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The latest findings in the use of aspirin in PAD patients from the Aspirin for Asymptomatic Atherosclerosis study - presented in Barcelona ESC 2009 showed clopidogrel as significantly more effective than aspirin in preventing major vascular events in PAD patients, but at a higher risk of major bleeding. We advise replacing aspirin with clopidogrel only 1) in PAD patients who have a vascular event despite taking aspirin (or clopidogrel in combination with aspirin in these patients) and 2) in PAD patients or who do not tolerate aspirin. In all other PAD patients prescribing low dose aspirin (75-325 mg/day) is first-line therapy.
Peripheral arterial disease (PAD) is one of the most prevalent manifestations of atherosclerosis. PAD is accompanied with increased morbidity and mortality from myocardial infarction and stroke. Atherosclerosis is related to diverse risk factors that cause damage to the arterial wall and most probably induce inflammation by activation of platelets. Platelet activation plays a key role in the atherosclerotic development of the disease and is responsible for thrombotic ischaemic events. As a consequence, antiplatelet treatment is one of the basic options in the prevention of thromboembolic cardiovascular events (1). However, while great emphasis has been placed on the pharmacological management of coronary artery disease (CAD), less attention has been devoted to the management of PAD, despite its significant morbidity and mortality. There is little evidence-based data regarding the efficacy of preventive measures on peripheral arterial occlusive disease. Furthermore, data on the efficacy of aspirin in preventing cardiovascular events in PAD patients are contradictory and in comparison to its effect in coronary heart disease (CHD) the effect of aspirin in PAD is probably suboptimal. Its limited efficacy could be the consequence of the different behaviour of platelet activity in PAD patients. Drugs that inhibit platelet activity through ADP receptors, such as ticlopidine and clopidogrel seem to be more effective in these patients than aspirin.
Aspirin is a well recognised antiplatelet drug that has clear benefits in patients with cardiovascular diseases. Numerous publications from the Antithrombotic Trialists Collaboration have concluded that patients with cardiovascular diseases will achieve a 25% odds reduction in cardiovascular events with the use of aspirin. However, specific studies in the PAD population have not shown a statistically significant reduction in cardiovascular events (2).
The ineffectiveness of aspirin in PAD was also shown in the Aspirin for Asymptomatic Atherosclerosis (AAA) study, that was presented at the ESC congress 2009 (Barcelona) by G. Fowkes. The study included 3350 subjects with asymptomatic PAD (ankle-brachial index-ABI≤0.95), randomised to either aspirin or placebo and followed for 8.2 years. The primary endpoint was a composite of initial fatal or non-fatal coronary event or stroke, or revascularisation. The results showed that aspirin produced no reduction in the number of cardiovascular and cerebrovascular events (HR 1.03, 95% CI 0.84-1.27). There was, however an increase in major haemorrhages and gastrointestinal ulcers in the aspirin patients. An initial event of major bleeding requiring admission to the hospital occurred in 34 - 2%- of subjects in the aspirin group and 20 (1.2%) in the placebo group. They concluded that findings of AAA study do not support the routine use of aspirin for the prevention of vascular events in the general population on the basis of pathological ABI.
However, in a more recent meta-analysis, when the PAD data were combined from trials not only with aspirin but also with more effective agents, such as clopidogrel and picotamide, there was a significant (23%) odds reduction in ischaemic events (3). The benefit was similar in different groups of patients with PAD: intermittent claudication, those having peripheral grafting and those having peripheral angioplasty. All these results therefore suggest that antiplatelet treatment with aspirin alone in PAD patients may be sub-optimal. The limited efficacy of aspirin in PAD patients could be a consequence of aspirin resistance. The data indicate that in patients with PAD, platelets behave differently than in coronary heart disease and that they are more resistant to aspirin (4), and further it was shown that patients with PAD represent the group presenting the most frequent resistance to aspirin. In the study of Halawani and co-workers, 19% of PAD patients did not obtain the expected antiplatelet effect from aspirin therapy (5), as in patients with acute myocardial infarction (6). Müller et al reported a 60% incidence of aspirin resistance in patients with intermittent claudication undergoing elective percutaneous angioplasty (7). According to these data, it is expected that a high proportion of patients, despite aspirin intake, have vascular events.
In order to overcome the ineffectiveness of aspirin in PAD patients, other drugs were introduced in secondary prevention of PAD, particularly drugs that inhibit platelet activity through inhibition of ADP receptors, like thienopyridine derivatives, e.g. ticlopidine and clopidogrel. Their mechanism of action is different from that of aspirin. The clinical effectiveness of thienopyridine derivatives is supported by trial-based evidence. Ticlopidine has been evaluated in several trials in patients with PAD and has been found beneficial in reducing the risk of myocardial infarction, stroke, and vascular death. However, the clinical usefulness of ticlopidine is limited by unacceptable adverse effects, such as neutropenia and thrombocytopenia (8). Clopidogrel was significantly more effective than aspirin in preventing major vascular events (myocardial infarction, stroke and vascular death) in a large randomised trial (Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events – CAPRIE). Patients with PAD showed a significantly greater benefit with clopidogrel than with aspirin, resulting in a relative risk reduction of 23.8% (p=0.0028) (8). This trial was not designed for subgroup analysis. Nevertheless, this interpretation is in agreement with previous reports of enhanced platelet activation and aspirin-resistance in PAD. Recent publications in patients with acute coronary syndromes indicate that combination therapy with aspirin and clopidogrel is more effective than therapy with aspirin alone, but at a higher risk for major bleeding (9). Whether combination therapy will be more effective in the PAD population is currently being studied, but preliminary data do not confirm better effect of combined treatment.
A switch from aspirin, an effective, inexpensive and widely prescribed drug in patients with PAD to clopidogrel requires additional evidence from comparative trials. This switch may only be reasonable 1) in PAD patients who have a vascular event despite taking aspirin (or in combination with aspirin) and 2) in PAD patients or who do not tolerate aspirin. In all other PAD patients prescribing low dose aspirin (75-325 mg/day) is first-line therapy.
1 Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, Browner D. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992; 326: 381-6. 2 Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ. 1994; 308: 81-106. 3 Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324: 71-86. 4 Matsagas MI, Geroulakos G, Mikhailidis DP. The role of platelets in peripheral arterial disease: therapeutic implications. Ann Vasc Surg. 2002; 16: 246-58. 10.1007/s10016-001-0159-8. 5 Halawani S, Brittenden J, Bachoo P, Greaves M, Ford I. Evaluation of Aspirin Resistance in Peripheral Arterial Disease. Journal of Thrombosis and Haemostasis 2005, S1, P1140. 6 Poulsen TS, Jorgensen B, Korsholm L, Bjorn Licht P, Haghfelt T, Mickley H. Prevalence of aspirin resistance in patients with an evolving acute myocardial infarction. Thromb Res. 2007; 119: 555-62. S0049-3848(06)00154-X [pii] 10.1016/j.thromres.2006.04.005. 7 Mueller MR, Salat A, Stangl P, Murabito M, Pulaki S, Boehm D, Koppensteiner R, Ergun E, Mittlboeck M, Schreiner W, Losert U, Wolner E. Variable platelet response to low-dose ASA and the risk of limb deterioration in patients submitted to peripheral arterial angioplasty. Thromb Haemost. 1997; 78: 1003-7. 8 Hynkey GJ, Sudlow CL, Dunbabin DW. Thienopyridine derivates (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patient. Cochrane Database Syst Rev 2000; CD001246. 9 A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996; 348: 1329-39. S0140673696094573 [pii] 10 Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
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