This report was reviewed for medical and scientific accuracy by John B. Kostis, MD, John G, Detwiler Professor of Cardiology, Professor of Medicine & Pharmacology, Chairman, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Editorial

Eric J. Topol, MD, Provost and Chief Academic Officer, Chairman, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio

If there ever were to be a year attached to a therapeutic, the year 2002 would be known as a giant step in the advances of our understanding and appreciation of aspirin's benefit. As in China, a year is denoted by a particular animal of special regard, in the field of cardiovascular medicine no therapeutic agent has had more profound an impact over the time course of decades, and especially the new findings that have become available in a matter of months.

The jump forward in aspirin can be divided into two segments—the availability of new data sets, and the transformation of major, new guidelines from professional societies and organizations.

The new data took shape from 3 major studies. First, the Antithrombotic Trialists' Collaboration published their meta-analysis of 287 randomized, placebo-controlled, antiplatelet trials in over 212,000 high risk patients, focused particularly on aspirin in cardiovascular disease.¹ This led to the demonstration of an overall potent benefit for the composite of vascular death, myocardial infarction and stroke. There was an apparent gradient of benefit with respect to individual outcomes: 34% reduction for myocardial infarction, 25% for stroke and 15% risk reduction for death. Of note, the maximum benefit was noted with doses of aspirin between 75-160 mg, and although the confidence intervals for the point estimate of benefit (32 vs 26% risk reduction) overlapped with the dose of 325 mg of aspirin, there was a noteworthy signal of low-dose aspirin being at least as good as standard-dose aspirin. Beyond the findings supportive of low-dose aspirin, the recommendations from the Trialists' were that diabetics should be considered for primary prevention with aspirin, and that there was utility in prophylaxis of systemic thromboembolism in patients with atrial fibrillation.

Second, the Clopidogrel for Unstable Angina Reduction of Endpoints (CURE) trial enrolled over 12,000 patients who received either aspirin and placebo or aspirin and clopidogrel on a double-dummy, double-blind basis.² The trial showed the benefit for the combination of aspirin and clopidogrel in the management of patients with acute ischemic heart disease. But for the first time in a very large prospective trial, which tracked bleeding complications, there was an impressive relationship of dose of aspirin (which ranged from 75-325 mg) and bleeding complications. There was a major two-fold increase of life-threatening, serious, or any bleeding complications for aspirin 325 mg as compared with aspirin <100 mg. The intermediate-dose (approximately 150-160 mg) trended more like low-dose aspirin, with a modest excess of bleeding complications. This dose-response relationship of aspirin and bleeding complications in the range of 75-325 mg had not been previously documented. Taken together with the efficacy results in CURE and the large meta-analysis, there is strong support to use the dose of 81-162 mg in the United States (doses of 75 mg or 150 mg are not available in this country) for primary or secondary prevention of atherothrombotic complications.

Third, recent data from Mangano et al in the setting of bypass surgery are quite remarkable.^3,4 In a large observational database of over 5,000 patients who were tracked for aspirin dosing in the first 48 hours after heart bypass surgery, there was a potent 60% reduction of fatalities, stroke, myocardial infarction, and virtually every important end-organ complication (eg, need for dialysis, encephalopathy) in the patients who received aspirin during this critical 48-hour window. Of note, the bleeding complications were actually lower with the use of early aspirin. The findings have had a major impact in changing the standard of initiating aspirin very soon (<6 hrs) after completion of cardiac surgery.

The new findings have led to some important changes in guidelines. The American Heart Association (AHA) issued a 2002 Update for primary prevention of cardiovascular diseases and stroke⁵ pointing out the recommended daily dose of aspirin of 75-160 mg is as effective as higher doses, and that this should be used in patients with a 10-year risk of coronary heart disease of ≥10%. Beyond the vital role of aspirin in diabetics who have documented vascular disease, the American Diabetes Association (ADA) now recommends aspirin therapy for primary prevention in diabetic patients with one additional risk factor.⁶ From a pooled analysis of all 5 major primary prevention aspirin trials, the United States Preventive Services Task Force (USPSTF) now recommends preventive aspirin therapy for all patients with an estimated 5-year event risk of ≥3% (≥2 risk factors).^7,8

More than 100 years after aspirin was introduced as a therapeutic agent, there continues to be critical refinement in our understanding and appropriate application of aspirin's cardiovascular benefit. Along the way, the year 2002 will go down as one of the most substantive steps of progress.

Re-emphasizing Primary and Secondary Prevention of Cardiovascular Disease

The benefit of aspirin therapy in the primary and secondary prevention of cardiovascular disease has been re-emphasized in updated guidelines from the AHA and ADA. The 2002 Update of the AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke⁵ acknowledged several advances in the field of primary prevention since the initial AHA guide was published in 1997. One result is the elimination of the 160 mg and 325 mg recommended doses of aspirin with the acknowledgement that 75-160 mg of aspirin is efficacious for primary prevention. This new dosing recommendation is convenient and cost-effective for patients since low-dose aspirin is only available in the United States in 81 mg tablets (St. Joseph 81 mg Adult Low Strength Aspirin; Bayer Aspirin Regimen; Ecotrin Adult Low Strength).

Similarly, in 2002, the ADA issued formal recommendations⁶ for the use of aspirin therapy as a primary prevention strategy in high-risk type 1 or type 2 diabetic patients. The ADA further mandated the use of aspirin therapy as a secondary prevention strategy in diabetic patients with evidence of large-vessel disease. Thus, the recommendations from two esteemed medical associations lend credence to a comprehensive mandate for using low-dose aspirin therapy as a safe, inexpensive, and effective means of preventing primary and secondary cardiovascular disease.

Risk Profiles and AHA Guidelines

The evidence that most cardiovascular disease is preventable continues to grow. Long-term prospective studies consistently demonstrate that persons with low levels of risk factors have less heart disease and stroke.^9,10 Low risk factors levels are related to healthy lifestyles, yet data from the Nurses Health Study¹¹ show that few people—only 3% of women in that study—fall into this category. Clearly, the majority of the causes of cardiovascular disease are known and modifiable through intervention.

There is an increasing emphasis on further stratifying patients by level of risk and matching the intensity of interventions to the hazard for cardiovascular events.¹² In its updated guidelines, the AHA recommends that adults learn the levels and significance of their own risk factors beginning at age 20 years as routinely assessed by their primary care provider. Such screening should include smoking status, diet, alcohol intake, physical activity, family history, blood pressure, body mass index, waist circumference, and pulse rate, and be re-evaluated at least every 2 years. Fasting serum lipoprotein profile (or total and high-density lipoprotein (HDL) cholesterol if fasting unavailable), in addition to fasting blood glucose, should be measured according to the patient's risk for hyperlipidemia and diabetes, respectively, at least every 5 years; every 2 years if risk factors are present.

After 40 years of age, each person should be aware of his or her absolute 10-year risk of developing coronary heart disease and stroke. This global risk estimation should be assessed every 5 years or more frequently, if risk factors change. The same risk assessment is also warranted for persons ≥40 years of age with two or more recognized risk factors. Recognized risk factors include age, sex, smoking, systolic and diastolic blood pressure, total cholesterol, and in some risk scores, diabetes. Persons with diabetes or 10-year risk >20% can be considered at a level of risk similar to a patient with established cardiovascular disease. According to the guidelines, the ultimate goal is to lower all risk factors as much as possible.

Risk Intervention and Goals

The 2002 AHA guidelines recommended low-dose aspirin therapy for persons at risk for coronary heart disease, especially those with a 10-year risk of coronary heart disease ≥10%. While aspirin use increases the risk for gastrointestinal bleeding and hemorrhagic stroke, it has been demonstrated that the benefits of cardiovascular risk reduction outweigh those risks in most patients at higher coronary risk.^1,7,8

The updated guidelines establish that aspirin doses of 75-160 mg daily are as effective as higher doses. Therefore, clinicians should consider 75-160 mg of aspirin daily for persons at higher risk [for coronary heart disease] as an appropriate dose. However, persons with aspirin intolerance and those at an increased risk for gastrointestinal bleeding or hemorrhagic stroke, should not be prescribed aspirin therapy.

The AHA guidelines on the use of aspirin therapy are in essential agreement with the information of risks and benefits of aspirin provided by the USPSTF, with the exception that the USPSTF identifies high-risk candidates for aspirin therapy as those with a coronary and stroke risk of at least 6% risk over 10 years.⁸ These parameters improve the likelihood of a positive balance of coronary risk reduction over bleeding and hemorrhagic stroke caused by aspirin.

Aspirin Therapy in Diabetes

Persons with diabetes have a two- to four-fold increased risk of dying from complications of cardiovascular disease. Although atherosclerosis and vascular thrombosis are major factors, it is believed that platelets play an important role in intravascular thrombosis contributing to this increased susceptibility. Platelets from diabetic patients are often hypersensitive (in vitro) to platelet aggregating agents. A major mechanism is increased production of thromboxane, a potent vasoconstrictor and platelet aggregant. In vivo studies have demonstrated excess thromboxane release in type 2 diabetic patients with cardiovascular disease. Aspirin blocks thromboxane synthesis by acetylating platelet cyclooxygenase leading to its use as a primary and secondary strategy to prevent cardiovascular events in diabetic, as well as non-diabetic individuals.

Beyond this biologic rationale, clinical evidence of aspirin's benefit in diabetic persons has been provided by numerous clinical trials, as cited by the updated ADA recommendations. Meta-analyses of large collaborative trials in men and women with diabetes support the view that low-dose aspirin therapy must be prescribed as a secondary prevention strategy, if no contraindications exist. Furthermore, the ADA recommendations contend that substantial evidence suggests that low-dose aspirin therapy should also be used as a primary prevention strategy in diabetic patients who are at high risk for cardiovascular events.

The ADA recommendations highlight several major trials that have established the benefit of aspirin for secondary prevention in patients after myocardial infarction, stroke or transient ischemic attack, or positive cardiovascular history (eg, angioplasty, angina):

• The Antiplatelet Trialists' meta-analysis of 145 prospective controlled trials of antiplatelet therapy.¹³ Reduction in vascular events was approximately 25%; trend toward increased risk reductions with doses of aspirin of 325 mg/day or less; estimated that 38 ±12 vascular events per 1,000 diabetic patients treated for two years would be prevented with aspirin therapy.
• Early Treatment Diabetic Retinopathy Study¹⁴: relative risk for myocardial infarction in 5 years in patients randomized to aspirin therapy was reduced significantly to 0.72 (95% Confidence Interval (CI), 0.55-0.95).
• Hypertension Optimal Treatment Trial¹⁵: aspirin 75 mg daily significantly reduced cardiovascular events by 15% (P = .03) and myocardial infarction by 36% (P = .002).

For primary prevention of cardiovascular events, the U.S. Physicians' Health Study evaluated an aspirin dose of 325 mg every other day.16 There was a 44% reduction in the risk of myocardial infarction (relative risk, 0.56; 95% CI, 0.45-0.70; P<.00001) associated with aspirin therapy. In the diabetic physicians, there was a documented reduction in myocardial infarction from 10.1% to 4.0%, yielding a relative risk of 0.39.¹⁶

Optimal Aspirin Dose

The ADA recommendations conclude that a 75 mg dose of aspirin is just as effective as higher doses of aspirin in inhibiting thromboxane synthesis. Furthermore, citing the Antiplatelet Trialists' meta-analysis, the ADA recommendations cite that trends for the greatest risk reductions in cardiovascular events were observed with the 75 mg dose. Based upon examination of clinical data, the AHA guidelines conclude that 75-160 mg of aspirin is the optimal dose for primary prevention of cardiovascular disease in high-risk patients.

Conclusion

It is imperative to prevent the first episode of an adverse cardiovascular event or stroke, many of which are fatal or disabling. While a multiple-intervention strategy for modifying cardiovascular risk factors is optimal, complete success is not always attainable. However, one simple intervention easily achieved, is the use of daily low-dose aspirin (75-160 mg), which has proven efficacy in reducing cardiovascular events by approximately 25%. Recommendations issued in 2002 by the American Heart Association and American Diabetes Association [and information from the United States Preventive Services Task Force] advocate this strategy in both primary and secondary prevention of cardiovascular events in high-risk patients.

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;324:71-86.
2. Peters RJG, Zao F, Lewis BS, Fox KAA, Yusuf S, for the CURE Investigators. Aspirin dose and bleeding events in the CURE study.Eur Heart J. 2002;(Abstract Suppl)4:510.
3. Mangano DT. Aspirin and mortality from coronary bypass surgery. N Engl J Med. 2002;347:1309-1317.
4. Topol EJ. Aspirin with bypass surgery-from taboo to new standard of care. N Engl J Med. 2002;347:1359-1360.
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. Aspirin therapy in diabetes. American Diabetes Association Position Statement. Diabetes Care. 2002;25:S78-S79.
7. Aspirin for the primary prevention of cardiovascular events: recommendations and rationale. U.S. Preventive Services Task Force. Ann Intern Med.2002;136:157-160.
8. Hayden M, Pignone M, Phillips C, et al. 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;136:161-172.
9. Rosengren A, Dotevall A, Eriksson H, et al. Optimal risk factors in the population: prognosis, prevalence, and secular trends; data from Goteborg population studies. Eur Heart J. 2001;22:136-144.
10. Stamler J, Stamler R, Neaton JD, et al. Low risk factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999;282:2012-2018.
11. Stampfer MJ, Hu FB, Manson JE, et al. Primary prevention of coronary heart disease in women through diet and lifestyle. N Engl J Med. 2000;343:16-22.
12. 27th Bethesda Conference. Matching the Intensity of Risk Factor Management with the Hazard for Coronary Disease Events. September 14-15, 1995. J Am Coll Cardiol. 1996;27:957-1047.
13. Collaborative overview of randomised trials of antiplatelet therapy-I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ. 1994;308:81-106.
14. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA. 1992;268:1292-1300.
15. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low dose aspirin on patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet. 1998;351:1755-1762.
16. Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group. N Engl J Med. 1989;321:129-135.

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Disclosure

Eric J. Topol, MD
Has no significant relationships to disclose.

John B. Kostis, MD
Grant/Research Support-Alteon, Bristol-Myers Squibb, Parke-Davis/Pfizer; Consultant-Bristol-Myers Squibb, Merck, Parke-Davis/Pfizer; Speakers Bureau-AstraZeneca, Aventis, Bristol-Myers Squibb, Merck, Parke-Davis/Pfizer

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.

© 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education