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Experts Challenge Aspirin Guidelines Based on Flawed Trial Reliance

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Recent guidelines have restricted aspirin use in the primary prevention of cardiovascular disease. The American Heart Association (AHA)/American College of Cardiology (ACC) guidelines restricted aspirin to patients under 70, and more recently, the United States Preventive Services Task Force restricted aspirin use to patients under 60. However, heart attack and stroke risks both rise with age, leaving health care providers unsure about when to stop prescribing aspirin, whether it should be used for primary prevention, and which patients would benefit most.

Researchers from 91����’s , and other distinguished collaborators who have led major trials of aspirin in primary prevention, have published their perspectives, “Aspirin in Primary Prevention: Undue Reliance on an Uninformative Trial Led to Misinformed Clinical Guidelines,” in , the official journal of the Society for Clinical Trials.  

The authors emphasize that best practices for the design, conduct, analysis and interpretation of randomized controlled trials should adhere to rigorous statistical principles. Failure to follow these principles can lead to conclusions inconsistent with the totality of evidence and inappropriate recommendations made by guideline committees. They believe that both the AHA/ACC Task Force and the U.S. Preventive Services Task Force were unduly influenced by the uninformative, not null, results of the Aspirin in Reducing Events in the Elderly (ASPREE) trial. Specifically, this trial did not provide reliable evidence that aspirin showed no benefit in the age groups they enrolled.

“The reliable evidence indicates that, to do the most good for the most patients in primary prevention of heart attacks and strokes, health care providers should make individual clinical judgments about prescribing aspirin on a case-by-case basis and based on benefit-to-risk not just age alone,” said Charles H. Hennekens, M.D., FACPM, co-author and the first Sir Richard Doll Professor of Medicine and Preventive Medicine, Schmidt College of Medicine. “Further, it seems counterintuitive among patients taking aspirin long term to stop it just because a birth milestone is reached. Finally, absence of evidence does not equate to evidence of absence of effect.”

The authors stress that patients should consult their primary care provider about whether they are candidates for aspirin, as providers have the most knowledge of all the benefits and risks for each of their individual patients. In brief, health providers are equipped to balance the benefits to each patient of clot prevention against their individual bleeding risks. Thus, whether to prescribe aspirin should be an individual clinical judgment.

“Health care providers also should be aware that all patients suffering from an acute heart attack should receive 325 milligrams of regular aspirin promptly, and daily thereafter, to reduce their death rate as well as subsequent risks of heart attacks and strokes,” said Hennekens. “In addition, health care providers and patients should remain cognizant that among survivors of prior heart attacks or occlusive strokes, aspirin should be prescribed long-term unless there is a specific contraindication.”

The authors highlight the growing burden of cardiovascular disease, stressing the need for broader lifestyle changes and effective as well as affordable drug therapies for primary prevention. These changes include quitting smoking, weight loss, increased physical activity, and using statins and other medications to manage blood pressure. With respect to costs, aspirin is a particularly attractive option.

“While patient preference is always important to consider in decision-making, this assumes even greater relevance among patients in whom the absolute benefits and risks of aspirin are similar,” said Hennekens. “Patient preference may include consideration of whether the prevention of a first heart attack or stroke is more important consideration to them than their risk of a significant gastrointestinal bleed.”

The authors also note that the absolute risk of a cerebral bleed without, as well as with aspirin, is too low to be of clinical relevance for the vast majority of patients. In the U.S. and most developed countries, the authors say that individual clinical judgments by health care providers about prescribing aspirin in primary prevention may affect a relatively large proportion of their patients. For example, metabolic syndrome, a constellation of overweight and obesity, hypertension, high cholesterol and insulin resistance, a precursor to diabetes mellitus, affects about 40% of Americans 40 years of age and older and is increasing globally. The high risks of patients with metabolic syndrome for a first heart attack and stroke may approach those of patients with a prior event.  

“Guidelines for aspirin in primary prevention do not seem to be justified,” said Hennekens. “As is generally the case, the primary care provider has the most complete knowledge about the overall benefits and risks for each patient and should make individual clinical decisions.”

According to the U.S. , more than 859,000 Americans die of heart attacks or stroke every year, which account for more than 1 in 3 of all U.S. deaths. These common and serious diseases take a very large economic toll, costing $213.8 billion each year to the health care system and $137.4 billion in lost productivity from premature death alone.

91���� collaborated with several distinguished academicians from the University of Wisconsin School of Medicine and Public Health, as well as the Harvard Medical School and Massachusetts General-Brigham Hospital.

Co-authors are Janet Wittes, Ph.D., an affiliate professor of biostatistics, 91���� Department of Population Health; David L. DeMets, Ph.D., the first Max Halperin Professor and Chair Emeritus of Biostatistics and Informatics; KyungMann Kim, Ph.D., a professor of biostatistics and informatics; and Dennis G. Maki, M.D., FACP, all with the University of Wisconsin School of Medicine and Public Health; J. Michael Gaziano, M.D., a professor of medicine; Marc A. Pfeffer, M.D., Ph.D., FACC, Distinguished Dzau Professor of Medicine; and Sarah K. Wood, M.D., director of the Harvard Macy Institute, all at the Harvard Medical School, with Gaziano and Pfeffer also affiliated with Massachusetts General-Brigham Hospital; and Panagiota Kitsantas, Ph.D., professor of biostatistics and epidemiology and chair of the Department of Health Administration and Policy, George Mason College of Public Health.  

Hennekens was the first to discover that aspirin prevents a first heart attack in men in the U.S. Physician’s Health Study and prevents a first stroke in women in the Women’s Health Study. He was the U.S. principal investigator on the worldwide Second International Study of Infarct Survival (ISIS02), which demonstrated the lifesaving benefits of aspirin when given within 24 hours of onset of symptoms of a heart attack as well as among long-term survivors of prior occlusive events affecting their heart, brain or peripheral arteries. Gaziano was the principal investigator of the Aspirin to Reduce Risks of Initial Vascular Events (ARRIVE) trial, one of the four major trials recently reported in the peer reviewed literature.  

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