s chest pain?

• Serum viral serologic testing
• Serum free light chain assay
• Nuclear myocardial perfusion study
• Cardiac magnetic resonance imaging (MRI)
• Endomyocardial biopsy

In this patient without ischemic coronary disease or valvular heart disease, the recent upper respiratory tract prodrome, active positional chest pain, and diffuse electrocardiographic changes raise the possibility of myocarditis with pericardial involvement.

Viral serologic tests

Viral serologic tests are often obtained in the workup of myocarditis as a noninvasive means of detecting an infectious cause.

However, this approach has several problems. First, a positive serologic result is a signal of the peripheral immune response to a pathogen but does not necessarily indicate active myocardial inflammation. Additionally, circulating immunoglobulin G against cardiotropic viruses is commonly found, even in the absence of myocarditis.¹ This is often the result of a high prevalence and exposure to these viruses in the general population. Further, trials have shown no correlation between serologic results and organisms identified by endomyocardial biopsy.²

Thus, serologic testing seems to be of limited utility, reserved for testing for infection with Borrelia burgdorferi (Lyme disease) in endemic areas, hepatitis C virus, human immunodeficiency virus in patients at high risk, Rickettsia conorii, and Rickettsia rickettsii.³

Serum free light chain testing for amyloidosis

Serum free light chain testing is replacing serum and urine protein electrophoresis in the workup of cardiac amyloidosis,⁴ as electrophoresis has poor sensitivity.^4,5

Cardiac amyloidosis often affects older persons, although in rare cases it can affect young patients who carry mutations in the transthyretin gene (ATTR amyloidosis).⁶ This diagnosis is unlikely in our patient, as he has no other affected organ systems (amyloidosis often affects the renal and neurologic systems), normal QRS voltages on electrocardiography (which are often but not always low in amyloidosis), and no left ventricular hypertrophy or diastolic dysfunction on echocardiography (which are often seen in amyloidosis).⁴

Nuclear perfusion imaging for sarcoidosis

Nuclear imaging has a limited role in evaluating myocarditis,³ but positron-emission tomography with fluorine-18 fluorodeoxyglucose has a diagnostic role in sarcoidosis, an immune-mediated cause of myocarditis.⁷

Based on the acuity of the patient’s presentation, preceded by upper respiratory tract symptoms, sarcoidosis is less likely. Sarcoidosis is difficult to diagnose, although when it is the cause of myocarditis, some clues exist, as patients usually present with heart failure symptoms, a second- or third-degree atrioventricular block, or a dilated left ventricle on echocardiography.³ All of these were absent in our patient.

Cardiac MRI

Cardiac MRI has undergone many advances, making it an extremely useful noninvasive test. It has excellent utility as a stand-alone test in diagnosing myocarditis and has synergistic value when combined with endomyocardial biopsy.⁸ It is indicated in hemodynamically stable patients with a clinical suspicion of myocarditis, persistent symptoms, absence of heart failure, and when imaging findings will change management. It is particularly useful to help elucidate a cause and guide tailored therapy.⁹ Therefore, it is a reasonable next step in the diagnostic pathway for this patient.¹⁰

Cardiac MRI also allows for concurrent assessment of scar. In myocardial infarction, the late gadolinium enhancement is subendocardial or transmural. In myocarditis, the pattern differs, being found in the subepicardial lateral free wall (in most patients with parvovirus B19) and mid-myocardial septum (in most patients with herpesvirus 6).^9,11 Cardiac MRI also confers prognostic information for patients with suspected myocarditis.¹²

The Lake Louise criteria⁹ for the diagnosis of myocarditis require 2 of the following:

• Evidence of myocardial edema
• Increased ratio of early gadolinium enhancement between myocardium and skeletal muscle (indicates hyperemia)
• At least 1 focal lesion with nonischemic late gadolinium enhancement (indicates cardiac myocyte injury or scarring).

The Lake Louise criteria may be replaced by T1 and T2 mapping, which was found to be considerably better for diagnosing myocarditis when the 2 were compared.^9,13,14

Endomyocardial biopsy

Endomyocardial biopsy should not be delayed while waiting for cardiac MRI in patients who are hemodynamically unstable or present with life-threatening features (ventricular arrhythmia, left ventricular failure, or resuscitation after sudden cardiac death).^3,10

The indications for endomyocardial biopsy have been highly debated. The 2013 guidelines from the European Society of Cardiology (ESC) recommending endomyocardial biopsy  in all clinically suspected cases of myocarditis have only heightened the controversy.³ The American Heart Association (AHA) guidelines reserve biopsy for patients with suspected myocarditis who have acute or subacute heart failure symptoms or who do not respond to standard medical therapy.¹⁵ Other reasonable indications may include the following: myocarditis with life-threatening ventricular arrhythmias, suspicion of giant cell myocarditis, necrotizing eosinophilic myocarditis, or cardiac sarcoidosis.¹⁶

Endomyocardial biopsy is the only way to make a definitive diagnosis of myocarditis.³ However, given the patchy distribution of myocardial involvement, a negative result does not rule out myocarditis. The diagnostic utility can be improved by increasing the number of samples taken (at least 3 but up to 10), obtaining samples from both ventricles, and using cardiac MRI data to determine which sites to biopsy.^3,13,17,18

Noninvasive testing such as cardiac MRI does not distinguish cell type or etiology (viral vs nonviral).³ Further, endomyocardial biopsy must be performed before immunosuppressive therapy can be safely started.^3,16 At experienced centers, the complication rate is 0% to 0.8%.³ The addition of immunohistochemical testing and viral genomic detection by polymerase chain reaction testing have increased the sensitivity of this technique.¹⁹ Finally, endomyocardial biopsy can help rule out some of the other possibilities in the differential diagnosis for myocarditis, including infiltrative and storage diseases, and possibly cardiac tumors.³

Of additional note, the diffuse ST-segment elevation seen on the patient’s electrocardiogram (Figure 1) is indicative of subepicardial inflammation. Since the distribution involves more than one epicardial coronary territory, this helps to differentiate the changes from those that occur with myocardial infarction.²⁰

Causes of myocarditis are numerous (Table 1),^3,21,22 but viral and postinfectious etiologies remain the most common causes of acute myocarditis.²³

• Parvovirus B19
• Coxsackievirus B
• Adenovirus species
• Human herpesvirus 6
• Staphylococcus aureus
• Corynebacterium diphtheria
• Trypanosoma cruzi
• Influenza H1/N1

INFECTIOUS CAUSES OF MYOCARDITIS

Coxsackievirus B was the agent most often linked to this condition from the 1950s through the 1990s. However, in the last 2 decades, adenovirus species and human herpesvirus 6 have been increasingly encountered, and recently, parvovirus B19 has been credited as the most common culprit,^11,23 at least in the Western world. In developing nations, T cruzi and C diphtheria are the most common offenders^.21

S aureus is a common cause of endocarditis, but it rarely plays a role in myocarditis. When it does, the myocarditis is often the sequela of profound bacteremia. This was much more common before antibiotics were invented.^24,25

Influenza H1/N1 is not among the most common causes of viral myocarditis, but it should be considered during flu season, given its ability to result in fulminant myocarditis.^3,26

TREATMENT FOR MYOCARDITIS

3. Which treatment is the most appropriate at this time?

• Intravenous immunoglobulin
• Interferon beta
• Acyclovir
• Prednisone
• Colchicine

Treatment for myocarditis depends on the cause but always includes supportive care to address the constellation of presenting symptoms. Standard therapies for tachy- or bradyarrhythmias, heart failure, and hemodynamic derangement should be started.

Supportive care

In patients with severe left ventricular dysfunction, an implantable cardiac electronic device, left ventricular assist device, or heart transplant may ultimately be needed. However, if possible these should be deferred for several months to determine response to treatment, since the myocardium can possibly recover.¹⁶

Diuretics, beta-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists should be given as part of guideline-directed medical therapy for patients with heart failure and reduced ejection fraction.^3,27 However, whether and how the patient should be weaned from these agents after disease recovery are unknown.³

Intravenous immunoglobulin

Intravenous immunoglobulin in high doses has had mixed results. Its efficacy is well documented in children,²¹ but limited supportive data are available in adults.³ As such, recent ESC guidelines do not provide recommendations regarding its use in adults.³

Interferon beta

Interferon beta has shown promise in improving New York Heart Association class and left ventricular ejection fraction.³ This is attributed to its effects on eliminating adenoviral species and enteroviruses. Treatment of enteroviral organisms in particular has been associated with improved 10-year prognosis.³ Interferon beta also has in vitro data showing efficacy at diminishing apoptosis from parvovirus B19.²⁸

Nucleoside analogues

Empiric treatment with nucleoside analogues (acyclovir, ganciclovir, and valacyclovir) has been tried for patients in whom human herpesvirus is suspected as the causative organism, although with unconfirmed effects.³ Consultation with an infectious disease specialist is recommended before starting these agents, and biopsy is often needed beforehand.³

Immunosuppressive agents

Immunosuppressive agents such as prednisone, azathioprine, and cyclosporine can be used in cases of biopsy-proven disease with manifestations of severe heart failure, especially if biopsy results reveal sarcoidosis, giant cell myocarditis, or necrotizing eosinophilic myocarditis. Although the results were neutral in the Myocarditis Treatment Trial,²⁹ the cause of myocarditis in this trial was unknown. Therapy with such agents should be initiated after active infection is ruled out, which also would require a biopsy.

Colchicine

Mechanisms of chest pain in myocarditis include associated pericarditis and coronary artery vasospasm.^3,23 Our patient’s chest pain changed when he changed position, possibly indicating associated pericarditis. In myocarditis with accompanying pericarditis symptoms, colchicine (1–2 mg as an initial dose and then 0.6 mg daily for up to 3 months) can be helpful in alleviating symptoms.^21,30 Thus, starting this agent in a patient who presents with myocarditis in absence of heart failure, arrhythmias, or left ventricular dysfunction is prudent.

Colchicine is used mainly to address the pain associated with pericarditis. For patients who present with pericarditis without myocarditis, nonsteroidal anti-inflammatory drugs (NSAIDs) remain the first-line treatment, with the addition of colchicine leading to faster symptom resolution.³⁰ The benefit of colchicine for isolated myocarditis is not well established, with only limited data showing some clinical effects.³¹

The patient was given colchicine 1.2 mg on the first day and then 0.6 mg daily. Within 2 days, his chest pain had resolved. He did not receive any immunosuppressive agents.

DISCHARGE INSTRUCTIONS

4. Before discharge, this patient should be instructed to do which of the following?

• Take over-the-counter NSAIDs to supplement the effects of colchicine
• Avoid competitive sports and athletics for at least 6 months
• Call to schedule repeat cardiac MRI
• No further instruction is needed

NSAIDs are used by themselves or in combination with colchicine in the treatment of pericarditis, but their use may be associated with worse outcomes in myocarditis.^3,21 Thus, their use is not recommended in most cases.³

Excessive physical activity should be avoided for at least 6 months after the clinical syndrome resolves. This recommendation is included in the most recent ESC guidelines but is based mainly on expert opinion and murine models with coxsackievirus B.³ Periodic reassessment is indicated with exercise stress testing before return to strenuous activity.^3,16,32 Testing should look for exercise tolerance, and exercise electrocardiography also helps to evaluate for clinically relevant arrythmias.

Cardiac MRI can help clarify the prognosis in myocarditis, but the role of repeat testing in guiding therapy is limited.³ Indications for repeat cardiac MRI include presence of 0 or 1 of the Lake Louise criteria (recall that 2 are necessary to make the diagnosis) with recurrence of symptoms and a high suspicion for myocardial inflammation.^3,9 Repeat cardiac MRI was not performed for our patient.

CASE CONCLUDED

The patient was evaluated in the cardiology clinic within 1 week of discharge. At that time, he was in sinus tachycardia with a heart rate of 102 bpm, and he was instructed to avoid any exercise until further notice.

At 6-month follow-up, the sinus tachycardia had resolved. However, because persistent tachycardia had been noted at the first postdischarge visit, and in view of the extent of myocardial involvement, he underwent exercise treadmill testing to evaluate for ventricular arrhythmias. The study did show premature ventricular complexes and 1 ventricular couplet at submaximal exercise levels. As this indicated a higher risk of exercise-induced arrhythmias, he was asked to continue normal activity levels but to abstain from exercise until the next evaluation.

During his 1-year follow-up, a repeat treadmill test showed no ventricular ectopy. Holter monitoring was ordered and showed no premature ventricular complexes, supraventricular arrhythmias, or atrioventricular block within the 48-hour period.

At his 2-year evaluation, he had returned to playing basketball and soccer on weekends and reported no recurrence of his initial symptoms.

KEY POINTS

• 

  Cardiac MRI has emerged as an excellent noninvasive imaging modality for the diagnosis of myocarditis.
• Treatment of myocarditis depends on the cause and severity of the patient’s presentation, spanning the spectrum from conservative care to immunosuppressive agents and even heart failure therapy.
• Excessive physical activity should be avoided for the first 6 months after disease diagnosis and treatment.
• If myocarditis is associated with pericardial involvement, colchicine is the agent of choice, and NSAIDs should be avoided.

Our suggested strategy for approaching myocarditis is shown in Figure 3.