Clopidogrel Loading Dose and Bleeding Outcomes in Patients Undergoing Urgent Coronary Artery Bypass Grafting

Nicholas L.M. Cruden, PhD, MBChB, MRCP; Kristin Morch; Daniel R. Wong, MD, MPH, FRCSC; W. Peter Klinke, MD, FRCPC; John Ofiesh, MD, FRCSC; J. David Hilton, MD, FRCPC

Disclosures

Am Heart J. 2011;161(2):404-410. 

In This Article

Abstract and Introduction

Abstract

Background Coronary artery bypass grafting (CABG) performed within 5 days of clopidogrel administration is associated with increased bleeding. The impact of clopidogrel loading dose is unknown. We examined the effect of clopidogrel loading dose on bleeding outcomes in patients undergoing urgent CABG.
Methods Clinical outcomes were examined retrospectively for 196 consecutive patients undergoing urgent CABG within 5 days of a clopidogrel loading dose between January 2003 and June 2009. Major bleeding was defined as a fall in hemoglobin >5g/dL, fatal or intracranial bleeding, or cardiac tamponade.
Results One hundred forty-eight patients received 300 mg and 48 patients received ≥600 mg clopidogrel loading. Patients were predominantly male (78%) with a mean age of 66 ± 10 years. Mean duration from clopidogrel loading to CABG was 3.0 ± 1.5 and 3.0 ± 1.6 days for the 300 and 600 mg loading doses, respectively. Major bleeding occurred in 47% of patients receiving 300 mg and 73% of patients receiving ≥600 mg clopidogrel loading (P = .002). Compared with 300 mg, patients receiving ≥600 mg had greater 24-hour chest tube output (391 ± 251 vs 536 ± 354 mL, P = .01), stayed longer in surgical intensive care (4.3 ± 4.1 vs 5.0 ± 3.1 days, P = .0001), and trended toward greater reoperation for bleeding (5% vs 12%, P = .09). Following multivariate analysis, clopidogrel loading dose ≥600 mg (odds ratio 2.8, CI 1.2–6.6), preoperative hemoglobin (3.4, 2.7–5.0 per 1 g/dL increase), and female gender (2.9, 1.1–7.4) predicted major bleeding.
Conclusions Higher clopidogrel loading doses are associated with increased bleeding when administered within 5 days of CABG. The development of shorter-acting, reversible, oral antiplatelet agents may reduce perioperative bleeding in this population.

Introduction

Oral administration of clopidogrel, in combination with aspirin, significantly reduces ischemic vascular events in patients presenting with an acute coronary syndrome (ACS)[1] or undergoing percutaneous coronary intervention (PCI).[2,3] Recent attention has focused on the increased bleeding potential associated with clopidogrel use and the impact of bleeding on clinical outcomes in these high-risk patient groups.[4]

Excess bleeding is of particular concern in patients undergoing coronary artery bypass grafting (CABG), with significant implications for patient morbidity and mortality, length of hospital stay, and health care costs.[5,6] In the United States, approximately 1 in 7 patients presenting with an ACS is referred for CABG during their index admission, with a median duration from hospital admission to CABG of 69 hours.[7,8] In the vast majority (~80%), CABG is performed within 5 days of admission.[7,8] Although not a universal finding,[9] a number of studies have demonstrated that CABG performed within 5 days of clopidogrel administration is associated with increased bleeding and bleeding-related complications, including cardiac tamponade and reoperation for bleeding.[10,11,12] As a result, current guidelines recommend that, where possible, CABG should be delayed for at least 5 days following the last dose of clopidogrel.[13] However, only in a minority of patients does this occur.[11]

Although a substantial body of evidence exists to support the use of a 300 mg loading dose of clopidogrel administered at least 6 hours before PCI,[14] platelet inhibition studies demonstrate more rapid and greater platelet inhibition with higher loading doses (≥600 mg).[15,16] Moreover, these pharmacodynamic benefits appear to translate to the clinical arena. Evidence of a reduction in ischemic vascular events with higher loading doses of clopidogrel in patients undergoing PCI is now emerging,[17,18,19] with the result that an increasing number of patients are likely to undergo CABG within 5 days of a 600 mg loading dose of clopidogrel.

Despite recent concerns,[20] the impact of higher loading doses of clopidogrel on bleeding outcomes in patients undergoing urgent CABG is unknown. The aim of this study was to examine the effect of clopidogrel loading dose, administered within 5 days of CABG, on bleeding and bleeding-related outcomes.

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