Millions of persons worldwide take aspirin on a daily basis for the prevention and treatment of cardiovascular disease. Aspirin inhibits platelets by irreversibly inactivating cyclooxygenase-1, thereby blocking the generation of thromboxane A₂, a potent vasoconstrictor and platelet agonist. Despite decades of research, some fundamental questions about aspirin have yet to be definitively answered. In this issue, 2 studies (1, 2) shed light on 2 of these key questions: What is the optimal dose of aspirin to administer to patients for secondary prevention and treatment of established cardiovascular disease and in whom, and when should aspirin be used for prevention of cardiovascular events in persons with no history of cardiovascular disease (primary prevention)?

As background, the Antithrombotic Trialists' Collaboration overview (3) found that antiplatelet therapy (chiefly aspirin) reduced the risk for a subsequent vascular event by about one quarter and vascular death alone by about 15%. Although most of the trials evaluating the effects of aspirin were performed before the widespread use of other effective therapies, such as statins, antihypertensives, and invasive vascular procedures, the combined evidence from these trials is compelling and has led to the universal recommendation of aspirin as standard therapy in patients with established vascular disease. However, because the dose of aspirin in these trials varied from as high as 1500 mg/d to as low as 50 mg/d, the optimal aspirin dose has been uncertain. In an effort to understand the impact of aspirin dosing, the Antithrombotic Trialists' Collaboration overview indirectly compared trials of different aspirin doses versus placebo and found that the relative benefit of aspirin was no greater in the trials of higher doses of aspirin than in trials of lower doses (3). Further observational analyses of aspirin dose in the CURE (Clopidogrel in Unstable angina to prevent Recurrent ischemic Events) trial (4, 5) and BRAVO (Blockade of the GP IIb/IIIa Receptor to Avoid Vascular Occlusion) trial (6) in acute coronary syndromes demonstrated that bleeding risks increase with increasing aspirin dose without any concomitant improvement in efficacy. These data seem to support the use of lower doses of aspirin.

With this background, Steinhubl and colleagues (1) present a carefully performed observational analysis evaluating aspirin dose from the large CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) study. The CHARISMA study was a double-blind, randomized trial of long-term clopidogrel (75 mg/d) versus placebo in patients age 45 years or older who had established atherosclerotic disease or were asymptomatic but at high risk because of a combination of risk factors (7). Aspirin was given to all patients in the trial at a dose of 75 to 162 mg/d and was determined locally by the attending physician. In pairwise adjusted comparisons between different doses, the hazard ratios for efficacy and for bleeding were not different than 1.0, which means that the doses were equivalent for efficacy and harm. In addition, the investigators did not find a significant trend toward higher bleeding events or lower ischemic events with increasing doses of aspirin in the combined (aspirin and placebo groups) population. Although the unadjusted rate of ischemic events was higher with higher aspirin doses in the clopidogrel group, these rates did not differ after statistical adjustment for differences between the patients receiving the various doses.

In the context of previous studies, the CHARISMA analysis supports the notion that higher doses of aspirin do not lead to improved efficacy and may be associated with more bleeding. Indeed, CHARISMA extends earlier observations made in the CURE trial because the median follow-up of 28 months is more than twice as long, allowing a more realistic evaluation of the efficacy and safety of different aspirin doses for cardiovascular disease prevention. Nevertheless, like previous analyses of aspirin dose, the CHARISMA analysis is based on post hoc, nonrandomized comparisons and is thus subject to bias, especially confounding by indication, whereby unmeasured factors that influence the choice of aspirin dose also influence the rates of vascular disease outcomes and bleeding. A randomized trial is needed to confirm these findings. The CURRENT-OASIS 7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent Events and Optimal Antiplatelet Strategy for Interventions) trial will be the first large-scale randomized trial to directly compare aspirin doses (8). The trial is a 2 x 2 factorial study, with the first randomization to high-dose versus standard-dose clopidogrel and the second randomization to daily high-dose (>=300 mg) versus low-dose (<=100 mg) aspirin. The trial will randomly assign approximately 25 000 patients, and the results are expected later this year (9).

In the second article, the U.S. Preventive Services Task Force (USPSTF) (2) updates its 2002 recommendations on the use of aspirin for the primary prevention of coronary heart disease. The 2002 USPSTF recommendations (10) focused on establishing the risk for future coronary heart disease events and for bleeding in individual patients in order to identify those who would derive net benefit from aspirin. The recommendations were largely based on 5 randomized trials, only 2 of which enrolled women. The new recommendations in this issue attempt to incorporate the results of the landmark Women's Health Study (WHS) and a new sex-based meta-analysis of aspirin trials (11, 12). The WHS was a randomized, double-blind trial of low-dose aspirin (100 mg every other day for a mean of 10.1 years) versus placebo in 39 876 women age 45 years or older (mean age, 55 years). The WHS trial found, somewhat unexpectedly, that aspirin had no overall effect on the risk for the primary outcome of cardiovascular death, myocardial infarction (MI), or stroke. Although aspirin did not reduce rates of MI and death, the risk for stroke decreased by 17% (relative risk, 0.83 [95% CI, 0.69 to 0.99]), accounted for mainly by a 24% reduction in ischemic stroke (relative risk, 0.76 [CI, 0.63 to 0.99]), with a modest, statistically nonsignificant increase in hemorrhagic stroke (relative risk, 1.24 [CI, 0.82 to 1.87]) (11).

On the basis of these new data, the 2009 version of the USPSTF recommendation encourages men age 45 to 79 years and women age 55 to 79 years to use aspirin when the potential benefit of a reduction in MI for men or stroke for women outweighs the potential harm of an increase in gastrointestinal hemorrhage. The USPSTF guidelines do not recommend aspirin for men under age 45 years or women under age 55 years, because of a paucity of data showing aspirin's benefit in these groups.

Is it reasonable to recommend the same drug for the prevention of 1 type of event in men and another in women? Although data support this in the case of aspirin, the concept is still debatable. It could be argued that the WHS enrolled a relatively low-risk population, which had too few cardiovascular events to detect a true difference if it existed. For example, only 10% of women were older than 65 years, 76% had 0 or 1 cardiac risk factor, and the 10-year risk for a major cardiovascular event was only about 2.6%. The latter is well below the threshold risk for starting aspirin therapy according to the recommendation of the 2002 USPSTF guideline. Furthermore, in women older than 65 years, the WHS did demonstrate a clear 26% reduction in MI (P = 0.008): the same risk reduction as occurred in primary prevention trials of aspirin in men. Thus, some would argue that, in some respects, the USPSTF's 2002 recommendations may still apply—that is, aspirin should be used in all individuals, men and women, with a reasonable risk for a major cardiovascular event (about 6% to 10% over 10 years). On the other hand, the WHS clearly demonstrated that, even in this low-risk population of women, stroke was a much more common event than MI (about 1.4 strokes for every MI), making a strong argument for using stroke risk reduction as the primary rationale for prescribing aspirin in women. Also, if aspirin is recommended to prevent 1 type of event (for example, stroke in women), the patient will also derive any benefit that aspirin may provide in preventing other vascular events (for example, MI).

A key issue for the practicing clinician is when to recommend against taking aspirin. Consider 1 possible rule of thumb: If the rate of harm (for example, increase in risk for bleeding events) exceeds the rate of benefit (for example, reduction in risk for vascular events), recommend against taking aspirin. However, this rule assumes that patients place the same value on avoiding a bleeding event as they do on avoiding a stroke or MI. Depending on the site of bleeding, some patients would rather avoid a stroke than avoid a bleeding event and would prefer to take aspirin. A valuable feature of the new USPSTF recommendations is the emphasis on shared decision making: discussing the benefits and risks of initiating aspirin and individualizing decision making to the specific patient or situation. The 1 group of patients that should absolutely avoid aspirin is persons who are at relatively high risk for intracranial bleeding.

The USPSTF has provided us with an important document that is clear and user-friendly for the busy clinician. Aspirin continues to be underused, and the routine incorporation of the USPSTF's recommendations into the daily practice of clinicians will no doubt increase the use of aspirin and, in turn, prevent many thousands of cardiovascular events every year.

  References

1. Steinhubl SR, Bhatt DL, Brennan DM, Montalescot G, Hankey GJ, Eikelboom JW; et al. CHARISMA Investigators. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med. 2009;150:379-86.

2. U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;150:396-404.

3. 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;324:71-86. [PMID: 11786451].

4. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL; et al. Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108:1682-7. [PMID: 14504182].

5. Jolly SS, Pogue J, Haladyn K, Peters RJ, Fox KA, Avezum A, et al. Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: insights from the PCI-CURE study. Eur Heart J. 2008. [PMID: 18819961].

6. Topol EJ, Easton D, Harrington RA, Amarenco P, Califf RM, Graffagnino C; et al. Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion Trial Investigators. Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease. Circulation. 2003;108:399-406. [PMID: 12874182].

7. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE; et al. CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706-17. [PMID: 16531616].

8. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KA, Granger CB; et al. CURRENT-OASIS 7 Steering Committee. Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J. 2008;156:1080-1088. [PMID: 19033002].

9. Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS7). Accessed at http://www.clinicaltrials.gov/ on 17 February 2009.

10. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:161-72. [PMID: 11790072].

11. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE; et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352:1293-304. [PMID: 15753114].

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