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Randomised controlled trial
Aspirin prophylaxis (100 mg daily) does not improve cardiovascular outcomes compared to placebo in asymptomatic individuals with incidental low-ankle brachial index
  1. S Marlene Grenon,
  2. Michael S Conte
  1. University of California, San Francisco, California, USA
  1. Correspondence to Dr S Marlene Grenon
    Vascular and Endovascular Surgery, Surgical Service (Mail Code 112 G), San Francisco VAMC, San Francisco, CA 94121, USA; marlene.grenon{at}

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Peripheral arterial disease: the beast

Peripheral arterial disease (PAD) affects a large number of individuals around the globe and is associated with a three- to six-fold increased risk in cardiovascular morbidity and mortality.1 Patients suffering from PAD are considered to be at an exceptionally high risk for cardiovascular events, with cardiac and cerebrovascular events being the leading cause of mortality.2 3 Critical-limb ischemia is a particularly severe form of PAD, and once patients have progressed to that level, the morbidity, mortality and economic burden are even more considerable.4 5 The ankle-brachial index (ABI) is a simple, noninvasive test that can be done in the practitioner's office to identify patients with PAD.6 At the present time, it is recommended that patients with PAD be treated with antiplatelet and lipid-lowering agents, along with management of their hypertension, hyperglycemia and lifestyle modifications7 in order to reduce the risk of cardiovascular complications.

An important contribution

In this important contribution, Fowkes and colleagues aimed to determine the effectiveness of aspirin in preventing events in an asymptomatic patient population screened with low ABI. The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat double-blind randomised controlled trial that included men and women aged between 50 and 75 years, free of clinical cardiovascular disease and recruited from a community health registry. Between 1998 and 2008, 3350 patients with an ABI ≤0.95 entered the trial and were treated with 100 mg of aspirin or placebo. The primary endpoint, a composite of initial fatal or nonfatal coronary event, stroke or revascularisation, was not statistically different between the two arms. With regards to secondary endpoints, there was no difference between the two groups in the number of vascular events (primary endpoint event, angina, intermittent claudication or transient ischemic attack) and all-cause mortality. The authors concluded that in a population with a low ABI but without clinical cardiovascular disease, the administration of aspirin did not result in a significant reduction in vascular events.

A not-so-unexpected conclusion

The merits of this study are high with regards to design, outcome measurements, sample size and follow-up. Fowkes and colleagues make an important contribution in an area where the evidence base supporting treatment decisions is thin. How does this relate to the present literature? In the CLIPS group study randomised trial, 366 patients (claudicants or asymptomatic PAD) with ABI < 0.85 were treated with aspirin 100 mg versus vitamins or placebo. There was a risk reduction of 64% of major vascular events among patients treated with antiplatelet therapy.8 This contrasts with a study from Belch and colleagues where 1276 asymptomatic adult patients with diabetes and ABI ≦ 0.99 did not benefit from aspirin 100 mg/d.9 From a recent meta-analysis including mostly symptomatic patients, aspirin resulted in a statistically non-significant decrease in the primary endpoint of cardiovascular events and a significant reduction in non-fatal stroke.10 Overall, the evidence for aspirin from the previous studies is equivocal for both the primary and secondary prevention of cardiovascular events.

In the present study, aspirin did not lead to lower cardiovascular events. Why could that be? In addition to factors mentioned by the authors in their discussion (female–male distribution, compliance etc.), two major areas should be addressed: the patient population and the effect size. First, the average ABI of this study was 0.86, which represents a mild reduction in the normal ABI. Hence, although these patients fall into the definition of PAD on the basis of their ABI, they represent a milder subset of PAD, one which may be at lesser risk of developing events and which may also take longer to develop symptoms and cardiovascular complications.11 Another point worth mentioning is the effect size anticipated by the investigators and the limited power of the study. A more modest effect (e.g. a 10% relative risk reduction) would likely have been missed by the present study but may still represent cost-effectiveness for aspirin treatment in the this population.

Clinical implications for Practice

As stated previously, present guidelines from the American Heart Association recommend treatment of patients with asymptomatic PAD with antiplatelet and lipid-lowering agents (Class I recommendation) to reduce the risk of adverse cardiovascular events. The evidence for antiplatelet therapy is classified as ‘C,’ meaning consensus options of experts, case studies or standard of care. Results from the present study bring valuable information on the treatment of patients with PAD. Applying these results may suggest that one should not treat the asymptomatic PAD patient with aspirin. However, is it worth withholding a drug with a potentially small but significant relative effect? Perhaps the answer lies in the risk of developing an adverse event such as bleeding or other characteristics of the patient. Overall, aspirin is a low-cost drug with a relatively safe profile. It is also important to bear in mind that greater declines in ambulatory function occur with lower baseline ABI,11 indicating that once patients reach a lower ABI, their condition tends to deteriorate at a faster rate.11 As is demonstrated in this study, although not different between the two arms, patients with relatively lower ABIs had more cardiovascular events.

What the future may hold

This study provides an important piece of information with regards to anti-platelet therapy in asymptomatic PAD and, in doing so, raises more questions with regards to optimal treatment, feeding into the controversy of screening. At the present time, it is not known whether screening for PAD is an effective public health strategy; thus, it may represent a double-edge sword. The American Heart Association recommends screening for individuals aged more than 70 years, those aged between 50 and 69 and with a history of smoking or diabetes, and those younger than 50, with diabetes and another risk factor for atherosclerosis.7 On the other hand, the US Preventive Services Task Force has recommended against routine screening for PAD12 on the basis of lack of benefit (supported by this study) and the potential harm (ie, false-positive results, labelling of patients, adverse events of angiographic work-up, complications of medical and surgical therapy). Cost would also be a significant issue. Do the potential disadvantages of screening outweigh the potential advantages related to possible improvement in survival, morbidity, quality of life and perhaps patient compliance with lifestyle modification? The answer may lie in the proper handling of the information. Subsequent questions also follow: (1) should these asymptomatic patients be placed on cholesterol-lowering therapy? (2) Would another screening strategy more effectively identify asymptomatic PAD patients at greater risk (eg, a combination of ABI and C-reactive protein) who are more likely to benefit from aspirin and other medical therapies?

What conclusion should we draw for clinical practice? In view of the burden of PAD on the overall population, and the established safety profile and low cost of aspirin, we will personally continue to recommend treatment of asymptomatic PAD patients with antiplatelet therapy. Hopefully, further studies will better clarify the role of screening and the optimal management of asymptomatic PAD.


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  • Competing interests None.