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Randomized Controlled Trial of Dual Antiplatelet Therapy in Patients Undergoing Surgery for Critical Limb Ischemia

Burdess, Anne MB, ChB*; Nimmo, Alastair F. MD†; Garden, O. James MD*; Murie, John A. MD‡; Dawson, A. Raymond W. MD‡; Fox, Keith A. A. BSc (Hons), MB ChB, FRCP, FESC, FMed Sci§; Newby, David E. PhD§

doi: 10.1097/SLA.0b013e3181e40dde
Randomized Controlled Trials

Background and Objective: Patients with critical limb ischemia have a perioperative cardiovascular morbidity comparable to patients with acute coronary syndromes. We hypothesized that perioperative dual antiplatelet therapy would improve biomarkers of atherothrombosis without causing unacceptable bleeding in patients undergoing surgery for critical limb ischemia.

Methods: In a double-blind randomized controlled trial, 108 patients undergoing infrainguinal revascularization or amputation for critical limb ischemia were maintained on aspirin (75 mg daily) and randomized to clopidogrel (600 mg prior to surgery, and 75 mg daily for 3 days; n = 50) or matched placebo (n = 58). Platelet activation and myocardial injury were assessed by flow cytometry and plasma troponin concentrations, respectively.

Results: Clopidogrel reduced platelet-monocyte aggregation before surgery (38%–30%; P = 0.007). This was sustained in the postoperative period (P = 0.0019). There were 18 troponin-positive events (8 [16.0%] clopidogrel vs. 10 [17.2%] placebo; relative risk [RR]: 0.93, 95% confidence interval [CI]: 0.39–2.17; P = 0.86). Half of troponin-positive events occurred preoperatively with clopidogrel causing a greater decline in troponin concentrations (P < 0.001). There was no increase in major life-threatening bleeding (7 [14%] vs. 6 [10%]; RR: 1.4, 95% CI: 0.49–3.76; P = 0.56) or minor bleeding (17 [34%] vs. 12 [21%]; RR 1.64, 95% CI: 0.87–3.1; P = 0.12), although blood transfusions were increased (28% vs. 12.6%, RR: 2.3, 95% CI: 1.0–5.29; P = 0.037).

Conclusions: In patients with critical limb ischemia, perioperative dual antiplatelet therapy reduces biomarkers of atherothrombosis without causing unacceptable bleeding. Large-scale randomized controlled trials are needed to establish whether dual antiplatelet therapy improves clinical outcome in high-risk patients undergoing vascular surgery.

We hypothesized that dual antiplatelet therapy would improve atherothrombotic biomarkers without unacceptable bleeding in patients undergoing surgery for critical limb ischemia. In a double-blind RCT, patients on aspirin were randomized to clopidogrel (n = 50) or placebo (n = 58). Clopidogrel significantly reduced perioperative platelet-activation, and tended to reduce troponin release, without significantly increasing life-threatening bleeding. Supplemental digital content is available in the article.

From the Departments of *Clinical and Surgical Sciences, and †Anaesthesiology, The University of Edinburgh, Edinburgh, United Kingdom; ‡Department of Vascular Surgery, The Royal Infirmary of Edinburgh, Edinburgh, United Kingdom; and §Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom.

Supported by grants from the British Heart Foundation (FS/05/038); European Society of Vascular Surgery Research Awards; Royal College of Surgeons of Edinburgh Research Grants and an unrestricted educational award from Sanofi Aventis.

This study was registered on the ISRCT and EUDRA websites. International Standardised RCT: ISRCTN22305120. Weblink: http://www.controlled-trials.com/ISRCTN22305120.

Trial start date: June 1, 2005. Eudract Number: 2005–000960–25. CTA Number: 11449/0002/001–0001 (Granted 05/04/05). REC reference number: 05/S0501/41 (Granted 29/04/05).

There was no involvement of Sanofi Aventis in any aspect of the trial including protocol design, study conduct or data analysis.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.annalsofsurgery.com).

Reprints: Anne Burdess, MB, ChB, Department of Clinical and Surgical Sciences, The University of Edinburgh, Room SU304, The Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, United Kingdom. E-mail: anne.burdess@ed.ac.uk.

© 2010 Lippincott Williams & Wilkins, Inc.