Epi-q.com

Clopidogrel-Associated Bleeding and Related Complications
in Patients Undergoing Coronary Artery Bypass Grafting
A. Simon Pickard, Ph.D., Richard C. Becker, M.D., Glen T. Schumock, Pharm.D., M.B.A., Objective. To determine if clopidogrel use before coronary artery bypass
grafting (CABG) is associated with an increase in major bleeding,hemorrhage-related complications, or transfusion requirements.
Methods. A structured literature search of English-language articles was
conducted by using MEDLINE, EMBASE, and the Cochrane CollaborationDatabase for the period of January 1, 1990–April 30, 2007. Studies wereincluded if they met the following criteria: randomized controlled trials,prospective observational trials, or retrospective trials; characteristics andoutcomes of patients who were exposed to clopidogrel within 7 days beforeCABG were analyzed; at least 20 patients were enrolled; and reportedoutcomes were related to transfusion requirements, resource utilization,clinical events, or hemorrhage-related reoperation rates. Patients wereconsidered exposed to clopidogrel if they discontinued the drug within aspecified time frame that was designated in each study. The rates of theoutcomes were compared between those patients exposed and those notexposed to clopidogrel.
Results. Twenty-three studies, with data on 3505 patients exposed to
clopidogrel before CABG, met the selection criteria. Results suggested thatclopidogrel exposure within 7 days before CABG increased the risk ofmajor bleeding and related complications, such as reoperation and bloodproduct transfusions. For other outcomes such as mortality, myocardialinfarction, or stroke, the studies’ designs lacked statistical power to detectsignificant differences. In five of the 23 studies, antifibrinolytic therapywith aprotinin was evaluated; in the other studies, aprotinin may have beenadministered, but it was not discussed in detail. In these studies, theclopidogrel-exposed patients typically had significantly higher chest tubeoutput volumes, reoperation rates due to bleeding, and greater transfusionrequirements. Although aprotinin appeared to mitigate hemorrhagic risk,the drug has been temporarily suspended from the market due to safetyconcerns.
Conclusion. Clopidogrel exposure within 7 days before CABG is associated
with an increase in major bleeding, hemorrhage-related complications, andtransfusion requirements, and leads to potentially greater consumption ofhealth care resources. The overall risks and benefits for each patientshould be considered before using the drug.
Key Words: acute coronary syndrome, adenosine diphosphate inhibitors,
bleeding, hemorrhage, clopidogrel, coronary artery bypass graft, CABG,thienopyridines.
(Pharmacotherapy 2008;28(3):376–392)
CLOPIDOGREL-ASSOCIATED BLEEDING IN PATIENTS UNDERGOING CABG Pickard et al Coronary artery bypass grafting (CABG) is an of therapy of at least 12 months has been established revascularization procedure for the recommended for patients who receive drug- eluting stents to minimize the risk for stent coronary artery disease.1 The National Center for procedures were performed on 249,000 patients patients with ACS clearly reflect the ability of in the United States in 2004.2 Antiplatelet drugs, clopidogrel, combined with aspirin, to reduce particularly aspirin, are considered a mainstay for cardiovascular events, they also emphasize caution in individuals who subsequently require atherothrombotic coronary artery disease.3 CABG, given the potential risk of perioperative However, newer agents, such as clopidogrel (one hemorrhagic complications. Specifically, published of two commercially marketed thienopyridine guidelines recommend that high-risk patients adenosine 5′-diphosphate [ADP]–receptor should not receive an ADP-receptor antagonist combined with aspirin are highly beneficial in until the coronary anatomy is defined and a clinical-pathologic states of heightened platelet decision has been made not to perform surgical activation and recommended strongly for use revascularization.5 Further, among patients among patients with non–ST-segment elevation taking clopidogrel who are scheduled for elective acute coronary syndrome (ACS).4, 5 Clopidogrel recently received approval by the United States preferably 7 days before surgery is recommended.8 Food and Drug Administration for a labeling Clopidogrel, like ticlopidine and the investi- change to include patients with ST-segment gational agent prasugrel, is a nonreversible platelet antagonist. As a prodrug, clopidogrel is The benefits of clopidogrel in patients with rapidly and extensively metabolized hepatically ACS were first demonstrated in the Clopidogrel to a carboxylic acid derivative (its active in Unstable Angina to Prevent Recurrent Events metabolite), with a plasma elimination half-life of (CURE) study.7 On the basis of these data, approximately 8 hours. Platelet exposure to the current American Heart Association–American active metabolite causes prolonged (7–10 days) inhibition of ADP-mediated platelet activation European Society of Cardiology (ESC)5 manage- and aggregation. Thus, from the time of drug ment guidelines recommend platelet-directed discontinuation, restoration of normal hemostasis pharmacotherapy with aspirin and clopidogrel in is dependent on the introduction of new platelets patients with ACS treated medically or after into the circulation from bone marrow and extramedullary sources. Because cardiothoracic minimum of 1 month (level of evidence A) and surgery represents a major hemostatic challenge up to 12 months (level of evidence B). A course and is required in greater than 15% of patientsadmitted to the hospital with ACS, clinicians are From the Center for Pharmacoeconomics Research and confronted regularly with complex decisions the Department of Pharmacy Practice, University of Illinoisat Chicago, Chicago, Illinois (Drs. Pickard and Schumock); concerning the acceptable risk of antithrombotic the Divisions of Cardiology and Hematology, Duke University Medical Center, Durham, North Carolina (Dr.
patients are at high risk requiring urgent or Becker); and EPI-Q, Inc., Oak Brook, Illinois (Dr. Frye).
emergency surgical revascularization.
This study was funded by AstraZeneca, LLP, Wilmington, To better understand the overall clinical impact Delaware. Drs. Pickard and Schumock served asconsultants to AstraZeneca and to EPI-Q, Inc., an and health care delivery implications associated independent health and economics research group with clopidogrel use before elective, isolated contracted by AstraZeneca, LLP. Dr. Becker receives CABG, we conducted a comprehensive review of research support from AstraZeneca, LLP. The sponsor had published studies reporting transfusion require- no role in the design or conduct of the structured review, ments, rates of major bleeding and related nor in the collection, management, analyses, orinterpretation of the data. AstraZeneca, LLP, was given the complications, resource utilization, and outcomes opportunity to review and comment on the final draft in patients exposed to clopidogrel before CABG.
manuscript. The authors had full editorial independence Our objective was to determine if clopidogrel use and full responsibility for the final version of the before CABG was associated with increases in bleeding and its complications, and if so, to use Address reprint requests to Carla B. Frye, Pharm.D., BCPS, EPI-Q, Inc., 1315 West 22nd Street, Suite 410, Oak this information to improve clinical decision Brook, IL 60523; e-mail: Carla.frye@epi-q.com.
PHARMACOTHERAPY Volume 28, Number 3, 2008 Table 1. Description of the 23 Studies That Met Selection Criteria
To investigate the independent effect of preoperative exposure to aspirin, heparin, and clopidogrel on early clinical outcomes of inpatients undergoing initial CABG13 To determine if the immediate preoperative use of clopidogrel is associated with increased occurrence of postoperative bleeding15 To evaluate the effect of preoperative clopidogrel on CABG To evaluate the effects of clopidogrel on bleeding and use of To evaluate potential role of off-pump CABG in eliminating need to delay surgery and in decreasing postoperative bleeding inpatients exposed to clopidogrel27 To explore the effects of clopidogrel on bleeding complications To evaluate the effect of clopidogrel on bleeding in urgent To analyze the effect of clopidogrel on bleeding, transfusion To evaluate the effect of preoperative clopidogrel exposure in To evaluate the effect of preoperative clopidogrel in patients To assess complications in patients who received clopidogrel To review the effect of preoperative clopidogrel on clinical outcomes, bleeding complications, and resource utilization after CABG22 To evaluate the impact of antiplatelet drugs on cardiac patients23 To characterize clopidogrel use before CABG and examine the impact on transfusion requirements in patients with non–ST-elevation ACS (ad hoc analysis from CRUSADE study)3 To evaluate the risk associated with use of aspirin and clopidogrel25 To examine the effect of clopidogrel received ≤ 6 days before CABG on postoperative need for transfusions14 To examine the benefits and risks of clopidogrel in patients undergoing CABG (CURE subgroup analysis)17 To report outcomes of CABG surgery (CLARITY-TIMI 28 To evaluate the influence of clopidogrel on postoperative bleeding and transfusion requirements in patients with myocardialrevascularization; all patients received aprotinin16 To compare the effect of preoperative aspirin with or without clopidogrel on postoperative bleeding and transfusion requirements;all patients received aprotinin29 CLOPIDOGREL-ASSOCIATED BLEEDING IN PATIENTS UNDERGOING CABG Pickard et al Table 1. (continued)
No. of Days Clopidogrel Discontinued Before Surgery A structured literature search was conducted to identify studies that evaluated the associationbetween clopidogrel exposure and bleeding- related outcomes in patients undergoing CABG.
The search was limited to original studiespublished in English for the period of January 1, 1990–April 30, 2007, and was conducted by Database for Systematic Reviews was also used toidentify relevant literature. Both Medical Index Subject Headings and free-text search terms wereused to identify pertinent literature. Search terms included clopidogrel and CABG andbleeding or hemorrhage.
Titles and abstracts of articles identified were reviewed for possible inclusion. Each title andabstract was screened by reviewers (A.S.P., G.T.S.,C.B.F.) using a standardized inclusion-exclusion form. Reviews, case reports, editorials, letters, orother non–original research articles were excluded. Articles that met the general inclusion criteria were retrieved for review of the full text.
Studies were included if they met the followingcriteria: they were randomized controlled trials, prospective observational studies, or retrospectivestudies; they analyzed characteristics and outcomes of patients who were exposed toclopidogrel within 7 days before CABG; and they reported postoperative bleeding-related outcomes, requirements, mortality, hospital length of stay, and reoperation. Studies were excluded if thenumber of patients exposed to clopidogrel wasnot reported, or if fewer than 20 patients were developed, piloted on several studies, and refined (the form is available on request). Data abstracted from each study included the study objective,study design, and demographic and clinical characteristics of exposed and nonexposedpatients. Patients were considered exposed if they discontinued clopidogrel within a specifiedtime frame up to 7 days before CABG that wasdesignated in each study. Data also were collected regarding the exposure (i.e., number ofdays between clopidogrel discontinuation andCABG), and peri- and postoperative clinical and resource utilization outcomes in the exposed andnonexposed groups. The abstraction process alsoinvolved confirmation of the inclusion criteria, PHARMACOTHERAPY Volume 28, Number 3, 2008 Table 1. Description of the 23 Studies That Met Selection Criteria (continued)
Studies that also analyzed aprotinin (continued) To investigate whether or not intraoperative use of aprotinin decreases bleeding and transfusion requirements after CABG inpatients treated with clopidogrel < 5 days before surgery24 To compare two treatment strategies: clopidogrel discontinued within 5 days before surgery, and clopidogrel continued untilsurgery; patients administered aprotinin at surgeon discretion12 To investigate if aprotinin decreases bleeding and transfusion requirements after urgent or emergency CABG in patients treatedwith clopidogrel < 5 days before surgery26 CABG = coronary artery bypass graft surgery; NR = not reported; NA = not applicable; CURE = Clopidogrel in Unstable Angina to PreventRecurrent Ischemic Events trial; CLARITY-TIMI 28 = Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction 28trial; ACS = acute coronary syndrome; CRUSADE = Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes withEarly Implementation of the ACC/AHA Guidelines.
aPatients were considered exposed if they discontinued clopidogrel within a specified time frame that was designated in each study.
bAnticoagulants used in this study were aspirin and intravenous unfractionated heparin.
cHospitalized group included patients who stopped clopidogrel and underwent CABG within 3–5 days of clopidogrel cessation; dischargedhome group included patients who stopped clopidogrel and went home but returned for CABG within 3–5 days of clopidogrel cessation.
and, if necessary, the exclusion of studies based been exposed to clopidogrel within 7 days before on information that was more detailed. Decisions The number of patients studied within the Mean differences (and confidence intervals 33–2359. The primary indication for clopidogrel clopidogrel-exposed and nonexposed patient administration was prevention of thrombotic groups were calculated from data in each study events in patients with ACS. Most studies did not cite a source of funding. A small proportion transfused was reported either in units or of the 23 studies were sponsored by a pharma- milliliters; for consistency, these volumes were ceutical company (five studies), hospital (two), converted to units, assuming 220 ml/unit. For the figures and tables, only studies reporting our The time of clopidogrel discontinuation before prespecified outcomes were included. Only CABG varied across studies (Table 1). Most studies that reported means were summarized in studies defined patients as clopidogrel exposed the figures. For the outcome of reoperation, when discontinuation occurred within 5 or 7 absolute risk and 95% CIs were calculated for days before CABG. In four studies, clopidogrel studies where sufficient data were reported.10 was discontinued within 4 days before surgery.15,16, 21, 27 In eight of the 23 studies, clopidogrel was discontinued within 5 days before surgery.13, 18, 24,26, 28–31 The titles and abstracts of 376 articles were tinued within 7 days before surgery.19, 20, 23, 25, 32 In reviewed; 325 were excluded due to failure to one study clopidogrel was discontinued within 6 meet inclusion criteria. Of the 51 articles that days before surgery14; one study compared underwent full review, only 23 studies met the clopidogrel discontinuation within 4 days before criteria for inclusion in our analysis.11–33 Only surgery with discontinuation 5–8 days before four studies (17%) were randomized trials.12, 17, 26, 30 surgery15; and one study compared clopidogrel Ten studies (43%) were retrospective, and eight discontinuation less than 4 days before surgery, (35%) used a prospective, observational design 4–7 days before surgery, and more than 7 days (Table 1). One study included analyses of both retrospectively and prospectively defined patient The dosage of clopidogrel received in the cohorts.14 Overall, the data from the studies qualifying studies varied. Ten of the studies did included 13,475 patients, 3505 of whom had not describe the clopidogrel dosage,14–16, 18, 19, 23, 25, CLOPIDOGREL-ASSOCIATED BLEEDING IN PATIENTS UNDERGOING CABG Pickard et al Table 1. (continued)
studies analyzed the effect of a loading dose on No. of Days Clopidogrel Discontinued Before Surgery Patients exposed to clopidogrel also received aspirin in at least 15 of the 23 studies.12, 13, 17–22, 25,27–30, 32, 33 included aspirin exposure in their analyses.19, 22, 25,29, 30, 33 In five studies, antifibrinolytic therapy withaprotinin during CABG was evaluated inclopidogrel-exposed patients.12, 16, 24, 26, 29 Tables 2 and 3 summarize the findings of the studies reporting differences in chest tube output, blood product transfusions, andreoperation due to bleeding. In four of sevencomparisons, clopidogrel-exposed patients hadsignificantly higher chest tube output based on95% CIs (Figure 1). In the studies whereaprotinin use was not specifically discussed, 28, 29, 31 seven studies analyzed patients who had clopidogrel-exposed patients had significantly received a 300-mg loading dose followed by a 75- greater platelet transfusion requirements in all mg/day regimen,11, 13, 17, 24, 26, 30, 33 and the but one study (Figure 2). Similarly, in these remaining six studies noted only that patients studies, clopidogrel-exposed patients were had received at least 75 mg/day in the period associated with a trend toward higher reoperation preceding the CABG.12, 20–22, 27, 32 None of the rates due to uncontrolled bleeding and/or cardiac Figure 1. Mean difference (in units) in chest tube output. Bar segments represent mean difference over 24 hours for patients
exposed to clopidogrel compared with nonexposed patients, with error bars representing 95% confidence intervals. A positive
value indicates that mean chest tube output was greater in the exposed group.
PHARMACOTHERAPY Volume 28, Number 3, 2008 Table 2. Chest Tube Output and Transfusion Requirements in Clopidogrel-Exposed and Nonexposed Patients
CLOPIDOGREL-ASSOCIATED BLEEDING IN PATIENTS UNDERGOING CABG Pickard et al Table 2. (continued)
In addition to the five studies where aprotinin reported the administration of aprotinin ingreater than 70% of patients in each cohort15; no additional data on aprotinin use were provided in that study. Concomitant administration ofaprotinin appeared to reduce or obscure the association between bleeding-related outcomesand clopidogrel exposure (Tables 2 and 3; No obvious trend was associated with clopidogrel exposure in studies that compared rates of mortality (17 studies), stroke (10 studies), and myocardial infarction (11 studies; Table 4).
In the studies that compared clopidogrel- exposed and nonexposed patients on the basis ofduration of mechanical ventilation, total intubation time, postoperative intensive care unit stay, or postoperative hospital length of stay, no consistent pattern was discerned across studies(Table 5). One study applied multivariate analysis and found that clopidogrel exposure 0–4 days before surgery was an independent predictorof longer stay in the intensive care unit and overall hospital stay, adjusting for aprotinin dosage and other patient and clinical factors.15 However, most studies did not find a significantdifference in resource utilization–related outcomes based on exposure or nonexposure to clopidogrel.
Discussion
Antithrombotic therapy represents a mainstay in the evidence-based management of patients with ACS. Although the potential benefit ofclopidogrel in combination with aspirin in this setting is incontrovertible,7 our literature reviewunderscores concerns among clinicians andsurgeons alike about the increased risk for important outcomes, including major bleeding, blood product transfusions, and hemorrhage-related reoperation among patients exposed to clopidogrel within 7 days before nonemergency CABG. For other outcomes such as mortality,stroke, and myocardial infarction, study designs tended to lack statistical power to detect signifi- cant differences between the clopidogrel-exposed and nonexposed groups, even if a true differenceexisted, because these events tended to be rare.
There were threats to the internal validity of many of the studies reviewed. Most of the studies were retrospective analyses, which can be suscep- tible to biases such as selective reporting of events and confounding by indication. More PHARMACOTHERAPY Volume 28, Number 3, 2008 Table 2. Chest Tube Output and Transfusion Requirements in Clopidogrel-Exposed and Nonexposed Patients (continued)
NR = not reported; NA = not applicable; CI = confidence interval.
aPatients were considered exposed if they discontinued clopidogrel within a specified time frame that was designated in each study.
bData are mean ± SD, median (range), or median (95% confidence interval).
cData are number (%) of patients, mean ± SD number of units, or median (range).
dStudy reported end points for more than one experimental group.
eAnticoagulants were aspirin and intravenous unfractionated heparin.
fThe nonexposed group did not receive clopidogrel for at least 8 days.
gClopidogrel was given with aspirin.
hNonexposed group was given placebo.
iNonexposed group was given aspirin.
jHospitalized group included patients who stopped clopidogrel and underwent CABG within 3–5 days of clopidogrel cessation; dischargedhome group included patients who stopped clopidogrel and went home but returned for CABG within 3–5 days of clopidogrel cessation.
kStudy reported the percentage of patients who bled greater than 100 ml/hr for 2 consecutive hours.
recent studies29, 32 used risk-adjusted models in nonexposed groups. Those studies found an attempt to reduce the effect of preoperative increased risk of reoperation for bleeding and variability between the clopidogrel-exposed and greater requirement for blood product trans- Figure 2. Mean difference in platelet transfusion requirements. Bar segments represent mean difference for patients exposed to
clopidogrel compared with nonexposed patients, with error bars representing 95% confidence intervals. A positive value
indicates that mean platelet transfusion requirements were greater in the exposed group.
CLOPIDOGREL-ASSOCIATED BLEEDING IN PATIENTS UNDERGOING CABG Pickard et al Table 2. (continued)
A decision to perform coronary angiography, percutaneous coronary intervention, or CABG in patients with ACS is based on several factors andderived from a wealth of clinical trial data (AHA- ACC, ESC).5, 8 Patients with high-risk coronaryanatomy, recurrent myocardial ischemia, and hemodynamic compromise benefit from surgical revascularization that may be required during the initial hospitalization, whereas others mayachieve sufficient clinical stability to undergosurgery on a more elective basis. Despite advancesin pharmacologic therapy, recent results from the fusion with preoperative exposure to clopidogrel.
The findings of our review are consistent with (GRACE) indicate that more than 7% of patients those generated from a post hoc analysis of data hospitalized with ACS undergo CABG during the index hospitalization.36 Although one might Syndromes (OASIS) and the CURE trials,34 as expect that surgery performed within several days of hospital admission is related to high-risk Figure 3. Absolute risk of reoperation associated with clopidogrel exposure. Bar segments represent mean difference in
reoperation risk for patients exposed to clopidogrel compared with nonexposed patients, with error bars representing 95%
confidence intervals.
PHARMACOTHERAPY Volume 28, Number 3, 2008 Table 3. Reoperation Rates and Cryoprecipitate and Fresh Frozen Plasma Transfusion Requirements Among Clopidogrel-
Exposed and Nonexposed Patients
NR = not reported; NA = not applicable.
aData are number (%) of patients or mean ± SD number of units.
bPatients were considered exposed if they discontinued clopidogrel within a specified time frame that was designated in each study.
cData are number (%) of patients.
dData are number (%) of patients, mean ± SD number of units, or median (range).
eStudy reported end points for more than one experimental group.
fAnticoagulants were aspirin and intravenous unfractionated heparin.
gStudy contained an additional table listing number of days of clopidogrel exposure before coronary artery bypass graft surgery and number ofmajor bleeds within 7 days of surgery.
hExposed subjects were considered the hospitalized group, which included patients who stopped clopidogrel and underwent CABG within 3–5days of clopidogrel cessation; nonexposed patients were considered the discharged home group, which included patients who stoppedclopidogrel and went home but returned for CABG within 3–5 days of clopidogrel cessation.
CLOPIDOGREL-ASSOCIATED BLEEDING IN PATIENTS UNDERGOING CABG Pickard et al Table 4. Postoperative Outcomes of Clopidogrel-Exposed and Nonexposed Patients
NR = not reported; NA = not applicable; CV = cardiovascular.
aPatients were considered exposed if they discontinued clopidogrel within a specified time frame that was designated in each study.
bStudy reported end points for more than one experimental group.
cAnticoagulants were aspirin and intravenous unfractionated heparin.
dPerioperative included the preoperative through postoperative periods; the study did not break this down into hours.
eExposed subjects were considered the hospitalized group, which included patients who stopped clopidogrel and underwent CABG within 3–5days of clopidogrel cessation; nonexposed patients were considered the discharged home group, which included patients who stoppedclopidogrel and went home but returned for CABG within 3–5 days of clopidogrel cessation.
Stratification of Unstable Angina Patients admission and 87% (739/852) of those patients undergoing CABG within 5 days of clopidogrel exposure. Consistent with the findings of our structured review, exposure to clopidogrel was conclusion. In addition, the CRUSADE study, associated with a significant increase in blood which included 2855 patients with non–ST- product transfusions, including a 70% increase in segment elevation ACS, showed considerable the requirement for more than 4 units of packed variance from the existing ACC-AHA guidelines, red blood cells. In the CURE trial,17 patients with 30% of patients (852/2855) receiving PHARMACOTHERAPY Volume 28, Number 3, 2008 Table 5. Resource Utilization Associated with Clopidogrel Exposure
NR = not reported; NA = not applicable; ICU = intensive care unit; OR = odds ratio.
aData are mean ± SD or median (range).
bPatients were considered exposed if they discontinued clopidogrel within a specified time frame that was designated in each study.
cStudy reported end points for more than one experimental group.
dAnticoagulants were aspirin and intravenous unfractionated heparin.
eStudy did not report hours of ventilation, only reported the “need for prolonged ventilation.”fExposed subjects were considered the hospitalized group, which was patients who stopped clopidogrel and underwent CABG within 3–5 daysof clopidogrel cessation; nonexposed patients were considered the discharged home group, which was patients who stopped clopidogrel andwent home but returned for CABG within 3–5 days of clopidogrel cessation.
clopidogrel within 5 days of surgery experienced for bleeding or need for blood product transfusion.37 a 2.8% absolute increase of life-threatening Ongoing randomized trials of ADP-receptor hemorrhagic complications. In contrast, aspirin antagonists represent a valuable opportunity to investigate fundamental mechanisms of peri- associated with a lower risk of postoperative operative hemostasis and optimal periprocedural mortality without a concomitant risk of reoperation CLOPIDOGREL-ASSOCIATED BLEEDING IN PATIENTS UNDERGOING CABG Pickard et al Table 5. (continued)
antagonists than those not exposed to clopi- dogrel.31 To clarify the impact of glycoproteinIIb-IIIa antagonists on bleeding-related outcomes, patients receiving this particular class of potent studies indicated an association of clopidogrel platelet antagonists were excluded from the analysis; the relationship between clopidogrel bleeding and an increased requirement for blood exposure and bleeding was directionally and product transfusion, the effect of concomitant use of other anticoagulants on outcomes was less studies revealed that selective outcomes were received clopidogrel and underwent CABG in less consistently reported (such as red blood cell than 5 days from clopidogrel loading were also transfusions), whereas other end points (such as more likely to receive glycoprotein IIb-IIIa mortality) were inconsistently reported in the PHARMACOTHERAPY Volume 28, Number 3, 2008 final article. The relatively small number of accuracy (c-statistic 0.72, p<0.0001).42 Among studies reporting mortality, a brief follow-up patients with a low likelihood of undergoing period, and a widely recognized challenge of early CABG, clopidogrel administration may diagnosing perioperative myocardial infarction limited our ability to discern differences in these Patients with ACS who undergo CABG should highly relevant clinical outcomes. However, the be considered for clopidogrel (and aspirin) potential impact of blood product transfusion on therapy after surgery, once hemostasis has been both the short- and long-term outcomes after achieved. This approach has been taken by several surgical groups, with reported safety43 and For instance, data collected on 8004 patients favorable outcomes,44 particularly after off-pump England from 1996–2004 showed that having a registry suggest that nearly 25% of patients with lower risk-adjusted hematocrit was associated non–ST-segment elevation ACS who undergo with an increased risk of developing low-output CABG during the index hospitalization receive heart failure, and the risk was increased further clopidogrel at the time of hospital discharge.45 when patients received red blood cell transfusions.38In a separate investigation, risk-adjusted probability of in-hospital mortality and morbiditywas modeled as a function of red blood cell and All systematic reviews synthesize data from collective blood product transfusion by using a existing research. Our review is subject to the logistic regression analysis.39 The investigators in reporting biases that occur when statistically that study concluded that perioperative red blood significant, positive studies are more likely to be independent predictor of postoperative morbid English, and be published rapidly and cited more events after isolated CABG. These investigators often than negative studies (i.e., publication subsequently evaluated the association between bias). It is not possible to evaluate unpublished perioperative red blood cell transfusion and long- overcome this bias. The Egger test10 was applied underwent isolated CABG.40 Survival among in this review where sufficient data were reported.
transfused patients was significantly reduced, A systematic review is also subject to the compared with nontransfused patients. Considered variability of end points reported, populations collectively, red blood cell transfusion was studied, and analytic techniques used by the associated with risk-adjusted reductions in individual studies and included in the article.
survival for both the early and late phases after CABG. Similarly, another group analyzed outcomes significantly heterogenous, a pooled summary for 3024 consecutive patients who underwent estimate was less meaningful. Many studies isolated CABG and reported that the adjusted 30- chose to report the median as a measure of day mortality rate for patients transfused with red central tendency, which is a statistic that does not blood cells was 1.9% compared with a mortality lend itself to aggregation. Instead, we chose to rate of 1.1% in patients not transfused.41 present the results in a disaggregated format,describing, when possible, the number of days Therapeutic Options and Approaches to Patient between clopidogrel discontinuation and CABG, concomitant use of aspirin, and use of aprotinin.
Finally, we were not able to assess the impact of Optimal care for patients with ACS is the goal for all practicing clinicians and health care conditions influencing decisions to continue providers. Clearly, the intent is not to withhold clopidogrel up to the time of surgery, nor were drugs of potential benefit, but to individualize we able to assess the potential protective benefit care based on carefully considered therapeutic of clopidogrel in patients undergoing CABG as options. Initially, calculation of a simple risk score at the time of hospital admission can beused to estimate the likelihood of CABG. A Conclusion
recently published risk score, based on clinicaland laboratory variables, predicted CABG during Results from this review of the literature the index hospitalization with considerable suggest that clopidogrel exposure within 7 days CLOPIDOGREL-ASSOCIATED BLEEDING IN PATIENTS UNDERGOING CABG Pickard et al bleeding and related complications, including 8. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007
guidelines for the management of patients with unstable reoperation and blood product transfusions.
angina/non–ST-elevation myocardial infarction: a report of the However, most of the evidence came from small American College of Cardiology/American Heart Association single-site studies conducted within a wide task force on practice guidelines (writing committee to revisethe 2002 guidelines for the management of patients with variety of surgical practices, and confounding unstable angina/non-ST-elevation myocardial infarction): circumstances. As a result, the impact of developed in collaboration with the American College of clopidogrel-related bleeding on mortality and risk Emergency Physicians, American College of Physicians, Societyfor Academic Emergency Medicine, Society for Cardiovascular of postoperative myocardial infarction could not Angiography and Interventions, and Society of Thoracic be determined. Antifibrinolytic therapy with Surgeons [online exclusive article]. J Am Coll Cardiol aprotinin in patients exposed to clopidogrel 2007;50:e1–157. Available from http://dx.doi.org/10.1016/j.
jacc.2007.02.013.
appeared to mitigate hemorrhagic risk, but 9. Grines CL, Bonow RO, Casey DE, et al. Prevention of
aprotinin has been temporarily suspended from premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from theAmerican Heart Association, American College of Cardiology, Although the decision to use clopidogrel must Society for Cardiovascular Angiography and Interventions, consider the overall balance of risks and benefits American College of Surgeons, and American Dental on an individualized basis, the available evidence Association, with representation from the American College ofPhysicians. Circulation 2007;115:813–18.
assessed in this review is congruent with current 10. Egger M, Smith GD, Altman DG, eds. Systematic reviews in
health care: meta-analysis in context. London, England: BMJ recommend clopidogrel cessation at least 5 days 11. Kuchulakanti P, Kapetanakis EI, Lew R, et al. Impact of
before elective CABG to reduce perioperative continued hospitalization in patients pre-treated with bleeding, health care resource utilization, and the clopidogrel prior to coronary angiography and undergoing risk associated with blood product transfusion.
coronary artery bypass grafting. J Invasive Cardiol 2005;17:5–7.
12. Akowuah E, Shrivastava V, Jamnadas B, et al. Comparison of
two strategies for the management of antiplatelet therapy registries indicate that these recommendations during urgent surgery. Ann Thorac Surg 2005;80:149–52.
13. Ascione R, Ghosh A, Rogers CA, Cohen A, Monk C, Angelini
GD. In-hospital patients exposed to clopidogrel before coronary
artery bypass graft surgery: a word of caution. Ann Thorac Surg
Acknowledgments
14. Chen L, Bracey AW, Radovancevic R, et al. Clopidogrel and
The authors wish to thank Kit Moulton for preparing bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg 2004;128:425–31.
15. Chu MWA, Wilson SR, Novick RJ, Stitt LW, Quantz MA. Does
clopidogrel increase blood loss following coronary artery References
bypass surgery? Ann Thorac Surg 2004;78:1536–41.
16. Englberger L, Faeh B, Berdat PA, Eberli F, Meier B, Carrel T.
1. Eisenberg MJ, Filion KB, Azoulay A, Brox AC, Haider S,
Impact of clopidogrel in coronary artery bypass grafting. Eur J Pilote L. Outcomes and cost of coronary artery bypass graft
surgery in the United States and Canada. Arch Intern Med 17. Fox KAA, Mehta SR, Peters R, et al. Benefits and risks of the
combination of clopidogrel and aspirin in patients undergoing 2. Rosamond W, Flegal K, Friday G, et al. Heart disease and
surgical revascularization for non–ST-elevation acute coronary stroke statistics—2007 update: a report from the American syndrome: the clopidogrel in unstable angina to prevent Heart Association statistics committee and stroke statistics recurrent ischemic events (CURE) trial. Circulation subcommittee [online exclusive article]. Circulation 2007;115:e69–171. Available from http://circ.ahajournals.org/ 18. Gansera B, Schmidtler F, Spiliopoulos K, Angelis I, Neumaier-
Prauser P, Kemkes B. Urgent or emergent coronary
3. Cannon CP, Mehta SR, Aranki SF. Balancing the benefit and
revascularization using bilateral internal thoracic artery after risk of oral antiplatelet agents in coronary artery bypass surgery.
previous clopidogrel antiplatelet therapy. Thorac Cardiovasc 4. Harrington R, Becker R, Ezekowitz M, et al. Antithrombotic
19. Hongo RH, Ley J, Dick SE, Yee RR. The effect of clopidogrel in
therapy for coronary artery disease: the seventh ACCP combination with aspirin when given before coronary artery conference on antithrombotic and thrombolytic therapy. Chest bypass grafting. J Am Coll Cardiol 2002;40:231–7.
20. Kapetanakis EI, Medlam DA, Boyce SW, et al. Clopidogrel
5. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the
administration prior to coronary artery bypass grafting surgery: diagnosis and treatment of non–ST-segment elevation acute the cardiologist’s panacea or the surgeon’s headache? Eur Heart coronary syndromes. The task force for the diagnosis and treatment of non-ST-segment elevation acute coronary 21. Karabulut H, Toraman F, Evrenkaya S, Goksel O, Tarcan S,
syndromes of the European Society of Cardiology. Eur Heart J Alhan C. Clopidogrel does not increase bleeding and allogenic
blood transfusion in coronary artery surgery. Eur J 6. Bristol-Myers Squibb–Sanofi Pharmaceutical Partnership.
Plavix (clopidogrel) package insert. New York, NY; August 22. Leong JY, Baker RA, Shah PJ, Cherian VK, Knight JL.
Clopidogrel and bleeding after coronary artery bypass graft 7. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox
surgery. Ann Thorac Surg 2005;80:928–33.
KK. Effects of clopidogrel in addition to aspirin in patients with
23. Ley SJ. Quality care outcomes in cardiac surgery: the role of
acute coronary syndromes without ST-segment elevation. N evidence-based practice. Am Assoc Crit Care Nurses Clin PHARMACOTHERAPY Volume 28, Number 3, 2008 Issues 2001;12:606–17; quiz 633–5.
acute coronary syndromes. Circulation 2006;114:774–82.
24. Lindvall G, Sartipy U, van der Linden J. Aprotinin reduces
35. Purkayastha S, Athanasiou T, Malinovski V, et al. Does
bleeding and blood product use in patients treated with clopidogrel affect outcome after coronary artery bypass clopidogrel before coronary artery bypass grafting. Ann Thorac grafting? A meta-analysis. Heart 2006;92:531–2.
36. Fox KAA, Anderson FA Jr, Dabbous OH, et al. Intervention in
25. Ray JG, Deniz S, Olivieri A, et al. Increased blood product use
acute coronary syndromes: do patients undergo intervention on among coronary artery bypass patients prescribed preoperative the basis of their risk characteristics? The global registry of aspirin and clopidogrel [online exclusive article]. BMC acute coronary events (GRACE). Heart 2007;93:177–82.
Cardiovasc Dis 2003;3:6. Available from http://www.biomed 37. Bybee KA, Powell BD, Valeti U, et al. Preoperative aspirin
therapy is associated with improved postoperative outcomes in 26. van der Linden J, Lindvall G, Sartipy U. Aprotinin decreases
patients undergoing coronary artery bypass grafting.
postoperative bleeding and number of transfusions in patients Circulation 2005;112(suppl I):I286–92.
on clopidogrel undergoing coronary artery bypass graft surgery: 38. Surgenor SD, DeFoe GR, Fillinger MP, et al. Intraoperative red
a double-blind, placebo-controlled, randomized clinical trial.
blood cell transfusion during coronary artery bypass graft Circulation 2005;112(suppl I):I276–80.
surgery increases the risk of postoperative low-output heart 27. Woo YJ, Grand T, Valettas N. Off-pump coronary artery bypass
failure. Circulation 2006;114(suppl I):I43–8.
grafting attenuates postoperative bleeding associated with 39. Koch CG, Li L, Duncan AI, et al. Morbidity and mortality risk
preoperative clopidogrel administration. Heart Surg Forum associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit 28. Yende S, Wunderink RG. Effect of clopidogrel on bleeding after
coronary artery bypass surgery. Crit Care Med 2001;29:2271–5.
40. Koch CG, Li L, Duncan AI, et al. Transfusion in coronary
29. Ouattara A, Bouzguenda H, Le Manach Y, et al. Impact of
artery bypass grafting is associated with reduced long-term aspirin with or without clopidogrel on postoperative bleeding survival. Ann Thorac Surg 2006;81:1650–7.
and blood transfusion in coronary surgical patients treated 41. Kuduvalli M, Oo AY, Newall N, et al. Effect of peri-operative
prophylactically with a low-dose of aprotinin. Eur Heart J red blood cell transfusion on 30-day and 1-year mortality following coronary artery bypass surgery. Eur J Cardiothorac 30. McLean DS, Sabatine MS, Guo W, McCabe CH, Cannon CP.
Benefits and risks of clopidogrel pretreatment before coronary 42. Sadanandan S, Cannon CP, Gibson CM, Murphy SA,
artery bypass grafting in patients with ST-elevation myocardial DiBattiste PM, Braunwald E. A risk score to estimate the
infarction treated with fibrinolytics in CLARITY-TIMI 28. J likelihood of coronary artery bypass surgery during the index Thromb Thrombolysis 2007;28:1025–32.
hospitalization among patients with unstable angina and non- 31. Mehta RH, Roe MT, Mulgund J, et al. Acute clopidogrel use
ST-segment elevation myocardial infarction. J Am Coll Cardiol and outcomes in patients with non–ST-segment elevation acute coronary syndromes undergoing coronary artery bypass 43. Halkos ME, Cooper WA, Petersen R, et al . Early
surgery. J Am Coll Cardiol 2006;48:281–6.
administration of clopidogrel is safe after off-pump coronary 32. Kapetanakis EI, Medlam DA, Petro KR, et al. Effect of
artery bypass surgery. Ann Thorac Surg 2006;81:815–19.
clopidogrel premedication in off-pump cardiac surgery: are we 44. Gurbuz AT, Zia AA, Vuran AC, Cui H, Aytac A. Postoperative
forfeiting the benefits of reduced hemorrhagic sequelae? clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study. Eur J 33. Kang W, Theman TE, Reed JF, Stoltzfus J, Weger N. The effect
of preoperative clopidogrel on bleeding after coronary artery 45. Tricoci P, Roe MT, Mulgund J, et al. Clopidogrel to treat
bypass surgery. J Surg Educ 2007;64:88–92.
patients with non–ST-segment elevation acute coronary 34. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KAA, Yusuf
syndromes after hospital discharge. Arch Intern Med S. Adverse impact of bleeding on prognosis in patients with

Source: https://www.epi-q.com/wp-content/uploads/2011/05/ClopidogrelAssocBleeding-2008-Pickard.pdf