Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease.pdf

Clinical Review & Education

Review

Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease Advances in Diagnosis and Treatment Samia Mora, MD, MHS; JoAnn E. Manson, MD, DrPH

IMPORTANCE Clinical decision making regarding the appropriate use of aspirin for the primary

prevention of atherosclerotic cardiovascular disease (ASCVD) events is complex, and requires an individualized benefit to risk assessment. OBJECTIVE To review advances in the individualized assessment for ASCVD and bleeding risk, and to provide an update of the randomized clinical trial evidence that examined the use of aspirin for primary prevention (primarily for ASCVD, and secondarily for colorectal cancer). The recently released 2016 US Preventive Services Task Force recommendations are discussed, as well as the role of ASCVD risk, age, sex, and aspirin dose/formulation in clinical decision making. EVIDENCE REVIEW We performed a detailed review of peer-reviewed publications that were identified through searches of MEDLINE and the Cochrane Database through 2016 using the literature search terms “aspirin,” “primary prevention,” “cardiovascular disease,” “mortality,” “cancer.” Bibliographies from these references as well as meta-analyses of these randomized clinical trials were also reviewed. FINDINGS Evidence from a total of 11 trials involving more than 118 000 patients is available to guide clinical decision making for aspirin use in the primary prevention of ASCVD. Clinicians should balance the benefit to risk ratio and the individual’s preferences, calculating the 10-year ASCVD risk and evaluating risk factors for gastrointestinal bleeding, to facilitate a safer and more personalized approach to appropriate selection of candidates for low-dose aspirin (75 to 81 mg/d) for the primary prevention of ASCVD, with secondary considerations for reducing colorectal cancer risk when taken for longer periods (>10 years). Both the net ASCVD benefit and the bleeding risk of aspirin therapy increased as the absolute ASCVD risk increased, but the net benefits generally exceeded the risks at higher baseline ASCVD risk (ⱖ10% ASCVD 10-year risk). The Aspirin-Guide is a clinical decision making support tool (app for mobile devices) with internal risk calculators to help clinicians with this dual assessment by calculating the ASCVD risk and the bleeding risk in the individual patient, and incorporating age- and sex-specific guidance based on randomized trial results. CONCLUSIONS AND RELEVANCE Balancing the benefit of ASCVD reduction with the risk of

bleeding from low-dose aspirin is difficult but essential for informed decision making and achieving a net clinical benefit from aspirin for primary prevention. This is facilitated by a free and readily-available evidence-based clinical decision support tool.

JAMA Intern Med. doi:10.1001/jamainternmed.2016.2648 Published online June 20, 2016.

Author Affiliations: Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts (Mora, Manson); Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts (Mora); Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts (Manson). Corresponding Author: Samia Mora, MD, MHS, Center for Lipid Metabolomics, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Ave E, Boston, MA 02215 ([email protected]).

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Clinical Review & Education Review

Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease

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ardiovascular death remains the leading cause of death in the United States, for both women and men.1 Over the past decades, death rates from cardiovascular disease (which include coronary heart disease and stroke) have declined in US men, and more recently over the past decade in US women.1,2 Approximately half of the decline in cardiovascular death rates may be accounted for by improvements in cardiovascular risk factors, including smoking cessation and lower rates of untreated cholesterol and blood pressure, while the other half may be accounted for by evidence-based therapies including aspirin, other antiplatelet medications, statins, and antihypertensives, among other advances.3 The use of aspirin in medicine dates as far back as 3500 years ago, when Assyrian and Egyptian physicians reported (on stone and papyrus, respectively) on the analgesic and antiinflammatory effects of the extract (salicin) of willow leaves.4-6 Aspirin remains one of the most widely used medications. Currently, approximately 40% of US adults older than 50 years use aspirin for the prevention of cardiovascular diseases.7-9 Aspirin irreversibly and nonselectively inactivates cyclooxygenase (COX), inhibiting both COX-1 and COX-2 enzymes.10 At the doses used for prevention of cardiovascular diseases, aspirin’s effect on COX-1 predominates,11 preventing platelets from synthesizing thromboxane A2, a potent vasoconstrictor and promoter of platelet aggregation. But inhibiting COX-1 also depletes prostaglandin production, resulting in gut injury and contributing to the main adverse effects of aspirin including gastrointestinal (GI) bleeding and ulceration. 11,12 Aspirin also has other antiinflammatory and vasodilatory effects that may be important.12,13 Randomized clinical trials14,15 confirm that, in the high-risk setting of prevalent atherosclerotic cardiovascular disease (ASCVD) or acute myocardial infarction (MI), aspirin decreases ASCVD events (approximately 20% reduction in coronary events and total stroke) and, to a lesser extent, total and cardiovascular mortality, with similar results in men and women. On an absolute scale, aspirin use for secondary prevention reduced ASCVD events by about 1% to 2% per year (greater reduction for nonfatal than fatal events), at a cost of bleeding that was generally an order of magnitude less than the ASCVD benefit.14,16 However, the picture is less clear for patients without established ASCVD (primary prevention), which has resulted in inconsistent guideline recommendations from various national and international organizations (Box). In 2014, the US Food and Drug Administration advised against aspirin use by patients to lower their risk of first heart attack or stroke unless it was prescribed by a health care professional and after a careful evaluation of the risks and benefits.24 This review focuses on advances in treatment and diagnosis that relate to the use of aspirin for primary prevention of cardiovascular disease, with discussion of additional benefits that relate to colorectal cancer, and evaluates the evidence base for recent clinical recommendations, including those of the 2016 US Preventive Services Task Force (USPSTF) (Box).17

Methods We identified English-language, peer-reviewed publications through searches of the electronic databases of MEDLINE and the Cochrane Database through April 2016 using the literature search terms “aspirin,” in combination with one of the following: “primary prevention,” “heart disease,” “stroke,” “cardiovascular disease,” E2

Key Points Question Which patients should be prescribed aspirin for the primary prevention of atherosclerotic cardiovascular disease? Findings In this review of advances in cardiovascular and bleeding risk assessment and the randomized clinical trial results for aspirin in primary prevention, the net cardiovascular benefit and the bleeding events increased as the absolute cardiovascular risk increased, but the benefits exceeded the risks among individuals with higher cardiovascular risk (approximate 10-year risk ⱖ10%). The Aspirin-Guide is a clinical decision making support tool (app for mobile devices ) with internal risk calculators to help clinicians with this dual assessment, and incorporates age- and sex-specific guidance based on randomized clinical trial results and secondary considerations for colorectal cancer prevention. Meaning For the primary prevention of cardiovascular disease, decisions regarding aspirin use should be individualized, balancing the benefit to risk ratio. This can be facilitated by a free and readily-available evidence-based clinical decision support tool.

“mortality,” “cancer,” “clinical trials.” Bibliographies from these references as well as meta-analyses of these randomized clinical trials, were also reviewed. We also reviewed the studies in the relevant systematic reviews on aspirin from the 2009 and 2016 USPSTF recommendations.

Advances in Treatment Randomized Clinical Trials and Meta-analyses in Primary Prevention In individuals without clinical ASCVD, the benefit to risk ratio for aspirin should be carefully weighed because the absolute ASCVD risk is lower than that associated with patients who have been diagnosed with ASCVD and the increased risk of aspirin-related bleeding (GI bleeding and, rarely, hemorrhagic stroke) is more closely matched with the potential for benefit.25 In the 2016 USPSTF systematic evidence review of the major aspirin primary prevention clinical trials (11 trials, total N = 118 445) (Table 1),17 aspirin significantly reduced nonfatal MI (22%), cardiovascular mortality (6%), and allcause mortality (6%), with a nonsignificant reduction in nonfatal stroke (5%).9 In the 8 trials (N = 87 524) (Table 1) that examined doses of 100 mg or less daily, aspirin significantly reduced nonfatal MI (17%), nonfatal stroke (14%), with a nonsignificant reduction in all-cause mortality (5%).9 These results are consistent with the earlier 2009 Antithrombotic Trialists’ (ATT) individual-level metaanalysis (N = 6 trials, 95 456 individuals),14 that found a 12% relative risk reduction of total ASCVD events (absolute risk reduction 0.51% vs 0.57%) in primary prevention trials (compared with 20% in secondary prevention trials), as well as results from several more recent meta-analyses. Since the ATT meta-analysis, 4 additional recent randomized trials37-41 have evaluated aspirin in primary prevention on a background of contemporary statin and other preventative therapies (included in the USPSTF analysis) (Table 1).33-36 In each of these trials individually, aspirin did not significantly reduce the primary endpoints of total ASCVD (nonfatal and fatal events), raising questions about the use of aspirin for primary prevention. However, reductions in nonfatal ASCVD events were seen in some

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Aspirin for Primary Prevention of Atherosclerotic Cardiovascular Disease

of these recent trials, although they may have been underpowered to detect significant differences in these events and had lower than expected incidence rates.

Cardiovascular Mortality In individuals without ASCVD, there has been little or no benefit from aspirin in reducing cardiovascular mortality (Table 1). However, the smaller reduction in cardiovascular mortality in primary prevention trials has to be viewed in the context of several important points: (1) recent advances in contemporary treatments (including antiplatelet and other regimens) and interventions (eg, revascularization and thrombolysis) for both MI and stroke, which have resulted in lower ASCVD death rates; (2) cross-contamination by crossover to active aspirin among individuals in the control arms once a nonfatal ASCVD event occurs, resulting in attenuation of the relative risk reduction of aspirin vs control for fatal ASCVD events; (3) lower absolute mortality rates in primary vs secondary prevention populations, which would necessitate much longer follow-up periods than the mean follow-up in these trials (5 to 10 years); and (4) significant reductions in nonfatal ASCVD events (MI and stroke) with aspirin in primary prevention populations would be expected to result in lower cardiovascular mortality if the duration of follow-up were adequate, because individuals with prior MI or stroke are at the highest risk for cardiovascular mortality.

Baseline ASCVD Risk There is a continuum of risk from primary to secondary prevention, and it is uncertain where along this continuum lies the threshold level of risk that warrants aspirin use in patients without clinical ASCVD (ie, when benefit exceeds risk). Importantly, the primary prevention trials reported so far have mostly enrolled subjects with low or very low estimated baseline ASCVD risk, with more than 90% of participants having an estimated risk of less than 1% per year (10-year risk