US Pharm. 2016;41(2):22-25.
ABSTRACT: The benefit of aspirin use for secondary prevention of cardiovascular disease is well established; the efficacy of aspirin use for primary prevention, however, is less evident. Trials evaluating aspirin for primary prevention provide little direction regarding when it should be used. Certain populations, such as patients who are at higher risk for cardiovascular disease or have multiple risk factors, may be candidates for low-dose aspirin therapy when the benefits of taking aspirin for cardiovascular protection outweigh the harms. Other high-risk populations, such as patients with diabetes and those with a 10-year cardiovascular risk exceeding 10%, may also benefit from low-dose aspirin therapy.
Aspirin has long been used for its anti-inflammatory and analgesic properties, and more recently it has been used for its antithrombotic effect in reducing cardiovascular disease risk. Making a recommendation for aspirin use in secondary prevention for most patients is clear: Aspirin is a mainstay of long-term drug therapy to reduce the risk of myocardial infarction (MI), stroke, and death related to vascular causes following a cardiovascular event. However, the use of aspirin for primary prevention in patients with no history of cardiovascular disease needs to be clarified. This article will provide a detailed examination of the evidence surrounding this clinical controversy.
Aspirin as an Antiplatelet Agent
Aspirin has been widely studied and used in both the treatment and the prevention of a number of conditions. Aspirin is well known as an analgesic, anti-inflammatory, and antipyretic. Studies evaluating outcomes in patients taking aspirin have found decreased rates of cardiovascular disease and death, hypothesized to be due in part to aspirin’s antiplatelet effects. The main mechanism of action of aspirin—the inactivation of cyclooxygenase (COX)-1 and COX-2—is responsible for the majority of aspirin’s effects. Platelet inhibition, which primarily results from irreversible inhibition of prostaglandins and platelet-generated thromboxane A2, is a COX-1–mediated effect.1 Other benefits of aspirin that might play a role in decreasing cardiovascular risk include decreasing proinflammatory markers and increasing the formation of the vasodilator nitric oxide.2
The effects of platelet inhibition are both time-dependent and dose-dependent. Aspirin doses used in clinical trials have typically been between 75 mg and 500 mg, with “low-dose” usually defined as 75 to 325 mg daily. However, because of its irreversibility, aspirin taken daily produces a cumulative antithrombotic effect even at low doses1; therefore, the most common dose recommendation when aspirin is taken for cardiovascular disease prevention based on availability in the United States is 81 mg (equivalent to one baby aspirin). When lower doses are given, many of the adverse effects associated with aspirin use, such as gastrointestinal upset or bleeding, may also be minimized. Higher doses provide no additional efficacy.3
Numerous studies have demonstrated the benefits of aspirin in secondary prevention of cardiovascular disease. The Antithrombotic Trialists’ (ATT) Collaboration conducted a meta-analysis of primary and secondary prevention trials that compared serious vascular events in patients taking aspirin versus placebo. The use of low-dose aspirin for secondary prevention corresponds to an approximate 20% decrease in atherosclerotic complications associated with MI, stroke, and transient cerebral ischemia.4 This meta-analysis further supports the notion that aspirin provides significant benefit in cardiovascular risk reduction in patients at highest risk for another cardiovascular event.
Evidence for Aspirin in Primary Cardiovascular Disease Prevention
There is less evidence guiding the use of aspirin for primary prevention of cardiovascular disease. Six primary prevention trials with 95,000 patients at low risk for cardiovascular events were included in the ATT meta-analysis. In the aspirin group, 1,671 events occurred during 330,000 person-years (0.51% per year), compared with 1,883 events (0.57% per year) in the control group. This represents an absolute risk reduction of 0.06% per year or a relative risk reduction of 12% for serious vascular events (0.51% for aspirin vs. 0.57% for placebo per year, P = .0001). It was concluded that this statistically significant reduction was largely due to a reduction in first nonfatal MI (0.18% for aspirin vs. 0.23% for placebo per year, P <.0001). Furthermore, no significant reduction in overall vascular mortality was found in patients taking aspirin for primary prevention (0.19% for aspirin vs. 0.19% for placebo per year, P = .7). Because of its antiplatelet effects, a clinically important adverse event of aspirin is major bleeding. In the six primary prevention trials, aspirin administration significantly increased the likelihood of bleeding, including major gastrointestinal bleeds and extracranial bleeds (0.10% for aspirin vs. 0.07% for placebo per year; relative risk [RR] 1.54 [1.30-1.82]; P <.0001).4
In a 2012 meta-analysis, Seshasai and colleagues assessed the use of aspirin in the primary prevention of cardiovascular and nonvascular outcomes, including cancer.5 This meta-analysis included nine good-quality randomized, controlled trials with a total of 102,621 participants. The researchers found a relative risk reduction of 10% in total cardiovascular events (odds ratio [OR] 0.90; 95% CI, 0.85-0.96; number needed to treat [NNT] = 120), which was mostly attributable to the statistically significant reduction in nonfatal MI (OR 0.80; 95% CI, 0.67-0.96; NNT = 162). Interestingly, when data from trials published after 2000 were analyzed, aspirin was no more effective than placebo at reducing the risk of nonfatal MI. The investigators suggested that aspirin may have less benefit than previously thought, especially when more effective cardiovascular disease risk-reduction modalities, including statins, antihypertensive medications, and smoking cessation, are considered. Furthermore, there were no statistically significant reductions in fatal MI, stroke, cardiovascular death, or all-cause mortality. There was also no convincing evidence to support aspirin use to reduce cancer mortality (OR 0.93; 95% CI, 0.84-1.03). Individuals taking aspirin had a statistically significant increased risk of total bleeding events (OR 1.70; 95% CI, 1.17-2.46) and nontrivial bleeding events (OR 1.31; 95% CI, 1.14-1.50). The benefit of aspirin for primary prevention was likely offset by the increased risk of bleeding. The NNT in order to prevent one nonfatal MI over 6 years was 162. In that same time frame, 120 individuals would need to be treated with aspirin in order to avoid one cardiovascular event. Conversely, one individual would experience a nontrivial bleed for every 73 persons administered aspirin over a 6-year period. Overall, results are consistent with those observed in the ATT Collaboration meta-analysis conducted in 2009.5
In 2015, the U.S. Preventive Services Task Force (USPSTF) published the most recent meta-analysis assessing the use of aspirin in primary prevention.3 Ten randomized, controlled trials (two considered to be of good quality and eight of fair quality) were included. The researchers found that aspirin reduced the risk of major cardiovascular events (i.e., total MI, total stroke, and cardiovascular mortality) by 11% (RR 0.89; 95% CI, 0.84-0.95). As was found in the two previous meta-analyses, this risk reduction was concluded to be greatly influenced by nonfatal MI (RR 0.80; 95% CI, 0.72-0.88). In all 10 trials, aspirin use failed to significantly reduce cardiovascular mortality. Unlike previously conducted meta-analyses, the USPSTF meta-analysis examined the dosages of aspirin administered to participants. Aspirin dosages ranging from 100 mg every other day to 650 mg daily effectively reduced nonfatal MI. Interestingly, the trials in which patients were given aspirin 100 mg or less resulted in a statistically significant reduction in nonfatal stroke (RR 0.85; 95% CI, 0.76-0.96). This reduction was not demonstrated in trials using higher dosages. The only consistent subgroup trend identified by investigators was that older patients showed a greater relative risk reduction in total MI/coronary events. Otherwise, data supporting the use of aspirin for primary prevention in other specific subgroups of interest were inconsistent. The USPSTF researchers concluded that their results confirmed the conclusions drawn from several other published meta-analyses.3
Based on the primary literature, several organizations have proposed recommendations for aspirin use in primary prevention of cardiovascular events. The three meta-analyses conducted by the ATT Collaboration, Seshasai and colleagues, and the USPSTF broadly recommend individualized treatment and the use of clinical judgment based on the risks versus benefits of aspirin administration.3-5 Seshasai and colleagues recommend against the routine use of aspirin in primary prevention; they also caution against using current practice guidelines, since recent data suggest that aspirin may be even less effective than previously thought for the reduction of nonfatal MI events.5 Additionally, there are newer, more effective treatment options for lowering cardiovascular disease risk. When aspirin is considered for primary prevention, the benefit of reducing the risk of the first nonfatal MI must be weighed against the absolute risk of major bleeding with long-term use. Because cardiovascular events are conceivably more serious than bleeding, it is necessary to consider aspirin therapy, especially in patients who possess risk factors or are at high risk for CVD. The data from these meta-analyses suggest that the higher the risk of cardiovascular events, the greater the potential for benefit.3-5 The USPSTF and Seshasai and colleagues recommend that additional trials be conducted to determine whether specific subgroups, such as patients with diabetes, may receive more benefit from aspirin use for primary prevention.3,5
The CHEST Guidelines (9th edition) recommend the use of aspirin for primary prevention based on data from trials suggesting that aspirin reduces total mortality, regardless of cardiovascular risk profile, if taken for more than 10 years.6 Therefore, for persons aged 50 years and older without symptomatic cardiovascular disease, low-dose aspirin 75 to 100 mg daily is suggested over no aspirin therapy (Grade 2B). The guidelines acknowledge that an individual’s cardiovascular profile must be taken into consideration when determining the appropriateness of commencing long-term aspirin use. For patients who fall into the moderate- to high-risk group for cardiovascular events, the reduction in nonfatal MI is likely proportional to the increase in major bleeds. The guidelines further emphasize the importance of individualizing treatment and including the patient in the decision-making process.6
The American Diabetes Association (ADA) recently released its 2016 Standards of Medical Care in Diabetes that included updated recommendations with regard to the use of aspirin for primary prevention.7 Based on the current primary literature, three recommendations were established:
1. Consider aspirin therapy (75-162 mg/day) as a primary prevention strategy in patients with type 1 or 2 diabetes who are at increased cardiovascular risk (10-year risk >10%). This includes most men and women with diabetes aged 50 years who have at least one additional major risk factor (family history of premature atherosclerotic cardiovascular disease, hypertension, smoking, dyslipidemia, or albuminuria) and are not at increased risk of bleeding (Level of Evidence C).
2. Aspirin should not be recommended for atherosclerotic cardiovascular disease prevention in adults with diabetes at low atherosclerotic cardiovascular disease risk (10-year atherosclerotic cardiovascular disease risk <5%), such as men and women with diabetes aged <50 years with no major additional atherosclerotic cardiovascular disease risk factors, as the potential adverse effects from bleeding offset the potential benefits (Level of Evidence C).
3. In patients with diabetes aged <50 years with multiple other risk factors (e.g., 10-year risk 5%-10%), clinical judgment is required (Level of Evidence E).
The ADA is currently following the ACCEPT-D and ASCEND trials, two ongoing primary prevention trials conducted in patients with diabetes. ACCEPT-D is an open-label trial comparing aspirin 100 mg with placebo in diabetic patients concomitantly taking simvastatin. Several predetermined subgroups, such as older versus younger patients and baseline use of statins, will be studied with the intent to detect differences in the effect of aspirin for primary prevention. ASCEND is a randomized, placebo-controlled trial in which patients older than 40 years with type 1 or 2 diabetes and without a previous vascular event will be studied to determine the effects of aspirin 100 mg versus placebo. A 2 2 factorial design will be used to determine how omega-3 fatty acid supplementation affects cardiovascular outcomes. The investigators aim to provide additional information regarding use of aspirin in specific populations with diabetes.8
Conclusion and Recommendations
Results from recent trials and meta-analyses have consistently found that aspirin reduces the risk of cardiovascular events by approximately 10% to 12%. This risk reduction has been largely attributed to the statistically significant reduction in nonfatal MI. No statistically significant reductions in fatal MI, stroke, cardiovascular death, or all-cause mortality have been identified in patients taking aspirin for primary prevention. Furthermore, it is well documented that aspirin increases the risk of bleeding. Based on these results, more convincing research is needed on the use of aspirin in primary cardiovascular disease prevention. The cardiovascular benefit of aspirin must be weighed against the risk—namely, bleeding. A shared decision-making process between the patient and the healthcare provider should be implemented when the net benefit of aspirin for primary prevention is being considered.
1. Patrono C. Low-dose aspirin in primary prevention: cardioprotection, chemoprevention, both, or neither? Eur Heart J. 2013;34:3403-3411.
2. Hennekens CH, Sechenova O, Hollar D, Serebruany VL. Dose of aspirin in the treatment and prevention of cardiovascular disease: current and future directions. J Cardiovasc Pharmacol Ther. 2006;11:170-176.
3. Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for the Primary Prevention of Cardiovascular Events: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 131. AHRQ Publication No. 13-05195-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
4. Antithrombotic Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849-1860.
5. Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172:209-216.
6. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e637S–e668S.
7. ADA. Standards of Medical Care in Diabetes—2016. 8. Cardiovascular disease and risk management. Diabetes Care. 2016;39(suppl 1):S60-S71.
8. Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Diabetes Care. 2010;33:1395-1402.
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