Aspirin: More Evidence That Low Dose is All That is Needed

March 19, 2009

March 19, 2009 (New York, New York) — New guidance on how aspirin should be used in both the primary and secondary prevention of coronary heart disease has come from three new reports published this week.

Two new studies deal with aspirin use in secondary prevention. These are a post hoc analysis of aspirin use in the CHARISMA trial [1] and results of the effect of aspirin use in the Women's Health Initiative (WHI) [2]. Both of these studies found that low-dose aspirin is just as effective as a full dose for secondary prevention.

The third paper outlines new recommendations from the US Preventive Services Task Force (USPSTF) on the use of aspirin for the primary prevention of coronary heart disease [3]. These encourage men aged between 45 and 79 years and women aged between 55 and 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. They say there are insufficient data to assess the balance of benefits and harms of aspirin for cardiovascular disease prevention in men and women 80 years or older and that aspirin use should not be encouraged for cardiovascular disease prevention in women younger than 55 years and in men younger than 45 years.

CHARISMA: Low-Dose Aspirin for Secondary Prevention

The CHARISMA study, published in the March 17, 2009 issue of the Annals of Internal Medicine, was a randomized trial of long-term clopidogrel vs placebo in patients with atherosclerotic disease or multiple risk factors for heart disease. Aspirin was given to all patients in the trial at a dose of 75 to 162 mg/day, but the actual dose was determined individually by each patient's doctor. The current paper is a post hoc observational analysis of the effect of aspirin by dose. Daily aspirin doses were categorized as <100 mg (n= 7180), 100 mg (n=4961), and >100 mg (n=3454).

Results showed no overall differences in efficacy or safety by aspirin dose. However, in the subgroup of patients randomly assigned to clopidogrel, there was a hint of reduced efficacy and increased harm with higher doses. The researchers conclude: "Lower aspirin doses (75 to 81 mg/day) may optimize efficacy and safety for patients requiring aspirin for long-term prevention, especially those taking clopidogrel."

More Reliable Data to Come From OASIS-7

In an accompanying editorial [4], Dr Shamir Mehta (McMaster University, Hamilton, ON) notes that these results extend earlier observations made in the CURE trial, with CHARISMA having a much longer follow-up and thus allowing a more realistic evaluation of the efficacy and safety of different aspirin doses for cardiovascular disease prevention.

But he points out that these results are still based on post hoc, nonrandomized comparisons and are thus subject to bias and that more reliable information on the question of aspirin dose should come from the ongoing CURRENT-OASIS-7 trial, which is the first large-scale randomized trial to directly compare aspirin doses. This trial is a 2x2 factorial study in 25 000 patients, with the first randomization to high-dose vs standard-dose clopidogrel and the second randomization to daily high-dose vs low-dose aspirin. Results are expected later this year.

WHI: Better Data on Women

The WHI study, published in the March 2009 issue of Circulation: Cardiovascular Quality and Outcomes, provides additional evidence that aspirin may reduce the risk of death in postmenopausal women who have heart disease or who have had a stroke and, in concurrence with the CHARISMA data, show that low-dose aspirin is just as effective as higher doses.

In an interview with heartwire , Dr Jacques Rossouw (chief of the WHI branch at the NationalHeart, Lung, and Blood Institute, Bethesda, MD), said that current recommendations for women to take aspirin for the secondary prevention of heart disease are based on clinical trials in which women have not been well represented. "Our study is wider than previous studies, in that it included women with any form of cardiovascular disease and women older than have been studied before. We found that total mortality and cardiovascular mortality were lowered in aspirin users and that the benefit does not seem to be dose-related, whereas the side effects are dose-related. So a low dose (75 mg) seems better overall than a full dose (325 mg). And if you can reduce risk with an intervention as simple as a low-dose aspirin every day, then that's quite something."

The WHI Observational Study followed 93 676 postmenopausal women between the ages of 50 and 79 for an average of eight years. Among 8928 women with stable cardiovascular disease, 4101 (46%) reported taking aspirin, of whom 30% were on 81 mg and 70% were on 325 mg. At 6.5 years of follow-up, no significant association was noted for aspirin use and all-cause mortality or cardiovascular events. However, after multivariate adjustment, regular aspirin users had a 25% lower risk of death from cardiovascular disease and a 14% lower risk of death from any cause. Aspirin use was associated with a trend toward lower risk of cardiovascular events, which did not meet statistical significance. Compared with 325 mg, use of 81 mg was not significantly different for all-cause mortality, cardiovascular events, or any individual end point.

Adjusted Hazard Ratio for Death or Cardiovascular Events in Aspirin Users vs Aspirin Nonusers

Outcome HR (95% CI) p
All-cause mortality 0.86 (0.75–0.99) 0.04
Cardiovascular mortality 0.75 (0.60–0.95) 0.01
Cardiovascular events (MI/stroke/CV death) 0.90 (0.78–1.04) 0.14

The researchers note that the 46% figure for aspirin use is low and that this underutilization was most pronounced in blacks and women with Medicaid insurance.

New Primary-Prevention Recommendations

The new USPSTF recommendations on the use of aspirin for primary prevention of heart disease are also published in the March 17, 2009, issue of the Annals of Internal Medicine.

They also favor low-dose aspirin, pointing out that a dose of 75 mg/day seems as effective as higher dosages, but that the risk of gastrointestinal bleeding may increase with dose.

In his editorial, Mehta notes that these guidelines were last published in 2002 and were based on trials with limited data on women, whereas the new recommendations incorporate the results of the landmark Women's Health Study (WHS), which showed no reduction in MI and death with aspirin but a significant reduction in stroke. The new recommendations thus advise use of aspirin in men to reduce MI and in women to reduce stroke.

Mehta points out that 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. But he adds that there is one group of patients who should absolutely avoid aspirin--those who are at relatively high risk for intracranial bleeding.

He concludes: "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."

  1. Steinhubl SR, Bhatt DL, Brennan DM, et al. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med 2009; 150:379-386. Abstract

  2. Berger JS, Brown DL, Burke GL. Aspirin use, dose, and clinical outcomes in postmenopausal women with stable cardiovascular disease--the Women's Health Initiative Observational Study. Circ Cardiovasc Qual Outcomes 2009; 2:78-87.

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

  4. Mehta SR. Aspirin for prevention and treatment of cardiovascular disease. Ann Intern Med 2009; 150:414-416. Abstract


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