No significant reduction of CV events with aspirin in peripheral artery disease

Susan Jeffrey

May 13, 2009

Boston, MA - A new meta-analysis of randomized trials assessing the effects of aspirin with or without dipyridamole in patients with peripheral artery disease (PAD) finds only a statistically nonsignificant 12% reduction in cardiovascular events with treatment[1].

There was a significant reduction in nonfatal stroke with aspirin therapy, but this was a secondary end point in their analysis.

Because aspirin has been proven beneficial in patients with established heart and cerebrovascular disease, said senior author Dr William R Hiatt (University of Colorado Denver School of Medicine), "I don't think it's a problem at all to continue aspirin in your patients with peripheral artery disease who have had a prior cardiac event or ischemic stroke; that's completely reasonable."

The more challenging question is what to do those with PAD but no established cardiovascular disease, which constitutes about half of PAD patients, he said in an interview. "I think my answer right now is that you probably would, if you could afford it, use clopidogrel, which has good evidence for its use in those patients. If you leave them on aspirin, then I think you're leaving them on a therapy that has unproven benefit and retains a bleeding risk."

Results of the new meta-analysis are published in the May 13 issue of the Journal of the American Medical Association (JAMA). First author on the paper is Dr Jeffrey S Berger (University of Pennsylvania, Philadelphia).

New evidence

The largest assessment of the effects of aspirin to date is the Antithrombotic Trialists' Collaboration (ATC) meta-analysis of 287 trials that showed a significant reduction in MI, death, and stroke in patients with symptomatic cardiovascular disease[2]. In a subset of 42 of these trials, antiplatelet therapy was associated with a similar significant decrease in risk, and on the basis of this, many guidelines documents recommend aspirin for those with PAD.

However, Hiatt points out that nearly two-thirds of the trials included in the ATC meta-analysis evaluated antiplatelet drugs other than aspirin, and a recently reported randomized study, the POPADAD trial, showed no benefit of aspirin therapy in patients with diabetes and asymptomatic PAD[3].

With these latter data reported, he said, there was sufficient new evidence to look again at the broader question of the role of aspirin in patients with PAD. The current meta-analysis included 18 randomized controlled trials of aspirin therapy with and without dipyridamole involving a total of 5269 participants with PAD. Primary end points of the trials were cardiovascular events, including nonfatal MI, nonfatal stroke, and cardiovascular death. Data on all-cause mortality, major bleeding, and the individual components of the primary end point were also collected.

They found a trend toward a lower rate of cardiovascular events with aspirin treatment, but this difference did not reach statistical significance. "The point estimate is a 12% reduction in myocardial infarction, stroke, and cardiovascular death," Hiatt said. There was a statistically significant reduction in the secondary outcome of nonfatal stroke, but no significant effect on other secondary end points.

Treatment with aspirin, with or without dipyridamole, vs control in PAD

End point Aspirin with or without dipyridamole (n =2823), n (%) Control (n =2446), n (%) Pooled relative risk 95% CI
CVD events 251 (8.9) 269 (11.0) 0.88 0.76-1.04
Nonfatal stroke events 52 (1.8) 76 (3.1) 0.66 0.47-0.94

Among the subset of 3019 patients taking aspirin alone, there was a 25% reduction in cardiovascular events, which was still not a significant difference vs controls. Again, a significant reduction in nonfatal stroke was seen in this analysis, and again no effect on the other secondary end points.

Treatment with aspirin alone vs control in PAD

End point Aspirin alone (n= 1516), n (%) Control ( n=1503), n (%) Pooled relative risk 95% CI
CVD events 125 (8.2) 144 (9.6) 0.75 0.48-1.18
Nonfatal stroke events 32 (2.1) 51 (3.4) 0.64 0.42-0.99

While the stroke finding is something that would be interesting to look at prospectively in future trials, Hiatt felt that as a secondary end point, not much should be made of that finding at this time.

"Larger prospective studies of aspirin and other antiplatelet agents are warranted among patients with PAD in order to draw firm conclusions about clinical benefit and risks," the authors conclude.

"But in the meantime, I think what we've reviewed is really all the evidence to date, and it doesn't suggest a strong signal of benefit," Hiatt added. Even if larger trials eventually showed a statistical difference, it would appear that it may still be a fairly modest effect compared with other cardiovascular therapies, he added.

A large primary-prevention trial is now ongoing in the United Kingdom looking at aspirin in patients with a low ankle-brachial index but no established cardiovascular disease, Hiatt noted. "Those results will probably be available in the next year or two, and we'll have more information," he said.

Cautious assessment

In an editorial accompanying the paper, Drs Mary McGrae McDermott (Northwestern University Feinberg School of Medicine, Chicago), a contributing editor to JAMA, and Dr Michael H Criqui (University of California, San Diego) are more cautious in their assessment of these new findings[4].

They point out that, relatively speaking, the sample size in this meta-analysis is small. In addition, about 25% of the participants were drawn from two studies of patients with PAD and diabetes, and those with diabetes are known to derive less benefit from aspirin therapy. Further, many of the trials did not use currently recommended aspirin doses.

Clopidogrel offered a small but statistically significant advantage over aspirin for secondary prevention among patients in the CAPRIE trial with cardiovascular disease, they write, but the suggestion in CAPRIE that clopidogrel might be more beneficial for patients with PAD than those with heart disease or stroke were not borne out by more recent results from the CHARISMA trial.

"The meta-analysis by Berger et al enriches our current understanding of the association of aspirin with cardiovascular outcomes in patients with PAD," they conclude.

"However, based on the limitations of data available, the findings should not alter recommendations for aspirin as an important therapeutic tool for secondary prevention in patients with PAD. To best inform evidence-based clinical practice guidelines, more high-quality clinical trials are needed."

The authors received funding through grants to individual coauthors from the National Heart, Lung, and Blood Institute and the American Heart Association . There was no funding support for this manuscript. Hiatt reports he has served on the US Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee in the review of antithrombotic therapies and previously reviewed the use of aspirin for primary prevention and treatment of PAD. He has received grant support for projects related to the use of clopidogrel and previously served on the speaker's bureau of the Bristol-Myers Squibb/Sanofi-Aventis Partnership, activities that ended in 2008. Disclosures for coauthors appear in the paper. Editorialist McDermott reports she has received consulting fees and honoraria for educational activities from Bristol-Myers Squibb and Sanofi-Aventis. Criqui reports he has received research funding from Bristol-Myers Squibb.

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