EDITORIAL

Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.

Hemorrhagic Complications Associated With Aspirin

An Underestimated Hazard in Clinical Practice?
Jolanta M. Siller-Matula, MD, PhD
SPIRIN IS WIDELY USED FOR PRIMARY AND SECONDary prevention of cardiovascular events. Substantial scientific evidence supports the beneficial role of aspirin in reducing the risk of cardiovascular events in secondary prevention.1,2 In a meta-analysis including 135 000 patients considered to be at high risk for vascular events (90% with known coronary artery disease, cerebral artery disease, or peripheral artery disease), aspirin was associated with a reduced relative risk of vascular events (myocardial infarction, stroke, and vascular death) by 22% (absolute risk reduction [ARR], 2.5%) but also was associated with an increased relative risk of major extracranial bleeding events by 60% (absolute risk increase [ARI], 0.42%).1 In another meta-analysis, aspirin used for secondary prevention was associated with a reduced relative risk of myocardial infarction by 31%, ischemic stroke by 22%, and cardiovascular death by 13%.2 For a hypothetical group of 10 000 patients, aspirin used for secondary prevention would be expected to prevent approximately 250 major vascular events (number needed to treat [NNT], 40) but would be expected to cause approximately 40 major extracranial bleeding events (number needed to harm [NNH], 240). Thus, the net benefit of aspirin for secondary prevention would substantially exceed the bleeding hazard. For 6 major vascular events prevented, approximately 1 major bleeding event would occur; therefore, the value of aspirin for secondary prevention is not disputed. In contrast, there is an ongoing debate surrounding use of aspirin for primary prevention. Published evidence does not support the assumption that the balance of benefits and harms of aspirin use is clearly favorable for primary prevention. In a meta-analysis using individual patient data from 6 randomized trials including 95 000 patients, aspirin was associated with a reduced relative risk of vascular events by 12% (ARR, 0.07%), but also was associated with an increased relative risk of extracranial bleeding events by 54% (ARI, 0.03%). Although aspirin was associated with reduced relative risk of myocardial infarction by 23% (ARR,

0.05%), there was no association between aspirin use and risk of stroke or vascular death.2 The proportional reduction of vascular events by aspirin in primary prevention was not affected by the predicted risk of coronary heart disease, age, sex, hypertension, or diabetes.2 For a hypothetical group of 10 000 patients, aspirin use for primary prevention would be expected to prevent 7 major vascular events (NNT, 1430) and cause 1 hemorrhagic stroke and 3 major extracranial bleeding events (NNH, 2500). This suggests that for 2 major vascular events prevented, approximately 1 major bleeding event would occur. A meta-analysis that focused on primary prevention suggested that the effects of aspirin were sex-related: aspirin was associated with a reduced relative risk of stroke by 24% among women and reduced relative risk of myocardial infarction by 32% among men, but these risk reductions were offset by an increase in the relative risk of major bleeding events by 68% among women and 72% among men.3 Another meta-analysis4 and a randomized trial5 support the findings that the magnitude of benefit with aspirin in primary prevention is small and at least partially balanced by the magnitude of harm. Before these clinical trial data were available, the US Preventive Services Task Force recommended use of aspirin for men aged 45 to 79 years and for women aged 55 to 79 years when the potential benefit due to a reduction in myocardial infarction outweighs the potential harm due to an increase in gastrointestinal hemorrhage.6 These recommendations seem to be mainly based on evidence extrapolated from large trials of populations at high risk of vascular events, under the assumption that age confers an elevated risk of cardiovascular disease. In light of more recent reports,2,4,5 the new European guidelines on cardiovascular disease prevention7 do not recommend aspirin for primary prevention because of its unfavorable risk-to-benefit profile. In this issue of JAMA, findings from the study by De Berardis et al8 reinforce the European recommendations for aspirin use.7 The authors performed a population-based coAuthor Affiliation: Department of Cardiology, Medical University of Vienna, Vienna, Austria. Corresponding Author: Jolanta M. Siller-Matula, MD, PhD, Medical University of Vienna, Wa hringer Gu rtel 18-20, Vienna 1090, Austria (jolanta.siller-matula @meduniwien.ac.at).

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hort study to investigate the relationship between aspirin use and risk of major bleeding events in a large sample of 372 850 aspirin users and nonusers matched by a propensity score. The investigators report that aspirin use was associated with a 55% relative risk increase in major hemorrhagic events (both intracranial and gastrointestinal; ARI, 0.2%), which corresponds to an excess of 20 major bleeding events among 10 000 treated patients (NNH, 500). This is comparable with the relative risk estimates derived from meta-analyses of randomized trials.1,2 Because of the uncertainty of the risk-to-benefit ratio for use of low-dose aspirin in patients with diabetes, the authors also evaluated the high-risk subgroup of patients with diabetes, including 27 066 patients without aspirin use and 29 030 with aspirin use. Aspirin use was not associated with a greater risk of bleeding among patients with diabetes, although diabetes was independently associated with an increased incidence of major bleeding events (relative risk, 1.36). This observation highlights 2 important issues: decreased antiplatelet efficacy of aspirin in patients with diabetes and the overlap of risk factors that predict vascular and bleeding events. In previous studies, diabetes mellitus was associated with a 2- to 2.6-fold increased risk of ischemic events and simultaneously with a 1.25- to 1.5-fold increased risk of bleeding events.2,9,10 The decreased antiplatelet effect of aspirin in patients with diabetes (which occurs in up to 50% of patients11), might be due to diabetes associated factors: increased platelet turnover, increased fraction of immature platelets, or increased glycation of platelets. The high platelet reactivity corresponds to lower aspirin efficacy12 and could be a plausible explanation for a better safety profile. The effect of aspirin for primary prevention of cardiovascular disease in patients with diabetes is unclear because previous evidence suggested that aspirin was associated with a nonsignificant (10%) relative risk reduction of the composite of major cardiovascular events (ARR, 1.2%) with no effect on risk of myocardial infarction, stroke, cardiovascular death, or bleeding events.13 Therefore, aspirin appears to produce a modest-sized reduction in cardiovascular events; this reduction is not statistically significant, but may be clinically relevant. For a hypothetical group of 10 000 treated patients with diabetes, aspirin would be expected to prevent 120 major vascular events (NNT, 84). Two ongoing studies ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes; ISRCTN48110081) and ASCEND (A Study of Cardiovascular Events in Diabetes; ISRCTN60635500) should provide additional information concerning the safety and benefit profile of aspirin in patients with diabetes. Given the uncertainty concerning aspirin use for patients with diabetes, guidelines by the American Diabetes Association, the American Heart Association, and the American College of Cardiology Foundation recommend lowdose aspirin for primary prevention for adults with diabe2012 American Medical Association. All rights reserved.

tes who are at increased risk of cardiovascular disease (10year risk of vascular events 10%) and who are not at increased risk for bleeding (history of previous gastrointestinal bleeding or peptic ulcer disease or concurrent use of other medications that increase bleeding risk, such as nonsteroidal anti-inflammatory drugs or warfarin).14 In contrast, the European guidelines on cardiovascular disease prevention do not recommend aspirin use in patients with diabetes who do not have clinical evidence of atherosclerotic disease.7 The study by De Berardis et al8 also identified other risk factors associated with a higher baseline risk for bleeding events (age, sex, hypertension, use of other antiplatelet agents or anticoagulants, or history of previous cardiovascular events), which in part match the factors included in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) bleeding score.9 Because these factors that were associated with bleeding events largely overlap with established atherothrombotic risk factors, guidelines advocating the routine use of aspirin for primary prevention for individuals above a moderate level of risk of coronary heart disease should be carefully considered as this approach may not be advisable for all patients. This rationale seems reasonable especially considering data showing that the reduction of vascular events associated with aspirin use does not depend on the predicted risk of coronary heart disease.2 Perhaps the most important contribution of the study by De Berardis et al8 is the addition of a large number of patients (370 000) and especially of patients with diabetes (56 000) that far exceed the numbers included in previous analyses (135 000 and 11 000, respectively).1,14 Moreover, the report is important because the risk of bleeding associated with aspirin use was assessed in real-world patients (ie, in a less selected patient population than participants in randomized clinical trials). Nevertheless, like other population-based studies, the study by De Berardis et al8 has limitations. Although the authors attempted to compensate for differences between the groups by propensity matching, it is possible that residual confounding and unmeasured selection bias could account for some of the observed differences. Furthermore, aspirin-associated risks were assessed in the entire population of hospitalized patients, therefore different risk estimates for primary and secondary prevention could not be measured. A decision-making process based on balancing an individual patients risk of bleeding and ischemic events is difficult. The study by De Berardis et al8 underscores that the potential risk of bleeding should be carefully considered in decision making. Assessment of bleeding risk and of net clinical benefit will merit further emphasis as issues inherent to aspirin use also apply to more potent platelet inhibitors and anticoagulants; there is only a thin line between efficacy and safety, and the reduction in ischemic events comes at the
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cost of increased major bleedings.15 Therefore, future studies investigating the risks and benefits for individual patients appear to be mandatory to help physicians appropriately make recommendations about aspirin use for primary prevention.
Conflict of Interest Disclosures: The author completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Siller-Matula reported receiving speaker fees from Eli Lilly and AstraZeneca. REFERENCES 1. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86. 2. Baigent C, Blackwell L, Collins R, et al; Antithrombotic Trialists (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009; 373(9678):1849-1860. 3. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006;295 (3):306-313. 4. Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: a meta-analysis of randomized trials. JAMA. 2009;301(18):1909-1919. 5. Fowkes FG, Price JF, Stewart MC, et al; Aspirin for Asymptomatic Atherosclerosis Trialists. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA. 2010;303(9):841-848. 6. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150(6):396-404. 7. Perk J, De Backer G, Gohlke H, et al; Authors/Task Force Members; Other experts who contributed to parts of the guidelines; ESC Committee for Practice Guide-

lines (CPG); Document Reviewers. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) * Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR) [published online May 3, 2012]. Eur Heart J. doi:10.1093/eurheartj/ehs092. 8. De Berardis G, Lucisano G, DEttorre A, et al. Association of aspirin use with major bleeding in patients with and without diabetes. JAMA. 2012;307(21): 2286-2294. 9. Subherwal S, Bach RG, Chen AY, et al. Baseline risk of major bleeding in nonST-segment-elevation myocardial infarction: the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) Bleeding Score. Circulation. 2009; 119(14):1873-1882. 10. Sarwar N, Gao P, Seshasai SR, et al; Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies [published correction appears in Lancet. 2010;376(9745):958]. Lancet . 2010;375(9733):22152222. 11. Angiolillo DJ. Antiplatelet therapy in diabetes: efficacy and limitations of current treatment strategies and future directions. Diabetes Care. 2009;32(4): 531-540. 12. Siller-Matula JM, Delle-Karth G, Christ G, et al. Dual non-responsiveness to antiplatelet treatment is a stronger predictor of cardiac adverse events than isolated non-responsiveness to clopidogrel or aspirin [published online February 1, 2012]. Int J Cardiol. doi:10.1016/j.ijcard.2012.01.016. 13. De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ. 2009;339:b4531. 14. Pignone M, Alberts MJ, Colwell JA, et al; American Diabetes Association; American Heart Association; American College of Cardiology Foundation. Aspirin for primary prevention of cardiovascular events in people with diabetes. J Am Coll Cardiol. 2010;55(25):2878-2886. 15. Siller-Matula JM, Krumphuber J, Jilma B. Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases. Br J Pharmacol. 2010;159(3):502-517.

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