Aspirin Studies in Primary Prevention | Ongoing Aspirin Studies

With the ARRIVE trial, Bayer continues its commitment to work in partnership with the scientific community to advance initiatives that bring the benefits of Aspirin to additional, appropriate patients, and help reduce the global burden of cardiovascular and cerebrovascular disease.

The effectiveness of low-dose Aspirin in the prevention of a first event associated with CVD is currently supported by six prospective, randomized clinical trials conducted by independent researchers, as well as a collective meta-analysis of these trials. The six studies are:

• BDT: British Doctors' Trial
• HOT: Hypertension Optimal Treatment Trial
• PHS: Physicians' Health Study
• PPP: Primary Prevention Project
• TPT: Thrombosis Prevention Trial
• WHS: Women's Health Study

These studies have been conducted in subjects with a variety of entry criteria, including elevated baseline cardiovascular risk in three of the studies. The data taken as a whole lend strong support to the view that Aspirin effectively prevents first events associated with CVD across a wide range of risk populations. An overview of these studies, including their methodologies, is summarized in the table below.

Summary of Studies Evaluating Aspirin Prevention of First Cardiovascular Event*

Separate meta-analyses of each of these endpoints across these six trials (Bartolucci AA, Howard G; Am J Cardiol 2006; 89: 746-750) reinforce these results and provide clear evidence of the benefit of Aspirin. Specifically, significant reductions in odds ratios (p= 0.001 for each) were seen for:

• Total coronary events (23%), including first fatal or non-fatal MI or coronary death
• Non-fatal MI (24%)
• Total events associated with CVD (15%), including a composite of CVD death, MI, or stroke

Additionally, a strong trend toward reduction in all-cause mortality (6.5%) was observed.

Overviews of Each of the Six Key Studies

A brief description of each of the six primary prevention trials follows.

British Doctors' Trial (BDT)

In this study involving 5,139 apparently healthy physicians, Aspirin (500 mg/day ordinary, soluble, or effervescent Aspirin or 300 mg enteric-coated Aspirin tablets) was used for an average of four years by 3,429 doctors, while the remaining 1,710 doctors were to avoid Aspirin. Total mortality was 10% lower in the Aspirin group than in the control group, but this difference was not statistically significant. The incidence of myocardial infarction or stroke was not reduced. However, the incidence of cerebral transient ischemic attacks (TIAs) was significantly reduced to 15.9% in the Aspirin group as compared to 27.5% in the control group. The lack of significance of key study endpoints was attributed by the authors to the fact that 30% of the participants in the Aspirin group ceased taking Aspirin and 12% of the control group started taking Aspirin. Additionally, it is likely that a much larger study population is necessary to demonstrate any clinically relevant effects in a healthy population.
British Medical Journal, Vol. 296. 30 Jan. 1988.

Physicians' Health Study (PHS)

The PHS was a randomized, double-blind, placebo-controlled primary prevention trial of 22,071 apparently healthy male U.S. physicians, using a 2 X 2 factorial design to evaluate the role of low-dose Aspirin (325 mg every other day) in the prevention of cardiovascular mortality and beta-carotene in the reduction of cancer incidence. Results impressively demonstrated a 44% decrease in the risk of first MI (p< 0.0001), attributable to those physicians 50 years of age or older. The risk of fatal MI was significantly lower with Aspirin therapy (66%, p= 0.007), as was the risk of non-fatal MI (41%, p< 0.0001). A combined endpoint consisting of non-fatal MI, non-fatal stroke, and death from CVD cause yielded a statistically significant 18% reduction in risk in those who were assigned to Aspirin (p=0.01).
N Engl J Med. 1989; 321.

Thrombosis Prevention Trial (TPT)

The TPT evaluated low-dose Aspirin (75 mg/day) and low-intensity oral anticoagulation with warfarin in the primary prevention of ischemic heart disease (IHD) in 5,499 high-risk men aged between 45 and 69 years recruited from 108 practices in the U.K. that belonged to the Medical Research Council's General Practice Research Framework. The primary endpoint was all IHD, defined as the sum of fatal and non-fatal events (i.e., coronary death, fatal MI, and non-fatal MI). Treatment effects on fatal and non-fatal MI also were separately examined. Fatal IHD was defined as the sum of coronary death and fatal MI (death within a month). Stroke was a secondary endpoint, with results for thrombotic and hemorrhagic events distinguished as far as possible. The primary effect of low-dose Aspirin was a 32% reduction in non-fatal MI (p=0.004). This robust finding was largely responsible for the 20% reduction of all IHD (p=0.04).
The Lancet, Vol. 351. 24 Jan. 1998.

Hypertension Optimal Treatment Study (HOT)

The HOT study evaluated the effects of antihypertensive and Aspirin therapy (75 mg/day) on the incidence of adverse cardiovascular outcomes in patients with elevated diastolic pressure. A total of 9,399 patients were randomly assigned low-dose Aspirin, and 9,391 patients were assigned placebo in combination with their antihypertensive therapy. Aspirin reduced all MI events (combined fatal and non-fatal MI) by 36% (p=0.002) and all major events associated with CVD by 15% (p= 0.03). The HOT study is the first to demonstrate a beneficial effect of low-dose Aspirin in addition to antihypertensive therapy in the prevention of myocardial infarction and major events associated with CVD in patients with treated high blood pressure. As the number of patients who had a previous cardiovascular event was small (1.6% had a previous MI, 1.2% had a previous stroke, approximately 6% had other previous coronary heart disease), the HOT study can be regarded as a major primary prevention study.
The Lancet. 1998; 351: 1755-1762.

Primary Prevention Project (PPP)

PPP investigated the efficacy of 100 mg Aspirin per day given as enteric-coated tablets and/or vitamin E (300 mg/day), utilizing an open, randomized, controlled 2X2 factorial design, in the primary prevention of cardiovascular events in addition to the treatment of specific risk factors. This study included 4,495 subjects with at least one cardiovascular risk factor (e.g., old age, hypertension, diabetes, obesity, hypercholesterolemia, and family history of premature myocardial infarction). The trial was prematurely stopped for ethical reasons because newly available evidence from the Thrombosis Prevention Trial and the HOT Study on the benefit of Aspirin in primary prevention was consistent with the results of the second interim analysis after a mean follow-up of 3.6 years. Specifically, Aspirin lowered the frequency of all endpoints, reaching statistical significance for cardiovascular deaths (44% decrease in relative risk, p= 0.049) and for any cardiovascular events, including cardiovascular death, non-fatal MI, non-fatal stroke, TIA, angina pectoris, peripheral artery disease, and revascularization procedures (33% decrease in relative risk, p= 0.014).
The Lancet, Vol. 357. 13 Jan. 2001.

Women's Health Study (WHS)

In the WHS, apparently healthy women at least 45 years old received either Aspirin 100 mg or placebo every other day in conjunction with vitamin E or placebo and followed for up to 10 years, assessing first major events associated with CVD. Nearly 40,000 women were studied. While there was a non-significant trend toward lowering risk of major events associated with CVD (9%), a key finding was that women taking Aspirin experienced an overall 17% decrease in the risk of stroke (p= 0.044), mostly due to significant reductions in ischemic stroke (24%, p= 0.009). Additionally, women taking Aspirin experienced a 19% reduced risk of non-fatal strokes (p= 0.02) and a 22 percent reduction in risk of TIAs (p= 0.01).
N Engl J Med. 2005; 352.