Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease

Opinion

VIEWPOINT

Samia Mora, MD, MHS Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts. Jeffrey M. Ames, BS, MEng Software and Mobile Application Development, Boston, Massachusetts. JoAnn E. Manson, MD, DrPH Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

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Corresponding Author: JoAnn E. Manson, MD, DrPH, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Ave, Third Floor, Boston, MA 02215 (jmanson@rics .bwh.harvard.edu).

Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease Shared Decision Making in Clinical Practice 50 years and aged 70 years or older, they considered the evidence to be insufficient (grade I).3 The USPSTF also conducted updated systematic reviews of aspirin use for primary prevention of ASCVD,4 cancer,5 all-cause mortality,5 and bleeding.6 In the updated study-wide meta-analysis of 11 primary prevention trials (N = 118 445 participants), random allocation to receiving aspirin vs control was associated with reductions during the trials’ follow-up periods (range, 5-10 years) in nonfatal myocardial infarction (MI) (from 14.4 to 11.6 per 1000; relative risk [RR], 0.78 [95% CI, 0.71-0.87]) and all-cause mortality (from 43.0 to 41.6 per 1000; RR, 0.94 [95% CI, 0.89-0.99]) with nonsignificant reductions in nonfatal total stroke (from 13.8 to 13.3 per 1000; RR, 0.95 [95% CI, 0.851.06]) and cardiovascular mortality (from 15.0 to 14.6 per 1000; RR, 0.94 [95% CI, Aspirin for primary prevention should 0.86-1.03]).4 In the 8 trials (N = 87 524 be highly individualized based on a participants) that tested aspirin dose benefit/risk ratio assessment for each (ⱕ100 mg/d), there was a statistically significant reduction in nonfatal total patient and a clinician-patient stroke (from 14.7 to 12.7 per 1000; RR, discussion regarding potential benefits, 0.86 [95% CI, 0.76-0.98]),4 despite the potential harms, and patient small increase in hemorrhagic stroke (from 2.0 to 2.5 per 1000; RR, 1.27 [95% preferences. CI, 0.96-1.68]) because only 15% of patients for treatment. Inappropriate use of aspirin for strokes are hemorrhagic.6 The risk of GI bleeding with primary prevention is common in clinical practice,2 high- aspirin use (ⱕ100 mg/d) significantly increased (from lighting the important need for improving evidence- 4.2 to 6.7 per 1000; RR, 1.58 [95% CI, 1.29-1.95]).6 based decision making about aspirin use and for providThe following 2 cases demonstrate the challenges of ing tools to facilitate this benefit/risk assessment. weighing potential benefits and risks of aspirin use for priThere is general consensus across clinical guide- mary prevention of ASCVD (eFigure in the Supplement). lines that aspirin for primary prevention should be highly individualized based on a benefit/risk ratio assessment Patient 1 for each patient and a clinician-patient discussion re- A 57-year-old nonsmoking man with diabetes and garding potential benefits, potential harms, and pa- treated hypertension (blood pressure, 120/75 mm Hg) tient preferences.1 The 2016 US Preventive Services Task and no prior GI disorders or bleeding has a calculated Force (USPSTF) gave a grade B recommendation (mod- 10-year ASCVD risk of 12.0% (calculated using the 2013 erate certainty for net benefit) for the use of low-dose American College of Cardiology and the American Heart aspirin (75-81 mg/d) for primary prevention of ASCVD Association pooled cohorts risk equations).7 He is reand colorectal cancer in adults aged 50 to 59 years who ceptive to the concept of long-term aspirin use. The 2016 meet all of the following criteria: (1) ASCVD 10-year risk USPSTF guidelines and the 2016 American Diabetes of at least 10%; (2) at least 10 years of life expectancy Association recommendations advise use of low-dose and willingness to take aspirin; and (3) no increased risk aspirin for a patient with his clinical history.8 of bleeding (eg, no recent bleeding, no recent history of The net benefit of aspirin for this patient would be gastrointestinal [GI] ulcers, and no use of medications moderate to substantial for preventing ASCVD (specifithat increase bleeding risk such as anticoagulant or cally MI) and also for preventing colorectal cancer. The antiplatelet agents).3 For adults aged 60 to 69 years patient, with an estimated 0.12% absolute annual risk of meeting the above criteria, the USPSTF gave a grade C GI bleeding, is not at increased risk of bleeding (10-year recommendation (not routinely recommended; indi- risk, 1.2%). With low-dose aspirin, the estimated bleedvidualize the decision), and for all adults younger than ing risk increases to 0.19% per year (10-year risk, 1.9%; Clinical decision making regarding the appropriate use of aspirin for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) events is a complex process that requires assessment of the benefits and risks for each patient. Critically important elements of the process include evaluation of the patient’s absolute risk of ASCVD (the primary determinant of potential benefit from aspirin), the patient’s absolute risk of bleeding (the primary determinant of potential risk), and the patient’s willingness to undergo long-term therapy.1 Despite numerous general guidelines on the use of aspirin for primary prevention, there is limited formal guidance in making these parallel assessments of benefit and risk or in using this information to identify appropriate

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Opinion Viewpoint

number needed to harm [NNH], 144).6,9 Conversely, the estimated 10-year number needed to treat (NNT) to prevent 1 ASCVD event is 56 (assuming 15% RR reduction of ASCVD with low-dose aspirin, which would reduce this patient’s 10-year ASCVD risk from 12.0% to 10.2%). Even without accounting for the potential 20% to 40% relative reduction in colorectal cancer risk with 10 years of daily aspirin use, the ASCVD benefit alone (10-year NNT, 56) outweighs the GI bleeding risk (10-year NNH, 144). Furthermore, randomized clinical trials of aspirin therapy indicate that the RR reduction for preventing MI for men 50 years and older may be even greater than 15%.1

Patient 2 A 68-year-old nondiabetic nonsmoking woman with treated hypertension (blood pressure, 155/82 mm Hg) and dyslipidemia (lowdensity lipoprotein cholesterol, 70 mg/dL while taking a statin) has a history of peptic ulcer disease. Despite a high 10-year ASCVD risk of 13.2%, the USPSTF would give this patient a grade C recommendation for aspirin use (individualize therapy). However, the guidelines would also consider her at high risk for GI bleeding (older age and prior peptic ulcer disease could increase her GI bleeding risk as much as 6-fold if an uncomplicated ulcer and as much as 10-fold if the ulcer was complicated by bleeding).10 Because the estimated risk of ASCVD for this patient is high (13.2%) and randomized clinical trial evidence suggests a benefit of aspirin for reducing both MI and stroke in women aged 65 years and older,1 this patient would be a candidate for low-dose aspirin (10year NNH of 133 compared with an NNT of 50) if she did not have a history of peptic ulcer disease and her blood pressure were well controlled (systolic