PURLs

ILLUSTRATIVE CASE

A 55-year-old man is brought to the emergency department with shortness of breath, pleuritic chest pain, and hypoxia shortly after returning from an overseas business trip. High-resolution spiral computed tomography (CT) reveals a PE.

How should he be treated?

Pulmonary embolism (PE) is fairly common—with an annual incidence estimated at 69 per 100,000²—and the cause of significant morbidity and mortality. Up to 30% of patients with venous thromboembolism (VTE) die within a month of diagnosis, mostly from PE, and in about 25% of cases, PE presents as sudden death.³

Warfarin has a significant downside
Standard therapy consists of either unfractionated heparin or LMWH followed by warfarin, a vitamin K antagonist (VKA), for ≥3 months.⁴ In addition to requiring frequent laboratory monitoring, warfarin has potentially significant interactions with many prescription drugs. Numerous trials have investigated novel anticoagulants for treatment of VTE in recent years. In one randomized controlled trial (RCT), rivaroxaban (Xarelto)was found to be noninferior to a VKA for treating acute deep vein thrombosis (DVT).⁵

STUDY SUMMARY: Major bleeding is less likely with rivaroxaban

The EINSTEIN PE investigators conducted a randomized, unblinded noninferiority trial to determine whether rivaroxaban was at least as effective as the standard therapy—enoxaparin, followed by a dose-adjusted VKA (warfarin [for US patients] or acenocoumarol) for acute symptomatic PE.¹ To be included, participants had to have PE confirmed by CT, ventilation perfusion scan, or pulmonary angiography, with or without accompanying DVT. Exclusion criteria included active bleeding, significant renal impairment (creatinine clearance <30 mL/min), >48 hours of heparin treatment, or more than one dose of a VKA.

Participants (N=4832 in 38 countries) were randomized to receive either rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once a day thereafter) or standard therapy. The intervention and control groups were similar. Just over half were male, with an average age of 58 years; three-quarters of the patients had an intermediate to extensive PE burden; and 90% were hospitalized for initial treatment. The researchers listed the etiology as unprovoked in 64% of the cases, followed by recent surgery or trauma and immobilization (17% and 16%, respectively).

After VKA initiation, the international normalized ratio (INR) was checked at least monthly. Patients in the control groups were within the target range (INR 1-2) 62% of the time, which is similar to other studies of anticoagulation in patients with VTE. Adherence to rivaroxaban was at least 80% in more than 94% of patients. Treatment lasted 3, 6, or 12 months, with the duration determined before randomization by the treating physician.

There was no difference in dropout rates (10.7% of rivaroxaban patients withdrew for any reason, vs 12.3% of the controls). Fewer than 0.5% of participants were lost to follow-up.

Symptomatic recurrent VTE, the primary outcome, occurred in 50 patients receiving rivaroxaban vs 44 of those on standard therapy (2.1% vs 1.8%; P=.003 for noninferiority using an intention-to-treat analysis). Major bleeding, defined as overt bleeding causing death, a drop in hemoglobin of ≥2 points, needing a transfusion, or bleeding in a critical site, occurred less often in the rivaroxaban group (1.1% vs 2.2%, P=.003, NNT=91). There was no significant difference in overall bleeding rates between the 2 groups.¹

WHAT’S NEW: Rivaroxaban is easier to use—and on label

This trial found rivaroxaban to be at least as effective as enoxaparin followed by a dose-adjusted VKA for acute symptomatic PE, with fewer major bleeding events. What’s more, rivaroxaban—which now has US Food and Drug Administration approval for the prevention and treatment of PE and DVT⁶—does not require laboratory monitoring.

CAVEATS: Questions about study population, duration remain

This was an open-label study—neither patients nor investigators were blinded to the group assignments after randomization. The investigators suspected more recurrent VTE in those receiving rivaroxaban, which could have biased their findings in favor of the standard treatment. However, actual rates of recurrence were similar.

Study participants were <60 years old, on average, which may limit extrapolation to an older population. This trial lasted 12 months; the effects of longer treatment with rivaroxaban are unknown. Bayer HealthCare and Janssen Pharmaceuticals, who jointly manufacture rivaroxaban, funded the study.

CHALLENGES TO IMPLEMENTATION: Cost and lack of antidote may limit use

Rivaroxaban is more expensive than warfarin: A one-month supply costs approximately $260, while a month’s supply of warfarin plus lab monitoring runs less than $100.⁷ What’s more, factor Xa inhibitors, unlike VKAs, do not have a readily available pharmacologic antidote.

Acknowledgement

The PURLs Surveillance System is 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 is brought to the emergency department with shortness of breath, pleuritic chest pain, and hypoxia shortly after returning from an overseas business trip. High-resolution spiral computed tomography (CT) reveals a PE.

How should he be treated?

Pulmonary embolism (PE) is fairly common—with an annual incidence estimated at 69 per 100,000²—and the cause of significant morbidity and mortality. Up to 30% of patients with venous thromboembolism (VTE) die within a month of diagnosis, mostly from PE, and in about 25% of cases, PE presents as sudden death.³

Warfarin has a significant downside
Standard therapy consists of either unfractionated heparin or LMWH followed by warfarin, a vitamin K antagonist (VKA), for ≥3 months.⁴ In addition to requiring frequent laboratory monitoring, warfarin has potentially significant interactions with many prescription drugs. Numerous trials have investigated novel anticoagulants for treatment of VTE in recent years. In one randomized controlled trial (RCT), rivaroxaban (Xarelto)was found to be noninferior to a VKA for treating acute deep vein thrombosis (DVT).⁵

STUDY SUMMARY: Major bleeding is less likely with rivaroxaban

The EINSTEIN PE investigators conducted a randomized, unblinded noninferiority trial to determine whether rivaroxaban was at least as effective as the standard therapy—enoxaparin, followed by a dose-adjusted VKA (warfarin [for US patients] or acenocoumarol) for acute symptomatic PE.¹ To be included, participants had to have PE confirmed by CT, ventilation perfusion scan, or pulmonary angiography, with or without accompanying DVT. Exclusion criteria included active bleeding, significant renal impairment (creatinine clearance <30 mL/min), >48 hours of heparin treatment, or more than one dose of a VKA.

Participants (N=4832 in 38 countries) were randomized to receive either rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once a day thereafter) or standard therapy. The intervention and control groups were similar. Just over half were male, with an average age of 58 years; three-quarters of the patients had an intermediate to extensive PE burden; and 90% were hospitalized for initial treatment. The researchers listed the etiology as unprovoked in 64% of the cases, followed by recent surgery or trauma and immobilization (17% and 16%, respectively).

After VKA initiation, the international normalized ratio (INR) was checked at least monthly. Patients in the control groups were within the target range (INR 1-2) 62% of the time, which is similar to other studies of anticoagulation in patients with VTE. Adherence to rivaroxaban was at least 80% in more than 94% of patients. Treatment lasted 3, 6, or 12 months, with the duration determined before randomization by the treating physician.

There was no difference in dropout rates (10.7% of rivaroxaban patients withdrew for any reason, vs 12.3% of the controls). Fewer than 0.5% of participants were lost to follow-up.

Symptomatic recurrent VTE, the primary outcome, occurred in 50 patients receiving rivaroxaban vs 44 of those on standard therapy (2.1% vs 1.8%; P=.003 for noninferiority using an intention-to-treat analysis). Major bleeding, defined as overt bleeding causing death, a drop in hemoglobin of ≥2 points, needing a transfusion, or bleeding in a critical site, occurred less often in the rivaroxaban group (1.1% vs 2.2%, P=.003, NNT=91). There was no significant difference in overall bleeding rates between the 2 groups.¹

WHAT’S NEW: Rivaroxaban is easier to use—and on label

This trial found rivaroxaban to be at least as effective as enoxaparin followed by a dose-adjusted VKA for acute symptomatic PE, with fewer major bleeding events. What’s more, rivaroxaban—which now has US Food and Drug Administration approval for the prevention and treatment of PE and DVT⁶—does not require laboratory monitoring.

CAVEATS: Questions about study population, duration remain

This was an open-label study—neither patients nor investigators were blinded to the group assignments after randomization. The investigators suspected more recurrent VTE in those receiving rivaroxaban, which could have biased their findings in favor of the standard treatment. However, actual rates of recurrence were similar.

Study participants were <60 years old, on average, which may limit extrapolation to an older population. This trial lasted 12 months; the effects of longer treatment with rivaroxaban are unknown. Bayer HealthCare and Janssen Pharmaceuticals, who jointly manufacture rivaroxaban, funded the study.

CHALLENGES TO IMPLEMENTATION: Cost and lack of antidote may limit use

Rivaroxaban is more expensive than warfarin: A one-month supply costs approximately $260, while a month’s supply of warfarin plus lab monitoring runs less than $100.⁷ What’s more, factor Xa inhibitors, unlike VKAs, do not have a readily available pharmacologic antidote.

Acknowledgement

The PURLs Surveillance System is 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 is brought to the emergency department with shortness of breath, pleuritic chest pain, and hypoxia shortly after returning from an overseas business trip. High-resolution spiral computed tomography (CT) reveals a PE.

How should he be treated?

Pulmonary embolism (PE) is fairly common—with an annual incidence estimated at 69 per 100,000²—and the cause of significant morbidity and mortality. Up to 30% of patients with venous thromboembolism (VTE) die within a month of diagnosis, mostly from PE, and in about 25% of cases, PE presents as sudden death.³

Warfarin has a significant downside
Standard therapy consists of either unfractionated heparin or LMWH followed by warfarin, a vitamin K antagonist (VKA), for ≥3 months.⁴ In addition to requiring frequent laboratory monitoring, warfarin has potentially significant interactions with many prescription drugs. Numerous trials have investigated novel anticoagulants for treatment of VTE in recent years. In one randomized controlled trial (RCT), rivaroxaban (Xarelto)was found to be noninferior to a VKA for treating acute deep vein thrombosis (DVT).⁵

STUDY SUMMARY: Major bleeding is less likely with rivaroxaban

The EINSTEIN PE investigators conducted a randomized, unblinded noninferiority trial to determine whether rivaroxaban was at least as effective as the standard therapy—enoxaparin, followed by a dose-adjusted VKA (warfarin [for US patients] or acenocoumarol) for acute symptomatic PE.¹ To be included, participants had to have PE confirmed by CT, ventilation perfusion scan, or pulmonary angiography, with or without accompanying DVT. Exclusion criteria included active bleeding, significant renal impairment (creatinine clearance <30 mL/min), >48 hours of heparin treatment, or more than one dose of a VKA.

Participants (N=4832 in 38 countries) were randomized to receive either rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once a day thereafter) or standard therapy. The intervention and control groups were similar. Just over half were male, with an average age of 58 years; three-quarters of the patients had an intermediate to extensive PE burden; and 90% were hospitalized for initial treatment. The researchers listed the etiology as unprovoked in 64% of the cases, followed by recent surgery or trauma and immobilization (17% and 16%, respectively).

After VKA initiation, the international normalized ratio (INR) was checked at least monthly. Patients in the control groups were within the target range (INR 1-2) 62% of the time, which is similar to other studies of anticoagulation in patients with VTE. Adherence to rivaroxaban was at least 80% in more than 94% of patients. Treatment lasted 3, 6, or 12 months, with the duration determined before randomization by the treating physician.

There was no difference in dropout rates (10.7% of rivaroxaban patients withdrew for any reason, vs 12.3% of the controls). Fewer than 0.5% of participants were lost to follow-up.

Symptomatic recurrent VTE, the primary outcome, occurred in 50 patients receiving rivaroxaban vs 44 of those on standard therapy (2.1% vs 1.8%; P=.003 for noninferiority using an intention-to-treat analysis). Major bleeding, defined as overt bleeding causing death, a drop in hemoglobin of ≥2 points, needing a transfusion, or bleeding in a critical site, occurred less often in the rivaroxaban group (1.1% vs 2.2%, P=.003, NNT=91). There was no significant difference in overall bleeding rates between the 2 groups.¹

WHAT’S NEW: Rivaroxaban is easier to use—and on label

This trial found rivaroxaban to be at least as effective as enoxaparin followed by a dose-adjusted VKA for acute symptomatic PE, with fewer major bleeding events. What’s more, rivaroxaban—which now has US Food and Drug Administration approval for the prevention and treatment of PE and DVT⁶—does not require laboratory monitoring.

CAVEATS: Questions about study population, duration remain

This was an open-label study—neither patients nor investigators were blinded to the group assignments after randomization. The investigators suspected more recurrent VTE in those receiving rivaroxaban, which could have biased their findings in favor of the standard treatment. However, actual rates of recurrence were similar.

Study participants were <60 years old, on average, which may limit extrapolation to an older population. This trial lasted 12 months; the effects of longer treatment with rivaroxaban are unknown. Bayer HealthCare and Janssen Pharmaceuticals, who jointly manufacture rivaroxaban, funded the study.

CHALLENGES TO IMPLEMENTATION: Cost and lack of antidote may limit use

Rivaroxaban is more expensive than warfarin: A one-month supply costs approximately $260, while a month’s supply of warfarin plus lab monitoring runs less than $100.⁷ What’s more, factor Xa inhibitors, unlike VKAs, do not have a readily available pharmacologic antidote.

Acknowledgement

The PURLs Surveillance System is 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 62-year-old patient comes to your office for follow-up of a primary unprovoked venous thromboembolus. He has been on an oral anticoagulant for 12 months. Should he continue anticoagulation therapy despite the increased risk for major bleeding?

Patients who survive VTE—defined as either deep venous thrombosis or pulmonary embolism—are put on anticoagulant therapy to prevent a recurrence, typically for 6 to 18 months. But about 20% of patients with unprovoked VTE have a recurrence within 2 years of anticoagulation withdrawal.² Extending anticoagulation prevents recurrences but increases the risk of bleeding.³

Is aspirin a viable alternative?
Until recently, the efficacy of aspirin for the prevention of recurrent VTE was unknown. Becattini et al investigated it in the multicenter RCT detailed in this PURL.

STUDY SUMMARY: Aspirin can prevent recurrence with minimal risk

To determine whether aspirin was a viable alternative to oral anticoagulation, the researchers compared aspirin with placebo in patients with primary unprovoked VTE who had completed a course of oral anticoagulation treatment. To be considered for the study, patients had to be >18 years and have had their first-ever objectively confirmed, symptomatic unprovoked proximal deep vein thrombosis, pulmonary embolism, or both. They also had to have completed 6 to 18 months of anticoagulant therapy, with a target international normalized ratio (INR) of 2.0 to 3.0. Exclusion criteria included a history of cancer, clinically significant thrombophilia, atrial fibrillation, and a bleeding event that occurred during the course of anticoagulation therapy.

Becattini et al identified 403 eligible patients. Two weeks after stopping anticoagulation, patients were randomly assigned to receive either aspirin 100 mg once daily (n=205) or placebo (n=198) for 2 years. (One patient in the placebo group never received treatment.) At baseline, there were no significant differences in patient characteristics. All were evaluated every 3 months in the first year and every 6 months in the second year.

The primary efficacy outcome was objectively confirmed recurrent VTE. The primary safety outcome was major bleeding, defined as bleeding that occurred in a critical location (eg, intracranial bleeding), was associated with a decrease of hemoglobin of at least 2 g/dL, required a transfusion of 2 units of whole blood or red blood cells, or was fatal. Overt bleeding, which required medical intervention but did not meet the criteria for major bleeding, was a secondary safety outcome.

Twenty-eight of the 205 patients in the aspirin group experienced a recurrence, compared with 43 of the 197 patients on placebo (6.6% vs. 11.2% per year; hazard ratio [HR]=0.58; 95% confidence interval [CI], 0.36-0.93; P=.02). Adverse events were reported by 7 patients in the aspirin therapy group and 6 in the placebo group. One patient in each group experienced major bleeding, and 3 in each group experienced clinically relevant but nonmajor bleeding. Withdrawal rates were similar (10 in the treatment group vs 9 controls), as were the number of patients who developed new indications for aspirin or anticoagulation therapy or were lost to follow-up.

An analysis adjusted for age, sex, index event (deep vein thrombosis or pulmonary embolism), and duration of initial anticoagulation treatment confirmed that aspirin reduced the risk of recurrence (adjusted HR=0.53; 95% CI, 0.32-0.85; P=.009). No association was found between recurrent VTE and duration of anticoagulation therapy (6 months vs longer). Nor was there a difference in recurrence rates based on the index event.

WHAT’S NEW: Aspirin has a key role in preventing recurrence

This study found that for patients with unprovoked VTE who completed a course of oral anticoagulation, aspirin was effective in preventing a recurrence, with no apparent increase in the risk of major bleeding. Protection in Year 2 was nearly as great as in Year one.¹

CAVEAT: Patients were followed for just 2 years

It is unclear whether continuing aspirin therapy beyond 2 years would continue to confer protection against a VTE recurrence without an increase in adverse effects.

CHALLENGE TO IMPLEMENTATION: Some patients can’t tolerate chronic aspirin therapy

Although this study investigated aspirin in a dosage of 100 mg/d, this strength is not readily available in the United States.⁴ There is no evidence to suggest that the 81-mg strength that is available in this country would provide a diminished antiplatelet effect. And, as is already customary, patients undergoing chronic aspirin therapy must be monitored for major bleeding, GI irritation, and renal compromise. A few patients will be ineligible for prophylaxis due to a history of intolerance to aspirin or nonsteroidal anti-inflammatory drugs.

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 62-year-old patient comes to your office for follow-up of a primary unprovoked venous thromboembolus. He has been on an oral anticoagulant for 12 months. Should he continue anticoagulation therapy despite the increased risk for major bleeding?

Patients who survive VTE—defined as either deep venous thrombosis or pulmonary embolism—are put on anticoagulant therapy to prevent a recurrence, typically for 6 to 18 months. But about 20% of patients with unprovoked VTE have a recurrence within 2 years of anticoagulation withdrawal.² Extending anticoagulation prevents recurrences but increases the risk of bleeding.³

Is aspirin a viable alternative?
Until recently, the efficacy of aspirin for the prevention of recurrent VTE was unknown. Becattini et al investigated it in the multicenter RCT detailed in this PURL.

STUDY SUMMARY: Aspirin can prevent recurrence with minimal risk

To determine whether aspirin was a viable alternative to oral anticoagulation, the researchers compared aspirin with placebo in patients with primary unprovoked VTE who had completed a course of oral anticoagulation treatment. To be considered for the study, patients had to be >18 years and have had their first-ever objectively confirmed, symptomatic unprovoked proximal deep vein thrombosis, pulmonary embolism, or both. They also had to have completed 6 to 18 months of anticoagulant therapy, with a target international normalized ratio (INR) of 2.0 to 3.0. Exclusion criteria included a history of cancer, clinically significant thrombophilia, atrial fibrillation, and a bleeding event that occurred during the course of anticoagulation therapy.

Becattini et al identified 403 eligible patients. Two weeks after stopping anticoagulation, patients were randomly assigned to receive either aspirin 100 mg once daily (n=205) or placebo (n=198) for 2 years. (One patient in the placebo group never received treatment.) At baseline, there were no significant differences in patient characteristics. All were evaluated every 3 months in the first year and every 6 months in the second year.

The primary efficacy outcome was objectively confirmed recurrent VTE. The primary safety outcome was major bleeding, defined as bleeding that occurred in a critical location (eg, intracranial bleeding), was associated with a decrease of hemoglobin of at least 2 g/dL, required a transfusion of 2 units of whole blood or red blood cells, or was fatal. Overt bleeding, which required medical intervention but did not meet the criteria for major bleeding, was a secondary safety outcome.

Twenty-eight of the 205 patients in the aspirin group experienced a recurrence, compared with 43 of the 197 patients on placebo (6.6% vs. 11.2% per year; hazard ratio [HR]=0.58; 95% confidence interval [CI], 0.36-0.93; P=.02). Adverse events were reported by 7 patients in the aspirin therapy group and 6 in the placebo group. One patient in each group experienced major bleeding, and 3 in each group experienced clinically relevant but nonmajor bleeding. Withdrawal rates were similar (10 in the treatment group vs 9 controls), as were the number of patients who developed new indications for aspirin or anticoagulation therapy or were lost to follow-up.

An analysis adjusted for age, sex, index event (deep vein thrombosis or pulmonary embolism), and duration of initial anticoagulation treatment confirmed that aspirin reduced the risk of recurrence (adjusted HR=0.53; 95% CI, 0.32-0.85; P=.009). No association was found between recurrent VTE and duration of anticoagulation therapy (6 months vs longer). Nor was there a difference in recurrence rates based on the index event.

WHAT’S NEW: Aspirin has a key role in preventing recurrence

This study found that for patients with unprovoked VTE who completed a course of oral anticoagulation, aspirin was effective in preventing a recurrence, with no apparent increase in the risk of major bleeding. Protection in Year 2 was nearly as great as in Year one.¹

CAVEAT: Patients were followed for just 2 years

It is unclear whether continuing aspirin therapy beyond 2 years would continue to confer protection against a VTE recurrence without an increase in adverse effects.

CHALLENGE TO IMPLEMENTATION: Some patients can’t tolerate chronic aspirin therapy

Although this study investigated aspirin in a dosage of 100 mg/d, this strength is not readily available in the United States.⁴ There is no evidence to suggest that the 81-mg strength that is available in this country would provide a diminished antiplatelet effect. And, as is already customary, patients undergoing chronic aspirin therapy must be monitored for major bleeding, GI irritation, and renal compromise. A few patients will be ineligible for prophylaxis due to a history of intolerance to aspirin or nonsteroidal anti-inflammatory drugs.

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 62-year-old patient comes to your office for follow-up of a primary unprovoked venous thromboembolus. He has been on an oral anticoagulant for 12 months. Should he continue anticoagulation therapy despite the increased risk for major bleeding?

Patients who survive VTE—defined as either deep venous thrombosis or pulmonary embolism—are put on anticoagulant therapy to prevent a recurrence, typically for 6 to 18 months. But about 20% of patients with unprovoked VTE have a recurrence within 2 years of anticoagulation withdrawal.² Extending anticoagulation prevents recurrences but increases the risk of bleeding.³

Is aspirin a viable alternative?
Until recently, the efficacy of aspirin for the prevention of recurrent VTE was unknown. Becattini et al investigated it in the multicenter RCT detailed in this PURL.

STUDY SUMMARY: Aspirin can prevent recurrence with minimal risk

To determine whether aspirin was a viable alternative to oral anticoagulation, the researchers compared aspirin with placebo in patients with primary unprovoked VTE who had completed a course of oral anticoagulation treatment. To be considered for the study, patients had to be >18 years and have had their first-ever objectively confirmed, symptomatic unprovoked proximal deep vein thrombosis, pulmonary embolism, or both. They also had to have completed 6 to 18 months of anticoagulant therapy, with a target international normalized ratio (INR) of 2.0 to 3.0. Exclusion criteria included a history of cancer, clinically significant thrombophilia, atrial fibrillation, and a bleeding event that occurred during the course of anticoagulation therapy.

Becattini et al identified 403 eligible patients. Two weeks after stopping anticoagulation, patients were randomly assigned to receive either aspirin 100 mg once daily (n=205) or placebo (n=198) for 2 years. (One patient in the placebo group never received treatment.) At baseline, there were no significant differences in patient characteristics. All were evaluated every 3 months in the first year and every 6 months in the second year.

The primary efficacy outcome was objectively confirmed recurrent VTE. The primary safety outcome was major bleeding, defined as bleeding that occurred in a critical location (eg, intracranial bleeding), was associated with a decrease of hemoglobin of at least 2 g/dL, required a transfusion of 2 units of whole blood or red blood cells, or was fatal. Overt bleeding, which required medical intervention but did not meet the criteria for major bleeding, was a secondary safety outcome.

Twenty-eight of the 205 patients in the aspirin group experienced a recurrence, compared with 43 of the 197 patients on placebo (6.6% vs. 11.2% per year; hazard ratio [HR]=0.58; 95% confidence interval [CI], 0.36-0.93; P=.02). Adverse events were reported by 7 patients in the aspirin therapy group and 6 in the placebo group. One patient in each group experienced major bleeding, and 3 in each group experienced clinically relevant but nonmajor bleeding. Withdrawal rates were similar (10 in the treatment group vs 9 controls), as were the number of patients who developed new indications for aspirin or anticoagulation therapy or were lost to follow-up.

An analysis adjusted for age, sex, index event (deep vein thrombosis or pulmonary embolism), and duration of initial anticoagulation treatment confirmed that aspirin reduced the risk of recurrence (adjusted HR=0.53; 95% CI, 0.32-0.85; P=.009). No association was found between recurrent VTE and duration of anticoagulation therapy (6 months vs longer). Nor was there a difference in recurrence rates based on the index event.

WHAT’S NEW: Aspirin has a key role in preventing recurrence

This study found that for patients with unprovoked VTE who completed a course of oral anticoagulation, aspirin was effective in preventing a recurrence, with no apparent increase in the risk of major bleeding. Protection in Year 2 was nearly as great as in Year one.¹

CAVEAT: Patients were followed for just 2 years

It is unclear whether continuing aspirin therapy beyond 2 years would continue to confer protection against a VTE recurrence without an increase in adverse effects.

CHALLENGE TO IMPLEMENTATION: Some patients can’t tolerate chronic aspirin therapy

Although this study investigated aspirin in a dosage of 100 mg/d, this strength is not readily available in the United States.⁴ There is no evidence to suggest that the 81-mg strength that is available in this country would provide a diminished antiplatelet effect. And, as is already customary, patients undergoing chronic aspirin therapy must be monitored for major bleeding, GI irritation, and renal compromise. A few patients will be ineligible for prophylaxis due to a history of intolerance to aspirin or nonsteroidal anti-inflammatory drugs.

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 28-year-old man comes to your clinic after suffering from fatigue, purulent nasal discharge, and unilateral facial pain for nearly 10 days. Overall, he appears healthy, and you diagnose acute rhinosinusitis. You suggest OTC remedies for supportive care and wonder if a course of amoxicillin would speed his recovery.

Each year, more than 30 million Americans—about one in 7 adults—are diagnosed with sinusitis.² No more than 2% of these cases are thought to be bacterial.³

Centers for Disease Control and Prevention (CDC) guidelines for the diagnosis of acute bacterial rhinosinusitis include symptoms that last 7 days or more, with maxillary pain or tenderness in the face or teeth and purulent nasal secretions.⁴ Patients with symptoms lasting less than 7 days are unlikely to have a bacterial infection. But the non-specific signs and symptoms included in the CDC guidelines limit their usefulness in determining whether the cause of the sinusitis is bacterial or viral on clinical grounds alone.

Most cases of sinusitis spontaneously resolve
In patients with acute bacterial sinusitis, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines advocate watchful waiting and symptom relief with nasal oxymetazoline, pseudoephedrine, and saline nasal irrigation.³ The rate of spontaneous resolution is high: 80% of patients with clinically diagnosed sinusitis improve without treatment within 2 weeks.^1,5

Traditional decongestants and mucolytics have not demonstrated efficacy in resolving sinusitis, although rigorous evaluation is lacking. Other treatments, such as saline irrigation and intranasal corticosteroids, are of unclear benefit and need further study.^6-8

Lack of evidence has done little to curtail antibiotic use
An earlier PURL based on a meta-analysis of antibiotic treatment trials for sinusitis recommended that we stop prescribing antibiotics for adults with acute sinusitis unless their symptoms are severe.^9,10 Yet antibiotics remain the mainstay of treatment.

Despite the AAO-HNS guidelines, evidence of spontaneous resolution, and accumulating data on the lack of efficacy of antimicrobials for sinusitis, 81% of patients diagnosed with acute sinusitis were given prescriptions for antibiotics, a study of primary care practices showed.¹¹ Frequent use of antibiotics contributes to high rates of drug resistance, and adverse events related to antibiotic use account for an estimated 142,500 emergency department visits annually.¹²

STUDY SUMMARY: Little benefit from amoxicillin, even for severe cases

Garbutt and colleagues revisited the issue, randomizing 166 patients from 10 primary care practices to amoxicillin plus symptomatic treatment or placebo plus symptomatic treatment for acute rhinosinusitis.¹ To be eligible for the study, patients had to be between the ages of 18 and 70 years, meet CDC diagnostic criteria for acute rhinosinusitis, and have moderate to very severe symptoms that were of 7- to-28-day duration and worsening or not improving or of <7-day duration but had worsened after an initial improvement. Exclusion criteria included complications from sinusitis, a history of allergy to penicillin or amoxicillin, antibiotic use in the past 4 weeks, comorbidities that impair immune function, cystic fibrosis, pregnancy, and mild symptoms.

Both groups had similar baseline characteristics, with participants who were predominantly white (79%) and female (64%). All the participants received a supply of symptomatic treatments: acetaminophen, guaifenesin, dextromethorphan, and sustained-release pseudoephedrine. The treatment group also received amoxicillin 1500 mg/d, divided into 3 doses; the placebo group received identical-looking placebo pills.

Patients were assessed with the Sino-nasal Outcome Test-16 (SNOT-16), a validated measure that asks patients to assess both the severity and frequency of 16 sinus symptoms. SNOT-16 uses a 0-to-3 rating scale (0=no problem; 3=severe problem), with a clinically important difference of ≥0.5 on the mean score. The test was administered at enrollment and at Days 3, 7, and 10. The disease-specific quality of life at Day 3 was the primary outcome.

There was no statistically significantly difference in SNOT-16 scores between the amoxicillin and placebo groups on Days 3 and 10. On Day 7, there was a small statistically significant improvement in the amoxicillin group, but it did not reach the level of clinical importance (≥0.5) based on SNOT-16’s mean score.

The authors also asked participants to retrospectively assess symptom change since enrollment on a 6-point scale. Those who reported that their symptoms were “a lot better” or “absent” were characterized as significantly improved. The results correlated with the data from the SNOT-16, showing no difference between the amoxicillin and control group at Days 3 and 10. On Day 7, 74% of patients treated with amoxicillin self- reported significant improvement in symptoms since the start of the study, vs 56% in the control group. The number needed to treat was 6 (95% confidence interval, 3-34; P= .02) for a reduction in symptoms at Day 7.

Patients in both groups had similar rates of absenteeism, inability to perform usual activities, relapse and recurrence, and use of additional health care. Satisfaction with treatment was similar, as well.

No serious adverse effects occurred. Both groups reported similar frequencies (<10%) of nausea, diarrhea, abdominal pain, or vaginitis.

WHAT’S NEW: Even severe sinusitis resolves without antibiotics

Previous studies recommended foregoing antibiotics for acute sinusitis, except when symptoms are severe. This study—in which more than half (52%) of patients in each group had symptoms rated severe or very severe—found no benefit to adding amoxicillin to supportive treatments.¹ Antibiotics did not shorten the duration of illness, prevent relapse and recurrence, or improve satisfaction with treatment. The researchers found a statistically significant difference between groups on Day 7 of 0.19 points, but no clinically meaningful difference (≥0.5) based on the SNOT-16 mean score.

CAVEATS: Guidelines, risk of complications may give reason to pause

The 2012 Infectious Diseases Society of America guidelines recommend amoxicillin with clavulanic acid as empiric therapy for acute bacterial rhinosinusitis.⁷ The findings of the study by Garbutt et al—conducted at a time when the incidence of beta-lactamase-producing organisms was low and amoxicillin was the treatment of choice—suggest otherwise.

Serious complications of sinusitis, such as brain abscess, periorbital cellulitis, and meningitis, can occur, however. Patients who deteriorate clinically or develop high fever or severe headache require close follow-up, which may include further diagnostic evaluation or consultation with an otolaryngologist. Evidence is lacking as to whether antibiotics prevent such complications.⁵

CHALLENGES TO IMPLEMENTATION: Managing patient expectations

Many patients with symptoms of acute rhinosinusitis think they need an antibiotic. Managing their expectations and providing instructions about supportive treatments are time consuming and may be difficult.

Nonetheless, we’re optimistic: We think that most patients today are aware of the problems associated with antibiotic resistance and wary of “superbugs,” and will therefore be receptive to this practice change. Physicians can help by reminding patients of the adverse effects of antibiotics and the natural course of rhino-sinusitis, as well as by offering symptomatic treatments.

Acknowledgement

The PURLs Surveillance System is 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 28-year-old man comes to your clinic after suffering from fatigue, purulent nasal discharge, and unilateral facial pain for nearly 10 days. Overall, he appears healthy, and you diagnose acute rhinosinusitis. You suggest OTC remedies for supportive care and wonder if a course of amoxicillin would speed his recovery.

Each year, more than 30 million Americans—about one in 7 adults—are diagnosed with sinusitis.² No more than 2% of these cases are thought to be bacterial.³

Centers for Disease Control and Prevention (CDC) guidelines for the diagnosis of acute bacterial rhinosinusitis include symptoms that last 7 days or more, with maxillary pain or tenderness in the face or teeth and purulent nasal secretions.⁴ Patients with symptoms lasting less than 7 days are unlikely to have a bacterial infection. But the non-specific signs and symptoms included in the CDC guidelines limit their usefulness in determining whether the cause of the sinusitis is bacterial or viral on clinical grounds alone.

Most cases of sinusitis spontaneously resolve
In patients with acute bacterial sinusitis, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines advocate watchful waiting and symptom relief with nasal oxymetazoline, pseudoephedrine, and saline nasal irrigation.³ The rate of spontaneous resolution is high: 80% of patients with clinically diagnosed sinusitis improve without treatment within 2 weeks.^1,5

Traditional decongestants and mucolytics have not demonstrated efficacy in resolving sinusitis, although rigorous evaluation is lacking. Other treatments, such as saline irrigation and intranasal corticosteroids, are of unclear benefit and need further study.^6-8

Lack of evidence has done little to curtail antibiotic use
An earlier PURL based on a meta-analysis of antibiotic treatment trials for sinusitis recommended that we stop prescribing antibiotics for adults with acute sinusitis unless their symptoms are severe.^9,10 Yet antibiotics remain the mainstay of treatment.

Despite the AAO-HNS guidelines, evidence of spontaneous resolution, and accumulating data on the lack of efficacy of antimicrobials for sinusitis, 81% of patients diagnosed with acute sinusitis were given prescriptions for antibiotics, a study of primary care practices showed.¹¹ Frequent use of antibiotics contributes to high rates of drug resistance, and adverse events related to antibiotic use account for an estimated 142,500 emergency department visits annually.¹²

STUDY SUMMARY: Little benefit from amoxicillin, even for severe cases

Garbutt and colleagues revisited the issue, randomizing 166 patients from 10 primary care practices to amoxicillin plus symptomatic treatment or placebo plus symptomatic treatment for acute rhinosinusitis.¹ To be eligible for the study, patients had to be between the ages of 18 and 70 years, meet CDC diagnostic criteria for acute rhinosinusitis, and have moderate to very severe symptoms that were of 7- to-28-day duration and worsening or not improving or of <7-day duration but had worsened after an initial improvement. Exclusion criteria included complications from sinusitis, a history of allergy to penicillin or amoxicillin, antibiotic use in the past 4 weeks, comorbidities that impair immune function, cystic fibrosis, pregnancy, and mild symptoms.

Both groups had similar baseline characteristics, with participants who were predominantly white (79%) and female (64%). All the participants received a supply of symptomatic treatments: acetaminophen, guaifenesin, dextromethorphan, and sustained-release pseudoephedrine. The treatment group also received amoxicillin 1500 mg/d, divided into 3 doses; the placebo group received identical-looking placebo pills.

Patients were assessed with the Sino-nasal Outcome Test-16 (SNOT-16), a validated measure that asks patients to assess both the severity and frequency of 16 sinus symptoms. SNOT-16 uses a 0-to-3 rating scale (0=no problem; 3=severe problem), with a clinically important difference of ≥0.5 on the mean score. The test was administered at enrollment and at Days 3, 7, and 10. The disease-specific quality of life at Day 3 was the primary outcome.

There was no statistically significantly difference in SNOT-16 scores between the amoxicillin and placebo groups on Days 3 and 10. On Day 7, there was a small statistically significant improvement in the amoxicillin group, but it did not reach the level of clinical importance (≥0.5) based on SNOT-16’s mean score.

The authors also asked participants to retrospectively assess symptom change since enrollment on a 6-point scale. Those who reported that their symptoms were “a lot better” or “absent” were characterized as significantly improved. The results correlated with the data from the SNOT-16, showing no difference between the amoxicillin and control group at Days 3 and 10. On Day 7, 74% of patients treated with amoxicillin self- reported significant improvement in symptoms since the start of the study, vs 56% in the control group. The number needed to treat was 6 (95% confidence interval, 3-34; P= .02) for a reduction in symptoms at Day 7.

Patients in both groups had similar rates of absenteeism, inability to perform usual activities, relapse and recurrence, and use of additional health care. Satisfaction with treatment was similar, as well.

No serious adverse effects occurred. Both groups reported similar frequencies (<10%) of nausea, diarrhea, abdominal pain, or vaginitis.

WHAT’S NEW: Even severe sinusitis resolves without antibiotics

Previous studies recommended foregoing antibiotics for acute sinusitis, except when symptoms are severe. This study—in which more than half (52%) of patients in each group had symptoms rated severe or very severe—found no benefit to adding amoxicillin to supportive treatments.¹ Antibiotics did not shorten the duration of illness, prevent relapse and recurrence, or improve satisfaction with treatment. The researchers found a statistically significant difference between groups on Day 7 of 0.19 points, but no clinically meaningful difference (≥0.5) based on the SNOT-16 mean score.

CAVEATS: Guidelines, risk of complications may give reason to pause

The 2012 Infectious Diseases Society of America guidelines recommend amoxicillin with clavulanic acid as empiric therapy for acute bacterial rhinosinusitis.⁷ The findings of the study by Garbutt et al—conducted at a time when the incidence of beta-lactamase-producing organisms was low and amoxicillin was the treatment of choice—suggest otherwise.

Serious complications of sinusitis, such as brain abscess, periorbital cellulitis, and meningitis, can occur, however. Patients who deteriorate clinically or develop high fever or severe headache require close follow-up, which may include further diagnostic evaluation or consultation with an otolaryngologist. Evidence is lacking as to whether antibiotics prevent such complications.⁵

CHALLENGES TO IMPLEMENTATION: Managing patient expectations

Many patients with symptoms of acute rhinosinusitis think they need an antibiotic. Managing their expectations and providing instructions about supportive treatments are time consuming and may be difficult.

Nonetheless, we’re optimistic: We think that most patients today are aware of the problems associated with antibiotic resistance and wary of “superbugs,” and will therefore be receptive to this practice change. Physicians can help by reminding patients of the adverse effects of antibiotics and the natural course of rhino-sinusitis, as well as by offering symptomatic treatments.

Acknowledgement

The PURLs Surveillance System is 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 28-year-old man comes to your clinic after suffering from fatigue, purulent nasal discharge, and unilateral facial pain for nearly 10 days. Overall, he appears healthy, and you diagnose acute rhinosinusitis. You suggest OTC remedies for supportive care and wonder if a course of amoxicillin would speed his recovery.

Each year, more than 30 million Americans—about one in 7 adults—are diagnosed with sinusitis.² No more than 2% of these cases are thought to be bacterial.³

Centers for Disease Control and Prevention (CDC) guidelines for the diagnosis of acute bacterial rhinosinusitis include symptoms that last 7 days or more, with maxillary pain or tenderness in the face or teeth and purulent nasal secretions.⁴ Patients with symptoms lasting less than 7 days are unlikely to have a bacterial infection. But the non-specific signs and symptoms included in the CDC guidelines limit their usefulness in determining whether the cause of the sinusitis is bacterial or viral on clinical grounds alone.

Most cases of sinusitis spontaneously resolve
In patients with acute bacterial sinusitis, the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) guidelines advocate watchful waiting and symptom relief with nasal oxymetazoline, pseudoephedrine, and saline nasal irrigation.³ The rate of spontaneous resolution is high: 80% of patients with clinically diagnosed sinusitis improve without treatment within 2 weeks.^1,5

Traditional decongestants and mucolytics have not demonstrated efficacy in resolving sinusitis, although rigorous evaluation is lacking. Other treatments, such as saline irrigation and intranasal corticosteroids, are of unclear benefit and need further study.^6-8

Lack of evidence has done little to curtail antibiotic use
An earlier PURL based on a meta-analysis of antibiotic treatment trials for sinusitis recommended that we stop prescribing antibiotics for adults with acute sinusitis unless their symptoms are severe.^9,10 Yet antibiotics remain the mainstay of treatment.

Despite the AAO-HNS guidelines, evidence of spontaneous resolution, and accumulating data on the lack of efficacy of antimicrobials for sinusitis, 81% of patients diagnosed with acute sinusitis were given prescriptions for antibiotics, a study of primary care practices showed.¹¹ Frequent use of antibiotics contributes to high rates of drug resistance, and adverse events related to antibiotic use account for an estimated 142,500 emergency department visits annually.¹²

STUDY SUMMARY: Little benefit from amoxicillin, even for severe cases

Garbutt and colleagues revisited the issue, randomizing 166 patients from 10 primary care practices to amoxicillin plus symptomatic treatment or placebo plus symptomatic treatment for acute rhinosinusitis.¹ To be eligible for the study, patients had to be between the ages of 18 and 70 years, meet CDC diagnostic criteria for acute rhinosinusitis, and have moderate to very severe symptoms that were of 7- to-28-day duration and worsening or not improving or of <7-day duration but had worsened after an initial improvement. Exclusion criteria included complications from sinusitis, a history of allergy to penicillin or amoxicillin, antibiotic use in the past 4 weeks, comorbidities that impair immune function, cystic fibrosis, pregnancy, and mild symptoms.

Both groups had similar baseline characteristics, with participants who were predominantly white (79%) and female (64%). All the participants received a supply of symptomatic treatments: acetaminophen, guaifenesin, dextromethorphan, and sustained-release pseudoephedrine. The treatment group also received amoxicillin 1500 mg/d, divided into 3 doses; the placebo group received identical-looking placebo pills.

Patients were assessed with the Sino-nasal Outcome Test-16 (SNOT-16), a validated measure that asks patients to assess both the severity and frequency of 16 sinus symptoms. SNOT-16 uses a 0-to-3 rating scale (0=no problem; 3=severe problem), with a clinically important difference of ≥0.5 on the mean score. The test was administered at enrollment and at Days 3, 7, and 10. The disease-specific quality of life at Day 3 was the primary outcome.

There was no statistically significantly difference in SNOT-16 scores between the amoxicillin and placebo groups on Days 3 and 10. On Day 7, there was a small statistically significant improvement in the amoxicillin group, but it did not reach the level of clinical importance (≥0.5) based on SNOT-16’s mean score.

The authors also asked participants to retrospectively assess symptom change since enrollment on a 6-point scale. Those who reported that their symptoms were “a lot better” or “absent” were characterized as significantly improved. The results correlated with the data from the SNOT-16, showing no difference between the amoxicillin and control group at Days 3 and 10. On Day 7, 74% of patients treated with amoxicillin self- reported significant improvement in symptoms since the start of the study, vs 56% in the control group. The number needed to treat was 6 (95% confidence interval, 3-34; P= .02) for a reduction in symptoms at Day 7.

Patients in both groups had similar rates of absenteeism, inability to perform usual activities, relapse and recurrence, and use of additional health care. Satisfaction with treatment was similar, as well.

No serious adverse effects occurred. Both groups reported similar frequencies (<10%) of nausea, diarrhea, abdominal pain, or vaginitis.

WHAT’S NEW: Even severe sinusitis resolves without antibiotics

Previous studies recommended foregoing antibiotics for acute sinusitis, except when symptoms are severe. This study—in which more than half (52%) of patients in each group had symptoms rated severe or very severe—found no benefit to adding amoxicillin to supportive treatments.¹ Antibiotics did not shorten the duration of illness, prevent relapse and recurrence, or improve satisfaction with treatment. The researchers found a statistically significant difference between groups on Day 7 of 0.19 points, but no clinically meaningful difference (≥0.5) based on the SNOT-16 mean score.

CAVEATS: Guidelines, risk of complications may give reason to pause

The 2012 Infectious Diseases Society of America guidelines recommend amoxicillin with clavulanic acid as empiric therapy for acute bacterial rhinosinusitis.⁷ The findings of the study by Garbutt et al—conducted at a time when the incidence of beta-lactamase-producing organisms was low and amoxicillin was the treatment of choice—suggest otherwise.

Serious complications of sinusitis, such as brain abscess, periorbital cellulitis, and meningitis, can occur, however. Patients who deteriorate clinically or develop high fever or severe headache require close follow-up, which may include further diagnostic evaluation or consultation with an otolaryngologist. Evidence is lacking as to whether antibiotics prevent such complications.⁵

CHALLENGES TO IMPLEMENTATION: Managing patient expectations

Many patients with symptoms of acute rhinosinusitis think they need an antibiotic. Managing their expectations and providing instructions about supportive treatments are time consuming and may be difficult.

Nonetheless, we’re optimistic: We think that most patients today are aware of the problems associated with antibiotic resistance and wary of “superbugs,” and will therefore be receptive to this practice change. Physicians can help by reminding patients of the adverse effects of antibiotics and the natural course of rhino-sinusitis, as well as by offering symptomatic treatments.

Acknowledgement

The PURLs Surveillance System is 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 24-year-old woman comes in for an annual exam, including Pap smear and testing for sexually transmitted diseases (STD). She tells you how painful her previous speculum exam was and how worried she is about having another. Should you apply lubricating gel or water to the speculum before vaginal insertion to ease her discomfort?

Physiology teaches us that vaginal entry requires lubrication. But traditional teaching has held that lubricating gel on a speculum can interfere with the results of a Pap smear and chlamydia tesing.² Pelvic exams performed without lubricating gel on the speculum can cause significant discomfort—possibly bad enough to prevent some women from undergoing the recommended screening tests.³

Until now, we’ve only evaluated gel’s impact on test results
Studies comparing lubricating gel and water have conclusively shown that a small amount of gel, used on the outside of the speculum blades, does not interfere with either Pap testing or detection of Chlamydia trachomatis.^4,5 One liquid-based cytology manufacturer, however, discourages the use of lubricants with “carbomers” or “carbopol polymers,” but states that water-based lubricants have not been shown to interfere with Pap smear results.⁶ No studies have evaluated lubricants from a patient perspective—until now.

STUDY SUMMARY: Lubricating gel eases discomfort

The study by Hill and Lamvu was a 6-month, single-blind, randomized trial of women ages 18 to 50 years who sought care at an Orlando, Florida obstetrics and gynecology department for conditions requiring vaginal speculum examination.¹ The study excluded women who might have an altered perception of pain during speculum insertion— those who were menopausal, pregnant, or within 6 weeks’ postpartum; had dyspareunia, vaginitis, vulvar pain, or vulvar lesions; were undergoing a procedure; or had never had vaginal intercourse. Women who were not fluent in English were excluded, as well.

The study included 120 women who underwent computer-generated randomization into 2 groups with no marked differences in demographics. A single examiner did all the speculum exams, using a standard protocol with a medium-size Graves speculum. The examiner applied 0.3 mL water-based lubricating gel to the speculum before insertion for the women in one group, and used 3 mL water for the other.

Immediately after the speculum was inserted and opened—before the examiner attempted to visualize the cervix—patients were given a visual analog scale and told to indicate the level of pain with insertion, using a scale of 0 (no pain) to 10 (the worst pain imaginable). The gel group had lower pain scores for speculum insertion compared with the water group (1.41±1.55 vs 2.15±1.93; P<.01), a statistically significant difference of 0.74. Twenty of the 59 patients in the gel group (33.9%) rated their pain as 0, compared with 6 of 60 (10%) in the water group (P=.002). Although pain, rather than sampling quality, was the primary outcome of the study, the authors also reported that all of the women who underwent Pap screening (73) had adequate cytology.

WHAT’S NEW?: It’s time for lubrication to become standard practice

This trial is the first to study speculum lubrication from this patient-oriented outcome, and to show that women experience less pain when lubricating gel is applied to the speculum, rather than water. This knowledge, combined with previous studies showing that a small amount of water-based lubricating gel does not interfere with liquid-based cytology or chlamydia test results, should make the use of lubricating gel standard practice when performing speculum examinations.

CAVEATS: We see no downside

The exclusion criteria of this study were meant to eliminate women who had an altered pain perception that could skew study results. Yet those who met the exclusion criteria may also benefit from a pelvic exam with gel lubrication. We see no harm in trying a small amount of lubricant when examining them, as well.

In addition, the study did not compare various types and sizes of specula. However, we see no reason why the benefit of a gel lubricant would be limited to the type of speculum used by the examiner.

Studies in emergency departments that have used visual analog scales to measure interventions that decrease pain have used a 0.9 mean difference as “clinically meaningful.”^7,8 By that criteria, the 0.74 difference observed in this study does not rise to the level of clinical meaningfulness. However, one in 3 patients in the gel group marked 0 on the pain scale, indicating that they had no pain, vs only one in 10 in the water group. We believe that the higher proportion of women experiencing no pain and the mean difference of 0.74 on the pain scale (both statistically significant), combined with the lack of risk associated with the use of a water-based lubricant, makes this a clinically useful practice changer.

CHALLENGES TO IMPLEMENTATION: There aren’t any

Other than clinical inertia, we see no challenges to the implementation of this recommendation.

Acknowledgement

The PURLs Surveillance System is 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 24-year-old woman comes in for an annual exam, including Pap smear and testing for sexually transmitted diseases (STD). She tells you how painful her previous speculum exam was and how worried she is about having another. Should you apply lubricating gel or water to the speculum before vaginal insertion to ease her discomfort?

Physiology teaches us that vaginal entry requires lubrication. But traditional teaching has held that lubricating gel on a speculum can interfere with the results of a Pap smear and chlamydia tesing.² Pelvic exams performed without lubricating gel on the speculum can cause significant discomfort—possibly bad enough to prevent some women from undergoing the recommended screening tests.³

Until now, we’ve only evaluated gel’s impact on test results
Studies comparing lubricating gel and water have conclusively shown that a small amount of gel, used on the outside of the speculum blades, does not interfere with either Pap testing or detection of Chlamydia trachomatis.^4,5 One liquid-based cytology manufacturer, however, discourages the use of lubricants with “carbomers” or “carbopol polymers,” but states that water-based lubricants have not been shown to interfere with Pap smear results.⁶ No studies have evaluated lubricants from a patient perspective—until now.

STUDY SUMMARY: Lubricating gel eases discomfort

The study by Hill and Lamvu was a 6-month, single-blind, randomized trial of women ages 18 to 50 years who sought care at an Orlando, Florida obstetrics and gynecology department for conditions requiring vaginal speculum examination.¹ The study excluded women who might have an altered perception of pain during speculum insertion— those who were menopausal, pregnant, or within 6 weeks’ postpartum; had dyspareunia, vaginitis, vulvar pain, or vulvar lesions; were undergoing a procedure; or had never had vaginal intercourse. Women who were not fluent in English were excluded, as well.

The study included 120 women who underwent computer-generated randomization into 2 groups with no marked differences in demographics. A single examiner did all the speculum exams, using a standard protocol with a medium-size Graves speculum. The examiner applied 0.3 mL water-based lubricating gel to the speculum before insertion for the women in one group, and used 3 mL water for the other.

Immediately after the speculum was inserted and opened—before the examiner attempted to visualize the cervix—patients were given a visual analog scale and told to indicate the level of pain with insertion, using a scale of 0 (no pain) to 10 (the worst pain imaginable). The gel group had lower pain scores for speculum insertion compared with the water group (1.41±1.55 vs 2.15±1.93; P<.01), a statistically significant difference of 0.74. Twenty of the 59 patients in the gel group (33.9%) rated their pain as 0, compared with 6 of 60 (10%) in the water group (P=.002). Although pain, rather than sampling quality, was the primary outcome of the study, the authors also reported that all of the women who underwent Pap screening (73) had adequate cytology.

WHAT’S NEW?: It’s time for lubrication to become standard practice

This trial is the first to study speculum lubrication from this patient-oriented outcome, and to show that women experience less pain when lubricating gel is applied to the speculum, rather than water. This knowledge, combined with previous studies showing that a small amount of water-based lubricating gel does not interfere with liquid-based cytology or chlamydia test results, should make the use of lubricating gel standard practice when performing speculum examinations.

CAVEATS: We see no downside

The exclusion criteria of this study were meant to eliminate women who had an altered pain perception that could skew study results. Yet those who met the exclusion criteria may also benefit from a pelvic exam with gel lubrication. We see no harm in trying a small amount of lubricant when examining them, as well.

In addition, the study did not compare various types and sizes of specula. However, we see no reason why the benefit of a gel lubricant would be limited to the type of speculum used by the examiner.

Studies in emergency departments that have used visual analog scales to measure interventions that decrease pain have used a 0.9 mean difference as “clinically meaningful.”^7,8 By that criteria, the 0.74 difference observed in this study does not rise to the level of clinical meaningfulness. However, one in 3 patients in the gel group marked 0 on the pain scale, indicating that they had no pain, vs only one in 10 in the water group. We believe that the higher proportion of women experiencing no pain and the mean difference of 0.74 on the pain scale (both statistically significant), combined with the lack of risk associated with the use of a water-based lubricant, makes this a clinically useful practice changer.

CHALLENGES TO IMPLEMENTATION: There aren’t any

Other than clinical inertia, we see no challenges to the implementation of this recommendation.

Acknowledgement

The PURLs Surveillance System is 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 24-year-old woman comes in for an annual exam, including Pap smear and testing for sexually transmitted diseases (STD). She tells you how painful her previous speculum exam was and how worried she is about having another. Should you apply lubricating gel or water to the speculum before vaginal insertion to ease her discomfort?

Physiology teaches us that vaginal entry requires lubrication. But traditional teaching has held that lubricating gel on a speculum can interfere with the results of a Pap smear and chlamydia tesing.² Pelvic exams performed without lubricating gel on the speculum can cause significant discomfort—possibly bad enough to prevent some women from undergoing the recommended screening tests.³

Until now, we’ve only evaluated gel’s impact on test results
Studies comparing lubricating gel and water have conclusively shown that a small amount of gel, used on the outside of the speculum blades, does not interfere with either Pap testing or detection of Chlamydia trachomatis.^4,5 One liquid-based cytology manufacturer, however, discourages the use of lubricants with “carbomers” or “carbopol polymers,” but states that water-based lubricants have not been shown to interfere with Pap smear results.⁶ No studies have evaluated lubricants from a patient perspective—until now.

STUDY SUMMARY: Lubricating gel eases discomfort

The study by Hill and Lamvu was a 6-month, single-blind, randomized trial of women ages 18 to 50 years who sought care at an Orlando, Florida obstetrics and gynecology department for conditions requiring vaginal speculum examination.¹ The study excluded women who might have an altered perception of pain during speculum insertion— those who were menopausal, pregnant, or within 6 weeks’ postpartum; had dyspareunia, vaginitis, vulvar pain, or vulvar lesions; were undergoing a procedure; or had never had vaginal intercourse. Women who were not fluent in English were excluded, as well.

The study included 120 women who underwent computer-generated randomization into 2 groups with no marked differences in demographics. A single examiner did all the speculum exams, using a standard protocol with a medium-size Graves speculum. The examiner applied 0.3 mL water-based lubricating gel to the speculum before insertion for the women in one group, and used 3 mL water for the other.

Immediately after the speculum was inserted and opened—before the examiner attempted to visualize the cervix—patients were given a visual analog scale and told to indicate the level of pain with insertion, using a scale of 0 (no pain) to 10 (the worst pain imaginable). The gel group had lower pain scores for speculum insertion compared with the water group (1.41±1.55 vs 2.15±1.93; P<.01), a statistically significant difference of 0.74. Twenty of the 59 patients in the gel group (33.9%) rated their pain as 0, compared with 6 of 60 (10%) in the water group (P=.002). Although pain, rather than sampling quality, was the primary outcome of the study, the authors also reported that all of the women who underwent Pap screening (73) had adequate cytology.

WHAT’S NEW?: It’s time for lubrication to become standard practice

This trial is the first to study speculum lubrication from this patient-oriented outcome, and to show that women experience less pain when lubricating gel is applied to the speculum, rather than water. This knowledge, combined with previous studies showing that a small amount of water-based lubricating gel does not interfere with liquid-based cytology or chlamydia test results, should make the use of lubricating gel standard practice when performing speculum examinations.

CAVEATS: We see no downside

The exclusion criteria of this study were meant to eliminate women who had an altered pain perception that could skew study results. Yet those who met the exclusion criteria may also benefit from a pelvic exam with gel lubrication. We see no harm in trying a small amount of lubricant when examining them, as well.

In addition, the study did not compare various types and sizes of specula. However, we see no reason why the benefit of a gel lubricant would be limited to the type of speculum used by the examiner.

Studies in emergency departments that have used visual analog scales to measure interventions that decrease pain have used a 0.9 mean difference as “clinically meaningful.”^7,8 By that criteria, the 0.74 difference observed in this study does not rise to the level of clinical meaningfulness. However, one in 3 patients in the gel group marked 0 on the pain scale, indicating that they had no pain, vs only one in 10 in the water group. We believe that the higher proportion of women experiencing no pain and the mean difference of 0.74 on the pain scale (both statistically significant), combined with the lack of risk associated with the use of a water-based lubricant, makes this a clinically useful practice changer.

CHALLENGES TO IMPLEMENTATION: There aren’t any

Other than clinical inertia, we see no challenges to the implementation of this recommendation.

Acknowledgement

The PURLs Surveillance System is 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 65-year-old man with a history of moderate to severe COPD schedules an appointment soon after discharge from the hospital—his second hospitalization for COPD exacerbations in 4 months. The patient uses inhaled glucocorticoids, a long-acting beta-agonist (LABA), and a long-acting anticholinergic. Should you add a macrolide to his medication regimen?

Acute exacerbations of COPD—the third highest cause of death in the United States²—have a major effect on quality of life, often resulting in repeat trips to the emergency department (ED) and numerous hospitalizations, office visits, and days lost from work. According to a new study that used 2006 data, there were 1.25 million hospitalizations for COPD exacerbations that year, with health care costs of $11.9 billion.³ Preventing exacerbations and the associated morbidity and mortality is a major challenge that primary care physicians face.

Can a macrolide help?
Corticosteroids, long-acting beta-agonists (LABAs), and the anticholinergic tiotropium are known to reduce COPD exacerbations,^4,5 but what about antibiotics? A Cochrane meta-analysis of 9 RCTs that assessed antibiotic use for COPD found that it did not decrease the number of exacerbations. Notably, however, macrolides were not used in any of the studies.⁶

Macrolides are known to have anti-inflammatory, antibacterial, and immunomodulatory properties that reduce pulmonary exacerbations in other chronic lung diseases. A recent meta-analysis found that patients with cystic fibrosis have fewer pulmonary exacerbations when they take azithromycin 3 times a week.⁷

Small studies of the effect of macrolides on the frequency of COPD exacerbations have had conflicting results.^8,9 The larger study detailed here evaluated the ability of daily azithromycin therapy to reduce COPD exacerbations.

STUDY SUMMARY: Daily dose led to fewer exacerbations

This double-blind RCT included close to 1150 participants from 12 US academic health centers, randomly assigned to receive azithromycin 250 mg daily or placebo, in addition to their usual care. (About 10% of patients in both groups died, withdrew, or were lost to follow-up.)

To be included, patients had to be ≥40 years old and have a clinical diagnosis of COPD, defined as a smoking history of 10 pack-years or more, a decreased forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio, and a decreased FEV1 after bronchodilation. In addition, participants had to be on long-term oxygen or have used systemic steroids within the previous year or have had an ED visit or hospital admission for COPD during that time frame. Exclusion criteria included a history of asthma, a resting heart rate >100 beats per minute, a prolonged corrected QT interval (QTc) on electrocardiogram or the use of a medication that might prolong QTc, and a documented hearing impairment.

At baseline, participants were similar in basic demographics, COPD severity, smoking history, and medication use: 49% of those in the azithromycin group and 46% of the placebo group were taking a combination of inhaled corticosteroids, LABAs, and a long-acting anticholinergic medication.

The primary outcome was the time to the first COPD exacerbation. This was defined as ≥3 days with 2 or more COPD symptoms—new onset or worsening cough, dyspnea, sputum production, chest tightness, or wheezing—for which antibiotics or steroids were required. Secondary outcomes were quality-of-life measurements on the St. George’s Respiratory Questionnaire (SGRQ) and the Medical Outcomes 36-item Short Form Health Survey (SF-36). Nasopharyngeal swabs were done every 3 months to check for colonization and resistance. Hearing was assessed with audiometry at the time of enrollment, and again at 3 and 12 months. All patients were followed for a year, with monthly telephone calls or clinic visits, to determine if an exacerbation had occurred in the previous month.

The median time to the first exacerbation in the azithromycin group was 266 days (95% confidence interval [CI], 227-313) vs 174 days (95% CI, 143-215) in the placebo group; P<.001. Frequency of acute exacerbations was 1.48 per patient-year for the azithromycin group compared with 1.83 for the placebo group (relative risk=0.83; 95% CI, 0.72–0.95; P=.01). The number needed to treat to prevent one acute exacerbation in a one-year period was 2.86.

There was no significant difference in the SGRQ and SF-36 scores for the azithromycin vs the placebo group. There was a small reduction in unscheduled office visits (0.11 per patient-year; P=.048) in the azithromycin group, and a decrease in hospitalization that was not statistically significant.

Azithromycin group had higher rates of adverse effects
Nasopharyngeal cultures from participants who became colonized during the course of the study found macrolide resistance in 81% of those in the azithromycin group vs 41% of the placebo group (P<.001). Twenty-five percent of patients in the azithromycin group developed measurable hearing loss, compared with 20% of those on placebo (P=0.04; number needed to harm=20).

WHAT’S NEW?: A better understanding of benefits and risks

This study shows that the addition of azithromycin (250 mg/d) to standard COPD treatment decreases the number of exacerbations, but does little to reduce hospital admissions. It also highlights the adverse effect profile of azithromycin and the importance of using the antibiotic only for carefully selected patients.

CAVEATS: Macrolide resistance is a key concern

Twenty-five percent of the azithromycin group had documented hearing loss—an additional one in 20 compared with patients in the placebo group. More importantly, there was an increase in the prevalence of macrolide-resistant respiratory pathogens in patients on daily azithromycin. The long-term impact of daily azithromycin on antibiotic resistance is unknown, both for patients themselves and the community at large.

Physicians will have to assess the benefit of a decrease in COPD exacerbations (approximately one every 3 years) vs the risk of an increase in hearing problems and macrolide resistance. A sensible approach would be to reserve daily use of azithromycin for patients with a history of multiple exacerbations, who potentially have more to gain.

CHALLENGES TO IMPLEMENTATION: There are none

There are no major challenges to implementation aside from the cost, which would be approximately $1200 per year (azithromycin 250 mg [30 tablets] at $98.99 per month).¹⁰

Acknowledgement

The PURLs Surveillance System is 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 65-year-old man with a history of moderate to severe COPD schedules an appointment soon after discharge from the hospital—his second hospitalization for COPD exacerbations in 4 months. The patient uses inhaled glucocorticoids, a long-acting beta-agonist (LABA), and a long-acting anticholinergic. Should you add a macrolide to his medication regimen?

Acute exacerbations of COPD—the third highest cause of death in the United States²—have a major effect on quality of life, often resulting in repeat trips to the emergency department (ED) and numerous hospitalizations, office visits, and days lost from work. According to a new study that used 2006 data, there were 1.25 million hospitalizations for COPD exacerbations that year, with health care costs of $11.9 billion.³ Preventing exacerbations and the associated morbidity and mortality is a major challenge that primary care physicians face.

Can a macrolide help?
Corticosteroids, long-acting beta-agonists (LABAs), and the anticholinergic tiotropium are known to reduce COPD exacerbations,^4,5 but what about antibiotics? A Cochrane meta-analysis of 9 RCTs that assessed antibiotic use for COPD found that it did not decrease the number of exacerbations. Notably, however, macrolides were not used in any of the studies.⁶

Macrolides are known to have anti-inflammatory, antibacterial, and immunomodulatory properties that reduce pulmonary exacerbations in other chronic lung diseases. A recent meta-analysis found that patients with cystic fibrosis have fewer pulmonary exacerbations when they take azithromycin 3 times a week.⁷

Small studies of the effect of macrolides on the frequency of COPD exacerbations have had conflicting results.^8,9 The larger study detailed here evaluated the ability of daily azithromycin therapy to reduce COPD exacerbations.

STUDY SUMMARY: Daily dose led to fewer exacerbations

This double-blind RCT included close to 1150 participants from 12 US academic health centers, randomly assigned to receive azithromycin 250 mg daily or placebo, in addition to their usual care. (About 10% of patients in both groups died, withdrew, or were lost to follow-up.)

To be included, patients had to be ≥40 years old and have a clinical diagnosis of COPD, defined as a smoking history of 10 pack-years or more, a decreased forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio, and a decreased FEV1 after bronchodilation. In addition, participants had to be on long-term oxygen or have used systemic steroids within the previous year or have had an ED visit or hospital admission for COPD during that time frame. Exclusion criteria included a history of asthma, a resting heart rate >100 beats per minute, a prolonged corrected QT interval (QTc) on electrocardiogram or the use of a medication that might prolong QTc, and a documented hearing impairment.

At baseline, participants were similar in basic demographics, COPD severity, smoking history, and medication use: 49% of those in the azithromycin group and 46% of the placebo group were taking a combination of inhaled corticosteroids, LABAs, and a long-acting anticholinergic medication.

The primary outcome was the time to the first COPD exacerbation. This was defined as ≥3 days with 2 or more COPD symptoms—new onset or worsening cough, dyspnea, sputum production, chest tightness, or wheezing—for which antibiotics or steroids were required. Secondary outcomes were quality-of-life measurements on the St. George’s Respiratory Questionnaire (SGRQ) and the Medical Outcomes 36-item Short Form Health Survey (SF-36). Nasopharyngeal swabs were done every 3 months to check for colonization and resistance. Hearing was assessed with audiometry at the time of enrollment, and again at 3 and 12 months. All patients were followed for a year, with monthly telephone calls or clinic visits, to determine if an exacerbation had occurred in the previous month.

The median time to the first exacerbation in the azithromycin group was 266 days (95% confidence interval [CI], 227-313) vs 174 days (95% CI, 143-215) in the placebo group; P<.001. Frequency of acute exacerbations was 1.48 per patient-year for the azithromycin group compared with 1.83 for the placebo group (relative risk=0.83; 95% CI, 0.72–0.95; P=.01). The number needed to treat to prevent one acute exacerbation in a one-year period was 2.86.

There was no significant difference in the SGRQ and SF-36 scores for the azithromycin vs the placebo group. There was a small reduction in unscheduled office visits (0.11 per patient-year; P=.048) in the azithromycin group, and a decrease in hospitalization that was not statistically significant.

Azithromycin group had higher rates of adverse effects
Nasopharyngeal cultures from participants who became colonized during the course of the study found macrolide resistance in 81% of those in the azithromycin group vs 41% of the placebo group (P<.001). Twenty-five percent of patients in the azithromycin group developed measurable hearing loss, compared with 20% of those on placebo (P=0.04; number needed to harm=20).

WHAT’S NEW?: A better understanding of benefits and risks

This study shows that the addition of azithromycin (250 mg/d) to standard COPD treatment decreases the number of exacerbations, but does little to reduce hospital admissions. It also highlights the adverse effect profile of azithromycin and the importance of using the antibiotic only for carefully selected patients.

CAVEATS: Macrolide resistance is a key concern

Twenty-five percent of the azithromycin group had documented hearing loss—an additional one in 20 compared with patients in the placebo group. More importantly, there was an increase in the prevalence of macrolide-resistant respiratory pathogens in patients on daily azithromycin. The long-term impact of daily azithromycin on antibiotic resistance is unknown, both for patients themselves and the community at large.

Physicians will have to assess the benefit of a decrease in COPD exacerbations (approximately one every 3 years) vs the risk of an increase in hearing problems and macrolide resistance. A sensible approach would be to reserve daily use of azithromycin for patients with a history of multiple exacerbations, who potentially have more to gain.

CHALLENGES TO IMPLEMENTATION: There are none

There are no major challenges to implementation aside from the cost, which would be approximately $1200 per year (azithromycin 250 mg [30 tablets] at $98.99 per month).¹⁰

Acknowledgement

The PURLs Surveillance System is 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 65-year-old man with a history of moderate to severe COPD schedules an appointment soon after discharge from the hospital—his second hospitalization for COPD exacerbations in 4 months. The patient uses inhaled glucocorticoids, a long-acting beta-agonist (LABA), and a long-acting anticholinergic. Should you add a macrolide to his medication regimen?

Acute exacerbations of COPD—the third highest cause of death in the United States²—have a major effect on quality of life, often resulting in repeat trips to the emergency department (ED) and numerous hospitalizations, office visits, and days lost from work. According to a new study that used 2006 data, there were 1.25 million hospitalizations for COPD exacerbations that year, with health care costs of $11.9 billion.³ Preventing exacerbations and the associated morbidity and mortality is a major challenge that primary care physicians face.

Can a macrolide help?
Corticosteroids, long-acting beta-agonists (LABAs), and the anticholinergic tiotropium are known to reduce COPD exacerbations,^4,5 but what about antibiotics? A Cochrane meta-analysis of 9 RCTs that assessed antibiotic use for COPD found that it did not decrease the number of exacerbations. Notably, however, macrolides were not used in any of the studies.⁶

Macrolides are known to have anti-inflammatory, antibacterial, and immunomodulatory properties that reduce pulmonary exacerbations in other chronic lung diseases. A recent meta-analysis found that patients with cystic fibrosis have fewer pulmonary exacerbations when they take azithromycin 3 times a week.⁷

Small studies of the effect of macrolides on the frequency of COPD exacerbations have had conflicting results.^8,9 The larger study detailed here evaluated the ability of daily azithromycin therapy to reduce COPD exacerbations.

STUDY SUMMARY: Daily dose led to fewer exacerbations

This double-blind RCT included close to 1150 participants from 12 US academic health centers, randomly assigned to receive azithromycin 250 mg daily or placebo, in addition to their usual care. (About 10% of patients in both groups died, withdrew, or were lost to follow-up.)

To be included, patients had to be ≥40 years old and have a clinical diagnosis of COPD, defined as a smoking history of 10 pack-years or more, a decreased forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio, and a decreased FEV1 after bronchodilation. In addition, participants had to be on long-term oxygen or have used systemic steroids within the previous year or have had an ED visit or hospital admission for COPD during that time frame. Exclusion criteria included a history of asthma, a resting heart rate >100 beats per minute, a prolonged corrected QT interval (QTc) on electrocardiogram or the use of a medication that might prolong QTc, and a documented hearing impairment.

At baseline, participants were similar in basic demographics, COPD severity, smoking history, and medication use: 49% of those in the azithromycin group and 46% of the placebo group were taking a combination of inhaled corticosteroids, LABAs, and a long-acting anticholinergic medication.

The primary outcome was the time to the first COPD exacerbation. This was defined as ≥3 days with 2 or more COPD symptoms—new onset or worsening cough, dyspnea, sputum production, chest tightness, or wheezing—for which antibiotics or steroids were required. Secondary outcomes were quality-of-life measurements on the St. George’s Respiratory Questionnaire (SGRQ) and the Medical Outcomes 36-item Short Form Health Survey (SF-36). Nasopharyngeal swabs were done every 3 months to check for colonization and resistance. Hearing was assessed with audiometry at the time of enrollment, and again at 3 and 12 months. All patients were followed for a year, with monthly telephone calls or clinic visits, to determine if an exacerbation had occurred in the previous month.

The median time to the first exacerbation in the azithromycin group was 266 days (95% confidence interval [CI], 227-313) vs 174 days (95% CI, 143-215) in the placebo group; P<.001. Frequency of acute exacerbations was 1.48 per patient-year for the azithromycin group compared with 1.83 for the placebo group (relative risk=0.83; 95% CI, 0.72–0.95; P=.01). The number needed to treat to prevent one acute exacerbation in a one-year period was 2.86.

There was no significant difference in the SGRQ and SF-36 scores for the azithromycin vs the placebo group. There was a small reduction in unscheduled office visits (0.11 per patient-year; P=.048) in the azithromycin group, and a decrease in hospitalization that was not statistically significant.

Azithromycin group had higher rates of adverse effects
Nasopharyngeal cultures from participants who became colonized during the course of the study found macrolide resistance in 81% of those in the azithromycin group vs 41% of the placebo group (P<.001). Twenty-five percent of patients in the azithromycin group developed measurable hearing loss, compared with 20% of those on placebo (P=0.04; number needed to harm=20).

WHAT’S NEW?: A better understanding of benefits and risks

This study shows that the addition of azithromycin (250 mg/d) to standard COPD treatment decreases the number of exacerbations, but does little to reduce hospital admissions. It also highlights the adverse effect profile of azithromycin and the importance of using the antibiotic only for carefully selected patients.

CAVEATS: Macrolide resistance is a key concern

Twenty-five percent of the azithromycin group had documented hearing loss—an additional one in 20 compared with patients in the placebo group. More importantly, there was an increase in the prevalence of macrolide-resistant respiratory pathogens in patients on daily azithromycin. The long-term impact of daily azithromycin on antibiotic resistance is unknown, both for patients themselves and the community at large.

Physicians will have to assess the benefit of a decrease in COPD exacerbations (approximately one every 3 years) vs the risk of an increase in hearing problems and macrolide resistance. A sensible approach would be to reserve daily use of azithromycin for patients with a history of multiple exacerbations, who potentially have more to gain.

CHALLENGES TO IMPLEMENTATION: There are none

There are no major challenges to implementation aside from the cost, which would be approximately $1200 per year (azithromycin 250 mg [30 tablets] at $98.99 per month).¹⁰

Acknowledgement

The PURLs Surveillance System is 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

Three months after undergoing surgical repair of an ankle fracture, a 50-year-old woman presents with acute onset dyspnea at rest and pleuritic chest pain. Her left calf is tender and swollen. The patient has a history of hypertension and smokes about 10 cigarettes per day. Her temperature is 37°C (99°F); pulse rate, 98; blood pressure, 135/85 mm Hg; respiratory rate, 25; and pulse oximetry, 92%.

You order a spiral CT, which reveals a contrast filling defect indicative of a PE. Her score on the Pulmonary Embolism Severity Index (PESI) is 50, an indication of low risk. She wants to know if she can be treated at home. What should you tell her?

In the past, intravenous unfractionated heparin, administered in an inpatient setting, was the recommended initial anticoagulation therapy for patients with venous thromboembolism (VTE). LMWH, which can be administered subcutaneously and does not require laboratory monitoring, has made it possible to treat VTE without hospitalization.

Outpatient PE care hindered by lack of evidence
Guidelines from the American College of Physicians, American Academy of Family Physicians, and British Thoracic Society recommend outpatient treatment of deep vein thrombosis with LMWH, which they find to be safe and cost effective for select patients.^2,3 Until recently, the safety and efficacy of out-patient management of PE has been less clear.

The lack of an accurate prediction tool to identify patients who could be treated safely outside of the hospital was one barrier to the development of evidence-based recommendations for outpatient PE treatment. In 2005, the PESI,⁴ a validated tool that identifies patients with low risk of death from PE, was developed. Until recently, the absence of an RCT comparing inpatient and outpatient treatment for acute PE was another barrier.

STUDY SUMMARY: Outpatient treatment measures up

The Outpatient Treatment of Pulmonary Embolism (OTPE) study was a multinational, randomized, noninferiority trial comparing outpatient vs inpatient treatment of low-risk patients with acute PE. Participants had to be ≥18 years old, have acute symptomatic and objectively verified PE, and be at low risk of death based on the PESI score.⁴ In addition to excluding patients at moderate or high risk, the researchers identified 14 other exclusion criteria, including hypoxia, chest pain requiring opiates, and high risk for bleeding.

Patients were randomly assigned to the outpatient (n=171) or inpatient (n=168) group. Both groups received subcutaneous LMWH (enoxaparin, 1 mg/kg twice a day) for ≥5 days, followed by oral anticoagulation with a vitamin K antagonist for ≥90 days. Patients in the outpatient group were discharged from the emergency department (ED) within 24 hours of randomization, after being trained by a nurse to self-inject. Therapy after discharge was managed either by the patient’s primary care physician or the hospital’s anticoagulation staff.

The LMWH was discontinued in patients with an INR ≥2.0 for 2 consecutive days. All patients were followed for 90 days, and contacted by the study team daily for the first week and then at 14, 30, 60, and 90 days. On each occasion, participants were asked about symptoms of recurrent VTE, bleeding, and the use of health care resources.

The primary outcome was the recurrence of symptomatic, objectively confirmed VTE within the study period. Secondary outcomes were major bleeding and all-cause mortality. Outcomes were confirmed by clinicians who were unaware of treatment assignments.

Patients were also asked to rate both their overall satisfaction with their care and their treatment preference 14 days after randomization, using a 5-point Likert questionnaire. Prior to the trial, the investigators decided that outpatient treatment would be considered noninferior to inpatient care if the difference between rates of recurrent VTE did not exceed 4%, a measure used in previous studies comparing treatment regimens for VTE and outpatient vs inpatient treatment of DVT.^5,6

Little difference in readmission rates, ED or office visits
One in 171 outpatients (0.6%) and none of the inpatients had recurrent VTE. Two out-patients (1.2%)—and no inpatients—developed major bleeding within 14 days, the result of intramuscular hematomas that occurred on Days 3 and 13. There was one additional bleeding event (menometrorrhagia) in the outpatient group on Day 50, but it was believed to be unrelated to the PE treatment. Per-protocol analysis, a more conservative measure used in noninferiority studies, found a difference in major bleeding rates of 3.8%. One person in each group died from non-VTE and nontreatment-related causes.

Almost all participants (99%) completed the satisfaction survey, which indicated that 92% of outpatients and 95% of inpatients were satisfied or very satisfied with their care. Hospital readmission rates, ED visits, and visits to primary care physicians were similar, with no significant differences between the 2 groups. The mean time spent in the hospital was 0.5 days (standard deviation [SD], 1.0) for outpatients and 3.9 days (SD, 3.1) for in-patients. Fourteen percent of outpatients and 6% of inpatients received home nursing visits for enoxaparin injection. The total number of home visits was higher among outpatients (348 vs 105). Because both groups had extreme outliers, however, this difference was not statistically significant.

WHAT’S NEW: It’s safe to keep low-risk patients at home

This is the first RCT comparing the safety and effectiveness of outpatient and inpatient treatment of acute, symptomatic PE. Results were statistically comparable, and patients were satisfied being treated at home. Outpatient treatment was less expensive because of the shorter length of stay (0.5 vs 3.9 days) and was associated with the same rates of hospital readmission, ED visits, and visits to primary care physicians. There were more home nursing visits in the outpatient treatment group. But even if you assume a cost of $200 per home visit, the additional cost would be about $282 per individual in the outpatient group—significantly less than the cost of the additional 3.4 days in the hospital for each individual in the inpatient group.

The study also confirmed that the PESI accurately identifies low-risk patients with PE who can be treated in an outpatient setting. Thirty percent of patients who were screened for the OTPE trial met the low-risk eligibility requirement.

CAVEATS: Use of risk assessment tool is essential

The average age of patients in this study was 47 years in the outpatient group and 49 years in the inpatient group. In addition, only 1% to 3% of the patients were diagnosed with cancer. Older patients who have both cancer and PE would be unlikely to qualify for outpatient care.

Physicians applying this practice changer should use the PESI to ensure that outpatient treatment for PE is used only for individuals at low risk.

CHALLENGES TO IMPLEMENTATION: ED coordination, training, and home care won’t be easy

This practice changer may be difficult for family physicians, who might not be included in emergency physicians’ decisions regarding the appropriate treatment for acute PE. In this study, primary care physicians were notified of the randomized treatment plan for their patients, and 17 potential participants were excluded from the trial because of their doctors’ opposition.

Outpatient management should be considered only if arrangements for adequate home nursing care can be made, if needed— and only for patients who are able to follow instructions and self-inject LMWH. Newer anticoagulation medications that are either injected once a day or taken orally might decrease the need for home nursing visits.

Acknowledgement

The PURLs Surveillance System is 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.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

Three months after undergoing surgical repair of an ankle fracture, a 50-year-old woman presents with acute onset dyspnea at rest and pleuritic chest pain. Her left calf is tender and swollen. The patient has a history of hypertension and smokes about 10 cigarettes per day. Her temperature is 37°C (99°F); pulse rate, 98; blood pressure, 135/85 mm Hg; respiratory rate, 25; and pulse oximetry, 92%.

You order a spiral CT, which reveals a contrast filling defect indicative of a PE. Her score on the Pulmonary Embolism Severity Index (PESI) is 50, an indication of low risk. She wants to know if she can be treated at home. What should you tell her?

In the past, intravenous unfractionated heparin, administered in an inpatient setting, was the recommended initial anticoagulation therapy for patients with venous thromboembolism (VTE). LMWH, which can be administered subcutaneously and does not require laboratory monitoring, has made it possible to treat VTE without hospitalization.

Outpatient PE care hindered by lack of evidence
Guidelines from the American College of Physicians, American Academy of Family Physicians, and British Thoracic Society recommend outpatient treatment of deep vein thrombosis with LMWH, which they find to be safe and cost effective for select patients.^2,3 Until recently, the safety and efficacy of out-patient management of PE has been less clear.

The lack of an accurate prediction tool to identify patients who could be treated safely outside of the hospital was one barrier to the development of evidence-based recommendations for outpatient PE treatment. In 2005, the PESI,⁴ a validated tool that identifies patients with low risk of death from PE, was developed. Until recently, the absence of an RCT comparing inpatient and outpatient treatment for acute PE was another barrier.

STUDY SUMMARY: Outpatient treatment measures up

The Outpatient Treatment of Pulmonary Embolism (OTPE) study was a multinational, randomized, noninferiority trial comparing outpatient vs inpatient treatment of low-risk patients with acute PE. Participants had to be ≥18 years old, have acute symptomatic and objectively verified PE, and be at low risk of death based on the PESI score.⁴ In addition to excluding patients at moderate or high risk, the researchers identified 14 other exclusion criteria, including hypoxia, chest pain requiring opiates, and high risk for bleeding.

Patients were randomly assigned to the outpatient (n=171) or inpatient (n=168) group. Both groups received subcutaneous LMWH (enoxaparin, 1 mg/kg twice a day) for ≥5 days, followed by oral anticoagulation with a vitamin K antagonist for ≥90 days. Patients in the outpatient group were discharged from the emergency department (ED) within 24 hours of randomization, after being trained by a nurse to self-inject. Therapy after discharge was managed either by the patient’s primary care physician or the hospital’s anticoagulation staff.

The LMWH was discontinued in patients with an INR ≥2.0 for 2 consecutive days. All patients were followed for 90 days, and contacted by the study team daily for the first week and then at 14, 30, 60, and 90 days. On each occasion, participants were asked about symptoms of recurrent VTE, bleeding, and the use of health care resources.

The primary outcome was the recurrence of symptomatic, objectively confirmed VTE within the study period. Secondary outcomes were major bleeding and all-cause mortality. Outcomes were confirmed by clinicians who were unaware of treatment assignments.

Patients were also asked to rate both their overall satisfaction with their care and their treatment preference 14 days after randomization, using a 5-point Likert questionnaire. Prior to the trial, the investigators decided that outpatient treatment would be considered noninferior to inpatient care if the difference between rates of recurrent VTE did not exceed 4%, a measure used in previous studies comparing treatment regimens for VTE and outpatient vs inpatient treatment of DVT.^5,6

Little difference in readmission rates, ED or office visits
One in 171 outpatients (0.6%) and none of the inpatients had recurrent VTE. Two out-patients (1.2%)—and no inpatients—developed major bleeding within 14 days, the result of intramuscular hematomas that occurred on Days 3 and 13. There was one additional bleeding event (menometrorrhagia) in the outpatient group on Day 50, but it was believed to be unrelated to the PE treatment. Per-protocol analysis, a more conservative measure used in noninferiority studies, found a difference in major bleeding rates of 3.8%. One person in each group died from non-VTE and nontreatment-related causes.

Almost all participants (99%) completed the satisfaction survey, which indicated that 92% of outpatients and 95% of inpatients were satisfied or very satisfied with their care. Hospital readmission rates, ED visits, and visits to primary care physicians were similar, with no significant differences between the 2 groups. The mean time spent in the hospital was 0.5 days (standard deviation [SD], 1.0) for outpatients and 3.9 days (SD, 3.1) for in-patients. Fourteen percent of outpatients and 6% of inpatients received home nursing visits for enoxaparin injection. The total number of home visits was higher among outpatients (348 vs 105). Because both groups had extreme outliers, however, this difference was not statistically significant.

WHAT’S NEW: It’s safe to keep low-risk patients at home

This is the first RCT comparing the safety and effectiveness of outpatient and inpatient treatment of acute, symptomatic PE. Results were statistically comparable, and patients were satisfied being treated at home. Outpatient treatment was less expensive because of the shorter length of stay (0.5 vs 3.9 days) and was associated with the same rates of hospital readmission, ED visits, and visits to primary care physicians. There were more home nursing visits in the outpatient treatment group. But even if you assume a cost of $200 per home visit, the additional cost would be about $282 per individual in the outpatient group—significantly less than the cost of the additional 3.4 days in the hospital for each individual in the inpatient group.

The study also confirmed that the PESI accurately identifies low-risk patients with PE who can be treated in an outpatient setting. Thirty percent of patients who were screened for the OTPE trial met the low-risk eligibility requirement.

CAVEATS: Use of risk assessment tool is essential

The average age of patients in this study was 47 years in the outpatient group and 49 years in the inpatient group. In addition, only 1% to 3% of the patients were diagnosed with cancer. Older patients who have both cancer and PE would be unlikely to qualify for outpatient care.

Physicians applying this practice changer should use the PESI to ensure that outpatient treatment for PE is used only for individuals at low risk.

CHALLENGES TO IMPLEMENTATION: ED coordination, training, and home care won’t be easy

This practice changer may be difficult for family physicians, who might not be included in emergency physicians’ decisions regarding the appropriate treatment for acute PE. In this study, primary care physicians were notified of the randomized treatment plan for their patients, and 17 potential participants were excluded from the trial because of their doctors’ opposition.

Outpatient management should be considered only if arrangements for adequate home nursing care can be made, if needed— and only for patients who are able to follow instructions and self-inject LMWH. Newer anticoagulation medications that are either injected once a day or taken orally might decrease the need for home nursing visits.

Acknowledgement

The PURLs Surveillance System is 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.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

Three months after undergoing surgical repair of an ankle fracture, a 50-year-old woman presents with acute onset dyspnea at rest and pleuritic chest pain. Her left calf is tender and swollen. The patient has a history of hypertension and smokes about 10 cigarettes per day. Her temperature is 37°C (99°F); pulse rate, 98; blood pressure, 135/85 mm Hg; respiratory rate, 25; and pulse oximetry, 92%.

You order a spiral CT, which reveals a contrast filling defect indicative of a PE. Her score on the Pulmonary Embolism Severity Index (PESI) is 50, an indication of low risk. She wants to know if she can be treated at home. What should you tell her?

In the past, intravenous unfractionated heparin, administered in an inpatient setting, was the recommended initial anticoagulation therapy for patients with venous thromboembolism (VTE). LMWH, which can be administered subcutaneously and does not require laboratory monitoring, has made it possible to treat VTE without hospitalization.

Outpatient PE care hindered by lack of evidence
Guidelines from the American College of Physicians, American Academy of Family Physicians, and British Thoracic Society recommend outpatient treatment of deep vein thrombosis with LMWH, which they find to be safe and cost effective for select patients.^2,3 Until recently, the safety and efficacy of out-patient management of PE has been less clear.

The lack of an accurate prediction tool to identify patients who could be treated safely outside of the hospital was one barrier to the development of evidence-based recommendations for outpatient PE treatment. In 2005, the PESI,⁴ a validated tool that identifies patients with low risk of death from PE, was developed. Until recently, the absence of an RCT comparing inpatient and outpatient treatment for acute PE was another barrier.

STUDY SUMMARY: Outpatient treatment measures up

The Outpatient Treatment of Pulmonary Embolism (OTPE) study was a multinational, randomized, noninferiority trial comparing outpatient vs inpatient treatment of low-risk patients with acute PE. Participants had to be ≥18 years old, have acute symptomatic and objectively verified PE, and be at low risk of death based on the PESI score.⁴ In addition to excluding patients at moderate or high risk, the researchers identified 14 other exclusion criteria, including hypoxia, chest pain requiring opiates, and high risk for bleeding.

Patients were randomly assigned to the outpatient (n=171) or inpatient (n=168) group. Both groups received subcutaneous LMWH (enoxaparin, 1 mg/kg twice a day) for ≥5 days, followed by oral anticoagulation with a vitamin K antagonist for ≥90 days. Patients in the outpatient group were discharged from the emergency department (ED) within 24 hours of randomization, after being trained by a nurse to self-inject. Therapy after discharge was managed either by the patient’s primary care physician or the hospital’s anticoagulation staff.

The LMWH was discontinued in patients with an INR ≥2.0 for 2 consecutive days. All patients were followed for 90 days, and contacted by the study team daily for the first week and then at 14, 30, 60, and 90 days. On each occasion, participants were asked about symptoms of recurrent VTE, bleeding, and the use of health care resources.

The primary outcome was the recurrence of symptomatic, objectively confirmed VTE within the study period. Secondary outcomes were major bleeding and all-cause mortality. Outcomes were confirmed by clinicians who were unaware of treatment assignments.

Patients were also asked to rate both their overall satisfaction with their care and their treatment preference 14 days after randomization, using a 5-point Likert questionnaire. Prior to the trial, the investigators decided that outpatient treatment would be considered noninferior to inpatient care if the difference between rates of recurrent VTE did not exceed 4%, a measure used in previous studies comparing treatment regimens for VTE and outpatient vs inpatient treatment of DVT.^5,6

Little difference in readmission rates, ED or office visits
One in 171 outpatients (0.6%) and none of the inpatients had recurrent VTE. Two out-patients (1.2%)—and no inpatients—developed major bleeding within 14 days, the result of intramuscular hematomas that occurred on Days 3 and 13. There was one additional bleeding event (menometrorrhagia) in the outpatient group on Day 50, but it was believed to be unrelated to the PE treatment. Per-protocol analysis, a more conservative measure used in noninferiority studies, found a difference in major bleeding rates of 3.8%. One person in each group died from non-VTE and nontreatment-related causes.

Almost all participants (99%) completed the satisfaction survey, which indicated that 92% of outpatients and 95% of inpatients were satisfied or very satisfied with their care. Hospital readmission rates, ED visits, and visits to primary care physicians were similar, with no significant differences between the 2 groups. The mean time spent in the hospital was 0.5 days (standard deviation [SD], 1.0) for outpatients and 3.9 days (SD, 3.1) for in-patients. Fourteen percent of outpatients and 6% of inpatients received home nursing visits for enoxaparin injection. The total number of home visits was higher among outpatients (348 vs 105). Because both groups had extreme outliers, however, this difference was not statistically significant.

WHAT’S NEW: It’s safe to keep low-risk patients at home

This is the first RCT comparing the safety and effectiveness of outpatient and inpatient treatment of acute, symptomatic PE. Results were statistically comparable, and patients were satisfied being treated at home. Outpatient treatment was less expensive because of the shorter length of stay (0.5 vs 3.9 days) and was associated with the same rates of hospital readmission, ED visits, and visits to primary care physicians. There were more home nursing visits in the outpatient treatment group. But even if you assume a cost of $200 per home visit, the additional cost would be about $282 per individual in the outpatient group—significantly less than the cost of the additional 3.4 days in the hospital for each individual in the inpatient group.

The study also confirmed that the PESI accurately identifies low-risk patients with PE who can be treated in an outpatient setting. Thirty percent of patients who were screened for the OTPE trial met the low-risk eligibility requirement.

CAVEATS: Use of risk assessment tool is essential

The average age of patients in this study was 47 years in the outpatient group and 49 years in the inpatient group. In addition, only 1% to 3% of the patients were diagnosed with cancer. Older patients who have both cancer and PE would be unlikely to qualify for outpatient care.

Physicians applying this practice changer should use the PESI to ensure that outpatient treatment for PE is used only for individuals at low risk.

CHALLENGES TO IMPLEMENTATION: ED coordination, training, and home care won’t be easy

This practice changer may be difficult for family physicians, who might not be included in emergency physicians’ decisions regarding the appropriate treatment for acute PE. In this study, primary care physicians were notified of the randomized treatment plan for their patients, and 17 potential participants were excluded from the trial because of their doctors’ opposition.

Outpatient management should be considered only if arrangements for adequate home nursing care can be made, if needed— and only for patients who are able to follow instructions and self-inject LMWH. Newer anticoagulation medications that are either injected once a day or taken orally might decrease the need for home nursing visits.

Acknowledgement

The PURLs Surveillance System is 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.

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