Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction...

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www.thelancet.com Vol 374 October 3, 2009 1149

Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trialRoxana Mehran, Alexandra J Lansky, Bernhard Witzenbichler, Giulio Guagliumi, Jan Z Peruga, Bruce R Brodie, Dariusz Dudek, Ran Kornowski, Franz Hartmann, Bernard J Gersh, Stuart J Pocock, S Chiu Wong, Eugenia Nikolsky, Louise Gambone, Lynn Vandertie, Helen Parise, George D Dangas, Gregg W Stone, for the HORIZONS-AMI Trial Investigators*

SummaryBackground In the HORIZONS-AMI trial, patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) who were treated with the thrombin inhibitor bivalirudin had substantially lower 30-day rates of major haemorrhagic complications and net adverse clinical events than did patients assigned to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI). Here, we assess whether these initial benefi ts were maintained at 1 year of follow-up.

Methods Patients aged 18 years or older were eligible for enrolment in this multicentre, open-label, randomised controlled trial if they had STEMI, presented within 12 h after the onset of symptoms, and were undergoing primary PCI. 3602 eligible patients were randomly assigned by interactive voice response system in a 1:1 ratio to receive bivalirudin (0·75 mg/kg intravenous bolus followed by 1·75 mg/kg per h infusion; n=1800) or heparin plus a GPI (control; 60 IU/kg intravenous bolus followed by boluses with target activated clotting time 200–250 s; n=1802). The two primary trial endpoints were major bleeding and net adverse clinical events (NACE; consisting of major bleeding or composite major adverse cardiovascular events [MACE; death, reinfarction, target vessel revascularisation for ischaemia, or stroke]). This prespecifi ed analysis reports data for the 1-year follow-up. Analysis was by intention to treat. Patients with missing data were censored at the time of withdrawal from the study or at last follow-up. This trial is registered with ClinicalTrials.gov, number NCT00433966.

Findings 1-year data were available for 1696 patients in the bivalirudin group and 1702 patients in the control group. Reasons for participant dropout were loss to follow-up and withdrawal of consent. The rate of NACE was lower in the bivalirudin group than in the control group (15·6% vs 18·3%, hazard ratio [HR] 0·83, 95% CI 0·71–0·97, p=0·022), as a result of a lower rate of major bleeding in the bivalirudin group (5·8% vs 9·2%, HR 0·61, 0·48–0·78, p<0·0001). The rate of MACE was similar between groups (11·9% vs 11·9%, HR 1·00, 0·82–1·21, p=0·98). The 1-year rates of cardiac mortality (2·1% vs 3·8%, HR 0·57, 0·38–0·84, p=0·005) and all-cause mortality (3·5% vs 4·8%, HR 0·71, 0·51–0·98, p=0·037) were lower in the bivalirudin group than in the control group.

Interpretation In patients with STEMI undergoing primary PCI, anticoagulation with bivalirudin reduced the rates of net adverse clinical events and major bleeding at 1 year compared with treatment with heparin plus a GPI. This fi nding has important clinical implications for the selection of optimum treatment strategies for patients with STEMI.

Funding Cardiovascular Research Foundation, with unrestricted grant support from Boston Scientifi c Corporation and The Medicines Company.

IntroductionGlycoprotein IIb/IIIa inhibitors (GPIs) are frequently used in the USA and Europe in patients with ST-segment elevation myocardial infarction (STEMI) who are undergoing primary percutaneous coronary intervention (PCI) to reduce ischaemic complications.1–3 These agents, however, increase the rates of haemorrhagic events and of thrombocytopenia,4–7 both of which have been strongly associated with early and late mortality.8–12 The direct thrombin inhibitor bivalirudin, when used instead of heparin plus a GPI during PCI, reduces the rates of major and minor bleeding and thrombocytopenia across a broad range of patients with coronary artery disease.13–17 In the large-

scale prospective HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial, patients with high-risk STEMI undergoing primary PCI were randomly assigned to receive bivalirudin alone or heparin plus a GPI. Patients in the bivalirudin group had lower 30-day rates of major bleeding and thrombocytopenia, similar rates of composite ischaemic events, and improved survival compared with those in the heparin plus GPI group.17 Whether the benefi cial eff ects of bivalirudin seen at 30 days are preserved, increased, or diminished at 1 year is not known. We report the prespecifi ed analysis of 1-year outcomes from the HORIZONS-AMI trial.

Lancet 2009; 374: 1149–59

Published OnlineAugust 30, 2009DOI:10.1016/S0140-6736(09)61484-7

See Comment page 1125

*Members listed at end of paper

Columbia University Medical Center/New York-Presbyterian Hospital and the Cardiovascular Research Foundation, New York, NY, USA (R Mehran MD, A J Lansky MD, E Nikolsky MD, L Gambone, L Vandertie, H Parise ScD, G D Dangas MD, Prof G W Stone MD); Charité Campus Benjamin Franklin, Berlin, Germany (B Witzenbichler MD); Ospedali Riuniti di Bergamo, Bergamo, Italy (G Guagliumi MD); Silesian Center for Heart Disease, Lodz, Poland (J Z Peruga MD); LeBauer Cardiovascular Research Foundation and Moses Cone Hospital, Greensboro, NC, USA (B R Brodie MD); Jagiellonian University, Krakow, Poland (D Dudek MD); Rabin Medical Center, Petach Tikva, Israel (R Kornowski MD); Universitätsklinikum Schleswig-Holstein, Lübeck, Germany (F Hartmann MD); Mayo Clinic, Rochester, MN, USA (Prof B J Gersh MB); London School of Hygiene and Tropical Medicine, London, UK (Prof S J Pocock PhD); and New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA (S C Wong MD)

Correspondence to: Dr Roxana Mehran, Columbia University Medical Center, 161 Fort Washington Avenue (5th Floor), New York, NY 10032, [email protected]

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1150 www.thelancet.com Vol 374 October 3, 2009

MethodsParticipantsThe study design of the HORIZONS-AMI trial has been reported elsewhere.17,18 Briefl y, consecutive patients aged 18 years or older were eligible for enrolment if they presented within 12 h after the onset of symptoms with STEMI of 1 mm or more in two or more contiguous leads, new left bundle branch block, or true posterior myocardial infarction. Exclusion criteria included contraindications to any of the study drugs; previous administration of fi brinolytic therapy, bivalirudin, GPI, low-molecular-weight heparin, or fondaparinux for the present admission (previous unfractionated heparin was allowed); current use of coumadin; history of bleeding diathesis, conditions predisposing to haemorrhagic risk or refusal to receive blood transfusions; stroke or transient ischaemic attack within 6 months or any permanent neurological defi cit; recent or known platelet count less than 100 000 cells per μL or haemoglobin concentration less than 100 g/L; planned elective surgical procedure that would necessitate thienopyridine interruption within 6 months of enrolment; coronary stent implantation within 30 days; and non-cardiac

comorbid conditions with life expectancy less than 1 year or that might result in protocol non-compliance. The study was approved by the institutional review board or ethics committee at each participating centre, and all patients provided written informed consent.

Randomisation and maskingPatients were randomly assigned in the emergency department, in an open-label manner, to receive bivalirudin (Angiomax, The Medicines Company, Parsippany, NJ, USA) alone (intervention) or un-fractionated heparin plus a GPI (control) in a 1:1 ratio. The randomisation codes were generated by use of a dynamic randomisation algorithm implemented by a computerised interactive voice response system (E-trials, Morrisville, NC, USA). The trial was single blinded for the pharmacology and stent arms. The following groups were masked to antithrombotic treatment and stent assignments: programmers, data analysis staff , statisticians, all core laboratories (angiographic, intra-vascular ultrasound, and electrocardiographic), and an independent clinical events committee.

ProceduresIn patients assigned to intervention, bivalirudin was given as an intravenous bolus of 0·75 mg/kg followed by an infusion of 1·75 mg/kg per h. In controls, heparin was given as an intravenous bolus of 60 IU/kg, with subsequent boluses titrated by nomogram to a target activated clotting time of 200–250 s. Both bivalirudin and heparin were discontinued, as specifi ed by the protocol, at the completion of angiography or PCI but could be continued at low doses if required at the discretion of the operator. A GPI was given before PCI to all patients in the control group, but was to be given only to those patients in the bivalirudin group who had refractory no refl ow or giant thrombus after PCI. Abciximab (0·25 mg/kg bolus plus 0·125 μg/kg per min infusion, maximum 10 μg/min) or double bolus eptifi batide (180 μg/kg bolus plus 2·0 μg/kg per min infusion, with a second bolus given in 10 min) were allowed as the GPI at the discretion of the investigator, adjusted for renal impairment as appropriate according to the US Food and Drug Administration label, and continued for 12 h (abciximab) or 12–18 h (eptifi batide).

Aspirin (324 mg chewed or 500 mg intravenous) was given in the emergency room, after which 300–325 mg was given orally every day during the hospital stay, and 75–81 mg every day thereafter indefi nitely. A loading dose of clopidogrel (either 300 mg or 600 mg at the discretion of the investigator) was given before insertion of the catheter, followed by 75 mg orally every day for at least 6 months; dual antiplatelet therapy was recommended for 1 year or longer. A dynamic (minimisation) allocation scheme was used to balance randomisation for administration of prerandomisation heparin, administration of clopidogrel 300 mg or

First randomisation (1:1)1800 assigned to bivalirudin

Second randomisation (3:1)1146 assigned to paclitaxel-eluting stent

381 assigned to bare-metal stent273 no second randomisation

3602 enrolled and randomised

29 not true myocardial infarction*

75 dropped out22 withdrew53 lost to follow-up

72 dropped out26 withdrew46 lost to follow-up

28 not true myocardial infarction*

13 dropped out 7 withdrew 6 lost to follow-up

11 dropped out 4 withdrew 7 lost to follow-up

1787 (99·3%) followed-up at day 30

1771 eligible for follow-up at 1 year

1696 (95·8%) followed-up at 1 year

1800 included in ITT analysis

1774 eligible for follow-up at 1 year

1702 (95·9%) followed-up at 1 year

1802 included in ITT analysis

1791 (99·4%) followed-up at day 30

First randomisation (1:1)1802 assigned to control

Second randomisation (3:1)1111 assigned to paclitaxel-eluting stent368 assigned to bare-metal stent323 no second randomisation

Figure 1: Trial profi leITT=intention-to-treat. We did not gather accurate data on the number of patients screened for eligibility. *Patients with normal serial cardiac biomarkers and no signifi cant angiographic coronary artery disease, in whom only 30-day clinical follow-up was required (see text for details).

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600 mg or ticlopidine 500 mg before insertion of the catheter, planned administration of abciximab versus eptifi batide if randomised to control, and US or non-US study site.

Emergency coronary angiography with left ventriculography was done after randomisation, followed by triage, at the discretion of the physician, to PCI, coronary artery bypass graft surgery (CABG), or medical management, as previously described.18 After angiography, patients undergoing PCI were randomly assigned again, in 3:1 ratio, to either paclitaxel-eluting stents (TAXUS Express, Boston Scientifi c, Natick, MA, USA) or otherwise identical uncoated bare-metal stents (Express, Boston

Scientifi c). However, in patients who had all measured cardiac biomarkers within normal limits and no coronary artery lesions with a diameter stenosis of more than 50% (by core laboratory determination), only 30-day follow-up was required.

Two primary endpoints were prespecifi ed: major bleeding (not related to coronary artery bypass graft surgery), and net adverse clinical events (NACE; major bleeding or composite major adverse cardiovascular events [MACE; consisting of death, reinfarction, target vessel revascularisation for ischaemia, or stroke]). This prespecifi ed analysis reports these endpoint measures and their components at 1 year of follow-up. Major bleeding was defi ned as intracranial or intraocular haemorrhage, bleeding at the access site with a haematoma that was 5 cm or larger in diameter or that required intervention, a decrease in haemoglobin concentration of 40 g/L or more without an overt source of bleeding or 30 g/L or more with an overt source of bleeding, reoperation for bleeding, or blood product transfusion.

Control group (n=1802)

Bivalirudin group (n=1800)

Age (years, median [range]) 60·7 (21·6–91·6) 59·8 (26·0–92·3)

Male 1372/1802 (76%) 1388/1800 (77%)

Diabetes 312/1800 (17%) 281/1799 (16%)

Insulin dependent 87/1800 (5%) 72/1799 (4%)

Hypertension 993/1800 (55%) 931/1799 (52%)

Hyperlipidaemia 769/1800 (43%) 781/1799 (43%)

Current smoker 807/1792 (45%) 845/1789 (47%)

Previous myocardial infarction

205/1800 (11%) 187/1799 (10%)

Previous PCI 198/1800 (11%) 188/1798 (10%)

Previous CABG 46/1800 (3%) 59/1799 (3%)

Creatinine clearance <60 mL/min

292/1676 (17%) 262/1661 (16%)

Baseline anaemia* 182/1693 (11%) 177/1696 (10%)

Time from symptom onset to hospital arrival, (h, median [IQR])

2·1 (1·3–3·9) 2·2 (1·3–4·0)

Time from symptom onset to fi rst balloon infl ation (h, median [IQR])

3·7 (2·7–5·6) 3·7 (2·7–5·6)

Killip class II–IV 152/1797 (8%) 153/1795 (8%)

Index procedure

PCI 1666/1802 (93%) 1679/1800 (93%)

Stent implanted 1591/1802 (88%) 1611/1800 (90%)

Stent implanted (in patients undergoing PCI)

1591/1666 (95%) 1611/1679 (96%)

Aspirin use

At discharge 1697/1748 (97%) 1729/1762(98%)

At 30 days† 1634/1690 (97%) 1648/1694 (97%)

At 6 months† 1570/1631 (96%) 1592/1642 (97%)

At 1 year† 1537/1606 (96%) 1562/1625 (96%)

Thienopyridine use

At discharge 1621/1748 (93%) 1652/1764 (94%)

At 30 days† 1573/1695 (93%) 1585/1698 (93%)

At 6 months† 1425/1634 (87%) 1443/1644 (88%)

At 1 year† 1059/1609 (66%) 1105/1626 (68%)

Data are n/N (%), unless otherwise indicated. PCI=percutaneous coronary intervention. CABG=cornonary artery bypass graft surgery. *Haematocrit value at initial presentation less than 39% for men and less than 36% for women. †Taken on more than 50% of days since the last visit.

Table 1: Baseline characteristics of study participants



p value (log-rank)

NACE 325 (18·3%) 275 (15·6%) 0·022

MACE 210 (11·9%) 209 (11·9%) 0·98

Mortality, all-cause 86 (4·8%) 61 (3·5%) 0·037

Cardiac 67 (3·8%) 38 (2·1%) 0·005

Non-cardiac 19 (1·1%) 23 (1·3%) 0·56

Reinfarction 76 (4·4%) 62 (3·6%) 0·22

Q wave 36 (2·1%) 38 (2·2%) 0·81

Non-Q wave 45 (2·7%) 24 (1·4%) 0·009

Death or reinfarction 151 (8·5%) 118 (6·7%) 0·041

Ischaemic TVR 100 (5·9%) 123 (7·2%) 0·12

Ischaemic TLR 77 (4·5%) 103 (6·0%) 0·051

Ischaemic remote TVR 34 (2·0%) 39 (2·3%) 0·60

Stroke 20 (1·2%) 20 (1·1%) 0·99

Stent thrombosis (defi nite or probable) 50 (3·2%) 57 (3·6%) 0·53

Defi nite 37 (2·4%) 52 (3·3%) 0·12

Probable 13 (0·8%) 5 (0·3%) 0·055

Bleeding endpoints

Protocol major, non-CABG 165 (9·2%) 103 (5·8%) <0·0001

Protocol major, all 210 (11·8%) 137 (7·7%) <0·0001

Blood transfusion 71 (4·0%) 47 (2·7%) 0·024

TIMI (major or minor) 182 (10·2%) 115 (6·5%) <0·0001

TIMI major 98 (5·5%) 63 (3·6%) 0·005

TIMI minor 85 (4·8%) 54 (3·0%) 0·008

GUSTO (life-threatening, severe, or moderate) 107 (6·0%) 77 (4·4%) 0·023

GUSTO life-threatening or severe 12 (0·7%) 14 (0·8%) 0·70

GUSTO moderate 96 (5·4 %) 65 (3·7%) 0·013

Data are number of events (rate [%], expressed as Kaplan-Meier estimate). No adjustment for alpha has been done. NACE=net adverse clinical events. MACE=major adverse cardiovascular events. TVR=target vessel revascularisation. TLR=target lesion revascularisation. CABG=coronary artery bypass graft surgery. TIMI=thrombolysis in myocardial infarction. GUSTO=Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. Stent thrombosis was defi ned according to the Academic Research Consortium classifi cation,19 and determined only in patients in whom stents were implanted (1591 patients assigned to control and 1611 patients assigned to bivalirudin).

Table 2: Adverse events at 1 year

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Bleeding was also assessed and adjudicated by the thrombolysis in myocardial infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen

Activator for Occluded Coronary Arteries (GUSTO) scales. The component defi nitions of MACE have been defi ned previously.17,18 Cardiac mortality was defi ned as death from myocardial infarction, cardiac perforation or pericardial tamponade, arrhythmia or conduction abnormality, stroke, procedural complications, or any death in which a cardiac cause could not be excluded. Non-cardiac death was defi ned as a death not caused by cardiac causes, including bleeding-related death. Stent thrombosis was defi ned as the defi nite or probable occurrence of a stent-related thrombotic event according to the Academic Research Consortium classifi cation.19 An independent clinical events committee, which was masked to treatment assignment, adjudicated all primary endpoint and stent thrombosis events using original source documents throughout the 1-year follow-up period.

Statistical analysisThe study was powered for two independent randomisations. For the fi rst (pharmacology) random-isation described in this report, the primary NACE endpoint and the primary safety endpoint of major bleeding (not related to CABG) were evaluated with sequential non-inferiority followed by superiority tests. We initially calculated that randomisation of 3332 patients in a 1:1 ratio aff orded 80% power to show non-inferiority for death, reinfarction, ischaemic target vessel revascularisation, stroke, or major bleeding at 30 days, assuming rates of 12% in both groups and delta 3·2%, using a one-sided binomial test of proportions, α=0·025. Additionally, randomisation of 3332 patients aff orded 99% power to show non-inferiority for major bleeding at 30 days, assuming rates of 6% in the bivalirudin group and 9% in the unfractionated heparin plus GPI group, delta 1%, using a one-sided binomial test of proportions, α=0·025. This number was increased to 3400 patients to account for a 2% anticipated loss to follow-up at 30 days. During the course of the trial, it was necessary to increase the overall number of randomised patients to 3600 to enrol at least 3000 patients into the stent group of the study (power and endpoints described elsewhere).17

Analysis was by intention to treat (all patients were analysed according to treatment assignment, irrespective of treatment received). Secondary analyses included patients who were randomised again to paclitaxel-eluting stent or bare-metal stent. Categorical outcomes were compared by χ² or Fisher’s exact test. Continuous variables were compared by the Wilcoxon rank sum test. The primary event analyses were done with time-to-event data (for which patients were censored at the time of withdrawal from the study or at last follow-up), determined with Kaplan-Meier methods, and compared by use of the log-rank test. 1-year event rates are expressed

A

C

B

18·3%

15·6%

9·2%

5·8%

11·9%11·9%

HR 0·83 (95% CI 0·71–0·97)p=0·022

HR 0·61 (95% CI 0·48–0·78)p<0·0001

HR 1·00 (95% CI 0·82–1·21)p=0·98

Number at riskBivalirudin

Control18001802

22

20

18

16

14

NAC

E (%

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12

10

8

6

4

2

0

12

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1110

987

MAC

E (%

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6543210

15591498

15141458

14831426

13431281


Control18001802

16201543

16011531

15861514

14481368


Control18001802

16271619

15791573

15441540

13941380

0 1 2 3 4 5 6Time (months)

7 8 9 10 11 12

Bivalirudin (n=1800)Control (n=1802)

Figure 2: Time-to-event curves (primary and major secondary endpoints) for patients in bivalirudin and control groups up to 1 year(A) Net adverse clinical events (NACE; major bleeding or composite major adverse cardiovascular events [MACE]). (B) Major bleeding (not related to coronary artery bypass surgery). (C) MACE (death, reinfarction, target vessel revascularisation for ischaemia, or stroke). HR=hazard ratio.

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as Kaplan-Meier estimates. For the patients randomly assigned to paclitaxel-eluting stent or bare-metal stent, formal interaction testing was done to establish whether any interactions were present between stent type and assigned drug on the two primary endpoints and the major secondary endpoint at 1 year. Cox proportional hazards regression was done to adjust for baseline diff erences between the groups. An interaction with time was included in the model to assess proportionality. Also, interactions were examined for the primary and major secondary endpoints for the two groups of the factorial design. Statistical analysis was done with SAS version 9.1. This trial is registered with ClinicalTrials.gov, number NCT00433966.

Role of the funding sourceThe sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication.

ResultsBetween March 25, 2005, and May 7, 2007, 3602 eligible patients at 123 centres in 11 countries were randomly assigned to receive bivalirudin (n=1800) or control (n=1802). Figure 1 shows the trial profi le. Following emergency angiography, the primary management strategy was primary PCI in 92·9% of patients (bivalirudin, n=1679; control, n=1666), deferred PCI in 0·1% (bivalirudin, n=2; control, n=0), CABG in 1·7% (bivalirudin, n=24; control, n=38), and medical management in 5·4% (bivalirudin, n=95; control, n=98).

Table 1 shows the baseline characteristics of the study participants. The proportion of patients with hypertension was higher in the control group than in the bivalirudin group. Compliance with protocol-specifi ed study drugs was high in both groups (reported elsewhere17), as was antithrombotic drug use. 126 (7·5%) of 1675 patients in the bivalirudin group undergoing primary PCI received a GPI during the procedure for ischaemic or thrombotic complications. 1625 (97·7%) of 1664 patients in the control group undergoing primary PCI received a GPI, including abciximab (864 [52·0%]), eptifi batide (758 [45·6%]), and tirofi ban (three [0·2%]; data were missing for four patients in the bivalirudin group and two in the control group).

Compared with patients with 1-year follow-up (n=3398), patients without 1-year follow-up (n=204) were younger (median 60·2 years [range 21·6–91·6] vs 59·0 years [28·8–92·3], p=0·015), less frequently had hyperlipid ae-mia (44% vs 33%, p=0·003), and less frequently had Killip class II or more on admission (9% vs 4%, p=0·019). Additionally, patients without 1-year follow-up received a clopidogrel loading dose of 300 mg less frequently (35% vs 28%, p=0·038) and a loading dose of 600 mg more frequently (65% vs 72%, p=0·050).

At 1 year, patients assigned to bivalirudin had a lower rate of NACE than did controls (15·6% vs 18·3%, HR 0·83, 95% CI 0·71–0·97, p=0·022), as a result of a lower rate of major bleeding in the bivalirudin group (5·8% vs 9·2%, HR 0·61, 0·48–0·78, p<0·0001), with a similar rate of MACE between groups (11·9% vs 11·9%, HR 1·00, 0·82–1·21, p=0·98; table 2 and fi gure 2). The lower rate of protocol-defi ned major bleeding in the bivalirudin group than in controls was caused by fewer patients with haematomas 5 cm or larger (1·2% vs control 2·6%, p=0·003) or a decrease in haemoglobin concentration of 40 g/L or more without an overt source of bleeding (2·8% vs 4·7%, p=0·002), and fewer patients who had blood transfusions (2·7% vs 4·0%, p=0·02). Additionally, the rate of a decrease in haemoglobin 30 g/L or more with an overt source of bleeding was lower in the bivalirudin group than in the control group, although the diff erence was not signifi cant (1·7% vs 2·5%, p=0·08). Rates of major and minor bleeding were also lower in patients assigned to bivalirudin than in controls according to TIMI and GUSTO criteria (table 2).

3006 patients were randomly assigned to paclitaxel-eluting stents or bare-metal stents (fi gure 1). Logistic regression showed no signifi cant interactions between assigned pharmacological intervention and assigned stent type on the relative rates of major bleeding, MACE, and NACE (table 3). There was also no interaction between stent type, assigned pharmacological intervention, and the occurrence of target lesion revascularisation for ischaemia at 1 year, as previously reported.20

At 1 year, the rate of cardiac mortality was lower in patients assigned to bivalirudin than in controls (2·1% vs 3·8%, HR 0·57, 0·38–0·84, p=0·005). All-cause mortality was also lower in the bivalirudin group than in the control group (3·5% vs 4·8%, HR 0·71, 0·51–0·98, p=0·037; table 2 and fi gure 3). The reduction in mortality at 1 year in the bivalirudin group was independent of stent type (p value for interaction 0·64; fi gure 3). Assignment to bivalirudin rather than to control remained an

Control group Bivalirudin group Hazard ratio (95% CI) pint

NACE (1 year)

Bare-metal stent 62/368 (16·8%) 57/381 (15·0%) 0·89 (0·64–1·24) 0·96

Paclitaxel-eluting stent 183/1111 (16·5%) 169/1146 (14·7%) 0·90 (0·74–1·08) ··

MACE (1 year)

Bare-metal stent 42/368 (11·4%) 49/381 (12·9%) 1·13 (0·77–1·66) 0·77


Major bleeding (1 year)

Bare-metal stent 28/368 (7·6%) 18/381 (4·7%) 0·66 (0·49–0·88) 0·88


Data are n/N (%). Major bleeding: not related to coronary artery bypass grafting. pint=p value for interaction. NACE=net adverse clinical events. MACE=major adverse cardiovascular events.

Table 3: Occurrence of the primary and major secondary endpoint events at 1 year by assigned pharmacological and stent groups

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independent predictor of survival in a prespecifi ed multivariable analysis that accounted for diff erences in baseline covariates (adjusted HR 0·68, 0·47–0·98, p=0·04). At 1 year, patients assigned to bivalirudin also had fewer events of non-Q-wave myocardial infarction, and had a lower rate of composite death or reinfarction than did controls (table 2). The rate of stent thrombosis was similar between study groups at 1 year (fi gure 3). The rate of target lesion revascularisation for ischaemia was higher in the bivalirudin group than in the control group, although the diff erence did not reach signifi cance (p=0·051). Rates of target vessel revascularisation, non-cardiac mortality, Q-wave myocardial infarction, and stroke did not diff er between the study groups (table 2).

Table 4 shows the adverse events between 30 days and 1 year. Cardiac death, reinfarction, and composite death or reinfarction occurred less frequently between 30 days and 1 year in patients assigned to bivalirudin than in patients assigned to control. Patients who had major bleeding had substantially higher 1-year rates of mortality (both cardiac and non-cardiac), reinfarction (both Q wave and non-Q wave), and stroke than did patients without major bleeding (table 5).

DiscussionIn this large-scale, prospective, randomised controlled trial of patients with STEMI undergoing primary PCI, procedural anticoagulation with the direct thrombin

Figure 3: Time-to-event curves (mortality and stent thrombosis outcomes) for patients in bivalirudin and control groups up to 1 year(A) All-cause mortality. (B) Cardiac and non-cardiac mortality. (C) All-cause mortality according to stent randomisation. (D) Defi nite or probable stent thrombosis. HR=hazard ratio. PES=paclitaxel-eluting stent. BMS=bare-metal stent.


Control

BivalirudinControl

6

4·8%

3·5%

5

All-c

ause

mor

talit

y (%

)

4

3

2

1

0

6

5

4·4%4·0%

3·6%




3·2%

HR 1·13 (95% CI 0·77–1·65) p=0·53

3·0%2·6%

All-c

ause

mor

talit

y (%

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talit

y (%

) 4

3

3·8%

CardiacHR 0·57 (95% CI 0·38–0·84) p=0·005

Non-cardiacp=0·56

2·1%

1·3%1·1%

2

1

0

5

Sten

t thr

ombo

sis (%

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4

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2

1

0

HR 0·71 (95% CI 0·51–0·98)p=0·037

18001802

17041678

16841663

16691646

15201486

Number at risk Number at riskControl/PES

Control/BMSBivalirudin/PES

Bivalirudin/BMS

Control/PES (n=1111)Control/BMS (n=368)Bivalirudin/BMS (n=1146)Bivalirudin/PES (n=381)

1111368

1146381

1064349

1116367

1058348

1103364

1049343

1098359

948313

1001335

16111591

15251495

15031475

14851457

13551315

18001802

17041678

16841663

16691646

15201486

A

C

B

D

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inhibitor bivalirudin reduced the rates of net adverse clinical events and major bleeding at 1 year compared with treatment with heparin plus routine use of a GPI. All-cause mortality and cardiac mortality at 1 year were also substantially reduced in patients assigned to bivalirudin compared with those assigned to heparin plus a GPI. Although the benefi ts of bivalirudin treatment were present at 30 days (including improved survival),

cardiac death, reinfarction, and composite death or reinfarction also occurred less frequently in the bivalirudin group than in the control group between 30 days and 1 year, contributing to the improved outcomes at 1 year. The diff erence in survival between study groups widened between 30 days and 1 year, with approximately 17 cardiac deaths and 13 all-cause deaths prevented per 1000 patients treated at 1 year (number needed to treat to prevent one cardiac death and one all-cause death approximately 59 and 77 patients, respectively). The benefi cial eff ects of bivalirudin were independent of stent type (paclitaxel-eluting stent or bare-metal stent).

The reduction in mortality in the bivalirudin group compared with the control group might be attributable to the prevention of iatrogenic haemorrhagic complications. The rates of all-cause mortality, cardiac mortality, and stroke were all fi ve times higher in patients who had major bleeding than in those who did not. Additionally, the rate of reinfarction in patients who had major bleeding was twice the rate in those without major bleeding. Previous trials have reported an independent association between major bleeding (with or without blood transfusions) and subsequent mortality in patients with acute coronary syndrome and in those undergoing PCI.8–12 Major bleeding was a more powerful predictor of mortality than periprocedural myocardial infarction after PCI in the double-blind, randomised REPLACE-2 trial.21 The reduction in bleeding with bivalirudin compared with heparin plus a GPI resulted in reduced mortality at 1 year after PCI in the fairly low-risk patients in that study; however, diff erences in mortality between groups did not reach signifi cance.14 Additionally, treatment with bivalirudin reduces the occurrence of severe thrombo cytopenia,13,17,22 the develop-ment of which has also been associated with mortality in patients with STEMI and after PCI.4–7 Moreover, reinfarction is one of the most common causes of death after primary PCI,23,24 and the reduction in non-Q-wave myocardial infarction with bivalirudin might have contributed to the survival advantage at 1 year in patients treated with this agent. Patients without STEMI who were assigned to treatment with fondaparinux had a lower rate of major bleeding at 9 days and improved 6-month survival compared with patients assigned to enoxaparin.25

The REPLACE-2,21 ACUITY,16 and HORIZONS-AMI17 trials assessed the use of bivalirudin compared with heparin plus a GPI in patients with stable and unstable ischaemic syndromes, unstable angina and non-STEMI, and STEMI, respectively. In a large meta-analysis (N=18 819) of these three randomised trials, mortality at



p value

NACE 131 (7·8%) 123 (7·3%) 0·52

MACE 123 (7·3%) 115 (6·8%) 0·52

Mortality, all-cause 30 (1·8%) 24 (1·4%) 0·38

Cardiac 15 (0·9%) 6 (0·4%) 0·046

Non cardiac 15 (0·9%) 18 (1·1%) 0·63

Reinfarction 46 (2·8%) 29 (1·7%) 0·041

Q wave 14 (0·8%) 13 (0·8%) 0·82

Non-Q wave 34 (2·1%) 16 (1·0%) 0·009

Death or reinfarction 74 (4·4%) 51 (3·0%) 0·031

Ischaemic TVR 71 (4·3%) 79 (4·7%) 0·57

Ischaemic TLR 48 (2·9%) 61 (3·6%) 0·24

Ischaemic remote TVR 28 (1·7%) 33 (2·0%) 0·56

Stroke 8 (0·5%) 7 (0·4%) 0·77

Stent thrombosis (defi nite or probable) 17 (1·1%) 15 (1·0%) 0·66

Defi nite 15 (1·0%) 14 (0·9%) 0·79

Probable 2 (0·1%) 1 (0·1%) 0·55

Bleeding endpoints

Protocol major, non-CABG 10 (0·6%) 13 (0·8%) 0·55

Protocol major, all 14 (0·8%) 17 (1·0%) 0·62

Blood transfusion 7 (0·4%) 10 (0·6%) 0·49

TIMI major or minor 9 (0·5%) 12 (0·7%) 0·53

TIMI major 5 (0·3%) 7 (0·4%) 0·58

TIMI minor 4 (0·2%) 5 (0·3%) 0·75

GUSTO (life-threatening, severe, or moderate) 7 (0·4%) 14 (0·8%) 0·13

GUSTO life-threatening or severe 1 (0·1%) 5 (0·3%) 0·11

GUSTO moderate 6 (0·4%) 11 (0·7%) 0·24

Data are number of events (rate [%], expressed as Kaplan-Meier estimate). No adjustment for alpha has been done. NACE=net adverse clinical events. MACE=major adverse cardiovascular events. TVR=target vessel revascularisation. TLR=target lesion revascularisation. CABG=coronary artery bypass graft surgery. TIMI=thrombolysis in myocardial infarction. GUSTO=Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. Stent thrombosis was defi ned according to the Academic Research Consortium classifi cation,19 and determined only in patients in whom stents were implanted (1591 patients assigned to control and 1611 patients assigned to bivalirudin).

Table 4: Adverse events between 30 days and 1 year

Patients with major bleeding (n=268)

Patients without major bleeding (n=3334)

p value

Mortality, all-cause 44 (16·6%) 103 (3·1%) <0·0001

Cardiac 29 (11·0%) 76 (2·3%) <0·0001

Non-cardiac 15 (6·3%) 27 (0·9%) <0·0001

Reinfarction 20 (8·0%) 118 (3·7%) 0·0003

Q wave 12 (4·7%) 62 (1·9%) 0·002

Non-Q wave 9 (3·7%) 60 (1·9%) 0·036

Stroke 11 (4·5%) 29 (0·9%) <0·0001

Ischaemic TVR 32 (13·1%) 191 (6·0%) <0·0001

MACE 87 (32·8%) 332 (10·2%) <0·0001

Data are number of events (rate [%], expressed as Kaplan-Meier estimate). TVR=target vessel revascularisation. MACE=major adverse cardiovascular events.

Table 5: Major adverse cardiovascular events within 1 year according to the occurrence of major bleeding not related to coronary artery bypass graft surgery

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30 days and at 1 year was examined by use of a fi xed eff ects Mantel-Haenszel model. Bivalirudin was associated with a non-signifi cant 9% reduction in 30-day mortality and a signifi cant 15% reduction in 1-year mortality in invasively managed patients across a wide cross-section of clinical acuity.26

We have previously reported that stent thrombosis within the fi rst 24 h occurred more frequently in patients assigned to bivalirudin than in those assigned to heparin plus a GPI.17 However, between 24 h and 1 year, stent thrombosis was more frequent in the heparin plus GPI group than in the bivalirudin group (46 vs 36 stent thrombosis events, respectively). As a result, at the end of the 1-year follow-up, the rate of stent thrombosis was similar in the two groups (3·1% vs 3·5%, respectively, p=0·53). Moreover, the hazard ratio for death within the fi rst month was greater after major bleeding than after reinfarction or stent thrombosis,17 emphasising the importance of selecting an anticoagulation regimen that will reduce the rate of haemorrhagic complications to a minimum (most of which are iatrogenic, occurring as a result of intense anticoagulation after femoral artery access) as well as reducing the rate of recurrent ischaemia.

Although the mechanisms through which bleeding complications either cause or are associated with mortality are unknown, they are likely to be multifactorial. Mechanisms might include the following: the rare occurrence of truly life-threatening or fatal bleeding, such as intracranial haemorrhage; hypotension, ischaemia, or arrhythmias as a result of volume depletion and decreased oxygen delivery (which might be especially relevant in vulnerable STEMI patients); procedures needed to treat major haemorrhage, which could themselves be complicated; systemic infl ammation, vasoconstriction, and apoptosis from red blood cell transfusions;27–31 discontinuation of medications such as antiplatelet agents, β blockers, and angiotensin-converting enzyme inhibitors to treat bleeding and hypotension;32–35 and the presence of other unmeasured confounders associated with bleeding (although the concordant reduction in both bleeding and mortality with bivalirudin, without any other obvious mechanism to explain this eff ect, suggests that the relation is at least in part causal).

Fewer patients in the bivalirudin group died between 30 days and 1 year of follow-up than did patients in the control group. Although this fi nding might be a result of chance, a similar observation was reported in the REPLACE-2 and ACUITY trials.13,14,16 Moreover, in the ACUITY trial,36 the occurrence of bleeding within 30 days was found to be an independent determinate of subsequent mortality occurring between 30 days and 1 year. These results, now replicated in three consecutive prospective trials in more than 23 000 patients, suggest that the prevention of early bleeding complications reduces the occurrence of both late and early mortality. Early bleeding might lead to late mortality through a

variety of mechanisms, including longlasting adverse eff ects from transfusions and the discontinuation of antiplatelet agents, β blockers, and angiotensin-converting enzyme inhibitors, which might not be restarted.37 Moreover, the fi nding of fewer episodes of late reinfarction in patients in the bivalirudin group than in controls has not previously been described, and requires confi rmation and further investigation into the possible mechanisms of this eff ect.

Although HORIZONS-AMI is one of the largest completed prospective, randomised trials in patients with STEMI undergoing primary PCI, this study has several limitations. The logistic complexities of the trial necessitated an open-label design. Potential bias was mitigated by masking laboratory technicians and clinical event adjudication committees to treatment assignment. Moreover, bias introduced by the open-label study design would be expected to diminish over time. In this regard, the early and even greater late reduction in mortality caused by bivalirudin—an endpoint less subject to ascertainment bias than other MACE components—provides reassurance that the results are reliable. Additionally, the mechanistic underpinnings for the observed reduction in mortality in the bivalirudin group (reduced bleeding, transfusions, and thrombocytopenia), together with the consistency of this fi nding in previous trials, further substantiate the validity of our results. Although the incremental reduction in rates of death and reinfarction between 30 days and 1 year in patients assigned to bivalirudin is encouraging, longer-term follow-up is needed to establish the robustness of this fi nding.

Thus, this 1-year analysis of the HORIZONS-AMI trial shows that in high-risk patients with STEMI undergoing primary PCI, procedural anticoagulation with bivalirudin alone seemed to reduce haemorrhagic complications, late reinfarction, and early and late cardiac and all-cause mortality compared with unfractionated heparin plus the routine use of a GPI.

ContributorsRM, GWS, and EN formed the core writing team for the report. GWS,

RM, BJG, and SJP contributed to study conception and design. GWS,

RM, BCJ, SJP, SCW, JZP, GG, BW, AJL, BRB, DD, EN, RK, FH, LG, LV,

HP, and GDD participated in acquisition of data, statistical analyses, or

interpretation of data. All authors reviewed and commented on a draft

of the report and gave fi nal approval to submit for publication.

The HORIZONS-AMI Trial InvestigatorsThe following investigators and institutions participated in the

HORIZONS-AMI trial:

Executive Committee: USA G W Stone (principal investigator and chair;

Columbia University Medical Center and the Cardiovascular Research

Foundation, New York, NY); B R Brodie (LeBauer Cardiovascular

Research Foundation and Moses Cone Hospital, Greensboro, NC);

D A Cox (Mid Carolina Cardiology, Charlotte, NC); C L Grines (William

Beaumont Hospital, Royal Oak, MI); B D Rutherford (St Luke’s Hospital,

Kansas City, MO).

Pharmacology Committee: USA D Bhatt (Cleveland Clinic Foundation,

Cleveland, OH); G Dangas (Columbia University Medical Center and

the Cardiovascular Research Foundation, New York, NY); F Feit

(New York University, New York, NY); M Ohman (Duke University

Medical Center, Durham, NC).

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European Steering Committee: Italy A Colombo (Colombus Hospital,

Milan); G Guagliumi (Ospedali Riuniti di Bergamo, Bergamo); E Garcia

(Hospital Universitario Gregorio Maranon, Madrid). Germany E Grube

(Heart Center Siegburg, Siegburg); A Kastrati (Deutsches Herzzentrum,

Technische Universität, Munich). Netherlands H Bonnier (Catharina

Hospital, Eindhoven); P Serruys (Thoraxcenter, Rotterdam);

H Suryapranata (Hospital De Weezenlanden, Zwolle).

Country Leaders: Argentina J Belardi, L Grinfeld. Austria K Huber.

Denmark L Rasmussen. Germany E Grube, A Kastrati. Israel Y Almagor.

Italy A Colombo, G Guagliumi. Netherlands H Bonnier, H Suryapranata.

Norway D Nilsen. Poland D Dudek. Spain E Garcia. Sweden

G Olivecrona. UK A Banning.

Clinical Endpoints Committee: Cardiovascular Research Foundation Data

Center, New York, NY, USA (S C Wong; chair).

Field Offi cers: M Farkouh (chair), M Attubato, G Dangas, F Feit,

R Mehran.

Site Management and Data Monitoring Europe: D-Target. South America

Tango. USA J Tyson and Associates.

Data Management: E-trials, Morrisville, NC, USA, D Winsted (manager).

Data Coordination and Analysis: Cardiovascular Research Foundation

Data Center, New York, NY, USA, R Mehran (director), I Bihl

(operations), H Parise (statistics).

Data Safety and Monitoring Board: UK S J Pocock (London School of

Hygiene and Tropical Medicine, London). USA B J Gersh (chair; Mayo

Clinic, Rochester, MN); D Faxon (Brigham and Women’s Hospital,

Boston, MA); S King (Fuqua Heart Center, Atlanta, GA); D O Williams

(Rhode Island Hospital, Providence, RI).

Qualitative and Quantitative Coronary Angiographic Core Laboratory Analysis: Cardiovascular Research Foundation, New York, NY, USA,

A J Lansky (director), E Cristea (operations).

Qualitative and Quantitative Electrocardiographic Core Laboratory Analysis: Cardiovascular Research Foundation, New York, NY, USA, J Reiff el

(director).

Intravascular Ultrasound Core Laboratory Analysis: Cardiovascular

Research Foundation, New York, NY, USA, G Mintz (director).

Biomarker Substudy Core Laboratory: BioSite, San Diego, CA, USA.

Participating countries (total enrolment) and hospitals (principal investigator): Argentina (207) Fundación Favaloro, Capital Federal, Buenos

Aires (Oscar A Mendiz); Hospital Alemán, Buenos Aires (Jose Amadeo

Alvarez); Hospital Britanico, Buenos Aires (Jose Alvarez); Hospital

Espanol de La Plata, La Plata, Buenos Aires (Diego David Grinfeld);

Hospital Gral de Agudos (Cosme Argerich); Capital Federal, Buenos

Aires (Miguel Angel Riccitelli); Hospital Italiano de Buenos Aires,

Capital Federal, Buenos Aries (Daniel Berrocal); Instituto Cardiovascular

de Buenos Aires, Capital Federal, Buenos Aires (Jorge Belardi); Instituto

Cardiovascular de Rosario, Rosario, Santa Fe (Anibal Agustin Damonte);

Sanatorio Argentino de la Plata, La Plata, Buenos Aires (Guillermo

Cugat); Sanatorio Otamendi, Buenos Aires (A Rodriguez); Sanatorio

Modelo Quilmes, Quilmes, Buenos Aires (Ernesto M Torresani);

Sanatorio Allende, Cordoba (Hugo F Londero). Austria (143) AKH Wien,

Vienna (Dietmar Glogar); Wilhelminen Hospital, Vienna (Kurt Huber);

Hanusch-Krankenhaus, Vienna (George Gaul); St Johanns-Spital,

Landesklinik fur Innere Medizin II und Kardiologie, Salzburg (Johann

Altenberger); Universitätsklinik für Innere Medizin II, Innsbruk

(Othmar Pachinger). Germany (791): Asklepios Klinik Langer, Langen

(Hans-Georg Olbrich); Charité Campus Benjamin Franklin, Berlin

(Bernhard Witzenbichler); Charité/CVK, Berlin (Martin Moeckel);

Charité Universitätsmedizin Campus Mitte, Berlin (Wolfgang Rutsch);

Heart Center Siegburg, Siegburg (Eberhard Grube); Herzzentrum

Segeberger Kliniken GmbH, Bad Segeberg (Gert Richardt); Klinik

Innere Medizin I Friedrich-Schiller-University Jena, Jena (Klaus Pethig);

Klinikum Dachau d Amperkliniken AG Kardiologie, Dachau

(Martin Desaga); Klinikum Darmstadt Medizinisch Klinik I, Darmstadt

(Gerald Werner); Klinikum Coburg, Coburg (Johannes Brachmann);

Universitätsklinikum Heidelberg/Kardiologie, Heidelberg

(Helmut Kuecherer); University Hospital Aachen, Aachen

(Rainer Hoff mann); Universitätsklinikum Schleswig-Holstein, Lübeck

(Franz Hartmann); University Hospital Eppendorf Department of

Cardiology, Hamburg (Stefan Willems); University of Ulm Head

Interventional Cardiology Leiter Forschungsgruppe Interventionelle,

Ulm (Jochen Wöhrle); Silesian Medical Academy, Munich

(Adnan Kastrati). Israel (526) Assaf Harofe Medical Center

Catheterization Laboratory, Cardiology Department, Zrifi n

(Ricardo Krakover); Bnei Zion Medical Center, Haifa (Uri Rosenschein);

Carmel Medical Center, Haifa (Basil S Lewis); Hadassah Hebrew

University Medical Center-Jerusalem, Jerusalem (Morris Mosseri);

Rabin Medical Center-Belinson Campus (Ran Petach-Tikva Kornowski);

Rambam Medical Center-Department of Radiology, Haifa

(Luis Gruberg); Shaare Zedek Medical Center-Jerusalem, Jerusalem

(Yaron Almagor); Sheba Medical Center-Tel-Hashomer Heart Institute,

Ramat-Gan (Victor Guetta); Sourasky Medical Center-Tel Aviv Head Dept

of Cardiology, Tel Aviv (Ariel Finkelstein); Wolfson Holon, Holon

(Yoseph Rozenman). Italy (219) Ospedali Riuniti di Bergamo,

Bergamo (Giulio Guagliumi); Ospedale San Raff aele Milano U O di

Emodinamica e di Cardiologia Interventistic, Milan (Antonio Colombo).

Netherlands (133) Catharina Hospital Dept R&D, Eindhoven

(Hans Bonnier); Hospital De Weezenlanden, Zwolle

(Harry Suryapranata) Medisch Centrum Rijnmond-Zuid, Rotterdam

(Peter Smits). Norway (79) Haukeland University Hospital, Department

of Heart Disease, Bergen (Jan Erik Nordrehaug); Stavanger University

Hospital, Rogaland (Dennis Nilsen). Poland (582) Institute of Cardiology-

Haemodynamics Dept, Warsawa, Witold Ruzyllo (Adam Witkowski);

Jagiellonian University, Krakow (Dariusz Dudek); Medical University of

Gdask, Gdask (Andrzej Rynkiewicz); Silesian Center for Heart Disease,

Lodz (Jan Z Peruga); Silesian Medical Academy, Katowice

(Andrzej Ochala); Szpital Jana PawlaII-Dept of Hemo and Angio,

Krakow (Krzysztof Zmudka); Klinika Kardiologii Inwazyjnej CSK

MSWiA, Warsaw (Robert Gil). Spain (6) Hospital General Universitario

de Alicante, Alicante (Pascual Bordes). UK (102) John Radcliff e Hospital,

Oxford (Adrian Banning); Leeds Teaching Hospital NHS Trust, Leeds

(Daniel Blackman); Manchester Heart Centre, Manchester

(Magdi El-Omar); Royal Sussex County Hospital, Brighton, East Sussex

(Adam De Belder); Northern General Hospital, Sheffi eld (Ever Grech);

Wythenshawe Hospital, Manchester (Bernard Prendergast). USA (814)

Alexian Brothers Medical Center, Elk Grove Village, IL (Sarah Johnson);

Anderson Area Medical Center, Anderson, SC (Brent McLaurin);

Bakersfi eld Memorial Hospital, Bakersfi eld, CA (Tommy Lee);

Beth Israel Deaconess Medical, Cardiovascular Division, Boston, MA

(Duane S Pinto); Bethesda North Hospital, Montgomery, OH (Joe Choo);

Brotman Medical Center, Culver City, CA (Ronald Karlsberg); Cannon

Cardiac & Vascular Research Ctr of Northern Michigan, Petoskey, MI

(Louis A Cannon); Cardiovascular Medicine Associates, Middleburg

Heights, OH (Trilok Sharma); Christiana Care Health Services, Newark,

DE (James Ritter); Columbia University, New York, NY (Leroy Rabbani);

Deaconess Medical Center, Spokane, WA (Pierre P Leimgruber); Doctors

Hospital at Renaissance, Edinburg, TX (Ofsman Quintana); Doylestown

Hospital, Doylestown, PA (Joseph McGarvey Jr); El Paso Heart Clinic,

El Paso, TX (Oscar Aguilar); Emory University School of Medicine

Emory Crawford, Atlanta, GA (Henry Liberman); Geisinger Medical

Center, Danville, PA (Jim Blankenship); Good Samaritan Hospital,

Cincinnati, OH (Ali Razavi); Harrisburg Hospital/Pinnacle Health,

Harrisburg, PA (Rajesh Dave); Heart Care Midwest/St Francis Medical

Center, Peoria, IL (John Rashid); Heart Care Research Foundation,

Merrionette Park, IL (Joseph F Stella); Innovis Health, South Fargo, ND

(Edmund Finkinski); Jersey Shore University Medical Center, Neptune,

NJ (Matthew Bach); LeBauer CV Research Foundation/Moses Cone

Hospital, Greensboro, NC (Bruce Brodie); Maine Medical Center,

Portland, ME (Mirle A Kellett Jr); McAllen Heart Hospital, McAllen, TX

(Ofsman Quintana); MedStar Research Institute, Cardiovascular

Research, Washington, DC (Ron Waksman); Mid Carolina Cardiology/

Presbyterian Hospital, Charlotte, NC (Robert Iwaoka); Mid Ohio Heart

Clinic Inc, Mansfi eld, OH (Gregory M Eaton); Northwest Indiana

Cardiovascular Physicians, Valparaiso, IN (Keith Atassi); NYU Medical

Center, New York, NY (Michael Attubato); Oklahoma Heart Institute,

Tulsa, OK (Raj Chandwaney); Providence Heart and Vascular Institute,

Portland, OR (Bradley Evans); Providence Memorial Hospital, El Paso,

TX (Oscar Aguilar); Research Associates of Jackson, Jackson, TN

(Henry Lui); Scottdale Healthcare-Osborn, Scottsdale, AZ, (David Rizik);

Scottsdale Healthcare-Shea, Scottsdale, AZ (David Rizik); Sentara

Virginia Beach General Hospital, Virginia Beach, VA (John Griffi n);

Somerset Medical Center, Bridgewater, NJ (Jason O Hall); South

Carolina Heart Center, Columbia, SC (Michael C Foster); Sparks

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Regional Medical Center, Fort Smith, AR (Jorge A Hernandez);

St James Hospital & Health Centers Chicago Heights, Chicago Heights,

IL (Noel Camba); St John Hospital, Detroit, MI (Thomas LaLonde);

St Josephs Regional Medical Center, Paterson, NJ (Mahesh Bikkina);

St Luke’s Hospital MAHI, Kansas City, MO (Barry Rutherford); Suncoast

Cardiovascular Research, Saint Petersburg, FL (Vibhuti Singh);

Tennessee Cardiovascular Research Institute, Nashville, TN

(John McPherson); Cardiovascular Specialists/Cape Cod Hospital,

Hyannis, MA (Richard B Zelman); Care Group Hospital: Heart Center of

Indiana Clinical Laboratory/St Vincent’s Hospital, Indianapolis, Indiana

(James B Hermiller); Charlton Memorial Hospital, Fall River, MA

(Kenneth S Korr); Heart Center/Cardiovascular Associates, PC,

Kingsport, TN (Christopher Metzger); Miriam Hospital, Providence, RI

(Paul Gordon); Valley Hospital, Ridgewood, NJ (Cary Hirsch); Western

Pennsylvania Hospital, Pittsburgh, PA (Venkatraman Srinivasan); Valley

Baptist Medical Center, Brownsville, TX (Kalim Habet); Washington

Adventist Hospital, Takoma Park, MD (Mark A Turco); Watson Clinic

Center for Research Inc, Lakeland, FL (Douglas Ebersole); William

Beaumont Hospital, Royal Oak, MI (Cindy L Grines).

Confl icts of interestRM has received lecture fees from Boston Scientifi c and The Medicines

Company. AJL has received grant support from The Medicines Company

and Boston Scientifi c. GG has received consulting fees from or has

served on advisory boards for Abbott Vascular and Boston Scientifi c and

has received grant support from Medtronic and Boston Scientifi c.

DD has received lecture fees from Nycomed. BJG has received

consulting fees from or has served on advisory boards for AstraZeneca,

Bristol-Myers Squibb, Abbott Laboratories, and Boston Scientifi c, and

has equity interest in CV Therapeutics. SJP has received consulting fees

from and has served on an advisory board for The Medicines Company.

EN, LG, LV, and HP are employed by the Cardiovascular Research

Foundation. GWS has received grant support from Boston Scientifi c,

The Medicines Company, and Abbott Vascular. The other authors declare

that they have no confl icts of interest.

AcknowledgmentsThe trial was sponsored by the Cardiovascular Research Foundation,

with unrestricted grant support from Boston Scientifi c Corporation and

The Medicines Company.

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Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction...

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