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Is aspirin still the antiplatelet drug of choice for patients with peripheral arterial disease?
Eur J Vasc Endovasc Surg 25, 281±282 (2003) doi:10.1053/ejvs.2002.1809, available online at http://www.sciencedirect.com on
CORRESPONDENCE
Is Aspirin Still the Antiplatelet Drug of Choice for Patients with Peripheral Arterial Disease? Sir, The comprehensive review by Burns et al. considers the best medical treatment for peripheral arterial disease (PAD).1 The antiplatelet therapy section states that aspirin is the first-line antiplatelet drug of choice. However, there is evidence of aspirin resistance in PAD.2 This suggests that antiplatelet treatment with aspirin alone in PAD patients may be sub-optimal. Thienopyridine derivatives (e.g., clopidogrel) act by a mechanism different to that of aspirin.2 They reduce platelet activation by inhibiting the amplifying effect of ADP.2 Their clinical effectiveness is supported by trial-based evidence.2 Thus, clopidogrel was significantly more effective than aspirin in preventing major vascular events (myocardial infarction, stroke and vascular death) in a large randomised doubleblind trial (CAPRIE; 19 185 patients).3 Heterogeneity was seen among the three CAPRIE patient subgroups (patients with myocardial infarction, stroke or PAD).3 The 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), compared with 8.7% overall (p 0.043).2±4 However, 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.2 Other trials demonstrated the effectiveness of the clopidogrel aspirin combination after coronary artery stenting5 and acute coronary syndrome.6 On the negative side, combination therapy may increase peri-operative bleeding in patients undergoing surgery.7 We showed that a loading dose of clopidogrel (300 mg) causes platelet inhibition within 2±4 h in patients with PAD (unpublished results). We also showed (unpublished results) that treatment with clopidogrel (75 mg/day) inhibits platelet shape change (PSC) in patients with PAD. PSC is an early phase of platelet activation that is essentially aspirin resistant, at least in vitro.8
A switch from aspirin, an effective, cheap and widely prescribed drug in patients with PAD requires evidence from comparative trials. However, in the light of currently available evidence, this replacement may be reasonable in PAD patients who have a vascular event despite taking aspirin. Another alternative in this situation is to add clopidogrel to aspirin. Clopidogrel is also probably the drug of choice for PAD patients who cannot tolerate aspirin, as stated by Burns et al.1 Although these options are currently not evidence based, they may be realistic choices for patients with PAD.
Declaration of Interest The authors have participated in advisory panels or received research grants and educational sponsorship from AstraZeneca, Merck Sharpe & Dohme Limited, Pfizer, Bayer, BMS, Fournier, Novartis, Roche, Servier and Sanofi-Synthelabo. M. I. Matsagas1, I. A. Jagroop2, D. P. Mikhailidis2 and G. Geroulakos3 1 Department of Surgery, Medical School, University of Ioannina, Ioannina, Greece, 2 Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Campus, Royal Free & University College Medical School, University of London, London, U.K. 3Department of Vascular Surgery, Charing Cross Hospital, Imperial College of Medicine, University of London, London, U.K.
References 1 Burns P, Lima E, Bradbury AW. What constitutes best medical therapy for peripheral arterial disease? Eur J Vasc Endovasc Surg 2002; 24: 6±12. 2 Matsagas MI, Geroulakos G, Mikhailidis DP. The role of platelets in peripheral arterial disease: therapeutic implications. Ann Vasc Surg 2002; 16: 246±258.
1078±5884/03/030281 02 $35.00/0 # 2003 Elsevier Science Ltd. All rights reserved.
282
Correspondence
3 Caprie Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329±1339. 4 Mikhailidis DP, Jagroop IA. Is clopidogrel markedly superior to aspirin in patients with peripheral vascular disease? Platelets 1998; 9: 273±278. 5 Bertrand M, Rupprecht H, Urban P, Gershlick A, Investigators FT. Double-blind Study of the safety of clopidogrel with and without a loading dose in combination with aspirincompared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102: 624±629.
Eur J Vasc Endovasc Surg Vol 25, March 2003
6 Yusuf S, Zhao F, Mehat SR, Chrolavicious S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494±502. 7 Chapman TWL, Bowley DMG, Lambert AW, Walker AJ, Ashley SA, Wilkins DC. Haemorrhage associated with combined clopidogrel and aspirin therapy. Eur J Vasc Endovasc Surg 2001; 22: 478±479. 8 Barradas MA, O'Donoghue S, Mikhailidis DP. Measurement of platelet volume using a channelyzer: Assessment of the effect of agonists and antagonists. In vivo 1992; 6: 629±634.
CORRESPONDENCE
Is Aspirin Still the Antiplatelet Drug of Choice for Patients with Peripheral Arterial Disease? Sir, The comprehensive review by Burns et al. considers the best medical treatment for peripheral arterial disease (PAD).1 The antiplatelet therapy section states that aspirin is the first-line antiplatelet drug of choice. However, there is evidence of aspirin resistance in PAD.2 This suggests that antiplatelet treatment with aspirin alone in PAD patients may be sub-optimal. Thienopyridine derivatives (e.g., clopidogrel) act by a mechanism different to that of aspirin.2 They reduce platelet activation by inhibiting the amplifying effect of ADP.2 Their clinical effectiveness is supported by trial-based evidence.2 Thus, clopidogrel was significantly more effective than aspirin in preventing major vascular events (myocardial infarction, stroke and vascular death) in a large randomised doubleblind trial (CAPRIE; 19 185 patients).3 Heterogeneity was seen among the three CAPRIE patient subgroups (patients with myocardial infarction, stroke or PAD).3 The 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), compared with 8.7% overall (p 0.043).2±4 However, 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.2 Other trials demonstrated the effectiveness of the clopidogrel aspirin combination after coronary artery stenting5 and acute coronary syndrome.6 On the negative side, combination therapy may increase peri-operative bleeding in patients undergoing surgery.7 We showed that a loading dose of clopidogrel (300 mg) causes platelet inhibition within 2±4 h in patients with PAD (unpublished results). We also showed (unpublished results) that treatment with clopidogrel (75 mg/day) inhibits platelet shape change (PSC) in patients with PAD. PSC is an early phase of platelet activation that is essentially aspirin resistant, at least in vitro.8
A switch from aspirin, an effective, cheap and widely prescribed drug in patients with PAD requires evidence from comparative trials. However, in the light of currently available evidence, this replacement may be reasonable in PAD patients who have a vascular event despite taking aspirin. Another alternative in this situation is to add clopidogrel to aspirin. Clopidogrel is also probably the drug of choice for PAD patients who cannot tolerate aspirin, as stated by Burns et al.1 Although these options are currently not evidence based, they may be realistic choices for patients with PAD.
Declaration of Interest The authors have participated in advisory panels or received research grants and educational sponsorship from AstraZeneca, Merck Sharpe & Dohme Limited, Pfizer, Bayer, BMS, Fournier, Novartis, Roche, Servier and Sanofi-Synthelabo. M. I. Matsagas1, I. A. Jagroop2, D. P. Mikhailidis2 and G. Geroulakos3 1 Department of Surgery, Medical School, University of Ioannina, Ioannina, Greece, 2 Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Campus, Royal Free & University College Medical School, University of London, London, U.K. 3Department of Vascular Surgery, Charing Cross Hospital, Imperial College of Medicine, University of London, London, U.K.
References 1 Burns P, Lima E, Bradbury AW. What constitutes best medical therapy for peripheral arterial disease? Eur J Vasc Endovasc Surg 2002; 24: 6±12. 2 Matsagas MI, Geroulakos G, Mikhailidis DP. The role of platelets in peripheral arterial disease: therapeutic implications. Ann Vasc Surg 2002; 16: 246±258.
1078±5884/03/030281 02 $35.00/0 # 2003 Elsevier Science Ltd. All rights reserved.
282
Correspondence
3 Caprie Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329±1339. 4 Mikhailidis DP, Jagroop IA. Is clopidogrel markedly superior to aspirin in patients with peripheral vascular disease? Platelets 1998; 9: 273±278. 5 Bertrand M, Rupprecht H, Urban P, Gershlick A, Investigators FT. Double-blind Study of the safety of clopidogrel with and without a loading dose in combination with aspirincompared with ticlopidine in combination with aspirin after coronary stenting: the clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000; 102: 624±629.
Eur J Vasc Endovasc Surg Vol 25, March 2003
6 Yusuf S, Zhao F, Mehat SR, Chrolavicious S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494±502. 7 Chapman TWL, Bowley DMG, Lambert AW, Walker AJ, Ashley SA, Wilkins DC. Haemorrhage associated with combined clopidogrel and aspirin therapy. Eur J Vasc Endovasc Surg 2001; 22: 478±479. 8 Barradas MA, O'Donoghue S, Mikhailidis DP. Measurement of platelet volume using a channelyzer: Assessment of the effect of agonists and antagonists. In vivo 1992; 6: 629±634.