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Assoc. Prof Mateja K. Jezovnik
Prof. Pavel Poredos,
Although clopidogrel is recognised as slightly more effective than aspirin in preventing major atherothrombotic events in patients with peripheral arterial disease (PAD), aspirin remains the first-line antiplatelet drug and clopidogrel is its effective alternative. Oral anticoagulant therapy alone or in combination with aspirin is not more effective than aspirin in prevention of cardiovascular events in PAD patients, however it is related to increased risk of bleeding.
As with other manifestations of atherosclerosis, platelets and clotting factors play a pivotal part in the progression of PAD and the genesis of complications. Studies have suggested that patients with PAD manifest platelet hyperaggregability, increased levels of soluble platelet activation markers, enhanced thrombin generation and an altered fibrinolytic potential. Many of the markers characterising the prothrombotic state of PAD are also predictive of future cardiovascular events. These data underline the importance of antithrombotic prophylaxis in patients with PAD (1, 2). Therefore, antiplatelet and antithrombotic drugs represent one of the basic options for prevention and treatment of such patients.
In contrast to coronary artery disease, there have been no trials including only patients with PAD that would have sufficient power to precisely estimate the preventive effect of these drugs on PAD. The effect of antiplatelet therapy on cardiovascular events has been systematically reviewed by the Antithrombotic Trialists' Collaboration (3). This report included also 42 randomised trials of antiplatelet treatment in 9214 patients with PAD. Among those patients with PAD treated with antiplatelet therapy, there was a 23 % odds reduction for adverse cardiovascular events, including MI, stroke, or vascular death. Similar benefits were observed in patients with intermittent claudication, those having had peripheral angioplasty, and those who had undergone peripheral bypass graft procedures.
Clopidogrel is an alternative antiplatelet agent that is commonly used for secondary prevention of atherothrombotic disease in place of low-dose aspirin in patients who have experienced gastrointestinal intolerance to aspirin-related adverse events or with aspirin allergy. In the subgroup of patients with PAD in CAPRI trial, clopidogrel was found to be more effective than aspirin in preventing atherothrombotic events and resulted in less gastrointestinal bleeding (4). Among the 6452 patients with PAD, clopidogrel reduced the risk of MI, stroke, or vascular death by 23.8 % more than aspirin. However like aspirin, clopidogrel may cause adverse bleeding events via its antiplatelet activity. Meta-analysis of adverse events of low dose aspirin and clopidogrel showed that compared with clopidogrel, aspirin increases the risk of gastrointestinal (GI) bleeding but not other bleeding and 883 patients would need to be treated with clopidogrel versus aspirin to prevent one major GI bleeding episode annually (5).
Dual antiplatelet therapy with clopidogrel, plus aspirin has been shown to reduce ischaemic events in coronary patients: unstable angina, myocardial infarction without ST-segment elevation, or myocardial infarction with ST-segment elevation, as well as those undergoing angioplasty and stenting (6, 7).
However, in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in patients with multiple cardiovascular risk factors, but there was a moderate benefit in reducing the secondary composite end point only in patients with established vascular disease (8).
The Antiplatelet Trialists' Collaboration found a 30 % reduction in the rate of lower arterial occlusion by antiplatelet treatment compared with no additional medical intervention over a 19 month period (9). A meta-analysis of randomized, controlled trials in patients with intermittent claudication showed that aspirin reduced the risk of arterial occlusion and ticlopidine reduced the need for revascularization procedures (10). The Physician Health Study confirmed that low dose aspirin impeded the progression to intermittent claudication and reduced the risk of undergoing peripheral arterial surgery (11). The recent Cochrane overview also showed the benefit of aspirin on the local circulation of revascularized PAD patients, with a 41 % reduction in the risk of graft occlusion after 12 months of therapy (12)
There are only a few studies evaluating the effect of oral anticoagulation and its efficacy in comparison to aspirin in PAD patients. In the Warfarin and Antiplatelet Vascular Evaluation (WAVE) trial 2161 patients with peripheral vascular disease were randomized to the combination of oral anticoagulation (target INR 2-3) plus aspirin, or to aspirin alone and followed for nearly 3 years (13). In the combination therapy no benefit on cardiovascular death, myocardial infarction or stroke was observed, but there was a 3.5 times increase in severe bleeding complications including cerebral haemorrhage.
Anand et al. recently reported a meta-analysis of nine randomized trials of oral anticoagulants involving 4889 PAD patients. OAC compared to control (no treatment) reduced graft occlusion by 37 % with a trend towards decreased mortality (OR 0.73). When compared with aspirin, OAC was not more effective in preventing graft occlusion or death; moreover the risk of major haemorrhage was nearly doubled (14).
In an open, multicentre, randomized trial of 831 US veterans undergoing elective infrainguinal vein by-pass grafting, in which patients received OAC (target INR 1.5-2.8) plus aspirin or aspirin alone, no difference in graft occlusion after 4 years was observed in combined treatment compared with the aspirin group (26 % vs. 23 %). Further, no difference in the incidence of MI or stroke was observed. A significant increase in all-cause mortality with OAC compared with aspirin was observed (15).
Oral anticoagulant therapy alone or in combination with aspirin is not more effective than aspirin alone in prevention of cardiovascular events in PAD patients and is related to increased risk of bleeding events. It is probably only more effective in prevention of graft occlusion.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Cassar K, Bochoo P, Ford I, Greaves M, Brittenden J. Platelet activation is increased in peripheral arterial disease, J Vasc Surg 2003; 38: 99-103. 2. Robless PA, Okonko D, Linton P. Increased platelet aggregation and activation in peripheral arterial disease. Eur J Vasc Endovasc Surg 2003; 25: 16-22. 3. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71-86. 4. A randomized blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348: 1329-39. 5. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. Amer J Med 2006; 119-624-38. 6. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu L; COMMIT (Clopidogrel and metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45.852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366: 1607-21. 7. Streinbuhl SR, Berger PB, Mann JT III, Fry ETA, DeLago A, Wilmer C, Topol EJ for the CREDO Investigators. Early and sustained dual oral antiplatelet therapy following PCI : a randomized placebo-controlled trial. JAMA 2002; 288: 2411-20. Erratum, JAMA 2003: 289: 987. 8. Bhatt DI, Flather MD, Hacke Werner, Berger PB, Black HR, Boden WE, Cohen EA, Creager MA, Easton DJ, Hamm CW, Hankey GJ, Johnston CS, Mak KHou, Mas JLouis, Montalescot G, Pearson TA, Steg GP, Steinbuhl SR, Weber MA, Fabry-Ribaudo L, Hu T, Topol EJ, Fox KAA. for the CHARISMA investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. JACC 2007; 49: 1984-8. 9. Antiplatelet Trialists' Collaboration. Collaborative overview of randomized trials of antiplatelet therapy – II: Maintenance of vascular graft of arterial patency by antiplatelet therapy. BMJ 1994; 308: 159-68. 10. Girolami B, Bernmardi E, Prins MH, ten Cate JW, Prandoni P, Hettiarachchi R, Marras E, Stefani PM, Girolami A, Buller HR. Antithrombotic drugs in the primary medical management of intermittent claudication: a meta-analysis. Thromb Haemost 1999; 81: 715-22. 11. Goldhaber SZ, Manson JE, Stampfer MJ, LaMotte F, Rosner B, Buring JE, Hennekens CH. Low-dose aspirin and subsequent peripheral arterial surgery in the Physicians' Health Study. Lancet 1992; 340: 143-5. 12. Dörffer Melly J, Koopman MM, Adam DJ, Buller HR, Prins MH. Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery. Cochrane Database Sys Rev 2003: CD000535. 13. The WAVE Investigators Hamilton, Ontario, Canada. The effects of oral anticoagulants in patients with peripheral arterial disease: rationale, design, and baseline characteristics of the Warfarin and Antiplatelet Vascular Elevation (WAVE) trial, including a meta-analysis of trials. Am Heart J 2005; 151: 1-9. 14. Anand S. Warfarin Antiplatelet Vascular Evaluation: a randomized controlled trial testing moderate intensity oral anticoagulation and antiplatelets therapy vs antiplatelet therapy alone in patients with peripheral arterial disease. World Congress of Cardiology. Hotline Session II; Barcelona, Spain 2006 (WAVE). 15. Johnson WC, Williford WO. Benefits, morbidity and mortality associated with long-term administration of oral anticoagulant therapy to patients with peripheral arterial bypass procedures: a prospective randomized study. J Vasc Surgery 2002; 35: 413-21.
Prof. P. Poredoš, Dr M.K. Ježovnik, Ljubljana, Slovenia. Past-president of the Working Group on Peripheral Arterial Diseases
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