IIIa inhibitors in non–ST-elevation acute coronary syndrome patients: The Canadian Global Registry of Acute Coronary Events (GRACE) experience

Clinical Investigations

Acute Ischemic Heart Disease

Underutilization of clopidogrel and glycoprotein IIb/IIIa inhibitors in non–ST-elevation acute coronary syndrome patients: The Canadian Global Registry of Acute Coronary Events (GRACE) experience Behnam Banihashemi, MD, a Shaun G. Goodman, MD, MSc, a Raymond T. Yan, MD, a Robert C. Welsh, MD, b Shamir R. Mehta, MD, MSc, c Gilles Montalescot, MD, d Jan M. Kornder, MD, e Graham C. Wong, MD, f Gabor Gyenes, MD, PhD, b Ph. Gabriel Steg, MD, g and Andrew T. Yan, MD a for Global Registry of Acute Coronary Events (GRACE/GRACE2) Investigators Ontario, Alberta, and British Columbia, Canada; and Paris, France

Background There are limited contemporary data on the early use of clopidogrel or glycoprotein (Gp) IIb/IIIa inhibitors, alone versus combination therapies, in non–ST-elevation acute coronary syndrome (NSTE-ACS). Methods

This study included 5,806 Canadian NSTE-ACS patients with elevated cardiac biomarker and/or ST deviation on presentation in the prospective GRACE between 2003-2007. We stratified the study population according to the management strategy (non-invasive vs invasive) and into low-(GRACE risk score ≤108), intermediate- (109-140), and high-risk groups (≥141).

Results Overall, 3,893 patients (67.1%) received early (≤24 hours of admission) antiplatelet therapy; the rates of use were 76%, 73%, and 57% in the low-, intermediate-, and high-risk groups, respectively (P for trend b .001). Only 54% of the conservatively managed patients and 12% of the invasively managed patients received early clopidogrel and GpIIb/IIIa inhibitors, respectively. High-risk patients were less likely (adjusted odds ratio = 0.48, 95% CI 0.39-0.59, P b .001) to receive early clopidogrel or GpIIb/IIIa inhibitors, whereas in-hospital catheterization was an independent positive predictor (adjusted odds ratio = 2.02, 95% CI 1.74-2.34, P b .001) of use. Conclusions In this contemporary NSTE-ACS population, both clopidogrel and GpIIb/IIIa inhibitors were targeted toward patients treated with an invasive strategy but paradoxically toward the lower-risk group. In particular, clopidogrel appeared to be underused among conservatively managed patients despite its proven efficacy, whereas GpIIb/IIIa inhibitors were administered to only a minority of the high-risk patients with elevated cardiac biomarkers. Our findings emphasize the ongoing need to promote the optimal use of evidence-based antiplatelet therapies among high-risk patients with NSTE-ACS. (Am Heart J 2009;158:917-24.)

Clopidogrel and glycoprotein (Gp) IIb/IIIa inhibitors have been shown in large randomized trials to improve outcomes in various subgroups of patients with non–STFrom the aTerrence Donnelly Heart Centre, Division of Cardiology, St. Michael's Hospital, University of Toronto, and the Canadian Heart Research Centre, Toronto, Ontario, Canada, bUniversity of Alberta, Edmonton, Alberta, Canada, cHamilton Health Sciences Corporation, McMaster University, Hamilton, Ontario, Canada, dDepartment of Cardiology, Centre Hospitalier Universitaire Pitié-Salpétrière, Paris, France, eSurrey Memorial Hospital, Surrey, British Columbia, Canada, fVancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada, and gUniversité Paris VII-Denis Diderot, Centre Hospitalier Bichat-Claude Bernard, Paris, France. Submitted June 19, 2009; accepted September 29, 2009. Reprint requests: Andrew T. Yan, MD, Division of Cardiology, St. Michael's Hospital, 30 Bond St, Room 6-030 Queen, Toronto, Ontario, Canada M5B 1W8 or Shaun G. Goodman, Division of Cardiology, St. Michael's Hospital, 30 Bond St, Room 6-034 Queen, Toronto, Ontario, Canada M5B 1W8. E-mail: [email protected] 0002-8703/$ - see front matter © 2009, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2009.09.016

elevation acute coronary syndrome (NSTE-ACS).1-3 These findings have led the American College of Cardiology/ American Heart Association to give a class IA treatment recommendation for the use of clopidogrel or GpIIb/IIIa inhibitors in patients with NSTE-ACS managed conservatively and a class IIA recommendation for the use of the combination in patients selected to undergo an invasive strategy.4 However, there is evidence that these therapies may be underused among eligible patients in the United States.5-8 There are limited data on the contemporary treatment patterns and safety of these agents in high-risk ACS patients in Canada. Furthermore, the use of clopidogrel and GpIIb/IIIa inhibitors, alone and in combination, has not been well characterized. Using data from the Global Registry of Acute Coronary Events (GRACE) in Canada, we examined the early use (within 24 hours of admission) of these therapies individually and in combination in

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relation to risk, initial cardiac biomarker status, and treatment strategy among patients with NSTE-ACS, as well as major bleeding complications associated with their use. To evaluate adherence to the evidence-based guidelines, we only included patients similar to those enrolled in relevant landmark trials.1,3,9-11

Methods Study population GRACE was established as a multinational, prospective registry to describe the epidemiology, treatment patterns, and clinical outcomes of an unselected population of patients with the entire spectrum of ACS. Details of GRACE have been published.12 In brief, patients entered in the registry had to be 18 years or older, alive at the time of presentation, and admitted with a presumptive diagnosis of ACS based on the history and at least one of the following: abnormal cardiac biomarkers, electrocardiographic changes consistent with ACS, and/or documented history of coronary artery disease. Patients who died within 24 hours of hospitalization, could still be enrolled in the registry provided that the cause of death was confirmed to be ACS. Patients with ACS precipitated or accompanied by surgery, trauma, or gastrointestinal bleeding; or those already hospitalized for other reasons and developed an ACS were excluded. Enrolling sites were encouraged to recruit the first 10 to 20 consecutive eligible patients each month. A combination of prospective and retrospective approaches for surveillance and case identification was used. Trained personnel at each site collected data on standardized case report forms consisting of the following: patient demographics, medical history, presenting symptoms and clinical characteristics, electrocardiographic findings, use of cardiac medications and interventional procedures, and in-hospital outcomes. The original GRACE was expanded in 2003 to include many additional hospitals and countries (GRACE2). In total, 53 hospitals across Canada participated in GRACE and GRACE2. Between January 2003 and December 2007, 13,522 patients with suspected ACS were enrolled in this registry across Canada. We excluded patients with final non-ACS diagnoses (n = 2,256), those with a final diagnosis of ST-elevation myocardial infarction (n = 3,110),12 and those without ST deviation and/or elevated cardiac biomarkers within the first 24 hours of presentation to the hospital (n = 2,210). Of the remaining 5,946 patients with a final diagnosis of NSTE-ACS, we included patients with complete data on the use of clopidogrel and/or GpIIb/IIIa use in the first 24 hours (n = 5,806).Where required, the local ethics review boards approved the study protocol and participating patients provided informed consent. GRACE was supported by an unrestricted grant from Sanofi-Aventis, Paris, France, and Laval, Quebec, Canada, and by Bristol-Myers-Squibb Canada, Montreal, Quebec, Canada. The authors are solely responsible for the design and conduct of this study, all study analyses, and the drafting and editing of the paper.

We categorized the study population based on their GRACE risk score (GRACE RS) into low- (GRACE RS b109), intermediate(109-140), and high-risk (N140) groups.13 The GRACE RS for inhospital mortality is composed of the following predictor variables on presentation: age, heart rate, systolic blood pressure, cardiac arrest, Killip class, serum creatinine, STsegment deviation, and cardiac biomarker status.14-16 To explore potential differences in the use of antiplatelet therapies in relation to the management strategy, we stratified the study population into the groups treated with an invasive (cardiac catheterization during the index admission) versus conservative approach. We further evaluated administration of these antiplatelet therapies in relation to the use of in-hospital coronary artery bypass graft surgery (CABG) and antithrombin therapies. Major bleeding during index hospitalization was defined as lifethreatening or fatal bleeding, bleeding requiring a transfusion of 2 or more units of packed red cells, or bleeding resulting in an absolute decrease in hematocrit of ≥10%. History of bleeding was defined as documented history of significant blood loss at any time from any site (e.g., peptic ulcer, genitourinary tract) not related to trauma, and requiring medical treatment.

Statistical analysis Continuous variables are reported as medians with interquartile ranges; and categorical variables, as percentages. Comparisons were made using χ2 tests for categorical variables and Kruskal-Wallis test for continuous variables. To characterize the relationship between early antiplatelet therapy use, GRACE RS, and management strategy, a multivariable logistic regression analysis was performed. We considered the early use of clopidogrel or GpIIb/IIIa inhibitor (alone or in combination) as the outcome variable because the guidelines strongly support (class I) the use of at least one of these agents,4 regardless of the management strategy. The model was adjusted for a number of patient and hospital factors that have been shown previously to be associated with early GpIIb/IIIa inhibitor use.5 These candidate explanatory variables included age, gender, prior percutaneous coronary intervention (PCI), current smoking, diabetes mellitus, peripheral vascular disease, prior stroke, Killip class, time of enrollment, and hospital type. Because age, Killip class, and creatinine are components of the GRACE RS, we did not enter these variables separately into the model because of potential collinearity. We used backward elimination (P N .05) to arrive at a parsimonious model. Because patients admitted to the same hospital tend to be more similar, we used generalized estimating equations to account for the clustering of patients within hospitals. We assessed model discrimination and calibration using the c-statistic and HosmerLemeshow goodness-of-fit test, respectively. Statistical analysis was performed using SPSS version 15.0 (SPSS Inc, Chicago, IL). A 2-sided P value b .05 was considered to indicate statistical significance.

Results Medication use and patient stratification In this study, we defined the early use of clopidogrel or GpIIb/ IIIa inhibitors as the administration of these agents (alone or in combination) within the first 24 hours of presentation to hospital, regardless of their use before or after this period.

Patient characteristics Table I shows the baseline characteristics, medical history, and presenting clinical features of the study population (n = 5,806). Despite having a normal initial biomarker level, patients with unstable angina (UA) had a

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Table I. Baseline demographics and presenting characteristics of patients subdivided based on the discharge diagnosis⁎ Discharge diagnosis Variable Age (y)† Male Medical history Angina Current smoker Myocardial infarction History of heart failure Diabetes mellitus Transient ischemic attack/stroke Peripheral artery disease Hypertension Hyperlipidemia PCI Coronary bypass surgery History of bleeding Presenting characteristics Heart rate (beat/min)† Systolic blood pressure (mm Hg)† Killip class I II III or IV Cardiac arrest Serum creatinine (μmol/L)† ECG ST deviation T wave inversion Positive initial biomarker GRACE RS† Year of presentation 2003-2004 2005-2006 2007

Overall (n = 5806)

NSTEMI (n = 5068)

UA (n = 738)

P value

68 (58-78) 65.1

68 (58-78) 65.7

66 (57-75) 61.2

b.001 .019

41.7 26.1 32.3 11.5 29.0 9.9 10.0 63.6 54.3 15.5 13.5 2.9

39.5 26.2 31.8 11.6 28.6 10.1 10.1 63.3 53.9 14.5 13.1 2.9

57.1 25.0 36.2 10.7 31.5 8.4 8.9 65.5 57.5 22.8 16.5 2.7

b.001 .49 .017 .49 .11 .16 .31 .26 .067 b.001 .012 .81

80 (68-95) 146 (127-165)

80 (68-96) 146 (128-166)

76 (64-90) 142 (124-160)

83.0 10.6 6.4 0.8 94 (79-115)

82.5 10.8 6.7 0.8 94 (79-116)

86.7 9.1 4.2 0.8 91 (77-111)

b.001 b.001 .011 – – – .96 b.001

40.3 23.6 58.4 130 (104-160)

35.9 23.8 66.8 129 (102-161)

100‡ 22.8 0 135 (114-155)

24.6 46.1 29.3

24.3 45.8 29.9

26.6 48.2 25.2

b.001 .55 – b.001 .031 – – –

⁎ Data are given as percentages of each group unless otherwise specified. † Data are presented as medians (25th-75th percentile). ‡ All patients in this study had ST deviation and/or positive biomarker.

slightly but significantly higher GRACE RS on presentation, as compared with non–ST-elevation myocardial infarction (NSTEMI) patients (P b .001). Overall, 40.4% and 31.0% of the study patients were in the GRACE highrisk and intermediate-risk categories, respectively. With respect to the management strategy, 3,439 patients (59.5%) underwent cardiac catheterization and 1,723 (31.1%) underwent PCI during the index admission. The median time to coronary angiography was 3 days (interquartile range 2-5).

Antiplatelet use in the first 24 hours of presentation Overall, 3,893 patients (67.1%) received early antiplatelet therapy with clopidogrel and/or GpIIb/IIIa inhibitor; the majority of these patients (3,808 [97.8%]) received clopidogrel. The numbers were only slightly different for patients who received clopidogrel and/or GpIIb/IIIa inhibitor after the first 24 hours (3,761 [64.8%]); the majority of these patients received clopidogrel (3,695 [98.2%]). The rates of GpIIb/IIIa inhibitor use after the

first 24 hours alone and in combination with clopidogrel were 9.6% and 8.5%, respectively. As illustrated in Table II, significantly fewer patients received early clopidogrel therapy in the high-risk group than in the intermediate- or low-risk groups. A similar treatment pattern was observed with early GpIIb/IIIa inhibitor use in relation to the GRACE RS. Early antiplatelet therapy use was associated with an invasive management strategy (Table III). Clopidogrel was used more commonly in hospitals without on-site catheterization facility, whereas GpIIb/IIIa inhibitors were used less frequently in these hospitals (P b .001). Similarly, there was a positive association between early antiplatelet therapy use and in-hospital PCI, whereas CABG was found to be negatively associated with early antiplatelet therapy use (Table IV). The rate of clopidogrel use after the first 24 hours was lower (P b .001) among patients who underwent in-hospital CABG (50.3%) versus patients who did not (64.3%). In addition, there was a statistically significant association between

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Table II. Early antiplatelet therapy use by GRACE risk groups and initial biomarker status⁎ Initial cardiac biomarker

GRACE RS Medication use in the first 24 h

Low (n = 1509)

Intermediate (n = 1643)

High (n = 2141)

P value (for trend)

Negative (n = 2409)

Positive (n = 3382)

P value

73.6 10.7 75.6

71.5 9.4 73.2

56.2 5.0 57.0

b.001 b.001 b.001

61.7 7.2 63.3

68.4 8.4 69.8

b.001 .083 b.001

8.7

7.7

4.2

b.001

5.6

7.0

.034

Clopidogrel† GpIIb/IIIa Inhibitor† Clopidogrel or GpIIb/IIIa inhibitor Both clopidogrel and GpIIb/IIIa Inhibitor

⁎ Data are given as percentages of each group unless otherwise specified. † Any use within the first 24 hours (alone or in combination).

Table III. Antiplatelet therapy use by in-hospital catheterization and presence of on-site catheterization laboratory⁎ Presence of on-site catheterization laboratory

In-hospital catheterization Antiplatelet therapy use

No (n = 2341)

Medication use in the first 24 h Clopidogrel† 54.0 GpIIb/IIIa inhibitor† 2.3 Clopidogrel or GpIIb/IIIa 54.8 inhibitor Both clopidogrel and 1.5 GpIIb/IIIa inhibitor Medication use after the first 24 h Clopidogrel† 47.7 GpIIb/IIIa inhibitor† 2.5 Clopidogrel or GpIIb/IIIa 48.4 inhibitor Both clopidogrel and 1.8 GpIIb/IIIa inhibitor

Within the first 24 h (n = 679)

After the first 24 h (n = 2760)

P value

No (n = 4535)

Yes (n = 1264)

P value

75.8 21.2 79.5

72.9 9.5 74.3

b.001 b.001 b.001

68.4 7.0 69.2

55.9 11.3 59.2

b.001 b.001 b.001

17.5

8.0

b.001

6.0

8.0

b.001

73.2 18.1 76.1

75.0 13.6 76.0

b.001 b.001 b.001

63.0 8.3 63.7

66.0 14.2 68.5

.045 b.001 .002

15.2

12.5

b.001

7.6

11.7

b.001

⁎ Data are given as percentages of each group unless otherwise specified. † Any use (alone or in combination).

the use of early antiplatelet therapies and the administration of other guideline-recommended therapies (Table V). Figure 1, A and B show early antiplatelet therapy use among patients treated with any heparin and low– molecular-weight heparin, respectively.

Multivariable analysis After adjusting for other potential confounders, inhospital cardiac catheterization was an independent predictor of the use of clopidogrel or GpIIb/IIIa inhibitors in the first 24 hours, whereas high-risk patients remained less likely to receive these therapies (Table VI). The model c-statistic was 0.71 and P value for HosmerLemeshow goodness-of-fit test was .32, demonstrating adequate discrimination and calibration, respectively. Antiplatelet therapy use and major bleeding in hospital Of the 3,350 patients who received early clopidogrel therapy alone, only 1.6% had major bleeding. The rate of

bleeding among patients who received neither clopidogrel nor GpIIb/IIIa inhibitor (n = 1,827) was 3.3% and was similar to rate of bleeding among 358 patients who received both agents (3.2%). No major bleeding occurred in the small group of patients (n = 85) who received GpIIb/IIIa inhibitor only.

Discussion In this study of high-risk NSTE-ACS patients in Canada, we found considerable underutilization of GpIIb/IIIa inhibitors and clopidogrel despite published randomized trials and clinical practice guidelines. In particular, clopidogrel was underused in the conservatively managed patients, whereas GpIIb/IIIa inhibitors were infrequently administered early even among high-risk patients who subsequently underwent PCI. Several randomized clinical trials have evaluated the efficacy of antiplatelet therapies in NSTE-ACS. The CURE

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Table IV. Early antiplatelet therapy use by in-hospital procedures⁎ In-hospital CABG Medication use in the first 24 h

In-hospital PCI

No (n = 5284)

Yes (n = 198)

P value

65.1 8.0 66.6 6.6

57.1 9.6 61.6 5.1

.02 .41 .001 .001

Clopidogrel† GpIIb/IIIa inhibitor† Clopidogrel or GpIIb/IIIa inhibitor Both clopidogrel and GpIIb/IIIa inhibitor

No (n = 3816)

Yes (n = 1723)

P value

58.9 4.6 60.2 3.2

78.1 16.0 80.0 14.0

b.001 b.001 b.001 b.001

⁎ Data are given as percentages of each group unless otherwise specified. † Any use within the first 24 hours (alone or in combination).

Table V. Early antiplatelet therapy use by early use of other medications⁎ Other medications use in the first 24 h ACEI or ARB Antiplatelet use in the first 24 h Clopidogrel† GpIIb/IIIa inhibitor† Clopidogrel or GpIIb/IIIa inhibitor Both clopidogrel and GpIIb/IIIa inhibitor

β-Blocker

Statin

No n = 2021

Yes n = 3706

P value

No n = 1773

Yes n = 3995

P value

No n = 1216

Yes n = 4512

P value

57.3 6.5 59.0

70.3 8.7 71.6

b.001 b.001 b.001

50.6 5.9 52.6

72.2 8.8 73.4

b.001 b.001 b.001

51.1 5.2 52.6

69.6 8.7 71.0

b.001 b.001 b.001

4.8

7.4

b.001

4.0

7.5

b.001

3.6

7.2

b.001

ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker. ⁎ Data are given as percentages. † Any use within the first 24 hours (alone or in combination).

trial demonstrated the benefits of clopidogrel in NSTEACS, including patients who were initially managed with a non-invasive strategy.1 A substudy of this trial also showed clinical benefit with pretreatment followed by longerterm use of clopidogrel in NSTE-ACS patients undergoing PCI.17 Our study population was similar to the CURE trial population with a similar age, but higher percentage of patients with initial positive cardiac biomarker. However, early clopidogrel was only given to 54% of our study patients who were managed non-invasively during the index hospitalization. This treatment gap was significantly greater in high-risk patients, despite the proven efficacy of clopidogrel in this patient population.2 Previous studies have also documented a similar treatment-risk paradox with respect to the use of other guideline-recommended therapies in NSTE-ACS.18,19 One possible explanation for the negative association between patients' risk scores and the early use of clopidogrel is the physician's anticipation that patients may require CABG post-catheterization. Indeed, in our study, patients who later underwent CABG were less likely to receive early clopidogrel therapy. The risk of bleeding is increased when CABG is performed within 5 to 7 days of clopidogrel use,1 and physicians may believe that significant coronary lesions requiring surgical revascularization are more common in higher-risk patients. However, these concerns should be viewed in light of the

proven benefits of clopidogrel even within 24 hours of initiation of therapy20 and the difficulty in predicting on presentation the subsequent need for CABG.21,22 In addition, there is no increase in blood transfusion with CABG after discontinuation of clopidogrel therapy for at least 5 days.23,24 A post hoc analysis of the CURE trial demonstrated that the benefits of starting clopidogrel on admission outweigh the risks, even among patients undergoing CABG during the initial hospitalization.24 The benefit of GpIIb/IIIa inhibitors in preventing PCI complications has also been proven in numerous trials composed largely of patients with UA.25-28 Multiple studies have also documented the efficacy of GpIIb/IIIa inhibitors specifically in NSTE-ACS.9-11,25 In these studies, the treatment effect appeared to be greater in higher-risk patients with elevated cardiac biomarker and/ or ST deviation on presentation, but primarily limited to patients who underwent PCI. Boersma et al29 verified these findings in a meta-analysis of 6 large, randomized, placebo-controlled trials of GpIIb/IIIa inhibitors. These data support using elevated troponin level as a major factor in decision making for the use of this group of agents in NSTE-ACS.4 Post-randomization subgroup analyses suggest that the benefit of “combination therapy” with clopidogrel and GpIIb/IIIa inhibitors may be limited to NSTE-ACS patients undergoing PCI with elevated cardiac biomarkers,3,30 but this finding should be

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Figure 1

Table VI. Independent predictors of antiplatelet use (clopidogrel and/or GpIIb/IIIa inhibitor) in the first 24 hours Independent predictors Presence of on-site cardiac catheterization facilities In-hospital Catheterization Within the first 24 h After the first 24 h Medical history Heart failure Major bleeding Previous PCI GRACE RS Low Intermediate High Year of presentation 2003-2004 2005-2006 2007 Cardiac arrest on presentation

A, Early antiplatelet therapy use among patients receiving early heparin (unfractioned and/or low–molecular-weight heparin). B, Early antiplatelet therapy use among patients receiving early low– molecular-weight heparin. LMWH, Low–molecular-weight heparin.

interpreted with caution.31 In our study, there was no significant association between elevated cardiac biomarkers and the early use of GpIIb/IIIa inhibitors or combination therapy. Although we observed a positive association between elevated cardiac biomarkers and early clopidogrel or GpIIb/IIIa inhibitor use, early antiplatelet therapy use was lower in the group with high GRACE RS. One possible explanation for this contrast is that other factors in the GRACE RS, such as renal insufficiency and old age, are also associated with an increased risk of bleeding. The concern over this increased bleeding risk could have deterred physicians from using these therapies in the higher–ischemic-risk patients. In addition, we did find a positive relationship between in-hospital PCI and the early use of both of these therapies, and a trend toward more frequent early use of GpIIb/IIIa inhibitor therapy in hospitals with onsite catheterization facility. This represents a treatment

Adjusted odds P Wald ratio (95% CI) value m2 0.44 (0.26-0.75)

.002

9.33

3.47 (2.45-4.92) 2.30 (1.76-3.02)

b.001 b.001

48.69 36.54

0.76 (0.64-0.90) 0.53 (0.41-0.69) 2.04 (1.66-2.51)

.002 b.001 b.001

9.81 22.26 45.73

[Reference] 0.91 (0.72-1.15) 0.55 (0.44-0.68)

.45 b.001

0.58 29.16

[Reference] 1.80 (1.24-2.62) 2.42 (1.39-4.20) 0.39 (0.18-0.86)

.002 .002 .019

9.53 9.85 5.52

gap that could potentially be narrowed with better risk stratification systems that incorporate a risk score assessment. Multiple trials have documented the increased bleeding risk with clopidogrel1,23 and GpIIb/IIIa inhibitor therapy.9,11 In our study population, there was no significant increase in major bleeding with GpIIb/IIIa inhibitor and/ or clopidogrel use. Although our observational study cannot establish any cause-and-effect relationship because of unmeasured confounders, the relatively low rate of major bleeding observed suggests that these antiplatelet therapies can be safely administered in the “real world” at the discretion of the treating physicians—it is also plausible that potent antiplatelet therapies were withheld from patients at high risk of bleeding. Although there have been a few studies looking at the early antiplatelet treatment patterns in NSTE-ACS population,5-8,32 our findings complement the results of these studies by evaluating the patterns of clopidogrel and GpIIb/IIIa inhibitor use, not only individually but also in relation to each other, in a real-world population. These data can also serve as a useful benchmark for future comparison, particularly in view of the recently published EARLY-ACS and ACUITY Timing trials.33,34 Several study limitations should be considered in interpretation of our results. First, although GRACE has been designed to recruit an unbiased study population, some participating hospitals are mandated to obtain informed consent from the patients before enrollment. Therefore, early deaths and patients with early clinical complications might be underrepresented. Furthermore, we defined invasive management strategy as the use of cardiac catheterization during index hospitalization, although patients who were initially intended for non-

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invasive management could have had an evolving clinical course necessitating an invasive approach subsequently. Moreover, we only evaluated antiplatelet therapy use in the first 24 hours of presentation, but not antiplatelet therapy administration in relation to PCI. However, our definition of early clopidogrel use in the general study population is relevant to current guideline recommendations. Furthermore, in the CURE trial, the benefit of clopidogrel was already apparent within hours of randomization after the initial loading dose.1 Because of the relatively small number of bleeding events in this study, we cannot precisely estimate the risk of bleeding among unselected ACS patients receiving these therapies. Furthermore, major bleeding events were reported by site investigators and not centrally adjudicated, although standard definitions were used, and GRACE did not collect data on nonmajor bleeding. In addition, the drop in hematocrit was not adjusted for blood transfusion. Although optimal antiplatelet therapy must be individualized by carefully considering both the risks and the benefits of treatment, bleeding risk could not be further characterized in our population using the CRUSADE risk score35 because we did not collect data on baseline hematocrit. Importantly, bleeding risk can be diminished by using lower doses of heparin and aspirin.4,36 Finally, data to calculate GRACE RS were incomplete in 8.8% of patients.

Conclusion In this contemporary NSTE ACS population, both clopidogrel and GpIIb/IIIa inhibitors were targeted toward patients treated with an invasive strategy but paradoxically toward the lower-risk group. In particular, clopidogrel appeared to be underused among conservatively managed patients despite its proven efficacy in this CURE-like population, whereas GpIIb/IIIa inhibitors were administered to only a minority of the high-risk patients with elevated biomarkers. Our findings emphasize the ongoing need to promote better risk stratification and the optimal use of evidence-based antiplatelet therapies among high-risk patients with NSTE ACS.

Acknowledgements We thank all the study coordinators, investigators, and patients who participated in GRACE and GRACE2. Dr Andrew Yan is supported by the Canadian Institutes of Health Research and a New Investigator Award from the Heart and Stroke Foundation of Canada.

Disclosures Dr. Shaun G. Goodman, Speaker and consulting honoraria and research grant support from Key Pharmaceuticals, Bristol-Myers Squibb, Sanofi Aventis, Pfizer,

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and Key Schering. Dr. Robert C. Welsh, Honoraria from Astra Zeneca, Eli Lilly, Boeringher Ingelheim, sanofiaventis, Johnson and Johnson, Hoffman LaRoche, Schering Plough. Dr. Shamir R. Mehta, Honoraria and research grants from GlaxoSmithKline and Sanofi-Aventis. Dr. Gilles Montalescot, Research Grants from: Bristol Myers Squibb, Sanofi-Aventis Group, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Fédération Française de Cardiologie, Société Française de Cardiologie; Consulting fees from: Sanofi-Aventis Group, Eli Lilly, Bristol-Myers Squibb, The Medicines Company, Schering-Plough; Lecture fees from: Sanofi-Aventis, Eli Lilly, Bristol-Myers Squibb, Merck Sharpe & Dohme, Cordis, GlaxoSmithKline, Schering-Plough. Dr. Ph. Gabriel Steg, Research grant: sanofiaventis; speakers bureau: Boehringer Ingelheim, BristolMyers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Nycomed, sanofi-aventis, Sankyo, Servier, ZLBBehring; consulting/advisory board: AstraZeneca, BristolMyers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, sanofi-aventis, Servier, Takeda; stockholding: none. Dr. Andrew T. Yan, Research grant support, speaker and consulting honoraria from Sanofi Aventis and Bristol-Myers Squibb. The remaining authors have no conflicts of interest to disclose.

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