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Abciximab and Heparin versus Bivalirudin for NonST-Elevation Myocardial Infarction

Adnan Kastrati, M.D., Franz-Josef Neumann, M.D., Stefanie Schulz, M.D., Steffen Massberg, M.D., Robert A. Byrne, M.B., B.Ch., Ph.D., Miroslaw Ferenc, M.D., Karl-Ludwig Laugwitz, M.D., Jrgen Pache, M.D., Ilka Ott, M.D., Jrg Hausleiter, M.D., Melchior Seyfarth, M.D., Michael Gick, M.D., David Antoniucci, M.D., Albert Schmig M.D., Peter B. Berger, M.D., and Julinda Mehilli, M.D., for the ISAR-REACT 4 Trial Investigators*

A bs t r ac t
Background
From Deutsches Herzzentrum (A.K., S.S., S.M., R.A.B., J.P., I.O., J.H., A.S., J.M.) and 1. Medizinische Klinik rechts der Isar (K.-L.L., A.S.), Technische Universitt, Munich; Herz-Zentrum, Bad Krozingen (F.-J.N., M.F., M.G.); and HELIOS Klinikum Wuppertal, Wuppertal, and Universitt Witten/Herdecke, Witten (M.S.) all in Germany; Careggi Hospital, Florence, Italy (D.A); and Geisinger Medical Center, Danville, PA (P.B.B.). Address reprint requests to Dr. Kastrati at Deutsches Herz zentrum, Lazarettstr. 36, 80636 Munich, Germany, or at kastrati@dhm.mhn.de. * The centers and investigators participating in the Intracoronary Stenting and Anti thrombotic Regimen: Rapid Early Action for Coronary Treatment 4 (ISAR-REACT 4) trial are listed in the Supplementary Appendix, available at NEJM.org. This article (10.1056/NEJMoa1109596) was published on November 13, 2011, at NEJM .org. N Engl J Med 2011;365:1980-9.
Copyright 2011 Massachusetts Medical Society.

The combination of glycoprotein IIb/IIIa inhibitors and heparin has not been compared with bivalirudin in studies specifically involving patients with nonST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). We compared the two treatments in this patient population.
Methods

Immediately before PCI, we randomly assigned, in a double-blind manner, 1721 patients with acute nonST-segment elevation myocardial infarction to receive abciximab plus unfractionated heparin (861 patients) or bivalirudin (860 patients). The study tested the hypothesis that abciximab and heparin would be superior to bivalirudin with respect to the primary composite end point of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days. Secondary end points included the composite of death, any recurrent myocardial infarction, or urgent target-vessel revascularization (efficacy end point) and major bleeding (safety end point) within 30 days.
Results

The primary end point occurred in 10.9% of the patients in the abciximab group (94 patients) and in 11.0% in the bivalirudin group (95 patients) (relative risk with abciximab, 0.99; 95% confidence interval [CI], 0.74 to 1.32; P=0.94). Death, any recurrent myocardial infarction, or urgent target-vessel revascularization occurred in 12.8% of the patients in the abciximab group (110 patients) and in 13.4% in the bivalirudin group (115 patients) (relative risk, 0.96; 95% CI, 0.74 to 1.25; P=0.76). Major bleeding occurred in 4.6% of the patients in the abciximab group (40 patients) as compared with 2.6% in the bivalirudin group (22 patients) (relative risk, 1.84; 95% CI, 1.10 to 3.07; P=0.02).
Conclusions

Abciximab and unfractionated heparin, as compared with bivalirudin, failed to reduce the rate of the primary end point and increased the risk of bleeding among patients with nonST-segment elevation myocardial infarction who were undergoing PCI. (Funded by Nycomed Pharma and others; ISAR-REACT 4 ClinicalTrials.gov number, NCT00373451.)
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Abciximab vs. Bivalirudin for NonST-Elevation MI

n invasive strategy of coronary angiography, with revascularization when appropriate, is recommended for highrisk patients who have an acute coronary syndrome.1,2 Owing to the key role that the rupture of an atherosclerotic plaque, which is highly prothrombotic, plays in the pathogenesis of these syndromes,3 identifying the most appropriate adjunctive antithrombotic therapy before, during, and after percutaneous coronary intervention (PCI) has been the target of extensive research for the past three decades. Abciximab is a glycoprotein IIb/IIIa inhibitor with potent platelet-antiaggregative effects.4 Although the administration of abciximab during PCI was not associated with a clinical benefit in patients in stable condition who were given a loading dose of clopidogrel before the intervention,5,6 it did reduce the risk of ischemic events in patients with an acute coronary syndrome, especially in those with nonST-segment elevation myocardial infarction.7 However, potent antiplatelet drugs increase the risk of bleeding, which in turn is strongly correlated with an unfavorable prognosis.8 Bivalirudin is a direct thrombin inhibitor that has increasingly been used in patients undergoing PCI since the time that the first study comparing heparin plus a IIb/IIIa inhibitor with bivalirudin (the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events 2 [REPLACE-2] trial) suggested the noninferiority of the bivalirudin strategy.9 Although bivalirudin, as compared with unfractionated heparin alone, did not provide a net clinical benefit in patients at low-to-moderate risk who were undergoing PCI,10 it was superior to heparin plus a glycoprotein IIb/IIIa inhibitor in patients with acute STsegment elevation myocardial infarction,11 as well as in patients with acute nonST-segment elevation coronary syndromes, as shown in the Acute Catheterization and Urgent Intervention Triage Strategy trial (ACUITY; ClinicalTrials.gov number, NCT00093158).12 In the latter trial, however, approximately 40% of the patients did not have elevated cardiac biomarkers, and more than 40% did not undergo PCI.12 Thus, the safety and efficacy of abciximab plus unfractionated heparin as compared with bivalirudin specifically in patients with nonST-segment elevation myocardial infarction undergoing PCI have not been fully investigated. The objective of the current trial was to determine whether the

combination of abciximab with unfractionated heparin, as compared with bivalirudin, improves the clinical outcomes in patients with acute non ST-segment elevation myocardial infarction who are undergoing PCI.

Me thods
Study Population

We enrolled patients 19 to 80 years of age who met the following criteria: an accelerating pattern of angina or prolonged angina (lasting >20 minutes) or recurrent episodes of angina, either at rest or during minimal exertion, within the preceding 48 hours; levels of cardiac biomarkers (troponin or creatine kinase MB isoenzymes) that were above the upper limit of the normal range; and coronary stenoses requiring PCI. The exclusion criteria are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org. All patients provided written informed consent.
Study Oversight

The study was designed by the authors. The data were collected and analyzed and the trial was monitored by the Intracoronary Stenting and Antithrombosis Research (ISAR) Center, which is affiliated with Deutsches Herzzentrum, Munich, Germany. Nycomed Pharma, the former distributor of bivalirudin in Europe and one of the sponsors of the study, had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. No agreement exists between the authors and this company with respect to confidentiality of the data. The first author wrote the first draft of the manuscript. All the authors participated in drafting the final version of the manuscript and made the decision to submit it for publication. The first author, who was the principal investigator of the study, and another author, who was the chair of the study group, vouch for the accuracy and completeness of the reported data and for the fidelity of the study to the protocol. The full study protocol and statistical analysis plan are available at NEJM.org.
Study Protocol

A strategy of early invasive intervention (within 24 hours after admission) was the standard of care at all the participating centers for patients
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presenting with an acute coronary syndrome and elevated biomarker levels. All the patients in the trial were given 325 to 500 mg of aspirin and 600 mg of clopidogrel before they received a study drug. After the decision to perform PCI was made, patients at each participating center underwent randomization in a double-blind manner by means of a double-dummy-drug strategy. Assignments were made with the use of sealed opaque envelopes (concealed assignments). Before the guide wire had crossed the lesion, patients who were assigned to the abciximab group received a bolus dose of 0.25 mg of abciximab per kilogram of body weight, followed by an infusion of 0.125 g of abciximab per kilogram per minute (maximum of 10 g per minute) for 12 hours, and a bolus dose of 70 units of heparin per kilogram. Patients in the bivalirudin group received a bolus dose of 0.75 mg of bivalirudin per kilogram, followed by an infusion of 1.75 mg per kilogram per hour for the duration of the procedure. No monitoring of activated clotting time was performed during the procedure, except at one center, where 32 patients were enrolled; at that center, a monitor of activated clotting time, who was unaware of the treatment assignments, administered additional boluses of heparin or placebo if the activated clotting time was less than 200 seconds. All the personnel involved in the care of the patients were unaware of the values for activated clotting time. Coronary stenting was the preferred method of PCI; most procedures were performed with access through the femoral artery, although access through the radial artery was permitted. For patients in whom no closure device was used, vascular sheaths were removed and manual compression was applied as soon as the activated prothrombin time fell below 50 seconds. Therapy administered after the procedure included aspirin, at a dose of 80 to 325 mg daily, for an indefinite duration; clopidogrel, at a dose of 75 to 150 mg per day until discharge, but for no longer than 3 days, followed by 75 mg per day for at least 6 months; and other cardiac medications that the patients physician deemed necessary. The protocol required the performance of electrocardiography and the measurement of cardiac biomarkers, hemoglobin levels, and platelet count every 8 hours for 24 hours after the procedure and daily thereafter, until the patient was discharged from the hospital. A telephone interview was conducted at 30 days, and all patients with
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cardiac symptoms underwent a complete clinical, electrocardiographic, and laboratory evaluation.

Study End Points and Definitions

The primary end point was a composite of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days after randomization. The diagnosis of large recurrent myocardial infarction required the development of pathologic Q waves (40 msec in duration and 0.1 mV in depth) in two or more contiguous precordial leads or in two or more adjacent limb leads or a level of the MB isoenzyme of creatine kinase (or total creatine kinase, if measures of the MB isoenzyme were not available) that was more than five times the upper limit of the normal range and at least 50% above the level recorded before the procedure. Major bleeding was defined as the presence of intracranial, intraocular, or retroperitoneal hemorrhage; a decrease in the hemoglobin level of more than 40 g per liter plus either overt bleeding or the need for transfusion of 2 or more units of packed red cells or whole blood. Bleeding was also assessed according to the Thrombolysis in Myocardial Infarction (TIMI) criteria.13 Two secondary end points were defined prospectively: a composite efficacy end point of death, any recurrent myocardial infarction, or urgent target-vessel revascularization and a safety end point of major bleeding both within 30 days after randomization. The diagnosis of any recurrent myocardial infarction required the development of pathologic Q waves or a level of the MB isoenzyme of creatine kinase (or total creatine kinase, if measures of the MB isoenzyme were not available) that was more than three times the upper limit of the normal range and at least 50% above the level recorded before the procedure. Stent thrombosis was considered to have occurred if the criteria for definite stent thrombosis of the Academic Research Consortium were met.14 Profound thrombocytopenia was defined as a platelet count of less than 20109 per liter. All events were adjudicated and classified by an event-adjudication committee whose members were unaware of the treatment assignments.
Statistical Analysis

The study was designed to show whether abciximab plus unfractionated heparin was superior to bivalirudin with respect to the primary end point.

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Abciximab vs. Bivalirudin for NonST-Elevation MI

On the basis of the findings related to the subgroup of patients with elevated troponin levels in a previous trial of abciximab in patients with acute coronary syndromes,7 we assumed that the incidence of the primary end point would be 10.7% in the abciximab group, versus 15.3% in the bivalirudin group. We estimated that a total sample of 1700 patients would be needed for the study to have 80% power to detect this 30% reduction in the primary end point with abciximab, at a two-sided alpha level of 0.05. The assumption of a higher event rate in the bivalirudin group was suggested by a trend toward an increased incidence of ischemic complications in the bivalirudin group as compared with the glycoprotein IIb/IIIa group in subsets of high-risk patients in the REPLACE-215 and ACUITY16 trials. All analyses were performed in a blinded manner on the basis of the intention-to-treat principle. The treatment codes were broken only after the database had been locked and the statistical analyses had been performed. Data are presented as means SD (or medians and interquartile ranges in the case of variables for which the data were skewed) or as numbers and percentages. Categorical data were compared with the use of a chi-square test or with the use of Fishers exact test when cell counts were less than 5. Continuous data were compared with the use of the t-test (or the Wilcoxon test in the case of variables for which the data were skewed). The KaplanMeier method was used to assess event-free survival; comparisons were made with the use of the logrank test. The primary end point was also assessed in prespecified subgroups defined according to age, sex, presence or absence of diabetes, body-mass index, renal function, and baseline troponin level. For continuous variables, dichotomization was performed with the use of the respective median value as the cutoff point. Twosided P values of less than 0.05 were considered to indicate statistical significance. S-Plus software, version 4.5 (Insightful), was used for all statistical analyses.

that they had been randomly assigned to receive. No patient in the bivalirudin group received provisional abciximab. The baseline characteristics of the patients are shown in Table 1; there were no significant differences between the two groups.
Intervention

Four patients did not undergo the intended PCI, and the infusion of the study drug was discontinued in all of them. The operators chose not to perform the planned intervention in 2 patients (both in the abciximab group) after deciding that the lesion was less severe than initially believed; in the other 2 patients (both in the bivalirudin group), the operators changed their treatment strategy before beginning the intervention and scheduled coronary-artery bypass surgery. Of the 1717 patients who underwent PCI, 55.7% (56.6% in the abciximab group and 54.9% in the bivalirudin group) underwent an intervention for more than one lesion. Radial-artery access was used in only 6 patients (2 in the abciximab group and 4 in the bivalirudin group, P=0.69). Closure devices were used in 188 patients in the abciximab group (21.8%) and 177 patients in the bivalirudin group (20.6%) (P=0.52). Table 2 shows the characteristics of the infarct-related lesion and data related to the procedure; no significant differences were observed between the two groups.
Outcomes

R e sult s
Patients

A total of 1721 patients were enrolled in the trial; 861 patients were assigned to receive abciximab plus unfractionated heparin (abciximab group) and 860 patients were assigned to receive bivalirudin. All the patients received the study drug

Information on 30-day outcomes was available for all but 2 patients (both in the abciximab group). Table 3 shows the clinical outcomes in the two study groups. The primary end point occurred in 94 patients (10.9%) in the abciximab group and 95 patients (11.0%) in the bivalirudin group (relative risk with abciximab, 0.99; 95% confidence interval [CI], 0.74 to 1.32; P=0.94) (Fig. 1A). The secondary efficacy end point occurred in 110 patients (12.8%) in the abciximab group and 115 patients (13.4%) in the bivalirudin group (relative risk, 0.96; 95% CI, 0.74 to 1.25; P=0.76) (Fig. 1B). Major bleeding occurred in 40 patients (4.6%) in the abciximab group and 22 patients (2.6%) in the bivalirudin group (relative risk, 1.84; 95% CI, 1.10 to 3.07; P=0.02) (Fig. 1C). The incidence of TIMI major bleeding did not differ significantly between the two groups (P=0.61) (Table 3); TIMI minor bleeding occurred more frequently in the abciximab group than in the bivalirudin group (66 patients [7.7%] vs. 37 patients [4.3%], P=0.003) (Table 3). Profound thrombocytopenia developed
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Table 1. Baseline Characteristics of the Patients.* Abciximab plus Unfractionated Heparin (N=861) 67.511.2 200 (23.2) 257 (29.8) 91 (10.6) 215 (25.0) 745 (86.5) 600 (69.7) 167 (19.4) 213 (24.7) 481 (55.9) 188 (21.8) 292 (33.9) 92 (10.7) 27.84.6 82 63105 0.12 0.040.37 51.511.5 Bivalirudin (N=860) 67.510.8 199 (23.1) 243 (28.3) 84 (9.8) 195 (22.7) 727 (84.5) 580 (67.4) 177 (20.6) 222 (25.8) 461 (53.6) 163 (19.0) 267 (31.0) 89 (10.3) 27.84.2 84 63108 0.12 0.040.35 51.311.5

Characteristic Age yr Female sex no. (%) Diabetes no. (%) Any Requiring insulin Current smoker no. (%) Arterial hypertension no. (%) Hypercholesterolemia no. (%) No. of diseased coronary vessels no. (%) 1 2 3 Previous myocardial infarction no. (%) Previous percutaneous coronary intervention no. (%) Previous coronary-artery bypass surgery no. (%) Body-mass index Glomerular filtration rate ml/min Median Interquartile range Troponin T g/liter Median Interquartile range Left ventricular ejection fraction %

* Plusminus values are means SD. There were no significant differences between the two groups in baseline characteristics (P>0.05 for all comparisons). Patients were considered to have hypercholesterolemia if they had a history of total cholesterol levels higher than 200 mg per deciliter (5.2 mmol per liter) or had received treatment with lipid-lowering agents. The body-mass index is the weight in kilograms divided by the square of the height in meters. Data were available for 1558 patients: 777 in the abciximab group and 781 in the bivalirudin group.

in 10 patients (1.2%) in the abciximab group and in none of the patients in the bivalirudin group (P=0.002). Figure 2 shows the frequency with which the criteria for the primary end point were met in prespecified subgroups. In no subgroup was there a suggestion of a beneficial effect of abciximab.

Discussion
In this double-blind, randomized study, abciximab plus unfractionated heparin, as compared with bivalirudin, was not associated with a reduction in the risk of death, large recurrent myocardial
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infarction, urgent target-vessel revascularization, or major bleeding at 30 days. The 95% confidence interval for the treatment effect of abciximab plus unfractionated heparin lies between a possible reduction of 26% and a possible increase of 25% in the risk of the occurrence of the primary end point. An analysis of the secondary efficacy end point of death, any recurrent myocardial infarction, or urgent target-vessel revascularization also failed to suggest a benefit with abciximab. The incidence of the secondary safety end point, major bleeding, was increased with abciximab plus unfractionated heparin. The incidence of the primary end point in the

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Abciximab vs. Bivalirudin for NonST-Elevation MI

Table 2. Characteristics of the Infarct-Related Lesion and Types of Intervention.* Abciximab plus Unfractionated Heparin (N=859) Bivalirudin (N=858)

Characteristic Target vessel no. (%) Left main coronary artery Left anterior descending coronary artery Left circumflex coronary artery Right coronary artery Venous bypass graft Complex (type B2 or C) lesions no. (%) TIMI flow grade before intervention no. (%) 0 1 2 3 Lesion length mm Vessel size mm Stenosis before procedure % of luminal diameter Maximal balloon pressure atm Balloon-to-vessel ratio Type of intervention no. (%) Placement of drug-eluting stent Placement of bare-metal stent Balloon angioplasty Length of stented segment mm Stenosis after procedure % of luminal diameter TIMI flow grade after intervention 0 1 2 3

27 (3.1) 316 (36.8) 241 (28.1) 236 (27.5) 39 (4.5) 732 (85.2) 168 (19.6) 52 (6.1) 184 (21.4) 455 (53.0) 17.610.8 3.00.6 7617 153 1.10.1 764 (88.9) 58 (6.8) 37 (4.3) 2714 1312 8 (0.9) 5 (0.6) 38 (4.4) 808 (94.1)

25 (2.9) 347 (40.4) 231 (26.9) 227 (26.5) 28 (3.3) 748 (87.2) 160 (18.6) 64 (7.5) 202 (23.5) 432 (50.3) 18.011.5 3.00.6 7616 153 1.10.1 757 (88.2) 65 (7.6) 36 (4.2) 2714 1414 12 (1.4) 11 (1.3) 32 (3.7) 803 (93.6)

* Plusminus values are means SD. Four patients did not undergo the intended PCI; the infusion of study drug was discontinued in all of them. TIMI denotes Thrombolysis in Myocardial Infarction.

abciximab group that was observed in this study is very close to the predicted event rate for that group, which is the event rate on which the calculation of sample size was, in part, based. However, the incidence of the primary end point in the bivalirudin group was lower than predicted. Although this favors the efficacy and safety of bivalirudin, it reduced to 73% the actual power of the study to detect a difference between the two treatment groups; the reduced power is a limitation of the study. In addition, the results of

this trial might not be generalizable to patients in whom either a smaller dose or no loading dose of clopidogrel is administered, newer adenosinediphosphate receptor antagonists are used, or PCI is performed through a radial artery. Establishing the diagnosis of recurrent myocardial infarction in patients presenting with nonST-segment elevation myocardial infarction is often challenging for clinical investigators. Myocardial infarction and the resultant elevation of biomarkers at study entry make it difficult to
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Table 3. Clinical Outcomes. Abciximab plus Unfractionated Heparin (N=861)

Outcome

Bivalirudin (N=860)

Relative Risk (95% CI)

number (percent) Primary end point: death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding Secondary efficacy end point: death, any recurrent myocardial infarction, or urgent target-vessel revascularization Secondary safety end point: major bleeding Intracranial bleeding Retroperitoneal bleeding Decrease in hemoglobin >40 g/liter with overt bleeding Pericardial bleeding Gastrointestinal bleeding Urogenital bleeding Access-site bleeding Bleeding at other site Decrease in hemoglobin >40 g/liter without overt bleeding but with transfusion of 2 units of packed red cells Death, any recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding Death or large recurrent myocardial infarction Death or any recurrent myocardial infarction Death Large recurrent myocardial infarction Any recurrent myocardial infarction Q-wave myocardial infarction Urgent target-vessel revascularization Percutaneous coronary intervention Coronary-artery bypass surgery Stroke Definite stent thrombosis* Bleeding according to TIMI criteria Major Minor 19 (2.2) 66 (7.7) 16 (1.9) 37 (4.3) 1.19 (0.612.31) 1.82 (1.222.70) 4 (0.5) 9 (1.0) 3 (0.3) 15 (1.7) 2 (0.2) 2 (0.2) 137 (15.9) 63 (7.3) 109 (12.7) 12 (1.4) 57 (6.6) 103 (12.0) 11 (1.3) 7 (0.8) 7 (0.8) 0 4 (0.5) 5 (0.6) 1 (0.1) 6 (0.7) 1 (0.1) 7 (0.8) 2 (0.2) 3 (0.3) 130 (15.1) 71 (8.3) 109 (12.7) 14 (1.6) 60 (7.0) 98 (11.4) 8 (0.9) 11 (1.3) 9 (1.0) 2 (0.2) 6 (0.7) 6 (0.7) 0.67 (0.202.34) 0.83 (0.252.72) 1.06 (0.841.35) 0.88 (0.631.24) 1.00 (0.771.31) 0.86 (0.401.85) 0.94 (0.661.36) 1.06 (0.801.39) 1.37 (0.563.40) 0.63 (0.251.62) 94 (10.9) 110 (12.8) 40 (4.6) 1 (0.1) 4 (0.5) 95 (11.0) 115 (13.4) 22 (2.6) 1 (0.1) 1 (0.1) 0.99 (0.741.32) 0.96 (0.741.25) 1.84 (1.103.07)

* Data are included for the 1644 patients (822 in each group) who received stents.

detect myocardial injury after the procedure. For the diagnosis of a recurrent and large myocardial infarction to be made, we required either the appearance of pathologic Q waves or an increase in creatine kinase levels or creatine kinase MB isoenzyme levels to more than five times the upper limit of the normal range, with at least a 50% increase above the level recorded before the procedure; procedural myocardial infarction usu1986

ally drives the frequency with which such composite primary end points are reached. The lack of protection against ischemic events with abciximab in this study is further suggested by the failure of the drug to reduce the frequency of even small recurrent myocardial infarction (defined by an increase in the creatine kinase or creatine kinase MB isoenzyme level to more than three times the upper limit of the normal

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Abciximab vs. Bivalirudin for NonST-Elevation MI

Cumulative Incidence (%)

Figure 1. Cumulative Incidence of Primary and Secondary End Points in the Two Study Groups. The primary end point (Panel A) was a composite of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding with in 30 days after percutaneous coronary intervention (PCI); the secondary efficacy end point (Panel B) was a composite of death, any recurrent myocardial infarction, or urgent target-vessel revascularization within 30 days after PCI; and the secondary safety end point (Panel C) was major bleeding within 30 days after PCI.

A Primary End Point

20

15 Abciximab 10 Bivalirudin Relative risk, 0.99 (95% CI, 0.741.32) P=0.94

range, with at least a 50% increase above the level before the procedure); similarly, no strong signal of a reduction in the risk of stent thrombosis or the risk of death was seen. These data suggest that bivalirudin alone provides antiischemic protection similar to that offered by abciximab and heparin in patients undergoing PCI for acute nonST-segment elevation myocardial infarction. Indeed, apart from its direct antithrombotic effects, bivalirudin was shown to reduce platelet activation and monocyte activation,17,18 both of which have previously been reported with abciximab.19 In the current study, abciximab and heparin increased the frequency of bleeding. The fact that many definitions of bleeding exist and have been used in clinical studies of antithrombotic drugs suggests that each of these definitions has limitations. Recently, a new bleeding classification has been recommended; this new classification may offer advantages, but prospective validation is needed.20 The definition of bleeding used in previous studies of bivalirudin11,12 has been considered by some to be too liberal, owing to the inclusion of even mild bleeding that may not have clinical relevance with respect to prognosis. For this reason, we adopted stricter bleeding criteria, in an effort to include only bleeding events that were likely to have an effect on prognosis. However, bivalirudin was associated with a reduced risk of bleeding even when the TIMI criteria for minor bleeding were used; the prognostic value of TIMI bleeding (both major and minor) has been documented.8 In the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction trial (HORIZONS-AMI; ClinicalTrials.gov number, NCT00433966), bivalirudin was superior to a glycoprotein IIb/IIIa inhibitor and heparin in patients undergoing primary PCI for ST-segment elevation myocardial infarction.11 Not only did

10

15

20

25

30

Days since Randomization

B Secondary Efficacy End Point

20

Cumulative Incidence (%)

15

Bivalirudin Abciximab

10

Relative risk, 0.96 (95% CI, 0.741.25) P=0.76

10

15

20

25

30

Days since Randomization

C Secondary Safety End Point

20

Cumulative Incidence (%)

15

10

Relative risk, 1.84 (95% CI, 1.103.07) P=0.02 Abciximab

Bivalirudin 0
0 5 10 15 20 25 30

Days since Randomization

bivalirudin reduce periprocedural bleeding, but it also reduced mortality at 30 days; the reduction in mortality has persisted through 3 years of follow-up.21 The results of the current trial sup1987

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Subgroup
Age >68.3 yr 68.3 yr Sex Male Female Diabetes Yes No Body-mass index >27.3 27.3 Glomerular filtration rate >83 ml/min 83 ml/min Troponin T >0.12 g/liter 0.12 g/liter

Abciximab

Bivalirudin

Relative Risk (95% CI)

P Value for Interaction

0.94

no. of patients with event/total no. (%) 48/450 (10.7) 46/411 (11.2) 31/200 (15.5) 63/661 (9.5) 27/257 (10.5) 67/604 (11.1) 42/435 (9.7) 52/426 (12.2) 47/421 (11.2) 47/440 (10.7) 56/424 (13.2) 38/437 (8.7) 49/443 (11.1) 46/417 (11.0) 0.27 25/199 (12.6) 70/661 (10.6) 0.71 24/243 (9.9) 71/617 (11.5) 0.51 46/426 (10.8) 49/434 (11.3) 0.41 44/440 (10.0) 51/420 (12.1) 0.15 66/425 (15.5) 29/435 (6.7)
0 1 2

Abciximab Better Bivalirudin Better

Figure 2. Thirty-Day Incidence and Relative Risk of the Primary End Point in Prespecified Subgroups. The primary end point was a composite of death, large recurrent myocardial infarction, urgent target-vessel revascularization, or major bleeding within 30 days after percutaneous coronary intervention. The body-mass index is the weight in kilograms divided by the square of the height in meters.

port the use of bivalirudin as an effective and safe antithrombotic drug during PCI in patients with nonST-segment elevation myocardial infarction. In conclusion, abciximab and unfractionated heparin, as compared with bivalirudin alone, failed to reduce the rate of the primary end point and increased the risk of bleeding in patients undergoing PCI for nonST-segment elevation myocardial infarction.
Supported in part by Nycomed Pharma, Unterschleiss heim, Germany (former distributor of bivalirudin in Europe), and a grant (KKF 04-06 [974404]) from Deutsches Herzzentrum, Munich, Germany. Dr. Kastrati reports receiving consulting fees from AstraZeneca, Bristol-Myers Squibb, and Daiichi Sankyo/Eli Lilly and lecture fees from Abbott, Biotronik, Cordis, and Medtronic; Dr. Neumann, reReferences
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ceiving consulting fees and grant support from Daiichi Sankyo/Eli Lilly and lecture fees from AstraZeneca, Daiichi Sankyo/Eli Lilly, the Medicines Company, Novartis, and Sanofi-Aventis; Dr. Ferenc, receiving lecture fees from AstraZeneca, Biotronic, Boston Scientific, Cordis, and Daiichi Sankyo/Eli Lilly; Dr. Hausleiter, receiving grant support and lecture fees from Siemens Medical; Dr. Seyfarth, receiving consulting fees from Abiomed and SanofiAventis and lecture fees from Daiichi Sankyo/Eli Lilly and Novartis; Dr. Antoniucci, holding board memberships with Cordis and CID and receiving consulting fees from Daiichi Sankyo/Eli Lilly and the Medicines Company; Dr. Berger, receiving consulting fees from Accumetrics, AstraZeneca, Boehringer-Ingelheim, Daiichi Sankyo/ Eli Lilly, Medicure, and Ortho-McNeil and grant support from Accumetrics, AstraZeneca, Corgenix/AspirinWorks, Haemoscope, Helena, the Medicines Company, and Thrombovision; and Dr. Mehilli, receiving lecture fees from Abbott, Daiichi Sankyo/Eli Lilly, and Terumo. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

et al. 2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/ American Heart Association Task Force

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et al. Angioscopic evaluation of coronaryartery thrombi in acute coronary syndromes. N Engl J Med 1992;326:287-91. 4. Neumann FJ, Hochholzer W, PogatsaMurray G, Schmig A, Gawaz M. Antiplatelet effects of abciximab, tirofiban and eptifibatide in patients undergoing coro-

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nary stenting. J Am Coll Cardiol 2001;37: 1323-8. 5. Kastrati A, Mehilli J, Schhlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232-8. 6. Mehilli J, Kastrati A, Schhlen H, et al. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 2004;110:3627-35. 7. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006;295:1531-8. 8. Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1-year outcome after percutaneous coronary interventions: appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008;51:690-7. 9. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853-63. [Erratum, JAMA 2003;289:1638.] 10. Kastrati A, Neumann FJ, Mehilli J, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008;359:688-96. [Erratum, N Engl J Med 2008;359:983.] 11. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30. 12. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355: 2203-16. 13. TIMI definitions for commonly used terms in clinical trials (http://www.timi .org/wp-content/uploads/2010/10/ TIMI-Definitions.pdf). 14. Mauri L, Hsieh W, Massaro JM, Ho KKL, DAgostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007; 356:1020-9. 15. Rajagopal V, Lincoff AM, Cohen DJ, et al. Outcomes of patients with acute coronary syndromes who are treated with bivalirudin during percutaneous coronary intervention: an analysis from the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial. Am Heart J 2006;152:149-54. 16. Stone GW, White HD, Ohman EM, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial. Lancet 2007;369:907-19. 17. Sibbing D, Busch G, Braun S, et al. Impact of bivalirudin or unfractionated heparin on platelet aggregation in patients pretreated with 600 mg clopidogrel undergoing elective percutaneous coronary intervention. Eur Heart J 2008;29:1504-9. 18. Busch G, Steppich B, Sibbing D, et al. Bivalirudin reduces platelet and monocyte activation after elective percutaneous coronary intervention. Thromb Haemost 2009; 101:340-4. 19. Neumann FJ, Zohlnhfer D, Fakhoury L, Ott I, Gawaz M, Schmig A. Effect of glycoprotein IIb/IIIa receptor blockade on platelet-leukocyte interaction and surface expression of the leukocyte integrin Mac-1 in acute myocardial infarction. J Am Coll Cardiol 1999;34:1420-6. 20. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-47. 21. Stone GW, Witzenbichler B, Guagliumi G, et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 2011;377:2193-204.
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