Cleveland Piggott, MD, MPH

ILLUSTRATIVE CASE

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

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

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

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

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

STUDY SUMMARY

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

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

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

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

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

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

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

WHAT'S NEW

RCT provides evidence to support use of CRP testing

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

CAVEATS

CRP testing may not be cost effective

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

CHALLENGES TO IMPLEMENTATION 

Virtual visits and variable access may limit use

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

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

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

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

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

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

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

STUDY SUMMARY

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

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

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

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

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

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

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

WHAT'S NEW

RCT provides evidence to support use of CRP testing

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

CAVEATS

CRP testing may not be cost effective

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

CHALLENGES TO IMPLEMENTATION 

Virtual visits and variable access may limit use

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

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

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

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

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

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

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

STUDY SUMMARY

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

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

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

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

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

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

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

WHAT'S NEW

RCT provides evidence to support use of CRP testing

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

CAVEATS

CRP testing may not be cost effective

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

CHALLENGES TO IMPLEMENTATION 

Virtual visits and variable access may limit use

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

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A healthy 72-year-old man with well-controlled hypertension on amlodipine 10 mg/d presents to you for an annual exam. He has no history of coronary artery disease or stroke. Should you recommend that he start aspirin for primary prevention of cardiovascular disease?

Cardiovascular disease (CVD) remains the leading cause of death in the United States.² Aspirin therapy remains the standard of care for secondary prevention of CVD in patients with known coronary artery disease (CAD).³ Aspirin reduces the risk of atherothrombosis by irreversibly inhibiting platelet function. At the same time, it increases the risk of major bleeding, including gastrointestinal bleeds and hemorrhagic strokes. Even though the benefit of aspirin in patients with known CAD is well established, the benefit of aspirin as primary prevention is less certain.

Two recent large randomized controlled trials (RCTs) examined the benefits and risks of aspirin in a variety of patient populations. The ARRIVE trial looked at more than 12,000 patients with a mean age of 63 years with moderate risk of CVD (approximately 15% risk of a cardiovascular event in 10 years) and randomly assigned them to receive aspirin or placebo.⁴ After an average follow-up period of 5 years, researchers observed that actual cardiovascular event risk was < 10% in both groups, and there was no significant difference in the primary outcome of first cardiovascular event or all-cause mortality. There was, however, a significant increase in bleeding events in the group receiving aspirin.⁴

The ASCEND trial evaluated aspirin vs placebo in more than 15,000 adult patients with type 2 diabetes mellitus and a low risk of CVD (< 10% risk of cardiovascular event in 5 years). ⁵ The primary endpoint of the study was first cardiovascular event. The authors found a significantly lower rate of cardiovascular events in the aspirin group, as well as more major bleeding events. Additionally, there was no difference between the aspirin and placebo groups in all-cause ­mortality after 7 years. The authors concluded that the benefits of aspirin in this group were ­counterbalanced by the harms.⁵

Currently, several organizations offer recommendations on aspirin use in people 40 to 70 years of age based on a patient’s risk of bleeding and risk of CVD.^6-8 Recommendations regarding aspirin use as primary prevention have been less clear for patients < 40 and > 70 years of age.⁶

Elderly patients are at higher risk of CVD and bleeding, but until recently, few studies had evaluated elderly populations to assess the benefits vs the risks of aspirin for primary CVD prevention. As of 2016, the US Preventive Services Task Force (USPSTF) stated the evidence was insufficient to assess the balance of the benefits and harms of initiating aspirin use for primary prevention of CVD in patients older than 70 years of age.⁶ This trial focuses on aspirin use for primary prevention of CVD in healthy elderly adults.

STUDY SUMMARY

Don’t use aspirin as primary prevention of CVD in the elderly

This secondary analysis of a prior double-blind RCT, which found low-dose aspirin did not prolong survival in elderly patients, examined the effect of aspirin on CVD and hemorrhage in 19,114 elderly patients without known CVD.¹ The patients were ≥ 70 years of age (≥ 65 years for blacks and Hispanics) with a mean age of 74 years and were from Australia (87%) and the United States (13%). Approximately one-third of the patients were taking a statin, and 14% were taking a nonsteroidal anti-inflammatory drug (NSAID) regularly. Patients were randomized to either aspirin 100 mg/d or matching placebo and were followed for an average of 4.7 years.

Continue to: Outcomes

Outcomes. The outcome of CVD was a composite of fatal coronary heart disease, nonfatal myocardial infarction (MI), fatal or nonfatal ischemic stroke, or hospitalization for heart failure, and the outcome of major adverse cardiovascular event was a composite of fatal cardiovascular disease (excluding death from heart failure), nonfatal MI, or fatal and nonfatal ischemic stroke.

Results. No difference was seen between the aspirin and placebo groups in CVD outcomes (10.7 events per 1000 person-years vs 11.3 events per 1000 person-years, respectively; hazard ratio [HR] = 0.95; 95% confidence interval [CI], 0.83-1.08) or major cardiovascular events (7.8 events per 1000 person-years vs 8.8 events per 1000 person-years, respectively; HR = 0.89; 95% CI, 0.77-1.03). The composite and individual endpoints of fatal cardiovascular disease, heart failure hospitalizations, fatal and nonfatal MI, and ischemic stroke also did not differ significantly between the groups.

Because of this trial, the ACC and AHA have updated their guidelines on primary prevention of CVD to recommend against the routine use of aspirin in patients > 70 years of age.

The rate of major hemorrhagic events (composite of hemorrhagic stroke, intracranial bleed, or extracranial bleed), however, was higher in the aspirin vs the placebo group (8.6 events per 1000 person-years vs 6.2 events per 1000 person-years, respectively; HR = 1.4; 95% CI, 1.2-1.6; number needed to harm = 98).

WHAT’S NEW

Finding of more harm than good leads to change in ACC/AHA guidelines

Although the most recent USPSTF guidelines state the evidence is insufficient to assess the risks and benefits of aspirin for the primary prevention of cardiovascular disease in this age group, this trial reveals there is a greater risk of hemorrhagic events than there is prevention of cardiovascular outcomes with aspirin use in healthy elderly patients > 70 years of age.⁶ Because of this trial, the American College of Cardiology (ACC) and the American Heart Association (AHA) have updated their guidelines on the primary prevention of cardiovascular disease to recommend that aspirin not be used routinely in patients > 70 years of age.⁷

CAVEATS

Potential benefit to people at higher risk?

The rate of cardiovascular disease was lower than expected in this overall healthy population, so it is not known if cardiovascular benefits may outweigh the risk of bleeding in a higher-risk population. The trial also didn’t address the potential harms of deprescribing aspirin. Additionally, although aspirin may not be protective for cardiovascular events and may lead to more bleeding, there may be other benefits to aspirin in this patient population that were not addressed by this study.

Continue to: CHALLENGES TO IMPLEMENTATION

CHALLENGES TO IMPLEMENTATION

Popular beliefs and wide availability may make tide difficult to change

Patients have been told for years to take a daily aspirin to “protect their heart”; this behavior may be difficult to change. And because aspirin is widely available over the counter, patients may take it without their physician’s knowledge.

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 healthy 72-year-old man with well-controlled hypertension on amlodipine 10 mg/d presents to you for an annual exam. He has no history of coronary artery disease or stroke. Should you recommend that he start aspirin for primary prevention of cardiovascular disease?

Cardiovascular disease (CVD) remains the leading cause of death in the United States.² Aspirin therapy remains the standard of care for secondary prevention of CVD in patients with known coronary artery disease (CAD).³ Aspirin reduces the risk of atherothrombosis by irreversibly inhibiting platelet function. At the same time, it increases the risk of major bleeding, including gastrointestinal bleeds and hemorrhagic strokes. Even though the benefit of aspirin in patients with known CAD is well established, the benefit of aspirin as primary prevention is less certain.

Two recent large randomized controlled trials (RCTs) examined the benefits and risks of aspirin in a variety of patient populations. The ARRIVE trial looked at more than 12,000 patients with a mean age of 63 years with moderate risk of CVD (approximately 15% risk of a cardiovascular event in 10 years) and randomly assigned them to receive aspirin or placebo.⁴ After an average follow-up period of 5 years, researchers observed that actual cardiovascular event risk was < 10% in both groups, and there was no significant difference in the primary outcome of first cardiovascular event or all-cause mortality. There was, however, a significant increase in bleeding events in the group receiving aspirin.⁴

The ASCEND trial evaluated aspirin vs placebo in more than 15,000 adult patients with type 2 diabetes mellitus and a low risk of CVD (< 10% risk of cardiovascular event in 5 years). ⁵ The primary endpoint of the study was first cardiovascular event. The authors found a significantly lower rate of cardiovascular events in the aspirin group, as well as more major bleeding events. Additionally, there was no difference between the aspirin and placebo groups in all-cause ­mortality after 7 years. The authors concluded that the benefits of aspirin in this group were ­counterbalanced by the harms.⁵

Currently, several organizations offer recommendations on aspirin use in people 40 to 70 years of age based on a patient’s risk of bleeding and risk of CVD.^6-8 Recommendations regarding aspirin use as primary prevention have been less clear for patients < 40 and > 70 years of age.⁶

Elderly patients are at higher risk of CVD and bleeding, but until recently, few studies had evaluated elderly populations to assess the benefits vs the risks of aspirin for primary CVD prevention. As of 2016, the US Preventive Services Task Force (USPSTF) stated the evidence was insufficient to assess the balance of the benefits and harms of initiating aspirin use for primary prevention of CVD in patients older than 70 years of age.⁶ This trial focuses on aspirin use for primary prevention of CVD in healthy elderly adults.

STUDY SUMMARY

Don’t use aspirin as primary prevention of CVD in the elderly

This secondary analysis of a prior double-blind RCT, which found low-dose aspirin did not prolong survival in elderly patients, examined the effect of aspirin on CVD and hemorrhage in 19,114 elderly patients without known CVD.¹ The patients were ≥ 70 years of age (≥ 65 years for blacks and Hispanics) with a mean age of 74 years and were from Australia (87%) and the United States (13%). Approximately one-third of the patients were taking a statin, and 14% were taking a nonsteroidal anti-inflammatory drug (NSAID) regularly. Patients were randomized to either aspirin 100 mg/d or matching placebo and were followed for an average of 4.7 years.

Continue to: Outcomes

Outcomes. The outcome of CVD was a composite of fatal coronary heart disease, nonfatal myocardial infarction (MI), fatal or nonfatal ischemic stroke, or hospitalization for heart failure, and the outcome of major adverse cardiovascular event was a composite of fatal cardiovascular disease (excluding death from heart failure), nonfatal MI, or fatal and nonfatal ischemic stroke.

Results. No difference was seen between the aspirin and placebo groups in CVD outcomes (10.7 events per 1000 person-years vs 11.3 events per 1000 person-years, respectively; hazard ratio [HR] = 0.95; 95% confidence interval [CI], 0.83-1.08) or major cardiovascular events (7.8 events per 1000 person-years vs 8.8 events per 1000 person-years, respectively; HR = 0.89; 95% CI, 0.77-1.03). The composite and individual endpoints of fatal cardiovascular disease, heart failure hospitalizations, fatal and nonfatal MI, and ischemic stroke also did not differ significantly between the groups.

Because of this trial, the ACC and AHA have updated their guidelines on primary prevention of CVD to recommend against the routine use of aspirin in patients > 70 years of age.

The rate of major hemorrhagic events (composite of hemorrhagic stroke, intracranial bleed, or extracranial bleed), however, was higher in the aspirin vs the placebo group (8.6 events per 1000 person-years vs 6.2 events per 1000 person-years, respectively; HR = 1.4; 95% CI, 1.2-1.6; number needed to harm = 98).

WHAT’S NEW

Finding of more harm than good leads to change in ACC/AHA guidelines

Although the most recent USPSTF guidelines state the evidence is insufficient to assess the risks and benefits of aspirin for the primary prevention of cardiovascular disease in this age group, this trial reveals there is a greater risk of hemorrhagic events than there is prevention of cardiovascular outcomes with aspirin use in healthy elderly patients > 70 years of age.⁶ Because of this trial, the American College of Cardiology (ACC) and the American Heart Association (AHA) have updated their guidelines on the primary prevention of cardiovascular disease to recommend that aspirin not be used routinely in patients > 70 years of age.⁷

CAVEATS

Potential benefit to people at higher risk?

The rate of cardiovascular disease was lower than expected in this overall healthy population, so it is not known if cardiovascular benefits may outweigh the risk of bleeding in a higher-risk population. The trial also didn’t address the potential harms of deprescribing aspirin. Additionally, although aspirin may not be protective for cardiovascular events and may lead to more bleeding, there may be other benefits to aspirin in this patient population that were not addressed by this study.

Continue to: CHALLENGES TO IMPLEMENTATION

CHALLENGES TO IMPLEMENTATION

Popular beliefs and wide availability may make tide difficult to change

Patients have been told for years to take a daily aspirin to “protect their heart”; this behavior may be difficult to change. And because aspirin is widely available over the counter, patients may take it without their physician’s knowledge.

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 healthy 72-year-old man with well-controlled hypertension on amlodipine 10 mg/d presents to you for an annual exam. He has no history of coronary artery disease or stroke. Should you recommend that he start aspirin for primary prevention of cardiovascular disease?

Cardiovascular disease (CVD) remains the leading cause of death in the United States.² Aspirin therapy remains the standard of care for secondary prevention of CVD in patients with known coronary artery disease (CAD).³ Aspirin reduces the risk of atherothrombosis by irreversibly inhibiting platelet function. At the same time, it increases the risk of major bleeding, including gastrointestinal bleeds and hemorrhagic strokes. Even though the benefit of aspirin in patients with known CAD is well established, the benefit of aspirin as primary prevention is less certain.

Two recent large randomized controlled trials (RCTs) examined the benefits and risks of aspirin in a variety of patient populations. The ARRIVE trial looked at more than 12,000 patients with a mean age of 63 years with moderate risk of CVD (approximately 15% risk of a cardiovascular event in 10 years) and randomly assigned them to receive aspirin or placebo.⁴ After an average follow-up period of 5 years, researchers observed that actual cardiovascular event risk was < 10% in both groups, and there was no significant difference in the primary outcome of first cardiovascular event or all-cause mortality. There was, however, a significant increase in bleeding events in the group receiving aspirin.⁴

The ASCEND trial evaluated aspirin vs placebo in more than 15,000 adult patients with type 2 diabetes mellitus and a low risk of CVD (< 10% risk of cardiovascular event in 5 years). ⁵ The primary endpoint of the study was first cardiovascular event. The authors found a significantly lower rate of cardiovascular events in the aspirin group, as well as more major bleeding events. Additionally, there was no difference between the aspirin and placebo groups in all-cause ­mortality after 7 years. The authors concluded that the benefits of aspirin in this group were ­counterbalanced by the harms.⁵

Currently, several organizations offer recommendations on aspirin use in people 40 to 70 years of age based on a patient’s risk of bleeding and risk of CVD.^6-8 Recommendations regarding aspirin use as primary prevention have been less clear for patients < 40 and > 70 years of age.⁶

Elderly patients are at higher risk of CVD and bleeding, but until recently, few studies had evaluated elderly populations to assess the benefits vs the risks of aspirin for primary CVD prevention. As of 2016, the US Preventive Services Task Force (USPSTF) stated the evidence was insufficient to assess the balance of the benefits and harms of initiating aspirin use for primary prevention of CVD in patients older than 70 years of age.⁶ This trial focuses on aspirin use for primary prevention of CVD in healthy elderly adults.

STUDY SUMMARY

Don’t use aspirin as primary prevention of CVD in the elderly

This secondary analysis of a prior double-blind RCT, which found low-dose aspirin did not prolong survival in elderly patients, examined the effect of aspirin on CVD and hemorrhage in 19,114 elderly patients without known CVD.¹ The patients were ≥ 70 years of age (≥ 65 years for blacks and Hispanics) with a mean age of 74 years and were from Australia (87%) and the United States (13%). Approximately one-third of the patients were taking a statin, and 14% were taking a nonsteroidal anti-inflammatory drug (NSAID) regularly. Patients were randomized to either aspirin 100 mg/d or matching placebo and were followed for an average of 4.7 years.

Continue to: Outcomes

Outcomes. The outcome of CVD was a composite of fatal coronary heart disease, nonfatal myocardial infarction (MI), fatal or nonfatal ischemic stroke, or hospitalization for heart failure, and the outcome of major adverse cardiovascular event was a composite of fatal cardiovascular disease (excluding death from heart failure), nonfatal MI, or fatal and nonfatal ischemic stroke.

Results. No difference was seen between the aspirin and placebo groups in CVD outcomes (10.7 events per 1000 person-years vs 11.3 events per 1000 person-years, respectively; hazard ratio [HR] = 0.95; 95% confidence interval [CI], 0.83-1.08) or major cardiovascular events (7.8 events per 1000 person-years vs 8.8 events per 1000 person-years, respectively; HR = 0.89; 95% CI, 0.77-1.03). The composite and individual endpoints of fatal cardiovascular disease, heart failure hospitalizations, fatal and nonfatal MI, and ischemic stroke also did not differ significantly between the groups.

Because of this trial, the ACC and AHA have updated their guidelines on primary prevention of CVD to recommend against the routine use of aspirin in patients > 70 years of age.

The rate of major hemorrhagic events (composite of hemorrhagic stroke, intracranial bleed, or extracranial bleed), however, was higher in the aspirin vs the placebo group (8.6 events per 1000 person-years vs 6.2 events per 1000 person-years, respectively; HR = 1.4; 95% CI, 1.2-1.6; number needed to harm = 98).

WHAT’S NEW

Finding of more harm than good leads to change in ACC/AHA guidelines

Although the most recent USPSTF guidelines state the evidence is insufficient to assess the risks and benefits of aspirin for the primary prevention of cardiovascular disease in this age group, this trial reveals there is a greater risk of hemorrhagic events than there is prevention of cardiovascular outcomes with aspirin use in healthy elderly patients > 70 years of age.⁶ Because of this trial, the American College of Cardiology (ACC) and the American Heart Association (AHA) have updated their guidelines on the primary prevention of cardiovascular disease to recommend that aspirin not be used routinely in patients > 70 years of age.⁷

CAVEATS

Potential benefit to people at higher risk?

The rate of cardiovascular disease was lower than expected in this overall healthy population, so it is not known if cardiovascular benefits may outweigh the risk of bleeding in a higher-risk population. The trial also didn’t address the potential harms of deprescribing aspirin. Additionally, although aspirin may not be protective for cardiovascular events and may lead to more bleeding, there may be other benefits to aspirin in this patient population that were not addressed by this study.

Continue to: CHALLENGES TO IMPLEMENTATION

CHALLENGES TO IMPLEMENTATION

Popular beliefs and wide availability may make tide difficult to change

Patients have been told for years to take a daily aspirin to “protect their heart”; this behavior may be difficult to change. And because aspirin is widely available over the counter, patients may take it without their physician’s knowledge.

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.