Vivek Rajagopal, MD; A. Michael Lincoff, MD; David J. Cohen, MD, MSc; Hitinder S. Gurm, MD; Tingfei Hu, MS; Walter J. Desmet, MD; Neal S. Kleiman, MD; John A. Bittl, MD; Frederick Feit, MD; Eric J. Topol, MD 

Am Heart J.  2006;152(1):149-154.  ?2006 Mosby, Inc.

Abstract and Introduction

Abstract

Background: The REPLACE-2 trial demonstrated that bivalirudin with provisional glycoprotein IIb/IIIa (GPIIb/IIIa) inhibition is not inferior to heparin plus GPIIb/IIIa inhibition in patients undergoing percutaneous coronary intervention. The extent to which this applies to patients with acute coronary syndromes (ACS) is unclear. Therefore, we sought to determine if bivalirudin has similar efficacy in ACS patients as compared with ?stable? patients in the REPLACE-2 trial.
Methods: We analyzed the outcomes of ACS patients compared with stable patients and the outcomes of ACS patients according to whether or not they had received bivalirudin, including the economic costs. The trial enrolled 1351 ACS patients (myocardial infarction within 7 days or unstable angina within 48 hours, but not on ongoing GPIIb/IIIa or heparin therapy) and 4554 stable patients.
Results: Patients with ACS had a similar rate of death or myocardial infarction at 30 days compared to stable patients (7.2% vs 6.7%, P = .51) and death at 1 year (1.6% vs 2.2%, P = .169), but a higher rate of urgent coronary artery bypass graft at 30 days (1.0% vs 0.3%, P = .002). Patients with ACS treated with bivalirudin had a similar rate of 30-day death, myocardial infarction, or urgent revascularization compared with ACS patients treated with heparin and GPIIb/IIIa inhibitors (8.7% vs 8.0%, P = .616) and death at 1 year (1.5% vs 1.8%, P = .701), but a higher rate of revascularization at 6 months (12% vs 8.4%, P = .04). Patients with ACS treated with bivalirudin had less major bleeding than ACS patients treated with heparin and GPIIb/IIIa inhibitors, although this was not statistically significant (2.7% vs 4.5%, P = .07). Mean 30-day costs for patients with ACS were $12415 for those treated with bivalirudin and $12806 for those treated with heparin plus GPIIb/IIIa inhibitors (P = .022).
Conclusion: Bivalirudin with provisional GPIIb/IIIa inhibitor use in low-risk ACS patients (not receiving preprocedural GPIIb/IIIa blockade) appears to provide similar protection against death and myocardial infarction as the combination of heparin and GPIIb/IIIa inhibitors, although we observed a higher rate of revascularization at 6 months.

Introduction

Compared with patients undergoing elective coronary revascularization, patients with acute coronary syndromes (ACS) experience higher rates of death and myocardial infarction after percutaneous coronary intervention (PCI). Several trials have demonstrated that glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors reduce these rates.^[1,2,3] For example, in the EPIC trial, treatment of unstable angina patients with abciximab resulted in a 38% reduction in the primary end point of death, myocardial infarction, or urgent repeat revascularization at 30 days.^[4] This beneficial effect also appears to confer a long-term survival advantage.^[5] Despite these data, some clinicians hesitate to use GPIIb/IIIa inhibitors because of bleeding and cost concerns.

Over the last decade, the direct thrombin inhibitor bivalirudin has emerged as an alternative to unfractionated heparin for patients with unstable angina undergoing PCI.^[6] Recently, the REPLACE-2 trial demonstrated that bivalirudin with provisional GPIIb/IIIa inhibitors provides comparable protection from ischemic events as heparin with routine GPIIb/IIIa inhibition in a broad spectrum of patients undergoing elective or urgent PCI.^[7] Importantly, patients randomized to bivalirudin had significantly less bleeding.

Concerns have been raised about the applicability of these findings to higher-risk patients. Given the striking benefit of GPIIb/IIIa inhibitors in these patients, it is unclear if bivalirudin provides similar benefit for ACS patients as do heparin plus GPIIb/IIIa inhibitors. Although the REPLACE-2 trial did not assess the highest-risk ACS patients, a lower-risk population of patients meeting clinical definitions for ACS was included in this trial. Therefore, we compared the outcomes of these ?lower-risk? ACS patients with ?stable? patients to determine their outcomes in the current era of PCI. We also assessed the safety, efficacy, and economic costs of bivalirudin compared with heparin plus GPIIb/IIIa inhibitors in these ACS patients who met prespecified criteria in REPLACE.

Methods

The design and outcome of the REPLACE-2 trial have been previously published.^[7] In brief, 6010 patients undergoing elective or urgent PCI were randomized in a double-blind fashion to receive intravenous bivalirudin (0.75 mg/kg bolus and 1.75 mg/kg per hour infusion for length of PCI) with provisional GPIIb/IIIa inhibition or to heparin (65 U/kg bolus) and planned GPIIb/IIIa inhibition with eptifibatide or abciximab. All patients received aspirin. Treatment with a clopidogrel 300-mg loading dose before the procedure was strongly encouraged, followed by 75 mg/d for at least 30 days. Provisional GPIIb/IIIa inhibition could be provided during the PCI at any time for angiographic or procedural complications, such as thrombus, distal embolization, slow flow, or prolonged myocardial ischemia.

The REPLACE-2 trial excluded patients undergoing primary PCI for acute myocardial infarction. In addition, patients were excluded from enrollment in REPLACE-2 if they had been treated with unfractionated heparin within 6 hours (except patients with activated partial thromboplastin time ≤50 seconds or activated clotting time ≤175 seconds), low-molecular-weight heparin within 8 hours, tirofiban or eptifibatide within 12 hours, bivalirudin within 24 hours, or abciximab within 7 days before randomization.

The primary end point of this subgroup analysis was the composite of death, myocardial infarction, or ischemia requiring urgent repeat revascularization within 30 days. Patients with ACS were a prespecified subgroup, with ACS being defined as myocardial infarction within 7 days or unstable angina within 48 hours of enrollment; unstable angina was not defined by protocol. Patients with unstable angina >48 hours preceding enrollment were considered to have an intermediate degree of acuity and were not included in the ACS group in our analysis. Myocardial infarction was defined as new Q waves on electrocardiogram or creatine kinase (CK) or CK-MB elevation ≥3 times the upper limit of normal. Major bleeding was defined as any hemoglobin drop >4 g/dL, overt bleeding with hemoglobin drop >3 g/dL, a blood transfusion of ≥2 units or retroperitoneal, intraocular, or intracranial hemorrhage. Minor bleeding was defined as overt bleeding not meeting criteria for major bleeding.

Economic Analysis

Medical care costs for the initial hospitalization and for the 30-day follow-up period among the entire REPLACE-2 trial cohort were assessed from a societal perspective as previously described for a prespecified economic analysis.^[8] Procedural costs, including costs of provisional GPIIb/IIIa use, were based on measured resource utilization and 2002 unit costs. All other hospital costs were determined using ?top-down? accounting methods based on itemized bills and each hospital's Medicare cost report.^[9] For 2500 randomly selected patients, itemized bills were obtained for the initial hospitalization and any subsequent cardiovascular hospitalizations during the follow-up period. In addition, we obtained billing data on all patients who experienced a major inhospital complication. Hospital costs were determined by multiplying itemized hospital charges by the cost center?specific cost-to-charge ratio obtained from the hospital's Medicare cost report as previously described.^[10] For those hospitalizations for which itemized bills were not obtained (n = 2041), hospital room and ancillary costs were imputed based on the coefficients from a regression model of nonprocedural costs from the 2821 hospitalizations in the REPLACE-2 trial for which billing data were available (R² = 0.74 for the model).

Statistical Analysis

χ² or Fisher exact test was used to analyze differences in categorical variables. Differences in continuous variables were evaluated by Wilcoxon rank sum tests. A multivariate stepwise Cox model was applied to determine independent predictors of the composite end point of death, myocardial infarction, or urgent revascularization at 30 days. Variables tested included age, race, sex, weight, diabetes, smoking within the last year, hypertension, congestive heart failure, history of cerebrovascular accident, intervention type, vessel intervened on, prior myocardial infarction, prior PCI, prior coronary artery bypass graft (CABG), medications on admission (angiotensin-converting enzyme inhibitors, β-blockers, statin), and pretreatment with thienopyridines. Version 8.0 of SAS (SAS Inc, Cary, NC) was used for all calculations.

Results

Patient Characteristics

In the REPLACE-2 trial, 1351 patients had ACS (855 with unstable angina within the prior 48 hours and 496 with myocardial infarction within the prior 7 days), and 4554 patients were considered stable with either unstable angina >48 hours before enrollment (1218) or elective indications for revascularization (3336). Table I shows the baseline and procedural characteristics for ACS and stable patients and for ACS patients according to treatment group. Patients with ACS tended to be younger and were more likely to represent minorities compared with stable patients. Patients with ACS were more likely to have history of myocardial infarction, smoking within the last year, or cerebrovascular accident. Patients with ACS were less likely to have diabetes, hypertension, or a history of PCI or CABG. Patients with ACS were less likely to have received thienopyridine pretreatment, but provisional GPIIb/IIIa inhibitor use was similar between ACS and stable patients. Among patients who did receive clopidogrel pretreatment, the time from pretreatment to PCI did not differ between ACS and stable patients. Patients with ACS randomized to bivalirudin were well matched to ACS patients randomized to heparin plus GPIIb/IIIa inhibitors, including a similar provisional GPIIb/IIIa use and time from clopidogrel treatment to PCI, but there was a greater incidence of congestive heart failure in the bivalirudin group.

Clinical Outcomes

Outcomes for ACS patients compared with stable patients are shown in Table II . The two groups did not differ in rates of death or myocardial infarction at any time point, although ACS patients did have a higher rate of urgent CABG by 30 days. The median time for urgent CABG at 30 days in ACS patients was 0.1 days (interquartile range 0.1-0.6 days) compared with 0.5 days (interquartile range 0.1-1.0 days) for stable patients (P = .54), suggesting that there was no difference in the reason for urgent CABG between the groups. Bleeding complications did not differ between stable and ACS patients. Table II also shows outcomes of ACS patients according to treatment group. Patients with ACS treated with bivalirudin had similar rates of death or myocardial infarction at every time point as did those treated with heparin and GPIIb/IIIa inhibitors. Patients with ACS treated with bivalirudin, however, had a trend toward greater rates of urgent CABG at 30 days and had significantly higher rates of revascularization at 6 months. The time to urgent CABG at 30 days did not differ significantly between ACS patients according to treatment group although small numbers limit statistical power; specifically, ACS patients treated with heparin plus GPIIb/IIIa had urgent CABG (n = 4) at a median 3.0 days with interquartile range 0.1 to 17.9 days, and ACS patients treated with bivalirudin patients had urgent CABG (n = 9) at a median 0.1 days with interquartile range 0.1 to 0.3 days (P = .59). Bleeding was more frequent with heparin plus GPIIb/IIIa blockade in both ACS and non-ACS patients. Median ACT levels at 5 minutes post study drug for ACS patients according to treatment group were comparable with those of the overall trial (316 seconds for heparin plus GPIIb/IIIa vs 355 seconds for bivalirudin, P < .001). Table III shows the independent predictors of death, myocardial infarction, or urgent revascularization at 30 days for ACS patients; notably, randomized treatment was not a significant predictor of this ischemic end point. The relative efficacy of bivalirudin versus heparin plus GPIIb/IIIa inhibitors was similar in ACS and stable patients (Figure 1).

Economic Outcomes

Medical care costs were significantly lower for patients treated with bivalirudin as compared with heparin plus GPIIb/IIIa inhibition, regardless of their ACS status. Among US patients (n = 4570), mean 30-day costs for patients without ACS were $10582 for patients treated with bivalirudin and $11010 for patients treated with heparin plus GPIIb/IIIa inhibitors (P < .001). Mean 30-day costs for patients with ACS were $12415 for those treated with bivalirudin and $12806 for those treated with heparin plus GPIIb/IIIa inhibitors (P = .022). There was no interaction between ACS/no ACS status and bivalirudin/GPIIb/IIIa treatment with respect to aggregate 30-day costs (P = .94).

Discussion

Previous studies have demonstrated that ACS patients have higher rates of ischemic events after PCI. It is unclear if this holds true in the current era because of the increased use of stents, statins, thienopyridines, and GPIIb/IIIa inhibitors. In particular, GPIIb/IIIa inhibitors provide protection from ischemic events to ACS patients undergoing PCI^[1,2,3]; for example, GPIIb/IIIa inhibitors can decrease the risk of death/MI for troponin-positive patients to nearly that of troponin-negative patients.^[11] The CAPTURE trial demonstrated that abciximab provides a 68% relative risk reduction in death or myocardial infarction at 6 months, reducing the incidence to 9.5% for patients with elevated troponin T levels compared with 9.4% for patients for patients without elevated troponin T levels. In the EPIC trial, patients with unstable angina derived a greater risk reduction with abciximab than other patients for death (interaction at 6 months: P = .002) and MI (interaction at 6 months: P = .003).^[4] These marked benefits of GPIIb/IIIa inhibitors raise the question of whether the REPLACE-2 results can be applied to ACS patients.

Although not conclusive, this current analysis provides some reassuring information regarding these uncertainties. First, these results suggest that ACS patients undergoing PCI in the contemporary era and receiving heparin plus adjunctive GPIIb/IIIa inhibition do not necessarily have worse outcomes than stable patients, although this finding might be related to some extent to the exclusion of ACS patients requiring ongoing GPIIb/IIIa inhibitor or heparin therapy from REPLACE-2. Except for higher rates of urgent revascularization at 30 days, ACS patients in REPLACE-2 had similar end point event rates as stable patients. Likewise, ACS patients had a similar treatment effect with bivalirudin as did stable patients.

This analysis of ACS patients also extends the principal findings of REPLACE-2, which showed that bivalirudin provided similar protection from ischemic outcomes as does heparin and GPIIb/IIIa inhibitors with less bleeding during contemporary percutaneous coronary revascularization. Rates of death and myocardial infarction at 30 days and 6 months for ACS patients were similar in the two treatment arms, although the rate of revascularization at 6 months was higher in ACS patients treated with bivalirudin. Mortality at 1 year was similar between groups; bleeding was reduced in bivalirudin-treated patients to a similar degree as in the overall trial, although this difference was statistically significant in the subgroup. These findings suggest that bivalirudin plus provisional GPIIb/IIIa blockade is a safe and effective adjunctive anticoagulant for lower-risk ACS patients who would have satisfied entry criteria for REPLACE-2.

Other data in fact suggest that direct thrombin inhibitors such as bivalirudin have similar or greater efficacy in more unstable patients. In the Bivalirudin Angioplasty Study, 4098 patients undergoing angioplasty for unstable angina or postinfarction angina were randomized to heparin or bivalirudin. The final report of this study utilizing a complete dataset with contemporary end point definitions demonstrated that patients randomized to bivalirudin had a lower incidence of the composite of death, myocardial infarction, or repeat revascularization at 90 days (15.7% vs 18.5%), whereas the highest-risk patients (postinfarction angina) had the most marked benefit (incidence of death, myocardial infarction, or revascularization at 90 days: 11.7% vs 20.2%, P = .04).^[6,12] Thus, in the era before the use of GPIIb/IIIa blockade among patients with unstable angina undergoing PCI, patients who were more unstable than those enrolled in REPLACE-2 derived benefit from direct thrombin inhibitors, including bivalirudin, as compared with heparin alone.

Heparin alone is inefficient at decreasing thrombin formation because it binds to plasma proteins, requires a cofactor, does not affect clot-bound thrombin,^[13] and can activate platelets.^[14] In contrast, bivalirudin not only neutralizes clot-bound thrombin, but also may limit thrombin-mediated platelet activation.^[15,16]

These differences between bivalirudin and heparin and the importance of platelet activation provide the pathophysiologic underpinnings for the observed superiority of bivalirudin over heparin before the GPIIb/IIIa era, particularly in high-risk patients.^[6,12] It is plausible that this superiority, as well as the antiplatelet effects of bivalirudin, provides the accretive advantage that resulted in the similarity of outcome with the two strategies in REPLACE 2.

Our study has several limitations. Foremost, we analyzed outcomes retrospectively for subgroups in REPLACE-2. Such analysis is limited by small sample sizes and by the inability to perform formal noninferiority testing on the end points. REPLACE-2 excluded patients with ongoing anticoagulation and acute myocardial infarction. Thus the ?hottest? of ACS patients were excluded from REPLACE-2, and it is unclear if findings of this substudy apply to these patients. Moreover, other standardized measures of acuity, such as the TIMI risk score, were not available for these patients. The efficacy of bivalirudin in these patients, with or without GPIIb/IIIa blockade, is being tested in the ongoing large-scale ACUITY trial. Troponin and markers of inflammation such as myeloperoxidase, C-reactive protein, and soluble CD40 ligand were not prospectively collected. The interaction of bivalirudin with these biomarkers remains to be determined.

A large body of clinical trial evidence has documented the benefit of GPIIb/IIIa inhibitors in the setting of ACS, and unless the ACUITY trial confirms similar efficacy with bivalirudin, GPIIb/IIIa blockade remains the strategy of choice for patients with acute myocardial infarction or highest-risk unstable angina on ongoing anticoagulation therapy. Nevertheless, for the population of patients with ACS who would meet the entry criteria for REPLACE-2, our analysis suggests that replacing heparin and GPIIb/IIIa inhibitors with bivalirudin provides similar protection against ischemic complications with a reduced risk of bleeding during percutaneous coronary revascularization.

	ACS hep + GPIIb/IIIa (n = 682)	ACS bivalirudin (n = 669)	P	ACS (n = 1351)	Stable (n = 4554)	P
Age (y), mean ? SD	61 ? 12	61 ? 11	.99	61 ? 11	63 ? 11	<.001
Age >75 y	14 (96)	12 (77)	.16	13 (173)	13 (623)	.41
Weight (kg), mean ? SD	87 ? 18	88 ? 18	.46	87 ? 18	87 ? 18	.84
Women	25 (169)	18 (188)	.17	26 (357)	25 (1154)	.42
White	91 (621)	91 (609)	.99	91 (1230)	93 (4234)	.02
Diabetes	26 (177)	24 (162)	.42	25 (339)	28 (1263)	.06
Prior MI	54 (362)	53 (350)	.85	53 (712)	32 (1446)	<.001
Prior PCI	31 (208)	28 (185)	.24	29 (393)	37 (1658)	<.001
Prior CABG	17 (113)	16 (108)	.81	16 (221)	19 (868)	<.03
Smoking in last year	34 (227)	34 (225)	.92	34 (452)	24 (1074)	<.001
Hypertension	65 (440)	63 (416)	.41	64 (856)	68 (3079)	.003
Congestive heart failure	5 (32)	7 (48)	.06	6 (80)	7 (328)	.10
History of CVA	3 (18)	4 (27)	.15	3 (45)	2 (92)	.005
Procedure type
Stent	91 (615)	89 (591)	.26	90 (1206)	87 (3927)	0.004
Atherectomy	3 (23)	3 (20)	.70	3 (43)	4 (186)	.13
Balloon only	6 (42)	8 (51)	.29	7 (93)	8 (379)	.08
Multivessel intervention	14 (94)	16 (110)	.17	15 (204)	16 (745)	.26
Target vessel (not mutually exclusive)
Left    anterior descending	39 (263)	41 (277)	.29	40 (540)	44 (2006)	.007
Left circumflex	30 (207)	31 (207)	.81	31 (414)	29 (1334)	.35
Right    coronary artery	37 (255)	37 (246)	.81	37 (501)	36 (1649)	.57
Left main    coronary artery	2 (10)	0.9 (6)	.33	1 (16)	1 (59)	.75
Bypass graft	6 (39)	6 (43)	.59	6 (82)	6 (277)	.98
Clopidogrel pretreatment	85 (576)	85 (566)	.99	85 (1145)	87 (3951)	.05
Time between clopidogrel loading and PCI (h), median (interquartile range)	2.6 (0.9-5.5)	2.7 (0.9-4.9)	.70	2.7 (0.9-5.1)	2.4 (1.0-4.6)	.30
Provisional GPIIb/IIIa	6 (43)	8 (55)	.18	7 (98)	6 (275)	.11

Values are presented as % (n) unless otherwise noted.

 

	ACS hep + GPIIb/IIIa (n = 682)	ACS bivalirudin (n = 669)	P	ACS (n = 1351)	Stable (n = 4554)	P
30-Day end points
Death/MI/urgent    revascularization/major    bleeding	11 (75)	10 (66)	.50	10.5 (141)	9.3 (424)	.21
Death/MI/urgent    revascularization	8.0 (54)	8.7 (58)	.62	8.3 (112)	7.1 (323)	.13
Death/MI	7.1 (48)	7.4 (49)	.84	7.2 (97)	6.7 (304)	.51
Death	0.4 (3)	0.4 (3)	.99	0.4 (6)	0.3 (13)	.41
MI	6.9 (47)	7.2 (48)	.84	7.1 (95)	6.5 (297)	.50
Urgent    revascularization	1.6 (11)	2.3 (15)	.40	1.9 (26)	1.1 (48)	.01
Urgent PCI	1.0 (7)	1.1 (7)	.97	1.0 (14)	0.8 (35)	34
Urgent CABG	0.6 (4)	1.4 (9)	.15	1.0 (13)	0.3 (14)	.002
Major bleeding	4.5 (31)	2.7 (18)	.07	3.6 (49)	3.0 (137)	.25
Minor bleeding	27 (183)	13 (86)	<.001	20 (269)	20 (899)	.89
6-Month end points
Death/MI	8.2 (56)	8.7 (58)	.76	8.4 (114)	8.7 (394)	.81
Death	1.3 (9)	0.9 (6)	.46	1.1 (15)	1.2 (54)	.82
MI	7.6 (52)	8.1 (54)	.76	7.8 (106)	7.8 (357)	.99
Revascularization	8.4 (57)	12 (78)	.04	10 (135)	11 (521)	.14
1-Year end point
Death	1.8 (12)	1.5 (10)	.70	1.6 (22)	2.2 (102)	.17

Values are presented as % (n).

 

Variable	Hazard ratio (95% CI)	P
Atherectomy	2.93 (1.47-5.82)	.002
CVA	2.41 (1.12-5.20)	.025
Graft intervention	1.95 (1.04-3.65)	.037
Bivalirudin	1.07 (0.74-1.56)	.713
ACE inhibitors in diabetics	0.29 (0.12-0.71)	.007

 

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Reprint Address

A. Michael Lincoff, MD, Department of Cardiovascular Medicine, Desk F25, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: lincofa@ccf.org