This report was reviewed for medical and scientific accuracy by Robert J. Hilkert, MD, FACC, Associate Professor of Medicine, Associate Fellowship Director, Cardiovascular Diseases, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

Cardiovascular disease (CVD) is still the leading cause of death in the United States and most developed countries, accounting for nearly 960,000 deaths annually in the United States alone.¹ This is 40.1% of all deaths or one of every 2.5 deaths, a staggering statistic. Along with lifestyle and medical management, the use of prophylactic aspirin in both acute and chronic care has become an integral component as the preferred treatment option in preventing CVD. Since ISIS-2,² one of the first clinical trials to demonstrate that aspirin alone can reduce mortality in acute myocardial infarction patients, aspirin has become one of the most important agents for preventing the adverse outcomes of CVD and has been the subject of hundreds of clinical studies and meta-analyses.

Despite its proven efficacy for primary and secondary prevention of CVD, prophylactic aspirin is underutilized in patients with CVD. In 2000, Stafford reported that although aspirin use in patients with coronary heart disease increased from 5.0% in 1980 to 26.2% in 1996,³ its use remains suboptimal. Moreover, despite its extensive clinical investigation, the critically important issue of the optimal dose of aspirin for primary prevention of CVD continues to be the subject of debate. The American Diabetes Association treatment guidelines on aspirin use in diabetes concludes that a 75 mg dose of aspirin is just as effective as higher doses of aspirin in inhibiting thromboxane synthesis and recommends aspirin therapy for primary prevention in diabetic patients.⁴ The American Heart Association recommends a daily dose of 75 to 160 mg of aspirin stating this dose is as effective as higher doses and this dose should be used in patients with a 10-year risk of coronary heart disease of ≥10%⁵ using the Framingham risk algorithm⁶. Thus, treatment guidelines would suggest the optimal dose of aspirin for prevention of CVD would be between 75 and 160 mg [81 to 162 mg in the United States].

This Cardiology Express Report will review the latest evidence-based medicine on prophylactic low-dose aspirin use highlighted during a recently held meeting of nationally, recognized cardiologists brought together to discuss guidelines for the use of aspirin in cardioprotective therapy.⁷

Efficacy Established for Low-dose Aspirin

The Antithrombotic Trialists' Collaboration (ATC) meta-analysis provided critical information about efficacy according to aspirin dose.⁸ The ATC meta-analysis determined the effects of antiplatelet therapy on serious vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death) among patients at high risk of occlusive vascular events. The meta-analysis reviewed 287 clinical studies involving 135,000 patients in comparisons of antiplatelet therapy versus control and 77,000 patients in comparisons of different antiplatelet regimens.

The ATC meta-analysis found that antiplatelet therapy reduced the risk of any serious vascular event by approximately 25%; non-fatal myocardial infarction was reduced by approximately 33%, non-fatal stroke by 25%, and vascular mortality by approximately 17%. Among the trials analyzed, aspirin was the most widely studied antiplatelet medication. Also, several dose ranges of aspirin were used throughout the trials, giving investigators an opportunity to compare antiplatelet efficacy at more specific doses of aspirin.

Three trials including 3,570 patients directly compared daily aspirin doses of <75 mg to ≥75 mg. Overall, there was no significant difference in efficacy between the aspirin regimens (Table 1). However, aspirin doses of <75 mg were less widely studied than daily aspirin doses of 75 mg to 150 mg. The proportional reduction in vascular events was 19% with aspirin 500 mg to 1,500 mg daily, 26% with aspirin 160 mg to 325 mg daily, and 32% with aspirin 75 mg to 150 mg daily. However, daily aspirin doses <75 mg seemed to have a somewhat smaller proportional reduction of 13% (P = .05 for trend). This finding along with fewer clinical studies involving aspirin doses of <75 mg compared to 75 to 150 mg led the ATC meta-analysis to support daily doses of aspirin in the range of 75 to 150 mg for long-term prevention of serious vascular events in high-risk patients. However, in acute settings, an initial loading dose of at least 150 mg may be required.

Putting the results of the ATC meta-analysis into context, Eric Topol, MD, Provost and Chief Academic Officer, Chairman, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio stated, "All the evidence suggests that doses in excess of 75 mg are associated with being the most efficacious, and in terms of efficacy, there is no advantage of dosing aspirin higher than 162 mg." Concurring with Dr. Topol, Steven Steinhubl, MD, Associate Director, Cardiac Center Lab, Associate Professor, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina stated, "I believe the optimal dose of aspirin is between 81 and 162 mg. The data are very compelling and there is no reason to think that a higher dose is more effective."

As a result of emerging data supporting the use of lower doses of aspirin and in an effort to minimize bleeding associated with aspirin use, the CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) study will assess the efficacy of clopidogrel 75 mg once daily in combination with aspirin 75 mg to 162 mg compared to daily aspirin alone (75 to 162 mg).⁹ The phase 3 study will compare the efficacy of the 2 treatment arms in preventing the occurrence of major cardiovascular complications (stroke, myocardial infarction, cardiovascular death) in high-risk patients receiving low-dose aspirin therapy. Additional safety endpoints include the incidence of fatal or severe bleeding.

Commenting on the study design, Deepak L. Bhatt, MD, Director, Interventional Cardiology Fellowship, Cleveland Clinic foundation, Cleveland, Ohio, and the principal investigator for CHARISMA, advised, "We had concluded that in terms of efficacy and safety, lower dose aspirin [75 to 162 mg] was the right dose. And that decision is supported by the ATC meta-analysis^[8] and the CURE^[10] data."

Greater Safety Associated with Low-dose Aspirin

Gastrointestinal adverse effects of aspirin have been well documented in medical literature; however, there is evidence to support a dose-dependent effect of aspirin on gastrointestinal toxicity, with higher doses of aspirin associated with higher gastrointestinal risk.¹¹ Recent studies have confirmed the association between higher aspirin doses and increased gastrointestinal intolerability.

A meta-analysis presented at the November 2002 Scientific Sessions of the American Heart Association by Serebruany et al,¹² evaluated 338,191 patients enrolled in 50 randomized controlled trials to investigate bleeding complications associated with antiplatelet agents. Only those studies in which patients had clinical follow-up for at least 1 month and in which a full description of bleeding episodes was reported were included. Antiplatelet agents were divided into 6 groups: aspirin <100 mg; aspirin >100 mg; dipyridamole; thienopyridines (ticlopidine, clopidogrel); intravenous glycoprotein IIb/IIIa inhibitors; and oral glycoprotein IIb/IIIa inhibitors.

Despite substantial differences in the reporting patterns of bleeding complications, low dose aspirin (<100 mg) was associated with the lowest risk of bleeding complications (Table 2). The overall frequency of new bleeding complications with <100 mg aspirin was 3.6% (n = 12,639) followed by dipyridamole at 6.7% (n = 3304). The incidence of bleeding complications associated with aspirin doses >100 mg was 9.5% (n = 24,285) which was slightly higher than that observed for thienopyridines (8.5%; n = 19,191). The glycoprotein IIb/IIIa inhibitors were associated with the highest rates of bleeding complications (44.6%, n = 11,057).

An analysis of aspirin dose and bleeding events in the CURE study was recently presented at the 2002 European Society of Cardiology Congress.¹³ In the CURE study,¹⁰ 12,562 patients with acute coronary syndromes without ST-segment elevation were randomized to clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo in addition to aspirin for 3 to 12 months. Based on aspirin dosage, the patients were classified into 4 groups: <100 mg, 100-150 mg, 151-300 mg, and >300 mg daily. This retrospective review showed that the lowest incidence of major life-threatening bleeding occurred among patients receiving the lowest doses of aspirin, with the incidence of bleeding increasing in a dose-related fashion (Table 3). Among patients taking aspirin <100 mg daily, the risk of bleeding was 1.92%, rising to 2.24% with 100-150 mg daily, to 3.32% with 151-300 mg daily and to 3.77% with >300 mg daily. The incidence of bleeding also increased in a dose-dependent fashion when aspirin was combined with clopidogrel, and the bleeding risks were even higher (2.82%-4.65%, respectively).

The findings from the two studies drew comment from Dr. Topol. "The two studies together-with an enormous number of aspirin-treated patients-indicates a true association between aspirin dose and bleeding. Interestingly, with the lowest dose, we still maintain efficacy. That's not what a lot of people would intuitively think."

Conclusion

Aspirin plays a critical role in the prevention of cardiovascular disease. Clinical evidence has shown low-dose aspirin to be effective in reducing the risk of ischemic events, especially in high-risk patients although low-dose aspirin therapy remains underutilized. Even though bleeding can occur, low-dose aspirin (ie, 81 mg) has been shown to lessen the risk of bleeding. Current clinical guidelines from the American Heart Association and the American Diabetes Association also support the use of low-dose aspirin (81 to 162 mg) for primary prevention of cardiovascular disease.

References

1. American Heart Association. 2002 Heart and Stroke Statistical Update. American Heart Association, Dallas, Texas.
2. Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. BMJ. 1998;316:1337-43.
3. Stafford RS. Aspirin use is low among United States outpatients with coronary artier disease. Circulation. 2000;101:1097-1101.
4. Aspirin therapy in diabetes. American Diabetes Association Position Statement. Diabetes Care. 2002;25:S78-S79.
5. Pearson TA, Blair SN, Daniels SR, et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update. Consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vascular diseases. AHA Scientific Statement. Circulation. 2002;106:388-391.
6. Estimate of 10-Year Risk for Coronary Heart Disease: Framingham Point Scores. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/risk_tbl.htm. Accessed August 17, 2003.
7. The Year 2002 Process of Care: Guidelines for the Use of Aspirin in Cardioprotective Therapy held November 16, 2002 in Chicago, Illinois. Millennium Medical Communications, 2003.
8. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ. 2002; 324:71-86.
9. Clopidogrel for high atherothrombotic risk and ischemic stabilization, management and avoidance (CHARISMA). NLM Identifier NCT00050817. Available at http://www.clinicaltrials.gov/ct/gui/show/ NCT00050817?order=6. Accessed August 17, 2003.
10. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The Clopidogrel in Unstable Angina to prevent Recurrent Events Trial Investigators. N Engl J Med. 2001;345:494-502.
11. Slattery J, Warlow CP, Shorrock CJ, Langman MJS. Risks of gastrointestinal bleeding during secondary prevention of vascular events with aspirin-analysis of gastrointestinal bleeding during the UK-TIA trial. Gut. 1995;37:509-511.
12. Serebruany VL, Malinin AI, Sane DC. The risk of bleeding complications with antiplatelet agents: a meta-analysis of 338,191 patients enrolled in 50 randomized controlled trials. Circulation. 2002;106. Abstract 3554.
13. Peters RJG, Zao F, Lewis BS, Fox KAA, Yusuf S, the CURE Investigators. Aspirin dose and bleeding events in the CURE study. Eur Heart J. 2002;4:510. Abstract 2692.

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Disclosure
Robert J. Hilkert, MD, FACC
No significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Cardiology Express Report™ does not include discussion of treatment and indications outside of current approved labeling. This Cardiology Express Report™ was made possible through an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

© 2003 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education