PURLs

ILLUSTRATIVE CASE

A 64-year-old overweight White man with a history of hypertension, hyperlipidemia, and HF with an ejection fraction (EF) of 40% presents for primary care follow-up after a recent inpatient admission for worsened HF symptoms. At baseline, he is comfortable at rest but becomes dyspneic upon walking to another room within his home. He is already taking a mineralocorticoid receptor antagonist, a high-intensity statin, a beta-blocker, and an angiotensin-converting enzyme (ACE) inhibitor. What other medication should be considered to minimize his cardiovascular (CV)risk?

An estimated 1% to 2% of the world’s adult population has HF.² Although the exact prevalence is difficult to quantify due to variations in definitions and diagnostic methods, the American Heart Association (AHA) estimated that 6.2 million Americans had HF between 2013 and 2016.³ Prevalence increases with age, with an annual incidence of approximately 35 per 1000 by age 85.⁴ Due to the significant morbidity and mortality associated with HF, advancements in treatment are needed.

SGLT2 inhibitors work within the proximal tubule of the kidneys, resulting in increased glucose and sodium excretion with secondary osmotic diuresis and therefore a modest reduction in serum glucose.^1,2,5,6 SGLT2 inhibitors are classically prescribed for hyperglycemia treatment in type 2 diabetes. However, preliminary data suggest that this class of medication also positively impacts cardiac function. The diuresis and natriuresis effects of SGLT2 inhibitors appear to optimize cardiac output and subsequent oxygen consumption through a reduction of afterload and preload.^1,2,5,6 Further, SGLT2 inhibitors may decrease inflammatory pathways and lead to a secondary reduction of cardiac remodeling via a reduction and modulation of inflammatory pathways. This reduction and modulation may also be associated with a reduction in development, and possibly a reversal, of hypertrophic cardiomyopathy, cardiac fibrosis, and atherosclerosis.^5,6 Some of the previously reported adverse effects of SGLT2 inhibitors include urinary tract infection, acute kidney injury, lower extremity amputation, bone fracture, and diabetic ketoacidosis.²

In several studies of patients with type 2 diabetes, SGLT2 inhibitors have shown benefit in reducing CV disease–related death and hospitalization for HF.^1,2,5,6 A recent expert consensus from the American College of Cardiology (ACC) states that SGLT2 therapy should be considered for any patient with type 2 diabetes who also has established atherosclerotic CV disease, HF (a clinical syndrome as defined in ACC/AHA guidelines), or diabetic kidney disease, or who is at a high risk for atherosclerotic CV disease (ie, has signs of end-organ damage, such as left ventricular hypertrophy or retinopathy, or multiple risk factors such as advanced age, smoking, hypertension, and family history).^7,8

Dapagliflozin demonstrated decreased HF exacerbations and CV deaths, improved patient-reported HF symptoms, and lower allcause mortality in patients both with and without diabetes.

Additionally, a 2019 randomized controlled trial (RCT) by Nassif et al showed that, compared to placebo, dapagliflozin significantly improved both patient-reported HF symptoms and cardiac natriuretic peptide levels over 12 weeks in patients with and without diabetes.⁹ In September 2020, ­UpToDate added SGLT2 inhibitors as an option for patients with continued symptoms of HF despite use of appropriate primary agents and mineralocorticoid receptor antagonists, whether or not they have type 2 diabetes; this update was based on 2 studies, 1 of which is reviewed here.¹⁰

STUDY SUMMARY

Dapagliflozin demonstrated better CV outcomes than placebo

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study is an RCT that compared dapagliflozin to placebo among 4744 patients ages 18 years and older who had HF with an EF ≤ 40% and NYHA class II, III, or IV symptoms. The study included patients with (41.8%) and without diabetes. Most patients were male (76.2%-77%), White (70%), and European (44.7%-46.1%).

Patients were randomized to receive either dapagliflozin 10 mg/d or a matching placebo in addition to standard HF therapy (including an ACE inhibitor, angiotensin receptor blocker, or sacubitril-valsartan plus a beta-blocker unless contraindicated; mineralocorticoid antagonist use was encouraged). Follow-up occurred at 14 days, 60 days, 4 months, and then every 4 months, for an average of about 18 months. Patients with diabetes continued to use their glucose-lowering therapies, with dose adjustments, as needed.

Continue to: The primary outcome...

The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous HF therapy) or death from a CV cause. Secondary outcomes included a composite of hospitalization for HF or CV death; total number of hospitalizations for HF (including repeat admissions) and CV death; a change in Kansas City Cardiomyopathy Questionnaire symptom score; a composite of worsening renal function including a sustained (≥ 28 d) decline in the estimated glomerular filtration rate (eGFR) of ≥ 50%, end-stage renal disease (defined as sustained eGFR of < 15 mL/min/1.73 m², sustained dialysis, or renal transplantation), or renal death; and death from any cause.

The primary outcome of worsening HF or death from CV causes occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio [HR] = 0.74; 95% CI, 0.65-0.85; P < .001). The composite score of hospitalizations for HF plus death from a CV cause was lower in the dapagliflozin group compared to the placebo group (HR = 0.75; 95% CI, 0.65-0.85; P < .001).

Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications.

A total of 276 patients (11.6%) in the dapagliflozin group and 329 patients (13.9%) in the placebo group died from any cause (HR = 0.83; 95% CI, 0.71-0.97). More patients in the dapagliflozin group than in the placebo group had an improvement in symptom score (58.3% vs 50.9%; odds ratio = 1.15; 95% CI, 1.08-1.23; P < .001). Renal composite outcome did not differ between the 2 treatment groups. Potential adverse effects included volume depletion, renal adverse event, and major hypoglycemia, which occurred at the same rate in the treatment and placebo groups. There was no difference in outcomes or adverse effects between patients with and without diabetes.¹

WHAT'S NEW

Evidence supports dapagliflozin use in a new patient population

The DAPA-HF study compared dapagliflozin to placebo in HF patients both with and without diabetes and demonstrated decreased HF exacerbations and CV deaths, improved ­patient-reported HF symptoms, and lower all-cause mortality in the treatment group. This study supports use of dapagliflozin in a new patient population—those with HF—rather than solely in patients with diabetes, as the drug was originally marketed.

CAVEATS

Specific study population may limit generalizability

The DAPA-HF study included mostly male, White, European patients followed for an average of 18.2 months as part of initial Phase III studies funded by AstraZeneca (the pharmaceutical company that developed dapagliflozin). Given the potential conflict due to funding, all statistical results were verified by an independent academic group, and analyses were completed with an intention-to-treat model. The outlined benefits described here were only studied in a population of patients with reduced EF (≤ 40%), so the impact remains unclear for patients with preserved EF. Safety and benefits beyond 24 months were not studied in this RCT; therefore long-term data are still unknown.

Continue to: CHALLENGES TO IMPLEMENTATION

Adding an SGLT2 inhibitor may be cost prohibitive for some patients

An SGLT2 inhibitor costs, on average, $500 to $600 for a 30-day supply, which may be prohibitive for some patients.¹¹ Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications, particularly glucose-lowering therapies, and the optimal prioritization of medications is not yet known.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 64-year-old overweight White man with a history of hypertension, hyperlipidemia, and HF with an ejection fraction (EF) of 40% presents for primary care follow-up after a recent inpatient admission for worsened HF symptoms. At baseline, he is comfortable at rest but becomes dyspneic upon walking to another room within his home. He is already taking a mineralocorticoid receptor antagonist, a high-intensity statin, a beta-blocker, and an angiotensin-converting enzyme (ACE) inhibitor. What other medication should be considered to minimize his cardiovascular (CV)risk?

An estimated 1% to 2% of the world’s adult population has HF.² Although the exact prevalence is difficult to quantify due to variations in definitions and diagnostic methods, the American Heart Association (AHA) estimated that 6.2 million Americans had HF between 2013 and 2016.³ Prevalence increases with age, with an annual incidence of approximately 35 per 1000 by age 85.⁴ Due to the significant morbidity and mortality associated with HF, advancements in treatment are needed.

SGLT2 inhibitors work within the proximal tubule of the kidneys, resulting in increased glucose and sodium excretion with secondary osmotic diuresis and therefore a modest reduction in serum glucose.^1,2,5,6 SGLT2 inhibitors are classically prescribed for hyperglycemia treatment in type 2 diabetes. However, preliminary data suggest that this class of medication also positively impacts cardiac function. The diuresis and natriuresis effects of SGLT2 inhibitors appear to optimize cardiac output and subsequent oxygen consumption through a reduction of afterload and preload.^1,2,5,6 Further, SGLT2 inhibitors may decrease inflammatory pathways and lead to a secondary reduction of cardiac remodeling via a reduction and modulation of inflammatory pathways. This reduction and modulation may also be associated with a reduction in development, and possibly a reversal, of hypertrophic cardiomyopathy, cardiac fibrosis, and atherosclerosis.^5,6 Some of the previously reported adverse effects of SGLT2 inhibitors include urinary tract infection, acute kidney injury, lower extremity amputation, bone fracture, and diabetic ketoacidosis.²

In several studies of patients with type 2 diabetes, SGLT2 inhibitors have shown benefit in reducing CV disease–related death and hospitalization for HF.^1,2,5,6 A recent expert consensus from the American College of Cardiology (ACC) states that SGLT2 therapy should be considered for any patient with type 2 diabetes who also has established atherosclerotic CV disease, HF (a clinical syndrome as defined in ACC/AHA guidelines), or diabetic kidney disease, or who is at a high risk for atherosclerotic CV disease (ie, has signs of end-organ damage, such as left ventricular hypertrophy or retinopathy, or multiple risk factors such as advanced age, smoking, hypertension, and family history).^7,8

Dapagliflozin demonstrated decreased HF exacerbations and CV deaths, improved patient-reported HF symptoms, and lower allcause mortality in patients both with and without diabetes.

Additionally, a 2019 randomized controlled trial (RCT) by Nassif et al showed that, compared to placebo, dapagliflozin significantly improved both patient-reported HF symptoms and cardiac natriuretic peptide levels over 12 weeks in patients with and without diabetes.⁹ In September 2020, ­UpToDate added SGLT2 inhibitors as an option for patients with continued symptoms of HF despite use of appropriate primary agents and mineralocorticoid receptor antagonists, whether or not they have type 2 diabetes; this update was based on 2 studies, 1 of which is reviewed here.¹⁰

STUDY SUMMARY

Dapagliflozin demonstrated better CV outcomes than placebo

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study is an RCT that compared dapagliflozin to placebo among 4744 patients ages 18 years and older who had HF with an EF ≤ 40% and NYHA class II, III, or IV symptoms. The study included patients with (41.8%) and without diabetes. Most patients were male (76.2%-77%), White (70%), and European (44.7%-46.1%).

Patients were randomized to receive either dapagliflozin 10 mg/d or a matching placebo in addition to standard HF therapy (including an ACE inhibitor, angiotensin receptor blocker, or sacubitril-valsartan plus a beta-blocker unless contraindicated; mineralocorticoid antagonist use was encouraged). Follow-up occurred at 14 days, 60 days, 4 months, and then every 4 months, for an average of about 18 months. Patients with diabetes continued to use their glucose-lowering therapies, with dose adjustments, as needed.

Continue to: The primary outcome...

The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous HF therapy) or death from a CV cause. Secondary outcomes included a composite of hospitalization for HF or CV death; total number of hospitalizations for HF (including repeat admissions) and CV death; a change in Kansas City Cardiomyopathy Questionnaire symptom score; a composite of worsening renal function including a sustained (≥ 28 d) decline in the estimated glomerular filtration rate (eGFR) of ≥ 50%, end-stage renal disease (defined as sustained eGFR of < 15 mL/min/1.73 m², sustained dialysis, or renal transplantation), or renal death; and death from any cause.

The primary outcome of worsening HF or death from CV causes occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio [HR] = 0.74; 95% CI, 0.65-0.85; P < .001). The composite score of hospitalizations for HF plus death from a CV cause was lower in the dapagliflozin group compared to the placebo group (HR = 0.75; 95% CI, 0.65-0.85; P < .001).

Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications.

A total of 276 patients (11.6%) in the dapagliflozin group and 329 patients (13.9%) in the placebo group died from any cause (HR = 0.83; 95% CI, 0.71-0.97). More patients in the dapagliflozin group than in the placebo group had an improvement in symptom score (58.3% vs 50.9%; odds ratio = 1.15; 95% CI, 1.08-1.23; P < .001). Renal composite outcome did not differ between the 2 treatment groups. Potential adverse effects included volume depletion, renal adverse event, and major hypoglycemia, which occurred at the same rate in the treatment and placebo groups. There was no difference in outcomes or adverse effects between patients with and without diabetes.¹

WHAT'S NEW

Evidence supports dapagliflozin use in a new patient population

The DAPA-HF study compared dapagliflozin to placebo in HF patients both with and without diabetes and demonstrated decreased HF exacerbations and CV deaths, improved ­patient-reported HF symptoms, and lower all-cause mortality in the treatment group. This study supports use of dapagliflozin in a new patient population—those with HF—rather than solely in patients with diabetes, as the drug was originally marketed.

CAVEATS

Specific study population may limit generalizability

The DAPA-HF study included mostly male, White, European patients followed for an average of 18.2 months as part of initial Phase III studies funded by AstraZeneca (the pharmaceutical company that developed dapagliflozin). Given the potential conflict due to funding, all statistical results were verified by an independent academic group, and analyses were completed with an intention-to-treat model. The outlined benefits described here were only studied in a population of patients with reduced EF (≤ 40%), so the impact remains unclear for patients with preserved EF. Safety and benefits beyond 24 months were not studied in this RCT; therefore long-term data are still unknown.

Continue to: CHALLENGES TO IMPLEMENTATION

Adding an SGLT2 inhibitor may be cost prohibitive for some patients

An SGLT2 inhibitor costs, on average, $500 to $600 for a 30-day supply, which may be prohibitive for some patients.¹¹ Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications, particularly glucose-lowering therapies, and the optimal prioritization of medications is not yet known.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 64-year-old overweight White man with a history of hypertension, hyperlipidemia, and HF with an ejection fraction (EF) of 40% presents for primary care follow-up after a recent inpatient admission for worsened HF symptoms. At baseline, he is comfortable at rest but becomes dyspneic upon walking to another room within his home. He is already taking a mineralocorticoid receptor antagonist, a high-intensity statin, a beta-blocker, and an angiotensin-converting enzyme (ACE) inhibitor. What other medication should be considered to minimize his cardiovascular (CV)risk?

An estimated 1% to 2% of the world’s adult population has HF.² Although the exact prevalence is difficult to quantify due to variations in definitions and diagnostic methods, the American Heart Association (AHA) estimated that 6.2 million Americans had HF between 2013 and 2016.³ Prevalence increases with age, with an annual incidence of approximately 35 per 1000 by age 85.⁴ Due to the significant morbidity and mortality associated with HF, advancements in treatment are needed.

SGLT2 inhibitors work within the proximal tubule of the kidneys, resulting in increased glucose and sodium excretion with secondary osmotic diuresis and therefore a modest reduction in serum glucose.^1,2,5,6 SGLT2 inhibitors are classically prescribed for hyperglycemia treatment in type 2 diabetes. However, preliminary data suggest that this class of medication also positively impacts cardiac function. The diuresis and natriuresis effects of SGLT2 inhibitors appear to optimize cardiac output and subsequent oxygen consumption through a reduction of afterload and preload.^1,2,5,6 Further, SGLT2 inhibitors may decrease inflammatory pathways and lead to a secondary reduction of cardiac remodeling via a reduction and modulation of inflammatory pathways. This reduction and modulation may also be associated with a reduction in development, and possibly a reversal, of hypertrophic cardiomyopathy, cardiac fibrosis, and atherosclerosis.^5,6 Some of the previously reported adverse effects of SGLT2 inhibitors include urinary tract infection, acute kidney injury, lower extremity amputation, bone fracture, and diabetic ketoacidosis.²

In several studies of patients with type 2 diabetes, SGLT2 inhibitors have shown benefit in reducing CV disease–related death and hospitalization for HF.^1,2,5,6 A recent expert consensus from the American College of Cardiology (ACC) states that SGLT2 therapy should be considered for any patient with type 2 diabetes who also has established atherosclerotic CV disease, HF (a clinical syndrome as defined in ACC/AHA guidelines), or diabetic kidney disease, or who is at a high risk for atherosclerotic CV disease (ie, has signs of end-organ damage, such as left ventricular hypertrophy or retinopathy, or multiple risk factors such as advanced age, smoking, hypertension, and family history).^7,8

Dapagliflozin demonstrated decreased HF exacerbations and CV deaths, improved patient-reported HF symptoms, and lower allcause mortality in patients both with and without diabetes.

Additionally, a 2019 randomized controlled trial (RCT) by Nassif et al showed that, compared to placebo, dapagliflozin significantly improved both patient-reported HF symptoms and cardiac natriuretic peptide levels over 12 weeks in patients with and without diabetes.⁹ In September 2020, ­UpToDate added SGLT2 inhibitors as an option for patients with continued symptoms of HF despite use of appropriate primary agents and mineralocorticoid receptor antagonists, whether or not they have type 2 diabetes; this update was based on 2 studies, 1 of which is reviewed here.¹⁰

STUDY SUMMARY

Dapagliflozin demonstrated better CV outcomes than placebo

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study is an RCT that compared dapagliflozin to placebo among 4744 patients ages 18 years and older who had HF with an EF ≤ 40% and NYHA class II, III, or IV symptoms. The study included patients with (41.8%) and without diabetes. Most patients were male (76.2%-77%), White (70%), and European (44.7%-46.1%).

Patients were randomized to receive either dapagliflozin 10 mg/d or a matching placebo in addition to standard HF therapy (including an ACE inhibitor, angiotensin receptor blocker, or sacubitril-valsartan plus a beta-blocker unless contraindicated; mineralocorticoid antagonist use was encouraged). Follow-up occurred at 14 days, 60 days, 4 months, and then every 4 months, for an average of about 18 months. Patients with diabetes continued to use their glucose-lowering therapies, with dose adjustments, as needed.

Continue to: The primary outcome...

The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring intravenous HF therapy) or death from a CV cause. Secondary outcomes included a composite of hospitalization for HF or CV death; total number of hospitalizations for HF (including repeat admissions) and CV death; a change in Kansas City Cardiomyopathy Questionnaire symptom score; a composite of worsening renal function including a sustained (≥ 28 d) decline in the estimated glomerular filtration rate (eGFR) of ≥ 50%, end-stage renal disease (defined as sustained eGFR of < 15 mL/min/1.73 m², sustained dialysis, or renal transplantation), or renal death; and death from any cause.

The primary outcome of worsening HF or death from CV causes occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio [HR] = 0.74; 95% CI, 0.65-0.85; P < .001). The composite score of hospitalizations for HF plus death from a CV cause was lower in the dapagliflozin group compared to the placebo group (HR = 0.75; 95% CI, 0.65-0.85; P < .001).

Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications.

A total of 276 patients (11.6%) in the dapagliflozin group and 329 patients (13.9%) in the placebo group died from any cause (HR = 0.83; 95% CI, 0.71-0.97). More patients in the dapagliflozin group than in the placebo group had an improvement in symptom score (58.3% vs 50.9%; odds ratio = 1.15; 95% CI, 1.08-1.23; P < .001). Renal composite outcome did not differ between the 2 treatment groups. Potential adverse effects included volume depletion, renal adverse event, and major hypoglycemia, which occurred at the same rate in the treatment and placebo groups. There was no difference in outcomes or adverse effects between patients with and without diabetes.¹

WHAT'S NEW

Evidence supports dapagliflozin use in a new patient population

The DAPA-HF study compared dapagliflozin to placebo in HF patients both with and without diabetes and demonstrated decreased HF exacerbations and CV deaths, improved ­patient-reported HF symptoms, and lower all-cause mortality in the treatment group. This study supports use of dapagliflozin in a new patient population—those with HF—rather than solely in patients with diabetes, as the drug was originally marketed.

CAVEATS

Specific study population may limit generalizability

The DAPA-HF study included mostly male, White, European patients followed for an average of 18.2 months as part of initial Phase III studies funded by AstraZeneca (the pharmaceutical company that developed dapagliflozin). Given the potential conflict due to funding, all statistical results were verified by an independent academic group, and analyses were completed with an intention-to-treat model. The outlined benefits described here were only studied in a population of patients with reduced EF (≤ 40%), so the impact remains unclear for patients with preserved EF. Safety and benefits beyond 24 months were not studied in this RCT; therefore long-term data are still unknown.

Continue to: CHALLENGES TO IMPLEMENTATION

Adding an SGLT2 inhibitor may be cost prohibitive for some patients

An SGLT2 inhibitor costs, on average, $500 to $600 for a 30-day supply, which may be prohibitive for some patients.¹¹ Integration of SGLT2 inhibitors into a patient’s medication regimen may require dose adjustments of other medications, particularly glucose-lowering therapies, and the optimal prioritization of medications is not yet known.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 55-year-old man with a history of chronic obstructive pulmonary disease (COPD) presents to you with increased sputum volume and increased dyspnea, but no fever. You diagnose a COPD exacerbation. Would point-of-care C-reactive protein (CRP) testing be a useful tool to guide antibiotic prescribing?

COPD is a common respiratory condition and one of the leading causes of death in the world.² COPD requires chronic therapy and frequent treatment for acute exacerbations.³ A systematic review found that exacerbations occur an average of 1.3 times per year for patients with known COPD.⁴ Antibiotics are often prescribed for COPD exacerbations, but which patients benefit most from antibiotic treatment is unclear and identification often is based on clinical features alone. Additionally, overprescribing of antibiotics can lead to unnecessary adverse effects, drive antibiotic resistance, and be a waste of resources.⁵

The European Respiratory Society/American Thoracic Society (ERS/ATS) provides a conditional recommendation to consider antibiotics in ambulatory patients with COPD exacerbation based on moderate-quality evidence.⁶ The 2020 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend antibiotics for moderately or severely ill patients with a COPD exacerbation who have increased cough and sputum purulence.⁷ While the ERS/ATS recommendations do not mention CRP, the GOLD guidelines discuss biomarkers as emerging tools in determining antibiotic utility.

Biomarkers such as procalcitonin and CRP are being examined as potential tools to distinguish which patients would benefit from antibiotic treatment in COPD exacerbations. In a 2013 study, CRP levels > 19.6 mg/L in the serum and > 15.2 mg/L in the sputum indicated a bacterial infection, but more research was needed to determine if CRP could help guide antibiotic prescribing.⁸ In a 2019 randomized trial of 101 patients with COPD exacerbations, researchers compared the GOLD strategy for antibiotic prescribing with a CRP-guided antibiotic strategy (CRP ≥ 50 mg/L) and found no difference in adverse events between study groups.⁹

This trial focused on point-of-care CRP-guided prescribing of antibiotics for patients with COPD exacerbations in the outpatient setting.

STUDY SUMMARY

Point-of-care CRP testing is noninferior to usual care

This open-label, multicenter, randomized controlled trial at 86 general medical practices in the United Kingdom examined whether the use of point-of-care CRP testing could reduce antibiotic use during acute exacerbations of COPD. Patients (N = 653; 650 needed to provide 81% to 90% power) were ages 40 years and older, had a diagnosis of COPD, and presented for an acute exacerbation of COPD based on the presence of at least 1 Anthonisen criteria (increased dyspnea, increase in sputum volume, and increase in purulent sputum).

Patients were randomized in a 1:1 fashion to receive care guided by point-of-care CRP testing (CRP-guided) or usual care for their COPD exacerbation. Patients in the CRP-guided group received a point-of-care CRP test as part of their assessment at presentation, or at any other appointments for COPD over the following 4 weeks.

The research team provided clinicians with CRP interpretation guidance based on the following CRP values: < 20 mg/L, antibiotics are typically not needed; 20 to 40 mg/L, antibiotics might be beneficial if purulent sputum is present; and > 40 mg/L, antibiotics are usually beneficial. Primary outcomes were patient-reported antibiotic use within 4 weeks and COPD-related health status. Of the patients who received a point-of-care CRP test, the median value was 6 mg/L; 76% had a value < 20 mg/L, 12% had values between 20 and 40 mg/L, and 12% had values > 40 mg/L. In the intention-to-treat analysis, fewer patients in the CRP-guided group reported antibiotic use vs those in the usual-care group (57% vs 77%; adjusted odds ratio [aOR] = 0.31; 95% CI, 0.20-0.47) within 4 weeks. The CRP-guided group also received fewer antibiotics at the initial visit compared to the usual-care group (48% vs 70%; aOR = 0.31; 95% CI, 0.21-0.45).

COPD-related health status was assessed with the Clinical COPD Questionnaire (score range, 0-6; a difference of 0.4 represents minimal clinical importance). At 2 weeks, the adjusted mean difference in the total health status score with the use of CRP was noninferior to usual care and was in favor of the CRP-guided group (mean difference = −0.19 points; two-sided 90% CI, −0.33 to −0.05). There was no evidence of clinically important between-group differences in pneumonia (3% vs 4%; aOR = 0.73; 95% CI, 0.29-1.82) at 6-month follow-up. Rates of hospitalization at 6 months were similar between groups (9.3% vs 8.6%; no P value provided).

Fewer patients in the CRPguided group reported antibiotic use vs those in the usual-care group within 4 weeks.

Limitations of this trial included patient report of antibiotic use and the lack of a sham test.

WHAT'S NEW

RCT provides evidence to support use of CRP testing

Point-of-care CRP testing can reduce antibiotic prescribing in patients presenting with a COPD exacerbation without affecting symptom improvement or adverse events.

CAVEATS

CRP testing may not be cost effective

CRP testing—especially point-of-care ­testing—remains expensive in many parts of the United States. A 2015 cost-effectiveness analysis of point-of-care CRP tests for respiratory tract infection in England concluded the cost of the test per patient was not cost effective.¹⁰ It is unknown if point-of-care CRP testing would be cost effective in guiding antibiotic prescribing for ­primary care providers with a focus on COPD exacerbations.

CHALLENGES TO IMPLEMENTATION 

Virtual visits and variable access may limit use

CRP-guided antibiotic prescribing may be challenging in some clinical scenarios or clinics with the rise of virtual visits and differential access in primary care clinics to point-of-care CRP tests. JFP

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. Copyright © 2021. The Family Physicians Inquiries Network. All rights reserved.

ILLUSTRATIVE CASE

A 55-year-old man with a history of chronic obstructive pulmonary disease (COPD) presents to you with increased sputum volume and increased dyspnea, but no fever. You diagnose a COPD exacerbation. Would point-of-care C-reactive protein (CRP) testing be a useful tool to guide antibiotic prescribing?

COPD is a common respiratory condition and one of the leading causes of death in the world.² COPD requires chronic therapy and frequent treatment for acute exacerbations.³ A systematic review found that exacerbations occur an average of 1.3 times per year for patients with known COPD.⁴ Antibiotics are often prescribed for COPD exacerbations, but which patients benefit most from antibiotic treatment is unclear and identification often is based on clinical features alone. Additionally, overprescribing of antibiotics can lead to unnecessary adverse effects, drive antibiotic resistance, and be a waste of resources.⁵

The European Respiratory Society/American Thoracic Society (ERS/ATS) provides a conditional recommendation to consider antibiotics in ambulatory patients with COPD exacerbation based on moderate-quality evidence.⁶ The 2020 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend antibiotics for moderately or severely ill patients with a COPD exacerbation who have increased cough and sputum purulence.⁷ While the ERS/ATS recommendations do not mention CRP, the GOLD guidelines discuss biomarkers as emerging tools in determining antibiotic utility.

Biomarkers such as procalcitonin and CRP are being examined as potential tools to distinguish which patients would benefit from antibiotic treatment in COPD exacerbations. In a 2013 study, CRP levels > 19.6 mg/L in the serum and > 15.2 mg/L in the sputum indicated a bacterial infection, but more research was needed to determine if CRP could help guide antibiotic prescribing.⁸ In a 2019 randomized trial of 101 patients with COPD exacerbations, researchers compared the GOLD strategy for antibiotic prescribing with a CRP-guided antibiotic strategy (CRP ≥ 50 mg/L) and found no difference in adverse events between study groups.⁹

This trial focused on point-of-care CRP-guided prescribing of antibiotics for patients with COPD exacerbations in the outpatient setting.

STUDY SUMMARY

Point-of-care CRP testing is noninferior to usual care

This open-label, multicenter, randomized controlled trial at 86 general medical practices in the United Kingdom examined whether the use of point-of-care CRP testing could reduce antibiotic use during acute exacerbations of COPD. Patients (N = 653; 650 needed to provide 81% to 90% power) were ages 40 years and older, had a diagnosis of COPD, and presented for an acute exacerbation of COPD based on the presence of at least 1 Anthonisen criteria (increased dyspnea, increase in sputum volume, and increase in purulent sputum).

Patients were randomized in a 1:1 fashion to receive care guided by point-of-care CRP testing (CRP-guided) or usual care for their COPD exacerbation. Patients in the CRP-guided group received a point-of-care CRP test as part of their assessment at presentation, or at any other appointments for COPD over the following 4 weeks.

The research team provided clinicians with CRP interpretation guidance based on the following CRP values: < 20 mg/L, antibiotics are typically not needed; 20 to 40 mg/L, antibiotics might be beneficial if purulent sputum is present; and > 40 mg/L, antibiotics are usually beneficial. Primary outcomes were patient-reported antibiotic use within 4 weeks and COPD-related health status. Of the patients who received a point-of-care CRP test, the median value was 6 mg/L; 76% had a value < 20 mg/L, 12% had values between 20 and 40 mg/L, and 12% had values > 40 mg/L. In the intention-to-treat analysis, fewer patients in the CRP-guided group reported antibiotic use vs those in the usual-care group (57% vs 77%; adjusted odds ratio [aOR] = 0.31; 95% CI, 0.20-0.47) within 4 weeks. The CRP-guided group also received fewer antibiotics at the initial visit compared to the usual-care group (48% vs 70%; aOR = 0.31; 95% CI, 0.21-0.45).

COPD-related health status was assessed with the Clinical COPD Questionnaire (score range, 0-6; a difference of 0.4 represents minimal clinical importance). At 2 weeks, the adjusted mean difference in the total health status score with the use of CRP was noninferior to usual care and was in favor of the CRP-guided group (mean difference = −0.19 points; two-sided 90% CI, −0.33 to −0.05). There was no evidence of clinically important between-group differences in pneumonia (3% vs 4%; aOR = 0.73; 95% CI, 0.29-1.82) at 6-month follow-up. Rates of hospitalization at 6 months were similar between groups (9.3% vs 8.6%; no P value provided).

Fewer patients in the CRPguided group reported antibiotic use vs those in the usual-care group within 4 weeks.

Limitations of this trial included patient report of antibiotic use and the lack of a sham test.

WHAT'S NEW

RCT provides evidence to support use of CRP testing

Point-of-care CRP testing can reduce antibiotic prescribing in patients presenting with a COPD exacerbation without affecting symptom improvement or adverse events.

CAVEATS

CRP testing may not be cost effective

CRP testing—especially point-of-care ­testing—remains expensive in many parts of the United States. A 2015 cost-effectiveness analysis of point-of-care CRP tests for respiratory tract infection in England concluded the cost of the test per patient was not cost effective.¹⁰ It is unknown if point-of-care CRP testing would be cost effective in guiding antibiotic prescribing for ­primary care providers with a focus on COPD exacerbations.

CHALLENGES TO IMPLEMENTATION 

Virtual visits and variable access may limit use

CRP-guided antibiotic prescribing may be challenging in some clinical scenarios or clinics with the rise of virtual visits and differential access in primary care clinics to point-of-care CRP tests. JFP

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. Copyright © 2021. The Family Physicians Inquiries Network. All rights reserved.

ILLUSTRATIVE CASE

A 55-year-old man with a history of chronic obstructive pulmonary disease (COPD) presents to you with increased sputum volume and increased dyspnea, but no fever. You diagnose a COPD exacerbation. Would point-of-care C-reactive protein (CRP) testing be a useful tool to guide antibiotic prescribing?

COPD is a common respiratory condition and one of the leading causes of death in the world.² COPD requires chronic therapy and frequent treatment for acute exacerbations.³ A systematic review found that exacerbations occur an average of 1.3 times per year for patients with known COPD.⁴ Antibiotics are often prescribed for COPD exacerbations, but which patients benefit most from antibiotic treatment is unclear and identification often is based on clinical features alone. Additionally, overprescribing of antibiotics can lead to unnecessary adverse effects, drive antibiotic resistance, and be a waste of resources.⁵

The European Respiratory Society/American Thoracic Society (ERS/ATS) provides a conditional recommendation to consider antibiotics in ambulatory patients with COPD exacerbation based on moderate-quality evidence.⁶ The 2020 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend antibiotics for moderately or severely ill patients with a COPD exacerbation who have increased cough and sputum purulence.⁷ While the ERS/ATS recommendations do not mention CRP, the GOLD guidelines discuss biomarkers as emerging tools in determining antibiotic utility.

Biomarkers such as procalcitonin and CRP are being examined as potential tools to distinguish which patients would benefit from antibiotic treatment in COPD exacerbations. In a 2013 study, CRP levels > 19.6 mg/L in the serum and > 15.2 mg/L in the sputum indicated a bacterial infection, but more research was needed to determine if CRP could help guide antibiotic prescribing.⁸ In a 2019 randomized trial of 101 patients with COPD exacerbations, researchers compared the GOLD strategy for antibiotic prescribing with a CRP-guided antibiotic strategy (CRP ≥ 50 mg/L) and found no difference in adverse events between study groups.⁹

This trial focused on point-of-care CRP-guided prescribing of antibiotics for patients with COPD exacerbations in the outpatient setting.

STUDY SUMMARY

Point-of-care CRP testing is noninferior to usual care

This open-label, multicenter, randomized controlled trial at 86 general medical practices in the United Kingdom examined whether the use of point-of-care CRP testing could reduce antibiotic use during acute exacerbations of COPD. Patients (N = 653; 650 needed to provide 81% to 90% power) were ages 40 years and older, had a diagnosis of COPD, and presented for an acute exacerbation of COPD based on the presence of at least 1 Anthonisen criteria (increased dyspnea, increase in sputum volume, and increase in purulent sputum).

Patients were randomized in a 1:1 fashion to receive care guided by point-of-care CRP testing (CRP-guided) or usual care for their COPD exacerbation. Patients in the CRP-guided group received a point-of-care CRP test as part of their assessment at presentation, or at any other appointments for COPD over the following 4 weeks.

The research team provided clinicians with CRP interpretation guidance based on the following CRP values: < 20 mg/L, antibiotics are typically not needed; 20 to 40 mg/L, antibiotics might be beneficial if purulent sputum is present; and > 40 mg/L, antibiotics are usually beneficial. Primary outcomes were patient-reported antibiotic use within 4 weeks and COPD-related health status. Of the patients who received a point-of-care CRP test, the median value was 6 mg/L; 76% had a value < 20 mg/L, 12% had values between 20 and 40 mg/L, and 12% had values > 40 mg/L. In the intention-to-treat analysis, fewer patients in the CRP-guided group reported antibiotic use vs those in the usual-care group (57% vs 77%; adjusted odds ratio [aOR] = 0.31; 95% CI, 0.20-0.47) within 4 weeks. The CRP-guided group also received fewer antibiotics at the initial visit compared to the usual-care group (48% vs 70%; aOR = 0.31; 95% CI, 0.21-0.45).

COPD-related health status was assessed with the Clinical COPD Questionnaire (score range, 0-6; a difference of 0.4 represents minimal clinical importance). At 2 weeks, the adjusted mean difference in the total health status score with the use of CRP was noninferior to usual care and was in favor of the CRP-guided group (mean difference = −0.19 points; two-sided 90% CI, −0.33 to −0.05). There was no evidence of clinically important between-group differences in pneumonia (3% vs 4%; aOR = 0.73; 95% CI, 0.29-1.82) at 6-month follow-up. Rates of hospitalization at 6 months were similar between groups (9.3% vs 8.6%; no P value provided).

Fewer patients in the CRPguided group reported antibiotic use vs those in the usual-care group within 4 weeks.

Limitations of this trial included patient report of antibiotic use and the lack of a sham test.

WHAT'S NEW

RCT provides evidence to support use of CRP testing

Point-of-care CRP testing can reduce antibiotic prescribing in patients presenting with a COPD exacerbation without affecting symptom improvement or adverse events.

CAVEATS

CRP testing may not be cost effective

CRP testing—especially point-of-care ­testing—remains expensive in many parts of the United States. A 2015 cost-effectiveness analysis of point-of-care CRP tests for respiratory tract infection in England concluded the cost of the test per patient was not cost effective.¹⁰ It is unknown if point-of-care CRP testing would be cost effective in guiding antibiotic prescribing for ­primary care providers with a focus on COPD exacerbations.

CHALLENGES TO IMPLEMENTATION 

Virtual visits and variable access may limit use

CRP-guided antibiotic prescribing may be challenging in some clinical scenarios or clinics with the rise of virtual visits and differential access in primary care clinics to point-of-care CRP tests. JFP

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health. Copyright © 2021. The Family Physicians Inquiries Network. All rights reserved.

ILLUSTRATIVE CASE

A 45-year-old woman with no chronic medical illness presents to your office for her annual physical examination. After a medical assistant (MA) applies an automatic BP cuff to the patient’s left arm, the BP reading is 155/92 mm Hg. The MA then rechecks the BP, and this time it reads 160/98 mm Hg. The MA performs a manual BP reading, which is 158/90 mm Hg (left arm) and 162/100 mm Hg (right arm). The patient denies any headache, visual changes, chest pain, or difficulty breathing and tells the MA that her BP is always high during a doctor visit. You are wondering if she has hypertension or if is this the white-coat effect.

Depending on the definition of hypertension, its prevalence among US adults 18 years or older varies from 46%, based on the American College of Cardiology guideline (≥ 130/80 mm Hg), to 29%, based on the Eighth Joint National Committee (JNC-8) guideline (≥ 140/90 mm Hg for adults ages 18–59 years and ≥ 150/90 mm Hg for adults ≥ 60 years without diabetes and/or chronic kidney disease).^2,3

According to JNC-8, the prevalence is similar among men (30.2%) and women (27.7%) and increases with age: 18 to 39 years, 7.5%; 40 to 59 years, 33.2%; and ≥ 60 years, 63.1%.^3,4 When ranked by risk-attributable ­disability-adjusted life-years (DALYs), high systolic blood pressure (SBP) is the leading risk factor, accounting for 10.4 million deaths and 218 million DALYs globally in 2017.⁵ National medical costs associated with hypertension are estimated to account for about $131 billion in annual health care expenditures, averaged over 12 years from 2003 to 2014.⁶

When performed correctly, the auscultatory method using a mercury sphygmomanometer correlates well with simultaneous intra-arterial BP and was considered the gold standard for office-based measurements for many years.^7,8 However, significant ­observer-related differences in auditory acuity and terminal digit rounding are sources of inaccurate measurement. White-coat hypertension cannot be detected with this method—another significant limitation. The inaccuracy of office-based BP readings leads to concerns about hypertension being inappropriately diagnosed in patients or delays in diagnosis occurring.⁹

A proposed solution to this problem is measurement using an oscillometric sphygmomanometer. This device uses a pressure transducer to assess the oscillations of pressure in a cuff during gradual deflation; it provides accurate BP measurements when fully automated and programmed to complete several BP measurements at appropriate intervals while the patient rests alone in a quiet room.¹⁰

The accuracy of this new method was tested in a 2009 cohort study of 309 patients referred to an ambulatory blood pressure (ABP) monitoring unit at an academic hospital for diagnosis or management of hypertension.¹¹ The study compared mean awake ABP, which continuously measures patients’ BP throughout the day, manual sphygmomanometer readings taken by the patient’s own physician, and an automated office blood pressure (AOBP) device called BpTRU (an automated oscillometric sphygmomanometer) while the patient rested alone in the exam room.¹¹ The awake ABP is a federally approved standard for the diagnosis of white-coat hypertension.¹² In this study, the white-coat response was negated with the use of the automated BpTRU device.¹¹

A 2019 meta-analysis that included 26 studies (N = 7116) comparing AOBP with other BP measurement techniques concluded that the use of automated oscillometric BP readings is more accurate for diagnosing hypertension and assists in negating the white-coat hypertension effect.⁹

Continue to: STUDY SUMMARY

STUDY SUMMARY

Automated office BP devices are just as accurate as more expensive ABP studies

This systematic review and meta-analysis (N = 9279; 23 cross-sectional, 1 cohort, and 7 randomized controlled trials [N = 1304], of which 17 studies overlapped with those included in the previously mentioned meta-analysis⁹) compared SBP and diastolic blood pressure measured by an oscillometric AOBP device to awake or daytime ABP (continuously monitoring BP while awake, used as a standard for BP measurement), routine manual office BP, or research BP measurements.

The study also explored the protocol by which the best AOBP results could be obtained. For AOBP measurement, the included trials had no more than 2 minutes of elapsed time between individual AOBP measurements and had at least 3 AOBP readings to calculate the mean.

Compared with AOBP, in samples with an SBP of ≥ 130 mm Hg, SBP readings were significantly higher for both routine office visits (mean difference [MD] = 14.5 mm Hg; 95% CI, 11.8–17.2) and research (MD = 7 mm Hg; 95% CI, 4.9–9.1). However, no difference was found between AOBP and awake ambulatory SBP values (MD = 0.3 mm Hg; 95% CI, −1.1 to 1.7). In all cases, heterogeneity of the included studies was high (I² was > 75%). There was no evidence of small-study effect or publication bias, and little evidence of potential financial bias. The most accurate methodology for AOBP measurements included multiple BP readings and the patient resting alone in a quiet location.

This meta-analysis supports the use of an automated office blood pressure device to accurately screen for hypertension and avoid the white-coat effect.

Although there was statistical heterogeneity, the results were confirmed in the authors’ analysis of studies with high methodologic quality. In addition, researchers performed multiple meta-regression analyses to evaluate the statistical heterogeneity and found no significant differences based on age, body mass index, number of treated patients, gender, measurement interval, or added rest before AOBP.

WHAT'S NEW

Study confirms unattended, automated office BP as preferred technique

This is the second recent comprehensive systematic review and meta-analysis to directly compare AOBP with other common techniques of BP measurement in screening for and diagnosing hypertension in the clinical setting. ⁹

Continue to: This meta-analysis...

This meta-analysis emphasized the technique (see below) by which to obtain the best AOBP vs ABP results, whereas the other ­meta-analysis⁹ did not. Thus the study provides practice-based settings with the information they need to more closely replicate the results of the studies included in the meta-analysis.

Also, the equivalency comparison with the more expensive and intrusive ABP monitoring may save money, improve patient adherence, and increase patient satisfaction. Given these advantages, along with its demonstrated accuracy, AOBP should be adopted in routine clinical practice to screen patients for hypertension.

CAVEATS

Close adherence to measurementprocedures is a necessity

Effective use of AOBP in clinical practice requires close adherence to the AOBP study procedures described in this meta-analysis. These include taking multiple (at least 3) BP readings, 1 to 2 minutes apart, recorded with a fully automated oscillometric sphygmomanometer while the patient rests alone in a quiet place.

CHALLENGES TO IMPLEMENTATION

Adjusting workflows, addressing cost

Physicians may be reluctant to adopt this technique because they may not be convinced of its advantages compared with the traditional methods of recording BP and because of difficulties with implementing new rooming workflows.¹² The cost of AOBP devices used in this study (Omron 907 and BpTRU; BpTRU ceased operations in 2017) were not disclosed, which may be a hindrance, as devices may cost $1000 or more.

Effective use of automated office blood pressure requires that one take multiple (at least 3) BP readings, 1 to 2 minutes apart, while the patient rests alone in a quiet place.

An online search for “automated oscillometric BP monitor” by one of the PURL authors (RCM) found oscillometric AOBP devices ranging from $150 to > $1000, depending on whether the device was medical grade; a search for “Omron 907” found devices for ≤ $599 on multiple sites. However, none of the lower-cost devices indicated the ability to take multiple, unattended BP readings.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 45-year-old woman with no chronic medical illness presents to your office for her annual physical examination. After a medical assistant (MA) applies an automatic BP cuff to the patient’s left arm, the BP reading is 155/92 mm Hg. The MA then rechecks the BP, and this time it reads 160/98 mm Hg. The MA performs a manual BP reading, which is 158/90 mm Hg (left arm) and 162/100 mm Hg (right arm). The patient denies any headache, visual changes, chest pain, or difficulty breathing and tells the MA that her BP is always high during a doctor visit. You are wondering if she has hypertension or if is this the white-coat effect.

Depending on the definition of hypertension, its prevalence among US adults 18 years or older varies from 46%, based on the American College of Cardiology guideline (≥ 130/80 mm Hg), to 29%, based on the Eighth Joint National Committee (JNC-8) guideline (≥ 140/90 mm Hg for adults ages 18–59 years and ≥ 150/90 mm Hg for adults ≥ 60 years without diabetes and/or chronic kidney disease).^2,3

According to JNC-8, the prevalence is similar among men (30.2%) and women (27.7%) and increases with age: 18 to 39 years, 7.5%; 40 to 59 years, 33.2%; and ≥ 60 years, 63.1%.^3,4 When ranked by risk-attributable ­disability-adjusted life-years (DALYs), high systolic blood pressure (SBP) is the leading risk factor, accounting for 10.4 million deaths and 218 million DALYs globally in 2017.⁵ National medical costs associated with hypertension are estimated to account for about $131 billion in annual health care expenditures, averaged over 12 years from 2003 to 2014.⁶

When performed correctly, the auscultatory method using a mercury sphygmomanometer correlates well with simultaneous intra-arterial BP and was considered the gold standard for office-based measurements for many years.^7,8 However, significant ­observer-related differences in auditory acuity and terminal digit rounding are sources of inaccurate measurement. White-coat hypertension cannot be detected with this method—another significant limitation. The inaccuracy of office-based BP readings leads to concerns about hypertension being inappropriately diagnosed in patients or delays in diagnosis occurring.⁹

A proposed solution to this problem is measurement using an oscillometric sphygmomanometer. This device uses a pressure transducer to assess the oscillations of pressure in a cuff during gradual deflation; it provides accurate BP measurements when fully automated and programmed to complete several BP measurements at appropriate intervals while the patient rests alone in a quiet room.¹⁰

The accuracy of this new method was tested in a 2009 cohort study of 309 patients referred to an ambulatory blood pressure (ABP) monitoring unit at an academic hospital for diagnosis or management of hypertension.¹¹ The study compared mean awake ABP, which continuously measures patients’ BP throughout the day, manual sphygmomanometer readings taken by the patient’s own physician, and an automated office blood pressure (AOBP) device called BpTRU (an automated oscillometric sphygmomanometer) while the patient rested alone in the exam room.¹¹ The awake ABP is a federally approved standard for the diagnosis of white-coat hypertension.¹² In this study, the white-coat response was negated with the use of the automated BpTRU device.¹¹

A 2019 meta-analysis that included 26 studies (N = 7116) comparing AOBP with other BP measurement techniques concluded that the use of automated oscillometric BP readings is more accurate for diagnosing hypertension and assists in negating the white-coat hypertension effect.⁹

Continue to: STUDY SUMMARY

STUDY SUMMARY

Automated office BP devices are just as accurate as more expensive ABP studies

This systematic review and meta-analysis (N = 9279; 23 cross-sectional, 1 cohort, and 7 randomized controlled trials [N = 1304], of which 17 studies overlapped with those included in the previously mentioned meta-analysis⁹) compared SBP and diastolic blood pressure measured by an oscillometric AOBP device to awake or daytime ABP (continuously monitoring BP while awake, used as a standard for BP measurement), routine manual office BP, or research BP measurements.

The study also explored the protocol by which the best AOBP results could be obtained. For AOBP measurement, the included trials had no more than 2 minutes of elapsed time between individual AOBP measurements and had at least 3 AOBP readings to calculate the mean.

Compared with AOBP, in samples with an SBP of ≥ 130 mm Hg, SBP readings were significantly higher for both routine office visits (mean difference [MD] = 14.5 mm Hg; 95% CI, 11.8–17.2) and research (MD = 7 mm Hg; 95% CI, 4.9–9.1). However, no difference was found between AOBP and awake ambulatory SBP values (MD = 0.3 mm Hg; 95% CI, −1.1 to 1.7). In all cases, heterogeneity of the included studies was high (I² was > 75%). There was no evidence of small-study effect or publication bias, and little evidence of potential financial bias. The most accurate methodology for AOBP measurements included multiple BP readings and the patient resting alone in a quiet location.

This meta-analysis supports the use of an automated office blood pressure device to accurately screen for hypertension and avoid the white-coat effect.

Although there was statistical heterogeneity, the results were confirmed in the authors’ analysis of studies with high methodologic quality. In addition, researchers performed multiple meta-regression analyses to evaluate the statistical heterogeneity and found no significant differences based on age, body mass index, number of treated patients, gender, measurement interval, or added rest before AOBP.

WHAT'S NEW

Study confirms unattended, automated office BP as preferred technique

This is the second recent comprehensive systematic review and meta-analysis to directly compare AOBP with other common techniques of BP measurement in screening for and diagnosing hypertension in the clinical setting. ⁹

Continue to: This meta-analysis...

This meta-analysis emphasized the technique (see below) by which to obtain the best AOBP vs ABP results, whereas the other ­meta-analysis⁹ did not. Thus the study provides practice-based settings with the information they need to more closely replicate the results of the studies included in the meta-analysis.

Also, the equivalency comparison with the more expensive and intrusive ABP monitoring may save money, improve patient adherence, and increase patient satisfaction. Given these advantages, along with its demonstrated accuracy, AOBP should be adopted in routine clinical practice to screen patients for hypertension.

CAVEATS

Close adherence to measurementprocedures is a necessity

Effective use of AOBP in clinical practice requires close adherence to the AOBP study procedures described in this meta-analysis. These include taking multiple (at least 3) BP readings, 1 to 2 minutes apart, recorded with a fully automated oscillometric sphygmomanometer while the patient rests alone in a quiet place.

CHALLENGES TO IMPLEMENTATION

Adjusting workflows, addressing cost

Physicians may be reluctant to adopt this technique because they may not be convinced of its advantages compared with the traditional methods of recording BP and because of difficulties with implementing new rooming workflows.¹² The cost of AOBP devices used in this study (Omron 907 and BpTRU; BpTRU ceased operations in 2017) were not disclosed, which may be a hindrance, as devices may cost $1000 or more.

Effective use of automated office blood pressure requires that one take multiple (at least 3) BP readings, 1 to 2 minutes apart, while the patient rests alone in a quiet place.

An online search for “automated oscillometric BP monitor” by one of the PURL authors (RCM) found oscillometric AOBP devices ranging from $150 to > $1000, depending on whether the device was medical grade; a search for “Omron 907” found devices for ≤ $599 on multiple sites. However, none of the lower-cost devices indicated the ability to take multiple, unattended BP readings.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 45-year-old woman with no chronic medical illness presents to your office for her annual physical examination. After a medical assistant (MA) applies an automatic BP cuff to the patient’s left arm, the BP reading is 155/92 mm Hg. The MA then rechecks the BP, and this time it reads 160/98 mm Hg. The MA performs a manual BP reading, which is 158/90 mm Hg (left arm) and 162/100 mm Hg (right arm). The patient denies any headache, visual changes, chest pain, or difficulty breathing and tells the MA that her BP is always high during a doctor visit. You are wondering if she has hypertension or if is this the white-coat effect.

Depending on the definition of hypertension, its prevalence among US adults 18 years or older varies from 46%, based on the American College of Cardiology guideline (≥ 130/80 mm Hg), to 29%, based on the Eighth Joint National Committee (JNC-8) guideline (≥ 140/90 mm Hg for adults ages 18–59 years and ≥ 150/90 mm Hg for adults ≥ 60 years without diabetes and/or chronic kidney disease).^2,3

According to JNC-8, the prevalence is similar among men (30.2%) and women (27.7%) and increases with age: 18 to 39 years, 7.5%; 40 to 59 years, 33.2%; and ≥ 60 years, 63.1%.^3,4 When ranked by risk-attributable ­disability-adjusted life-years (DALYs), high systolic blood pressure (SBP) is the leading risk factor, accounting for 10.4 million deaths and 218 million DALYs globally in 2017.⁵ National medical costs associated with hypertension are estimated to account for about $131 billion in annual health care expenditures, averaged over 12 years from 2003 to 2014.⁶

When performed correctly, the auscultatory method using a mercury sphygmomanometer correlates well with simultaneous intra-arterial BP and was considered the gold standard for office-based measurements for many years.^7,8 However, significant ­observer-related differences in auditory acuity and terminal digit rounding are sources of inaccurate measurement. White-coat hypertension cannot be detected with this method—another significant limitation. The inaccuracy of office-based BP readings leads to concerns about hypertension being inappropriately diagnosed in patients or delays in diagnosis occurring.⁹

A proposed solution to this problem is measurement using an oscillometric sphygmomanometer. This device uses a pressure transducer to assess the oscillations of pressure in a cuff during gradual deflation; it provides accurate BP measurements when fully automated and programmed to complete several BP measurements at appropriate intervals while the patient rests alone in a quiet room.¹⁰

The accuracy of this new method was tested in a 2009 cohort study of 309 patients referred to an ambulatory blood pressure (ABP) monitoring unit at an academic hospital for diagnosis or management of hypertension.¹¹ The study compared mean awake ABP, which continuously measures patients’ BP throughout the day, manual sphygmomanometer readings taken by the patient’s own physician, and an automated office blood pressure (AOBP) device called BpTRU (an automated oscillometric sphygmomanometer) while the patient rested alone in the exam room.¹¹ The awake ABP is a federally approved standard for the diagnosis of white-coat hypertension.¹² In this study, the white-coat response was negated with the use of the automated BpTRU device.¹¹

A 2019 meta-analysis that included 26 studies (N = 7116) comparing AOBP with other BP measurement techniques concluded that the use of automated oscillometric BP readings is more accurate for diagnosing hypertension and assists in negating the white-coat hypertension effect.⁹

Continue to: STUDY SUMMARY

STUDY SUMMARY

Automated office BP devices are just as accurate as more expensive ABP studies

This systematic review and meta-analysis (N = 9279; 23 cross-sectional, 1 cohort, and 7 randomized controlled trials [N = 1304], of which 17 studies overlapped with those included in the previously mentioned meta-analysis⁹) compared SBP and diastolic blood pressure measured by an oscillometric AOBP device to awake or daytime ABP (continuously monitoring BP while awake, used as a standard for BP measurement), routine manual office BP, or research BP measurements.

The study also explored the protocol by which the best AOBP results could be obtained. For AOBP measurement, the included trials had no more than 2 minutes of elapsed time between individual AOBP measurements and had at least 3 AOBP readings to calculate the mean.

Compared with AOBP, in samples with an SBP of ≥ 130 mm Hg, SBP readings were significantly higher for both routine office visits (mean difference [MD] = 14.5 mm Hg; 95% CI, 11.8–17.2) and research (MD = 7 mm Hg; 95% CI, 4.9–9.1). However, no difference was found between AOBP and awake ambulatory SBP values (MD = 0.3 mm Hg; 95% CI, −1.1 to 1.7). In all cases, heterogeneity of the included studies was high (I² was > 75%). There was no evidence of small-study effect or publication bias, and little evidence of potential financial bias. The most accurate methodology for AOBP measurements included multiple BP readings and the patient resting alone in a quiet location.

This meta-analysis supports the use of an automated office blood pressure device to accurately screen for hypertension and avoid the white-coat effect.

Although there was statistical heterogeneity, the results were confirmed in the authors’ analysis of studies with high methodologic quality. In addition, researchers performed multiple meta-regression analyses to evaluate the statistical heterogeneity and found no significant differences based on age, body mass index, number of treated patients, gender, measurement interval, or added rest before AOBP.

WHAT'S NEW

Study confirms unattended, automated office BP as preferred technique

This is the second recent comprehensive systematic review and meta-analysis to directly compare AOBP with other common techniques of BP measurement in screening for and diagnosing hypertension in the clinical setting. ⁹

Continue to: This meta-analysis...

This meta-analysis emphasized the technique (see below) by which to obtain the best AOBP vs ABP results, whereas the other ­meta-analysis⁹ did not. Thus the study provides practice-based settings with the information they need to more closely replicate the results of the studies included in the meta-analysis.

Also, the equivalency comparison with the more expensive and intrusive ABP monitoring may save money, improve patient adherence, and increase patient satisfaction. Given these advantages, along with its demonstrated accuracy, AOBP should be adopted in routine clinical practice to screen patients for hypertension.

CAVEATS

Close adherence to measurementprocedures is a necessity

Effective use of AOBP in clinical practice requires close adherence to the AOBP study procedures described in this meta-analysis. These include taking multiple (at least 3) BP readings, 1 to 2 minutes apart, recorded with a fully automated oscillometric sphygmomanometer while the patient rests alone in a quiet place.

CHALLENGES TO IMPLEMENTATION

Adjusting workflows, addressing cost

Physicians may be reluctant to adopt this technique because they may not be convinced of its advantages compared with the traditional methods of recording BP and because of difficulties with implementing new rooming workflows.¹² The cost of AOBP devices used in this study (Omron 907 and BpTRU; BpTRU ceased operations in 2017) were not disclosed, which may be a hindrance, as devices may cost $1000 or more.

Effective use of automated office blood pressure requires that one take multiple (at least 3) BP readings, 1 to 2 minutes apart, while the patient rests alone in a quiet place.

An online search for “automated oscillometric BP monitor” by one of the PURL authors (RCM) found oscillometric AOBP devices ranging from $150 to > $1000, depending on whether the device was medical grade; a search for “Omron 907” found devices for ≤ $599 on multiple sites. However, none of the lower-cost devices indicated the ability to take multiple, unattended BP readings.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

An otherwise healthy 56-year-old woman presents to the emergency department (ED) with a productive cough of 4 days’ duration. A review of her history is negative for recurrent upper respiratory infections, smoking, or environmental exposures. Her physical exam is unremarkable and, more specifically, her pulmonary exam and vital signs (temperature, respiratory rate, and heart rate) are within normal limits. The patient states that last year her friend had similar symptoms and was given a diagnosis of pneumonia. Is it necessary to order a chest x-ray in this patient to rule out community-acquired pneumonia (CAP)?

CAP is a common pulmonary condition seen in the outpatient setting in the United States, representing more than 4.5 million outpatient visits in the years 2009 to 2010.² Historically, a diagnosis of CAP has been based on clinical findings in conjunction with infiltrates seen on chest x-ray.

In 2017, more than 5 million visits to the ED were due to a cough.³ The use of radiographic imaging in EDs has been increasing. There were 49 million x-rays and 2.7 million noncardiac chest computed tomography (CT) scans performed in 2016, many of which were for patients with cough.^3,4 Although imaging is an extremely useful tool and indicated in many instances, the ability to rule out CAP in an adult who presents with a cough by using a set of simple, clinically based heuristics without requiring imaging would help to increase efficiency, limit cost, and decrease exposure of patients to unnecessary and potentially harmful diagnostic studies.

Clinical decision rules (CDRs) are simple heuristics that can stratify patients as either high risk or low risk for specific diseases. Two older large, prospective cross-­sectional studies developed CDRs to determine the probability of CAP based on symptoms (eg, night sweats, myalgias, and sputum production) and clinical findings (eg, temperature > 37.8 °C [100 °F], tachypnea, tachycardia, rales, and decreased breath sounds).^5,6 This meta-analysis includes these studies and more recent studies^7-9 used to develop a CDR that focuses solely on a few specific signs and symptoms that can reliably rule out CAP without imaging, and so prove highly useful for busy primary care clinicians.

STUDY SUMMARY

This simple approach rules out CAP in outpatients 99.6% of the time

This systematic review and meta-analysis included studies that used 2 or more signs, symptoms, or point-of-care tests to determine the patient’s risk for CAP.¹ Twelve studies (N = 10,254) met inclusion criteria by applying a CDR to adults or adolescents presenting with respiratory signs or symptoms potentially suggestive of CAP to either an outpatient setting or an ED. Prospective cohort, cross-sectional, and case-control studies were included when a chest x-ray or CT was utilized as the primary reference standard. Exclusion criteria included studies of military or nursing home populations and studies in which the majority of patients had hospital- or ventilator-associated pneumonia or were immunocompromised.

For adult outpatients who present with acute cough, this clinical decision rule can quickly and accurately rule out CAP without the need for diagnostic imaging.

A simple, highly useful CDR emerged from 3 of the studies (N = 1865).^7-9 Two of these studies were described as case-control studies with prospective enrollment of patients older than 17 years in both outpatient and ED settings.^7,8 One study was conducted in the United States (mean age, 65 years) and the other in Iran (mean age, 60 years). The third was a Chilean prospective cohort study of ED patients older than 15 years (mean age, 53 years).⁹ In each of these studies, the outpatient or ED physicians collected all clinical data and documented their physical exam prior to receiving the chest radiograph results. The radiologists were masked to the clinical findings at the time of their interpretation.

Results. From the meta-analysis, a simple CDR emerged for patients with normal vital signs (temperature, respiratory rate, and heart rate) and a normal pulmonary exam that virtually ruled out CAP (sensitivity = 96%; 95% CI, 92%–98%; and negative likelihood ratio = 0.10; 95% CI, 0.07–0.13). In patients presenting to an outpatient clinic with acute cough with a 4% baseline prevalence rate of pneumonia, this CDR ruled out CAP 99.6% of the time.

Continue to: WHAT'S NEW

A clinical decision rule validated for accuracy

This is the first validated CDR that accurately rules out CAP in the outpatient or ED setting using parameters easily obtainable during a clinical exam.

CAVEATS

Proceed with caution in the young and the very old

Two of the 3 studies in this CDR had an overall moderate risk of bias, whereas the third study was determined to be at low risk of bias, based on appraisal with the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) framework.¹⁰

The mean age range in these 3 studies was 53 to 66 years (without further data such as standard deviation), suggesting that application of the CDR to adults who fall at extremes of age should be done with a modicum of caution.

Additionally, although the symptom complex of COVID-19 pneumonia would suggest that this CDR would likely remain accurate today, it has not been validated in patients with COVID-19 infection.

CHALLENGES TO IMPLEMENTATION

Potential reluctance to forgo imaging

Beyond the caveats regarding COVID-19, the use of a simple CDR to reliably exclude pneumonia should have no barrier to implementation in an outpatient primary care setting or ED, although there could be reluctance on the part of both providers and patients to fully embrace this simple tool without a confirmatory chest x-ray.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

An otherwise healthy 56-year-old woman presents to the emergency department (ED) with a productive cough of 4 days’ duration. A review of her history is negative for recurrent upper respiratory infections, smoking, or environmental exposures. Her physical exam is unremarkable and, more specifically, her pulmonary exam and vital signs (temperature, respiratory rate, and heart rate) are within normal limits. The patient states that last year her friend had similar symptoms and was given a diagnosis of pneumonia. Is it necessary to order a chest x-ray in this patient to rule out community-acquired pneumonia (CAP)?

CAP is a common pulmonary condition seen in the outpatient setting in the United States, representing more than 4.5 million outpatient visits in the years 2009 to 2010.² Historically, a diagnosis of CAP has been based on clinical findings in conjunction with infiltrates seen on chest x-ray.

In 2017, more than 5 million visits to the ED were due to a cough.³ The use of radiographic imaging in EDs has been increasing. There were 49 million x-rays and 2.7 million noncardiac chest computed tomography (CT) scans performed in 2016, many of which were for patients with cough.^3,4 Although imaging is an extremely useful tool and indicated in many instances, the ability to rule out CAP in an adult who presents with a cough by using a set of simple, clinically based heuristics without requiring imaging would help to increase efficiency, limit cost, and decrease exposure of patients to unnecessary and potentially harmful diagnostic studies.

Clinical decision rules (CDRs) are simple heuristics that can stratify patients as either high risk or low risk for specific diseases. Two older large, prospective cross-­sectional studies developed CDRs to determine the probability of CAP based on symptoms (eg, night sweats, myalgias, and sputum production) and clinical findings (eg, temperature > 37.8 °C [100 °F], tachypnea, tachycardia, rales, and decreased breath sounds).^5,6 This meta-analysis includes these studies and more recent studies^7-9 used to develop a CDR that focuses solely on a few specific signs and symptoms that can reliably rule out CAP without imaging, and so prove highly useful for busy primary care clinicians.

STUDY SUMMARY

This simple approach rules out CAP in outpatients 99.6% of the time

This systematic review and meta-analysis included studies that used 2 or more signs, symptoms, or point-of-care tests to determine the patient’s risk for CAP.¹ Twelve studies (N = 10,254) met inclusion criteria by applying a CDR to adults or adolescents presenting with respiratory signs or symptoms potentially suggestive of CAP to either an outpatient setting or an ED. Prospective cohort, cross-sectional, and case-control studies were included when a chest x-ray or CT was utilized as the primary reference standard. Exclusion criteria included studies of military or nursing home populations and studies in which the majority of patients had hospital- or ventilator-associated pneumonia or were immunocompromised.

For adult outpatients who present with acute cough, this clinical decision rule can quickly and accurately rule out CAP without the need for diagnostic imaging.

A simple, highly useful CDR emerged from 3 of the studies (N = 1865).^7-9 Two of these studies were described as case-control studies with prospective enrollment of patients older than 17 years in both outpatient and ED settings.^7,8 One study was conducted in the United States (mean age, 65 years) and the other in Iran (mean age, 60 years). The third was a Chilean prospective cohort study of ED patients older than 15 years (mean age, 53 years).⁹ In each of these studies, the outpatient or ED physicians collected all clinical data and documented their physical exam prior to receiving the chest radiograph results. The radiologists were masked to the clinical findings at the time of their interpretation.

Results. From the meta-analysis, a simple CDR emerged for patients with normal vital signs (temperature, respiratory rate, and heart rate) and a normal pulmonary exam that virtually ruled out CAP (sensitivity = 96%; 95% CI, 92%–98%; and negative likelihood ratio = 0.10; 95% CI, 0.07–0.13). In patients presenting to an outpatient clinic with acute cough with a 4% baseline prevalence rate of pneumonia, this CDR ruled out CAP 99.6% of the time.

Continue to: WHAT'S NEW

A clinical decision rule validated for accuracy

This is the first validated CDR that accurately rules out CAP in the outpatient or ED setting using parameters easily obtainable during a clinical exam.

CAVEATS

Proceed with caution in the young and the very old

Two of the 3 studies in this CDR had an overall moderate risk of bias, whereas the third study was determined to be at low risk of bias, based on appraisal with the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) framework.¹⁰

The mean age range in these 3 studies was 53 to 66 years (without further data such as standard deviation), suggesting that application of the CDR to adults who fall at extremes of age should be done with a modicum of caution.

Additionally, although the symptom complex of COVID-19 pneumonia would suggest that this CDR would likely remain accurate today, it has not been validated in patients with COVID-19 infection.

CHALLENGES TO IMPLEMENTATION

Potential reluctance to forgo imaging

Beyond the caveats regarding COVID-19, the use of a simple CDR to reliably exclude pneumonia should have no barrier to implementation in an outpatient primary care setting or ED, although there could be reluctance on the part of both providers and patients to fully embrace this simple tool without a confirmatory chest x-ray.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

An otherwise healthy 56-year-old woman presents to the emergency department (ED) with a productive cough of 4 days’ duration. A review of her history is negative for recurrent upper respiratory infections, smoking, or environmental exposures. Her physical exam is unremarkable and, more specifically, her pulmonary exam and vital signs (temperature, respiratory rate, and heart rate) are within normal limits. The patient states that last year her friend had similar symptoms and was given a diagnosis of pneumonia. Is it necessary to order a chest x-ray in this patient to rule out community-acquired pneumonia (CAP)?

CAP is a common pulmonary condition seen in the outpatient setting in the United States, representing more than 4.5 million outpatient visits in the years 2009 to 2010.² Historically, a diagnosis of CAP has been based on clinical findings in conjunction with infiltrates seen on chest x-ray.

In 2017, more than 5 million visits to the ED were due to a cough.³ The use of radiographic imaging in EDs has been increasing. There were 49 million x-rays and 2.7 million noncardiac chest computed tomography (CT) scans performed in 2016, many of which were for patients with cough.^3,4 Although imaging is an extremely useful tool and indicated in many instances, the ability to rule out CAP in an adult who presents with a cough by using a set of simple, clinically based heuristics without requiring imaging would help to increase efficiency, limit cost, and decrease exposure of patients to unnecessary and potentially harmful diagnostic studies.

Clinical decision rules (CDRs) are simple heuristics that can stratify patients as either high risk or low risk for specific diseases. Two older large, prospective cross-­sectional studies developed CDRs to determine the probability of CAP based on symptoms (eg, night sweats, myalgias, and sputum production) and clinical findings (eg, temperature > 37.8 °C [100 °F], tachypnea, tachycardia, rales, and decreased breath sounds).^5,6 This meta-analysis includes these studies and more recent studies^7-9 used to develop a CDR that focuses solely on a few specific signs and symptoms that can reliably rule out CAP without imaging, and so prove highly useful for busy primary care clinicians.

STUDY SUMMARY

This simple approach rules out CAP in outpatients 99.6% of the time

This systematic review and meta-analysis included studies that used 2 or more signs, symptoms, or point-of-care tests to determine the patient’s risk for CAP.¹ Twelve studies (N = 10,254) met inclusion criteria by applying a CDR to adults or adolescents presenting with respiratory signs or symptoms potentially suggestive of CAP to either an outpatient setting or an ED. Prospective cohort, cross-sectional, and case-control studies were included when a chest x-ray or CT was utilized as the primary reference standard. Exclusion criteria included studies of military or nursing home populations and studies in which the majority of patients had hospital- or ventilator-associated pneumonia or were immunocompromised.

For adult outpatients who present with acute cough, this clinical decision rule can quickly and accurately rule out CAP without the need for diagnostic imaging.

A simple, highly useful CDR emerged from 3 of the studies (N = 1865).^7-9 Two of these studies were described as case-control studies with prospective enrollment of patients older than 17 years in both outpatient and ED settings.^7,8 One study was conducted in the United States (mean age, 65 years) and the other in Iran (mean age, 60 years). The third was a Chilean prospective cohort study of ED patients older than 15 years (mean age, 53 years).⁹ In each of these studies, the outpatient or ED physicians collected all clinical data and documented their physical exam prior to receiving the chest radiograph results. The radiologists were masked to the clinical findings at the time of their interpretation.

Results. From the meta-analysis, a simple CDR emerged for patients with normal vital signs (temperature, respiratory rate, and heart rate) and a normal pulmonary exam that virtually ruled out CAP (sensitivity = 96%; 95% CI, 92%–98%; and negative likelihood ratio = 0.10; 95% CI, 0.07–0.13). In patients presenting to an outpatient clinic with acute cough with a 4% baseline prevalence rate of pneumonia, this CDR ruled out CAP 99.6% of the time.

Continue to: WHAT'S NEW

A clinical decision rule validated for accuracy

This is the first validated CDR that accurately rules out CAP in the outpatient or ED setting using parameters easily obtainable during a clinical exam.

CAVEATS

Proceed with caution in the young and the very old

Two of the 3 studies in this CDR had an overall moderate risk of bias, whereas the third study was determined to be at low risk of bias, based on appraisal with the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS-2) framework.¹⁰

The mean age range in these 3 studies was 53 to 66 years (without further data such as standard deviation), suggesting that application of the CDR to adults who fall at extremes of age should be done with a modicum of caution.

Additionally, although the symptom complex of COVID-19 pneumonia would suggest that this CDR would likely remain accurate today, it has not been validated in patients with COVID-19 infection.

CHALLENGES TO IMPLEMENTATION

Potential reluctance to forgo imaging

Beyond the caveats regarding COVID-19, the use of a simple CDR to reliably exclude pneumonia should have no barrier to implementation in an outpatient primary care setting or ED, although there could be reluctance on the part of both providers and patients to fully embrace this simple tool without a confirmatory chest x-ray.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 37-year-old woman with moderate persistent asthma, controlled on the ICS fluticasone (110 μg twice a day) presents to you for an annual exam. She uses her rescue albuterol inhaler a few times per month. Her last exacerbation was 2 years ago. She has never smoked. She is concerned about continuing to take an ICS every day. What alternative regimen would you recommend for this patient?

According to the Centers for Disease Control and Prevention, asthma affected 24.7 million children and adults in the United States in 2018, accounting for 9.8 million physician visits and 1.6 million emergency department (ED) visits.² The National Institutes of Health (NIH) asthma care guidelines, updated in 2020, recommend a SABA prn as step 1 for intermittent asthma, along with nonpharmacologic management.³ Once a patient has persistent asthma, treatment escalation to step 2 calls for use of daily maintenance inhalers as the preferred treatment option.³

However, the 2020 Global Initiative for Asthma (GINA) warns that an as-needed SABA does not protect patients from severe exacerbations, and regular use of a SABA alone (> 3 inhalers/year) can increase the risk of exacerbations.⁴ A meta-analysis and systematic review from 2018 showed that using an ICS/LABA—scheduled and prn for rescue—had lower risk of asthma exacerbations compared with scheduled ICS/LABA with SABA prn for rescue in patients with ­moderate-to-severe persistent asthma.⁵ Interestingly, the updated 2020 NIH guidelines have adopted this strategy. SABA use prn is no longer recommended for rescue in mild and moderate persistent asthma, and the guidelines now suggest that ICS/LABA be used as rescue in addition to daily medication.³

Although evidence has been mounting for adding the as-needed ICS/LABA for rescue in patients on daily medication, the mainstay has been to provide a SABA prn for rescue use.⁵ Confusing matters more, evidence is emerging that as-needed ICS/LABA for rescue alone in certain patients is safe and effective. The randomized controlled Novel START study, an open-label, parallel-group study, compared ICS/LABA prn vs scheduled ICS with SABA prn vs SABA alone prn in adult patients with intermittent or mild persistent asthma.⁶ ICS/LABA prn prevented more exacerbations and provided better daily control than as-needed SABA alone.⁶ In addition, ICS/LABA as needed resulted in fewer severe exacerbations but potentially poorer daily control than ICS with SABA as needed.⁶

The PRACTICAL study investigated treatment of patients with intermittent, mild persistent, and moderate persistent asthma.¹

STUDY SUMMARY

ICS/LABA prn reduced risk of severe exacerbations

The randomized controlled PRACTICAL study was a 52-week, open-label, parallel-group, superiority trial in New Zealand that compared as-needed ICS/LABA (n = 437) to scheduled ICS plus as-needed SABA (n = 448). Patients were 18 to 75 years old, with a diagnosis of asthma. Applying NIH guideline definitions, these patients would fall into intermittent, mild persistent, or moderate persistent asthma categories, and were on either as-needed SABA alone or a scheduled low- to moderate-dose ICS plus an as-needed SABA in the previous 12 weeks.

Patients on an as-needed SABA prerandomization had to have at least 1 of the following: (1) asthma symptoms or need for a SABA at least twice in the past 4 weeks; (2) at least 1 nighttime awakening due to asthma in the past 4 weeks; or (3) a severe exacerbation requiring oral corticosteroids in the past year. Patients on scheduled ICS plus SABA prn prerandomization were required to have either: (1) low or moderate ICS dosing with partly or well-controlled asthma; or (2) if uncontrolled, poor inhaler technique or adherence.

Continue to: Patients in the ICS/LABA group...

Patients in the ICS/LABA group were given budesonide 200 µg/formoterol 6 µg, 1 puff prn, and patients in the ICS plus as-needed SABA group were given budesonide 200 µg, 1 puff twice daily, and terbutaline 250 µg, 2 puffs prn. All patients received an asthma action plan that provided guidance on when to seek medical care if asthma worsened, as well as a log to note urgent medical visits and use of systemic corticosteroids. A subset of patients had adherence and dosing monitored by electronic inhaler usage monitors. Patients were seen at 0, 4, 16, 28, 40, and 52 weeks.

Outcomes. The primary outcome was the number of severe exacerbations per patient per year, defined as treatment with oral corticosteroids for ≥ 3 days or ED visit or hospital admission requiring systemic corticosteroids. Among the secondary outcomes were number of moderate and severe exacerbations per patient per year (defined as an unplanned medical visit: primary care, ED, hospital admission, and any duration of steroids); time to first severe exacerbation; assessment with the Asthma Control Questionnaire (ACQ-5); adverse outcomes; and quantity of ICS used (analysis done only for the subset with electronic inhaler monitoring).

This study represents a compelling, real-world look at emerging asthma recommendations.

ACQ-5 takes the mean of 5 questions assessing asthma control in the previous week, with each question ranging from 0 (no impairment) to 6 (maximum impairment). The statistician was blinded to the primary outcome.

Results. The rate of severe exacerbations per patient per year was 0.119 in the as-needed ICS/LABA group vs 0.172 in the scheduled ICS plus as-needed SABA group (relative rate [RR] = 0.69; 95% confidence interval [CI], 0.48–1.00). Time to first severe asthma exacerbation was longer in the as-needed ICS/LABA group (hazard ratio = 0.60; 95% CI, 0.40–0.91). The rate of moderate and severe exacerbations per patient per year was lower in the as-needed ICS/LABA group: 0.165 vs 0.237 (RR = 0.70; 95% CI, 0.51–0.95).

ACQ-5 scores were similar at all time points (mean difference = 0.07; 95% CI, –0.03 to 0.17). Adverse events were similar between groups (most commonly nasopharyngitis in both groups). Less ICS was used in the ICS/LABA group (difference = –126.5 µg per day; 95% CI, –171.0 to –81.9).

Continue to: WHAT'S NEW

WHAT’S NEW

Study lends support to recent recommendations

This study represents a compelling, real-world look at emerging asthma recommendations. This was the first comprehensive study to show that as-needed ICS/LABA therapy prevents more moderate and severe exacerbations and lengthens the time to first severe exacerbation, compared with scheduled ICS plus SABA prn in intermittent, mild persistent, or moderate persistent asthma. These data have been incorporated into the GINA guidelines, which recommend ICS/LABA prn for step 2.

CAVEATS

Potential bias in study design

The LABA used in this study was formoterol, which has a quicker onset than other LABAs. It is likely that not all LABAs can be used the same way, and both the NIH and GINA guidelines call it out specifically. Additionally, the study’s open-label design can introduce bias but may be the only way to simulate the real-world actions of our patients. Prior studies used placebo inhalers to keep participants and providers blinded but then could not capitalize on the behavior of using only an inhaler prn (as with the ICS/LABA of this study). Finally, there is discordance between the NIH and GINA asthma guidelines on how to use these data.

CHALLENGES TO IMPLEMENTATION

Cost of ICS/LABA may limit its use

Cost is the largest barrier to implementation. Budesonide costs 6 to 10 times more than albuterol per inhaler (retail price of $281-$427 vs $17-$92, respectively).^7,8 However, cost differences are likely negated for patients already on a maintenance inhaler.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 37-year-old woman with moderate persistent asthma, controlled on the ICS fluticasone (110 μg twice a day) presents to you for an annual exam. She uses her rescue albuterol inhaler a few times per month. Her last exacerbation was 2 years ago. She has never smoked. She is concerned about continuing to take an ICS every day. What alternative regimen would you recommend for this patient?

According to the Centers for Disease Control and Prevention, asthma affected 24.7 million children and adults in the United States in 2018, accounting for 9.8 million physician visits and 1.6 million emergency department (ED) visits.² The National Institutes of Health (NIH) asthma care guidelines, updated in 2020, recommend a SABA prn as step 1 for intermittent asthma, along with nonpharmacologic management.³ Once a patient has persistent asthma, treatment escalation to step 2 calls for use of daily maintenance inhalers as the preferred treatment option.³

However, the 2020 Global Initiative for Asthma (GINA) warns that an as-needed SABA does not protect patients from severe exacerbations, and regular use of a SABA alone (> 3 inhalers/year) can increase the risk of exacerbations.⁴ A meta-analysis and systematic review from 2018 showed that using an ICS/LABA—scheduled and prn for rescue—had lower risk of asthma exacerbations compared with scheduled ICS/LABA with SABA prn for rescue in patients with ­moderate-to-severe persistent asthma.⁵ Interestingly, the updated 2020 NIH guidelines have adopted this strategy. SABA use prn is no longer recommended for rescue in mild and moderate persistent asthma, and the guidelines now suggest that ICS/LABA be used as rescue in addition to daily medication.³

Although evidence has been mounting for adding the as-needed ICS/LABA for rescue in patients on daily medication, the mainstay has been to provide a SABA prn for rescue use.⁵ Confusing matters more, evidence is emerging that as-needed ICS/LABA for rescue alone in certain patients is safe and effective. The randomized controlled Novel START study, an open-label, parallel-group study, compared ICS/LABA prn vs scheduled ICS with SABA prn vs SABA alone prn in adult patients with intermittent or mild persistent asthma.⁶ ICS/LABA prn prevented more exacerbations and provided better daily control than as-needed SABA alone.⁶ In addition, ICS/LABA as needed resulted in fewer severe exacerbations but potentially poorer daily control than ICS with SABA as needed.⁶

The PRACTICAL study investigated treatment of patients with intermittent, mild persistent, and moderate persistent asthma.¹

STUDY SUMMARY

ICS/LABA prn reduced risk of severe exacerbations

The randomized controlled PRACTICAL study was a 52-week, open-label, parallel-group, superiority trial in New Zealand that compared as-needed ICS/LABA (n = 437) to scheduled ICS plus as-needed SABA (n = 448). Patients were 18 to 75 years old, with a diagnosis of asthma. Applying NIH guideline definitions, these patients would fall into intermittent, mild persistent, or moderate persistent asthma categories, and were on either as-needed SABA alone or a scheduled low- to moderate-dose ICS plus an as-needed SABA in the previous 12 weeks.

Patients on an as-needed SABA prerandomization had to have at least 1 of the following: (1) asthma symptoms or need for a SABA at least twice in the past 4 weeks; (2) at least 1 nighttime awakening due to asthma in the past 4 weeks; or (3) a severe exacerbation requiring oral corticosteroids in the past year. Patients on scheduled ICS plus SABA prn prerandomization were required to have either: (1) low or moderate ICS dosing with partly or well-controlled asthma; or (2) if uncontrolled, poor inhaler technique or adherence.

Continue to: Patients in the ICS/LABA group...

Patients in the ICS/LABA group were given budesonide 200 µg/formoterol 6 µg, 1 puff prn, and patients in the ICS plus as-needed SABA group were given budesonide 200 µg, 1 puff twice daily, and terbutaline 250 µg, 2 puffs prn. All patients received an asthma action plan that provided guidance on when to seek medical care if asthma worsened, as well as a log to note urgent medical visits and use of systemic corticosteroids. A subset of patients had adherence and dosing monitored by electronic inhaler usage monitors. Patients were seen at 0, 4, 16, 28, 40, and 52 weeks.

Outcomes. The primary outcome was the number of severe exacerbations per patient per year, defined as treatment with oral corticosteroids for ≥ 3 days or ED visit or hospital admission requiring systemic corticosteroids. Among the secondary outcomes were number of moderate and severe exacerbations per patient per year (defined as an unplanned medical visit: primary care, ED, hospital admission, and any duration of steroids); time to first severe exacerbation; assessment with the Asthma Control Questionnaire (ACQ-5); adverse outcomes; and quantity of ICS used (analysis done only for the subset with electronic inhaler monitoring).

This study represents a compelling, real-world look at emerging asthma recommendations.

ACQ-5 takes the mean of 5 questions assessing asthma control in the previous week, with each question ranging from 0 (no impairment) to 6 (maximum impairment). The statistician was blinded to the primary outcome.

Results. The rate of severe exacerbations per patient per year was 0.119 in the as-needed ICS/LABA group vs 0.172 in the scheduled ICS plus as-needed SABA group (relative rate [RR] = 0.69; 95% confidence interval [CI], 0.48–1.00). Time to first severe asthma exacerbation was longer in the as-needed ICS/LABA group (hazard ratio = 0.60; 95% CI, 0.40–0.91). The rate of moderate and severe exacerbations per patient per year was lower in the as-needed ICS/LABA group: 0.165 vs 0.237 (RR = 0.70; 95% CI, 0.51–0.95).

ACQ-5 scores were similar at all time points (mean difference = 0.07; 95% CI, –0.03 to 0.17). Adverse events were similar between groups (most commonly nasopharyngitis in both groups). Less ICS was used in the ICS/LABA group (difference = –126.5 µg per day; 95% CI, –171.0 to –81.9).

Continue to: WHAT'S NEW

WHAT’S NEW

Study lends support to recent recommendations

This study represents a compelling, real-world look at emerging asthma recommendations. This was the first comprehensive study to show that as-needed ICS/LABA therapy prevents more moderate and severe exacerbations and lengthens the time to first severe exacerbation, compared with scheduled ICS plus SABA prn in intermittent, mild persistent, or moderate persistent asthma. These data have been incorporated into the GINA guidelines, which recommend ICS/LABA prn for step 2.

CAVEATS

Potential bias in study design

The LABA used in this study was formoterol, which has a quicker onset than other LABAs. It is likely that not all LABAs can be used the same way, and both the NIH and GINA guidelines call it out specifically. Additionally, the study’s open-label design can introduce bias but may be the only way to simulate the real-world actions of our patients. Prior studies used placebo inhalers to keep participants and providers blinded but then could not capitalize on the behavior of using only an inhaler prn (as with the ICS/LABA of this study). Finally, there is discordance between the NIH and GINA asthma guidelines on how to use these data.

CHALLENGES TO IMPLEMENTATION

Cost of ICS/LABA may limit its use

Cost is the largest barrier to implementation. Budesonide costs 6 to 10 times more than albuterol per inhaler (retail price of $281-$427 vs $17-$92, respectively).^7,8 However, cost differences are likely negated for patients already on a maintenance inhaler.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 37-year-old woman with moderate persistent asthma, controlled on the ICS fluticasone (110 μg twice a day) presents to you for an annual exam. She uses her rescue albuterol inhaler a few times per month. Her last exacerbation was 2 years ago. She has never smoked. She is concerned about continuing to take an ICS every day. What alternative regimen would you recommend for this patient?

According to the Centers for Disease Control and Prevention, asthma affected 24.7 million children and adults in the United States in 2018, accounting for 9.8 million physician visits and 1.6 million emergency department (ED) visits.² The National Institutes of Health (NIH) asthma care guidelines, updated in 2020, recommend a SABA prn as step 1 for intermittent asthma, along with nonpharmacologic management.³ Once a patient has persistent asthma, treatment escalation to step 2 calls for use of daily maintenance inhalers as the preferred treatment option.³

However, the 2020 Global Initiative for Asthma (GINA) warns that an as-needed SABA does not protect patients from severe exacerbations, and regular use of a SABA alone (> 3 inhalers/year) can increase the risk of exacerbations.⁴ A meta-analysis and systematic review from 2018 showed that using an ICS/LABA—scheduled and prn for rescue—had lower risk of asthma exacerbations compared with scheduled ICS/LABA with SABA prn for rescue in patients with ­moderate-to-severe persistent asthma.⁵ Interestingly, the updated 2020 NIH guidelines have adopted this strategy. SABA use prn is no longer recommended for rescue in mild and moderate persistent asthma, and the guidelines now suggest that ICS/LABA be used as rescue in addition to daily medication.³

Although evidence has been mounting for adding the as-needed ICS/LABA for rescue in patients on daily medication, the mainstay has been to provide a SABA prn for rescue use.⁵ Confusing matters more, evidence is emerging that as-needed ICS/LABA for rescue alone in certain patients is safe and effective. The randomized controlled Novel START study, an open-label, parallel-group study, compared ICS/LABA prn vs scheduled ICS with SABA prn vs SABA alone prn in adult patients with intermittent or mild persistent asthma.⁶ ICS/LABA prn prevented more exacerbations and provided better daily control than as-needed SABA alone.⁶ In addition, ICS/LABA as needed resulted in fewer severe exacerbations but potentially poorer daily control than ICS with SABA as needed.⁶

The PRACTICAL study investigated treatment of patients with intermittent, mild persistent, and moderate persistent asthma.¹

STUDY SUMMARY

ICS/LABA prn reduced risk of severe exacerbations

The randomized controlled PRACTICAL study was a 52-week, open-label, parallel-group, superiority trial in New Zealand that compared as-needed ICS/LABA (n = 437) to scheduled ICS plus as-needed SABA (n = 448). Patients were 18 to 75 years old, with a diagnosis of asthma. Applying NIH guideline definitions, these patients would fall into intermittent, mild persistent, or moderate persistent asthma categories, and were on either as-needed SABA alone or a scheduled low- to moderate-dose ICS plus an as-needed SABA in the previous 12 weeks.

Patients on an as-needed SABA prerandomization had to have at least 1 of the following: (1) asthma symptoms or need for a SABA at least twice in the past 4 weeks; (2) at least 1 nighttime awakening due to asthma in the past 4 weeks; or (3) a severe exacerbation requiring oral corticosteroids in the past year. Patients on scheduled ICS plus SABA prn prerandomization were required to have either: (1) low or moderate ICS dosing with partly or well-controlled asthma; or (2) if uncontrolled, poor inhaler technique or adherence.

Continue to: Patients in the ICS/LABA group...

Patients in the ICS/LABA group were given budesonide 200 µg/formoterol 6 µg, 1 puff prn, and patients in the ICS plus as-needed SABA group were given budesonide 200 µg, 1 puff twice daily, and terbutaline 250 µg, 2 puffs prn. All patients received an asthma action plan that provided guidance on when to seek medical care if asthma worsened, as well as a log to note urgent medical visits and use of systemic corticosteroids. A subset of patients had adherence and dosing monitored by electronic inhaler usage monitors. Patients were seen at 0, 4, 16, 28, 40, and 52 weeks.

Outcomes. The primary outcome was the number of severe exacerbations per patient per year, defined as treatment with oral corticosteroids for ≥ 3 days or ED visit or hospital admission requiring systemic corticosteroids. Among the secondary outcomes were number of moderate and severe exacerbations per patient per year (defined as an unplanned medical visit: primary care, ED, hospital admission, and any duration of steroids); time to first severe exacerbation; assessment with the Asthma Control Questionnaire (ACQ-5); adverse outcomes; and quantity of ICS used (analysis done only for the subset with electronic inhaler monitoring).

This study represents a compelling, real-world look at emerging asthma recommendations.

ACQ-5 takes the mean of 5 questions assessing asthma control in the previous week, with each question ranging from 0 (no impairment) to 6 (maximum impairment). The statistician was blinded to the primary outcome.

Results. The rate of severe exacerbations per patient per year was 0.119 in the as-needed ICS/LABA group vs 0.172 in the scheduled ICS plus as-needed SABA group (relative rate [RR] = 0.69; 95% confidence interval [CI], 0.48–1.00). Time to first severe asthma exacerbation was longer in the as-needed ICS/LABA group (hazard ratio = 0.60; 95% CI, 0.40–0.91). The rate of moderate and severe exacerbations per patient per year was lower in the as-needed ICS/LABA group: 0.165 vs 0.237 (RR = 0.70; 95% CI, 0.51–0.95).

ACQ-5 scores were similar at all time points (mean difference = 0.07; 95% CI, –0.03 to 0.17). Adverse events were similar between groups (most commonly nasopharyngitis in both groups). Less ICS was used in the ICS/LABA group (difference = –126.5 µg per day; 95% CI, –171.0 to –81.9).

Continue to: WHAT'S NEW

WHAT’S NEW

Study lends support to recent recommendations

This study represents a compelling, real-world look at emerging asthma recommendations. This was the first comprehensive study to show that as-needed ICS/LABA therapy prevents more moderate and severe exacerbations and lengthens the time to first severe exacerbation, compared with scheduled ICS plus SABA prn in intermittent, mild persistent, or moderate persistent asthma. These data have been incorporated into the GINA guidelines, which recommend ICS/LABA prn for step 2.

CAVEATS

Potential bias in study design

The LABA used in this study was formoterol, which has a quicker onset than other LABAs. It is likely that not all LABAs can be used the same way, and both the NIH and GINA guidelines call it out specifically. Additionally, the study’s open-label design can introduce bias but may be the only way to simulate the real-world actions of our patients. Prior studies used placebo inhalers to keep participants and providers blinded but then could not capitalize on the behavior of using only an inhaler prn (as with the ICS/LABA of this study). Finally, there is discordance between the NIH and GINA asthma guidelines on how to use these data.

CHALLENGES TO IMPLEMENTATION

Cost of ICS/LABA may limit its use

Cost is the largest barrier to implementation. Budesonide costs 6 to 10 times more than albuterol per inhaler (retail price of $281-$427 vs $17-$92, respectively).^7,8 However, cost differences are likely negated for patients already on a maintenance inhaler.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.