Michal Poplawski, MD

ILLUSTRATIVE CASE

A 67-year-old man with a history of coronary artery stenting 7 years prior and nonvalvular AF that is well controlled with a beta-blocker comes in for a routine health maintenance visit. You note that the patient takes warfarin, metoprolol, and aspirin. The patient has not had any thrombotic or bleeding events in his lifetime. Does this patient need to take both warfarin and aspirin? Do the antithrombotic benefits of dual therapy outweigh the risk of bleeding?

Antiplatelet agents have long been recommended for secondary prevention of cardiovascular (CV) events in patients with IHD. The goal is to reduce the risk of coronary artery thrombosis.² Many patients with IHD also develop AF and are treated with OACs such as warfarin or direct oral anticoagulants (DOACs) to prevent thromboembolic events.

There has been a paucity of data to determine the risks and benefits of OAC monotherapy compared to OAC plus single antiplatelet therapy (SAPT). Given research that shows increased risks of bleeding and all-cause mortality when aspirin is used for primary prevention of CV disease,^3,4 it is prudent to examine if the harms of aspirin outweigh its benefits for the secondary prevention of acute coronary events in patients already taking antithrombotic agents.

STUDY SUMMARY

Reduced bleeding risk, with no difference in major adverse cardiovascular events

This study by Lee and colleagues¹ was a meta-analysis of 8855 patients with nonvalvular AF and stable coronary artery disease (CAD), from 6 trials comparing OAC monotherapy vs OAC plus SAPT. The meta-analysis involved 3 studies using patient registries, 2 cohort studies, and an open-label randomized trial that together spanned the period from 2002 to 2016. The longest study period was 9 years (1 study) and the shortest, 1 year (2 studies). Oral anticoagulation consisted of either vitamin K antagonist (VKA) therapy (the majority of the patients studied) or DOAC therapy (8.6% of the patients studied). SAPT was either aspirin or clopidogrel.

The primary outcome measure was major adverse CV events (MACE). Secondary outcome measures included major bleeding, stroke, all-cause mortality, and net adverse events. The definitions used by the studies for major bleeding were deemed “largely consistent” with the International Society on Thrombosis and Haemostasis major bleeding criteria, ie, fatal bleeding, symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular causing compartment syndrome), or a drop in hemoglobin (≥ 2 g/dL or requiring transfusion of ≥ 2 units of whole blood or red cells).⁵

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom single antiplatelet therapy should not be prescribed as a preventive medication.

There was no difference in MACE between the monotherapy and OAC plus SAPT groups (hazard ratio [HR] = 1.09; 95% CI, 0.92-1.29). Similarly, there were no differences in stroke and all-cause mortality between the groups. However, there was a significant association of higher risk of major bleeding (HR = 1.61; 95% CI, 1.38-1.87) and net adverse events (HR = 1.21; 95% CI, 1.02-1.43) in the OAC plus SAPT group compared with the OAC monotherapy group.

This study’s limitations included its low percentage of patients taking a DOAC. Also, due to variations in methods of reporting CHA₂DS₂-VASc and HAS-BLED scores among the studies (for risk of stroke in patients with nonrheumatic AF and for risk of bleeding in AF patients taking anticoagulants), this meta-analysis could not determine if different outcomes might be found in patients with different CHA₂DS₂-VASc and HAS-BLED scores.

Continue to: WHAT'S NEW

OAC monotherapy benefit for patients with nonvalvular AF

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom SAPT should not be prescribed as a preventive medication: patients with nonvalvular AF who are receiving OAC therapy. This study concurs with the results of the 2019 AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial in Japan, in which 2236 patients with stable IHD (coronary artery bypass grafting, stenting, or cardiac catheterization > 1 year earlier) were randomized to receive rivaroxaban either alone or with an antiplatelet agent. All-cause mortality and major bleeding were lower in the monotherapy group.⁶

This meta-analysis calls into question the baseline recommendation from the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline to prescribe aspirin indefinitely for patients with stable CAD unless there is a contraindication (oral anticoagulation is not listed as a contraindication).² The 2020 ACC Expert Consensus Decision Pathway⁷ published in February 2021 stated that for patients requiring long-term anticoagulation therapy who have completed 12 months of SAPT after percutaneous coronary intervention, anticoagulation therapy alone “could be used long-term”; however, the 2019 study by Lee was not listed among their references. Inclusion of the Lee study might have contributed to a stronger recommendation.

Also, the new guidelines include clinical situations in which dual therapy could still be continued: “… if perceived thrombotic risk is high (eg, prior myocardial infarction, complex lesions, presence of select traditional cardiovascular risk factors, or extensive [atherosclerotic cardiovascular disease]), and the patient is at low bleeding risk.” The guidelines state that in this situation, “… it is reasonable to continue SAPT beyond 12 months (in line with prior ACC/AHA recommendations).”⁷ However, the cited study compared dual therapy (dabigatran plus APT) to warfarin triple therapy. Single OAC therapy was not studied.⁸

CAVEATS

DOAC patient populationwas not well represented

The study had a low percentage of patients taking a DOAC. Also, because there were variations in how the studies reported CHA₂DS₂-VASc and HAS-BLED scores, this meta-analysis was unable to determine if different scores might have produced different outcomes. However, the studies involving registries had the advantage of looking at the data for this population over long periods of time and included a wide variety of patients, making the recommendation likely valid.

CHALLENGES TO IMPLEMENTATION

Primary care approach may not sync with specialist practice

We see no challenges to implementation except for potential differences between primary care physicians and specialists regarding the use of antiplatelet agents in this patient population.

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 67-year-old man with a history of coronary artery stenting 7 years prior and nonvalvular AF that is well controlled with a beta-blocker comes in for a routine health maintenance visit. You note that the patient takes warfarin, metoprolol, and aspirin. The patient has not had any thrombotic or bleeding events in his lifetime. Does this patient need to take both warfarin and aspirin? Do the antithrombotic benefits of dual therapy outweigh the risk of bleeding?

Antiplatelet agents have long been recommended for secondary prevention of cardiovascular (CV) events in patients with IHD. The goal is to reduce the risk of coronary artery thrombosis.² Many patients with IHD also develop AF and are treated with OACs such as warfarin or direct oral anticoagulants (DOACs) to prevent thromboembolic events.

There has been a paucity of data to determine the risks and benefits of OAC monotherapy compared to OAC plus single antiplatelet therapy (SAPT). Given research that shows increased risks of bleeding and all-cause mortality when aspirin is used for primary prevention of CV disease,^3,4 it is prudent to examine if the harms of aspirin outweigh its benefits for the secondary prevention of acute coronary events in patients already taking antithrombotic agents.

STUDY SUMMARY

Reduced bleeding risk, with no difference in major adverse cardiovascular events

This study by Lee and colleagues¹ was a meta-analysis of 8855 patients with nonvalvular AF and stable coronary artery disease (CAD), from 6 trials comparing OAC monotherapy vs OAC plus SAPT. The meta-analysis involved 3 studies using patient registries, 2 cohort studies, and an open-label randomized trial that together spanned the period from 2002 to 2016. The longest study period was 9 years (1 study) and the shortest, 1 year (2 studies). Oral anticoagulation consisted of either vitamin K antagonist (VKA) therapy (the majority of the patients studied) or DOAC therapy (8.6% of the patients studied). SAPT was either aspirin or clopidogrel.

The primary outcome measure was major adverse CV events (MACE). Secondary outcome measures included major bleeding, stroke, all-cause mortality, and net adverse events. The definitions used by the studies for major bleeding were deemed “largely consistent” with the International Society on Thrombosis and Haemostasis major bleeding criteria, ie, fatal bleeding, symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular causing compartment syndrome), or a drop in hemoglobin (≥ 2 g/dL or requiring transfusion of ≥ 2 units of whole blood or red cells).⁵

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom single antiplatelet therapy should not be prescribed as a preventive medication.

There was no difference in MACE between the monotherapy and OAC plus SAPT groups (hazard ratio [HR] = 1.09; 95% CI, 0.92-1.29). Similarly, there were no differences in stroke and all-cause mortality between the groups. However, there was a significant association of higher risk of major bleeding (HR = 1.61; 95% CI, 1.38-1.87) and net adverse events (HR = 1.21; 95% CI, 1.02-1.43) in the OAC plus SAPT group compared with the OAC monotherapy group.

This study’s limitations included its low percentage of patients taking a DOAC. Also, due to variations in methods of reporting CHA₂DS₂-VASc and HAS-BLED scores among the studies (for risk of stroke in patients with nonrheumatic AF and for risk of bleeding in AF patients taking anticoagulants), this meta-analysis could not determine if different outcomes might be found in patients with different CHA₂DS₂-VASc and HAS-BLED scores.

Continue to: WHAT'S NEW

OAC monotherapy benefit for patients with nonvalvular AF

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom SAPT should not be prescribed as a preventive medication: patients with nonvalvular AF who are receiving OAC therapy. This study concurs with the results of the 2019 AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial in Japan, in which 2236 patients with stable IHD (coronary artery bypass grafting, stenting, or cardiac catheterization > 1 year earlier) were randomized to receive rivaroxaban either alone or with an antiplatelet agent. All-cause mortality and major bleeding were lower in the monotherapy group.⁶

This meta-analysis calls into question the baseline recommendation from the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline to prescribe aspirin indefinitely for patients with stable CAD unless there is a contraindication (oral anticoagulation is not listed as a contraindication).² The 2020 ACC Expert Consensus Decision Pathway⁷ published in February 2021 stated that for patients requiring long-term anticoagulation therapy who have completed 12 months of SAPT after percutaneous coronary intervention, anticoagulation therapy alone “could be used long-term”; however, the 2019 study by Lee was not listed among their references. Inclusion of the Lee study might have contributed to a stronger recommendation.

Also, the new guidelines include clinical situations in which dual therapy could still be continued: “… if perceived thrombotic risk is high (eg, prior myocardial infarction, complex lesions, presence of select traditional cardiovascular risk factors, or extensive [atherosclerotic cardiovascular disease]), and the patient is at low bleeding risk.” The guidelines state that in this situation, “… it is reasonable to continue SAPT beyond 12 months (in line with prior ACC/AHA recommendations).”⁷ However, the cited study compared dual therapy (dabigatran plus APT) to warfarin triple therapy. Single OAC therapy was not studied.⁸

CAVEATS

DOAC patient populationwas not well represented

The study had a low percentage of patients taking a DOAC. Also, because there were variations in how the studies reported CHA₂DS₂-VASc and HAS-BLED scores, this meta-analysis was unable to determine if different scores might have produced different outcomes. However, the studies involving registries had the advantage of looking at the data for this population over long periods of time and included a wide variety of patients, making the recommendation likely valid.

CHALLENGES TO IMPLEMENTATION

Primary care approach may not sync with specialist practice

We see no challenges to implementation except for potential differences between primary care physicians and specialists regarding the use of antiplatelet agents in this patient population.

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 67-year-old man with a history of coronary artery stenting 7 years prior and nonvalvular AF that is well controlled with a beta-blocker comes in for a routine health maintenance visit. You note that the patient takes warfarin, metoprolol, and aspirin. The patient has not had any thrombotic or bleeding events in his lifetime. Does this patient need to take both warfarin and aspirin? Do the antithrombotic benefits of dual therapy outweigh the risk of bleeding?

Antiplatelet agents have long been recommended for secondary prevention of cardiovascular (CV) events in patients with IHD. The goal is to reduce the risk of coronary artery thrombosis.² Many patients with IHD also develop AF and are treated with OACs such as warfarin or direct oral anticoagulants (DOACs) to prevent thromboembolic events.

There has been a paucity of data to determine the risks and benefits of OAC monotherapy compared to OAC plus single antiplatelet therapy (SAPT). Given research that shows increased risks of bleeding and all-cause mortality when aspirin is used for primary prevention of CV disease,^3,4 it is prudent to examine if the harms of aspirin outweigh its benefits for the secondary prevention of acute coronary events in patients already taking antithrombotic agents.

STUDY SUMMARY

Reduced bleeding risk, with no difference in major adverse cardiovascular events

This study by Lee and colleagues¹ was a meta-analysis of 8855 patients with nonvalvular AF and stable coronary artery disease (CAD), from 6 trials comparing OAC monotherapy vs OAC plus SAPT. The meta-analysis involved 3 studies using patient registries, 2 cohort studies, and an open-label randomized trial that together spanned the period from 2002 to 2016. The longest study period was 9 years (1 study) and the shortest, 1 year (2 studies). Oral anticoagulation consisted of either vitamin K antagonist (VKA) therapy (the majority of the patients studied) or DOAC therapy (8.6% of the patients studied). SAPT was either aspirin or clopidogrel.

The primary outcome measure was major adverse CV events (MACE). Secondary outcome measures included major bleeding, stroke, all-cause mortality, and net adverse events. The definitions used by the studies for major bleeding were deemed “largely consistent” with the International Society on Thrombosis and Haemostasis major bleeding criteria, ie, fatal bleeding, symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular causing compartment syndrome), or a drop in hemoglobin (≥ 2 g/dL or requiring transfusion of ≥ 2 units of whole blood or red cells).⁵

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom single antiplatelet therapy should not be prescribed as a preventive medication.

There was no difference in MACE between the monotherapy and OAC plus SAPT groups (hazard ratio [HR] = 1.09; 95% CI, 0.92-1.29). Similarly, there were no differences in stroke and all-cause mortality between the groups. However, there was a significant association of higher risk of major bleeding (HR = 1.61; 95% CI, 1.38-1.87) and net adverse events (HR = 1.21; 95% CI, 1.02-1.43) in the OAC plus SAPT group compared with the OAC monotherapy group.

This study’s limitations included its low percentage of patients taking a DOAC. Also, due to variations in methods of reporting CHA₂DS₂-VASc and HAS-BLED scores among the studies (for risk of stroke in patients with nonrheumatic AF and for risk of bleeding in AF patients taking anticoagulants), this meta-analysis could not determine if different outcomes might be found in patients with different CHA₂DS₂-VASc and HAS-BLED scores.

Continue to: WHAT'S NEW

OAC monotherapy benefit for patients with nonvalvular AF

This study strongly suggests that there is a large subgroup of patients with stable CAD for whom SAPT should not be prescribed as a preventive medication: patients with nonvalvular AF who are receiving OAC therapy. This study concurs with the results of the 2019 AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial in Japan, in which 2236 patients with stable IHD (coronary artery bypass grafting, stenting, or cardiac catheterization > 1 year earlier) were randomized to receive rivaroxaban either alone or with an antiplatelet agent. All-cause mortality and major bleeding were lower in the monotherapy group.⁶

This meta-analysis calls into question the baseline recommendation from the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline to prescribe aspirin indefinitely for patients with stable CAD unless there is a contraindication (oral anticoagulation is not listed as a contraindication).² The 2020 ACC Expert Consensus Decision Pathway⁷ published in February 2021 stated that for patients requiring long-term anticoagulation therapy who have completed 12 months of SAPT after percutaneous coronary intervention, anticoagulation therapy alone “could be used long-term”; however, the 2019 study by Lee was not listed among their references. Inclusion of the Lee study might have contributed to a stronger recommendation.

Also, the new guidelines include clinical situations in which dual therapy could still be continued: “… if perceived thrombotic risk is high (eg, prior myocardial infarction, complex lesions, presence of select traditional cardiovascular risk factors, or extensive [atherosclerotic cardiovascular disease]), and the patient is at low bleeding risk.” The guidelines state that in this situation, “… it is reasonable to continue SAPT beyond 12 months (in line with prior ACC/AHA recommendations).”⁷ However, the cited study compared dual therapy (dabigatran plus APT) to warfarin triple therapy. Single OAC therapy was not studied.⁸

CAVEATS

DOAC patient populationwas not well represented

The study had a low percentage of patients taking a DOAC. Also, because there were variations in how the studies reported CHA₂DS₂-VASc and HAS-BLED scores, this meta-analysis was unable to determine if different scores might have produced different outcomes. However, the studies involving registries had the advantage of looking at the data for this population over long periods of time and included a wide variety of patients, making the recommendation likely valid.

CHALLENGES TO IMPLEMENTATION

Primary care approach may not sync with specialist practice

We see no challenges to implementation except for potential differences between primary care physicians and specialists regarding the use of antiplatelet agents in this patient population.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 55-year-old man with well-controlled diabetes, hypertension, and sleep apnea arrives at your office for a routine annual physical. In reviewing his medications, you note that he takes a low-dose aspirin daily for “heart health.” He has no known cardiovascular disease (CVD). His calculated 10-year risk of a major cardiovascular event is 11%.

Should this patient continue taking a daily aspirin for primary prevention of CVD?

Many patients in the United States take aspirin for primary prevention of CVD as recommended by the US Preventive Services Task Force (USPSTF).² This recommendation was based on older studies of populations in which smoking rates were higher and statin use was less common, leading to an overall higher risk of CVD.³ (The USPSTF is currently in the process of updating its recommendation.) More recent RCTs have been done in patients with a lower baseline risk of CVD, and these outcomes are more generalizable to today’s population. This new meta-analysis includes recent RCTs that evaluated whether there is value in using aspirin for the primary prevention of CVD.

STUDY SUMMARY

No reduction in risk, increased chance of bleeding

Mahmoud and colleagues conducted a meta-analysis of 11 randomized controlled trials that included 157,248 patients and assessed the efficacy and safety of aspirin for primary prevention of cardiovascular events.¹ The mean age of the total population was 61.3 years; 52% were women and 14% were smokers. The doses of aspirin used in most of the studies were ≤ 100 mg/d, although 2 of the studies examined doses that were higher. Patients were followed for a mean of 6.6 years. The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding (as defined by each study). The secondary outcomes included cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), and fatal and ­nonfatal ischemic stroke.

Aspirin did not lower all-cause mortality (risk ratio [RR] = 0.98; 95% confidence ­interval [CI], 0.93-1.02) and was associated with an increased risk of major bleeding (RR = 1.47; 95% CI, 1.31-1.65; number needed to harm = 250) and intracranial hemorrhage (RR = 1.33; 95% CI, 1.13-1.58). Aspirin also had no effect on all-cause mortality in subgroup analyses of patients with diabetes mellitus or high cardiovascular risk (10-year risk > 7.5%). There was (again) an increased risk of major bleeding.

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice.

Aspirin had no effect on the secondary outcomes—with the exception of the incidence of MI (RR = 0.82; 95% CI, 0.71-0.94; number needed to treat = 333). However, this outcome was associated with considerable heterogeneity (I² = 67%), and the reduction was no longer evident after limiting the analysis to the more recent trials.

WHAT’S NEW?

Study is emblematic of a shift away from daily aspirin

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice, but the change has been gradual. Newer studies—large RCTs such as ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) and ASCEND (A Study of Cardiovascular Events iN Diabetes)—found no mortality benefit (all-cause or cardiovascular) from using aspirin in this context.

Continue to: The USPSTF guidelines...

The USPSTF guidelines in 2016 recommended prescribing daily aspirin for adults ages 50 to 59 who have a > 10% 10-year CVD risk and discussing with adults ages 60 to 69 the risks and benefits of daily aspirin.²

The 2019 American College of ­Cardiology/American Heart Association guidelines state that aspirin should no longer be used routinely for primary prevention, given the lack of net benefit. Patients ages 40 to 70 who are not at increased risk of bleeding with a higher risk of CVD may be considered for daily low-dose aspirin. The guidelines also state that adults > 70 years or those with increased risk of ­bleeding should not be started on a daily aspirin.⁴

CAVEATS

Jury is still out regarding very high-risk patients

While the meta-analysis by Mahmoud and colleagues makes a good case for discontinuing aspirin for primary prevention in most patients, the data do not examine in detail whether there is a benefit in patients with very high risk (> 20%) for atherosclerotic CVD. More studies are needed before making recommendations for that specific subgroup.

CHALLENGES TO IMPLEMENTATION

Patients may not be eager to give up an accepted practice

Physicians have been recommending aspirin for primary prevention of CVD for decades and many patients, who purchase aspirin themselves, are vested in the notion that aspirin protects them. It will take time for this change in practice to be accepted. Some patients may continue taking aspirin despite recommendation to stop. Primary care physicians will need to educate patients and clearly explain the rationale for stopping daily aspirin.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 55-year-old man with well-controlled diabetes, hypertension, and sleep apnea arrives at your office for a routine annual physical. In reviewing his medications, you note that he takes a low-dose aspirin daily for “heart health.” He has no known cardiovascular disease (CVD). His calculated 10-year risk of a major cardiovascular event is 11%.

Should this patient continue taking a daily aspirin for primary prevention of CVD?

Many patients in the United States take aspirin for primary prevention of CVD as recommended by the US Preventive Services Task Force (USPSTF).² This recommendation was based on older studies of populations in which smoking rates were higher and statin use was less common, leading to an overall higher risk of CVD.³ (The USPSTF is currently in the process of updating its recommendation.) More recent RCTs have been done in patients with a lower baseline risk of CVD, and these outcomes are more generalizable to today’s population. This new meta-analysis includes recent RCTs that evaluated whether there is value in using aspirin for the primary prevention of CVD.

STUDY SUMMARY

No reduction in risk, increased chance of bleeding

Mahmoud and colleagues conducted a meta-analysis of 11 randomized controlled trials that included 157,248 patients and assessed the efficacy and safety of aspirin for primary prevention of cardiovascular events.¹ The mean age of the total population was 61.3 years; 52% were women and 14% were smokers. The doses of aspirin used in most of the studies were ≤ 100 mg/d, although 2 of the studies examined doses that were higher. Patients were followed for a mean of 6.6 years. The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding (as defined by each study). The secondary outcomes included cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), and fatal and ­nonfatal ischemic stroke.

Aspirin did not lower all-cause mortality (risk ratio [RR] = 0.98; 95% confidence ­interval [CI], 0.93-1.02) and was associated with an increased risk of major bleeding (RR = 1.47; 95% CI, 1.31-1.65; number needed to harm = 250) and intracranial hemorrhage (RR = 1.33; 95% CI, 1.13-1.58). Aspirin also had no effect on all-cause mortality in subgroup analyses of patients with diabetes mellitus or high cardiovascular risk (10-year risk > 7.5%). There was (again) an increased risk of major bleeding.

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice.

Aspirin had no effect on the secondary outcomes—with the exception of the incidence of MI (RR = 0.82; 95% CI, 0.71-0.94; number needed to treat = 333). However, this outcome was associated with considerable heterogeneity (I² = 67%), and the reduction was no longer evident after limiting the analysis to the more recent trials.

WHAT’S NEW?

Study is emblematic of a shift away from daily aspirin

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice, but the change has been gradual. Newer studies—large RCTs such as ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) and ASCEND (A Study of Cardiovascular Events iN Diabetes)—found no mortality benefit (all-cause or cardiovascular) from using aspirin in this context.

Continue to: The USPSTF guidelines...

The USPSTF guidelines in 2016 recommended prescribing daily aspirin for adults ages 50 to 59 who have a > 10% 10-year CVD risk and discussing with adults ages 60 to 69 the risks and benefits of daily aspirin.²

The 2019 American College of ­Cardiology/American Heart Association guidelines state that aspirin should no longer be used routinely for primary prevention, given the lack of net benefit. Patients ages 40 to 70 who are not at increased risk of bleeding with a higher risk of CVD may be considered for daily low-dose aspirin. The guidelines also state that adults > 70 years or those with increased risk of ­bleeding should not be started on a daily aspirin.⁴

CAVEATS

Jury is still out regarding very high-risk patients

While the meta-analysis by Mahmoud and colleagues makes a good case for discontinuing aspirin for primary prevention in most patients, the data do not examine in detail whether there is a benefit in patients with very high risk (> 20%) for atherosclerotic CVD. More studies are needed before making recommendations for that specific subgroup.

CHALLENGES TO IMPLEMENTATION

Patients may not be eager to give up an accepted practice

Physicians have been recommending aspirin for primary prevention of CVD for decades and many patients, who purchase aspirin themselves, are vested in the notion that aspirin protects them. It will take time for this change in practice to be accepted. Some patients may continue taking aspirin despite recommendation to stop. Primary care physicians will need to educate patients and clearly explain the rationale for stopping daily aspirin.

ACKNOWLEDGEMENT

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

ILLUSTRATIVE CASE

A 55-year-old man with well-controlled diabetes, hypertension, and sleep apnea arrives at your office for a routine annual physical. In reviewing his medications, you note that he takes a low-dose aspirin daily for “heart health.” He has no known cardiovascular disease (CVD). His calculated 10-year risk of a major cardiovascular event is 11%.

Should this patient continue taking a daily aspirin for primary prevention of CVD?

Many patients in the United States take aspirin for primary prevention of CVD as recommended by the US Preventive Services Task Force (USPSTF).² This recommendation was based on older studies of populations in which smoking rates were higher and statin use was less common, leading to an overall higher risk of CVD.³ (The USPSTF is currently in the process of updating its recommendation.) More recent RCTs have been done in patients with a lower baseline risk of CVD, and these outcomes are more generalizable to today’s population. This new meta-analysis includes recent RCTs that evaluated whether there is value in using aspirin for the primary prevention of CVD.

STUDY SUMMARY

No reduction in risk, increased chance of bleeding

Mahmoud and colleagues conducted a meta-analysis of 11 randomized controlled trials that included 157,248 patients and assessed the efficacy and safety of aspirin for primary prevention of cardiovascular events.¹ The mean age of the total population was 61.3 years; 52% were women and 14% were smokers. The doses of aspirin used in most of the studies were ≤ 100 mg/d, although 2 of the studies examined doses that were higher. Patients were followed for a mean of 6.6 years. The primary efficacy outcome was all-cause mortality, and the primary safety outcome was major bleeding (as defined by each study). The secondary outcomes included cardiovascular mortality, fatal and nonfatal myocardial infarction (MI), and fatal and ­nonfatal ischemic stroke.

Aspirin did not lower all-cause mortality (risk ratio [RR] = 0.98; 95% confidence ­interval [CI], 0.93-1.02) and was associated with an increased risk of major bleeding (RR = 1.47; 95% CI, 1.31-1.65; number needed to harm = 250) and intracranial hemorrhage (RR = 1.33; 95% CI, 1.13-1.58). Aspirin also had no effect on all-cause mortality in subgroup analyses of patients with diabetes mellitus or high cardiovascular risk (10-year risk > 7.5%). There was (again) an increased risk of major bleeding.

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice.

Aspirin had no effect on the secondary outcomes—with the exception of the incidence of MI (RR = 0.82; 95% CI, 0.71-0.94; number needed to treat = 333). However, this outcome was associated with considerable heterogeneity (I² = 67%), and the reduction was no longer evident after limiting the analysis to the more recent trials.

WHAT’S NEW?

Study is emblematic of a shift away from daily aspirin

Review of current guidelines and studies regarding the use of aspirin for primary prevention of CVD shows that the tide has been turning against this practice, but the change has been gradual. Newer studies—large RCTs such as ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) and ASCEND (A Study of Cardiovascular Events iN Diabetes)—found no mortality benefit (all-cause or cardiovascular) from using aspirin in this context.

Continue to: The USPSTF guidelines...

The USPSTF guidelines in 2016 recommended prescribing daily aspirin for adults ages 50 to 59 who have a > 10% 10-year CVD risk and discussing with adults ages 60 to 69 the risks and benefits of daily aspirin.²

The 2019 American College of ­Cardiology/American Heart Association guidelines state that aspirin should no longer be used routinely for primary prevention, given the lack of net benefit. Patients ages 40 to 70 who are not at increased risk of bleeding with a higher risk of CVD may be considered for daily low-dose aspirin. The guidelines also state that adults > 70 years or those with increased risk of ­bleeding should not be started on a daily aspirin.⁴

CAVEATS

Jury is still out regarding very high-risk patients

While the meta-analysis by Mahmoud and colleagues makes a good case for discontinuing aspirin for primary prevention in most patients, the data do not examine in detail whether there is a benefit in patients with very high risk (> 20%) for atherosclerotic CVD. More studies are needed before making recommendations for that specific subgroup.

CHALLENGES TO IMPLEMENTATION

Patients may not be eager to give up an accepted practice

Physicians have been recommending aspirin for primary prevention of CVD for decades and many patients, who purchase aspirin themselves, are vested in the notion that aspirin protects them. It will take time for this change in practice to be accepted. Some patients may continue taking aspirin despite recommendation to stop. Primary care physicians will need to educate patients and clearly explain the rationale for stopping daily aspirin.

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.