Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI):

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www.thelancet.com Vol 377 June 25, 2011 2193

Lancet 2011; 377: 2193–204

Published OnlineJune 13, 2011DOI:10.1016/S0140-6736(11)60764-2

See Comment page 2154

*For members of the HORIZONS-AMI Trial Investigators see Articles Lancet 2009; 374: 1149–59

New York-Presbyterian Hospital, Columbia University Medical Center and The Cardiovascular Research Foundation, New York, NY, USA (Prof G W Stone MD, M Fahy MSc, H Parise ScD); Charité Campus Benjamin Franklin, Berlin, Germany (B Witzenbichler MD); Ospedali Riuniti di Bergamo, Bergamo, Italy (G Guagliumi MD); Silesian Centre 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 Centre, Petach Tikva, Israel (R Kornowski MD); Universitätsklinikum Schleswig-Holstein, Lübeck, Germany (F Hartmann MD); Mayo Clinic, Rochester, MN, USA (Prof B J Gersh DPhil); London School of Hygiene and Tropical Medicine, London, UK (Prof S J Pocock PhD); Mount Sinai Medical Center and the Cardiovascular Research Foundation, New York, NY, USA (Prof G Dangas MD, Prof R Mehran MD); and New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA (S C Wong MD)

Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): fi nal 3-year results from a multicentre, randomised controlled trialGregg W Stone, Bernhard Witzenbichler, Giulio Guagliumi, Jan Z Peruga, Bruce R Brodie, Dariusz Dudek, Ran Kornowski, Franz Hartmann, Bernard J Gersh, Stuart J Pocock, George Dangas, S Chiu Wong, Martin Fahy, Helen Parise, Roxana Mehran, on behalf of the HORIZONS-AMI Trial Investigators*

SummaryBackground Primary results of the HORIZONS-AMI trial have been previously reported. In this fi nal report, we aimed to assess 3-year outcomes.

Methods HORIZONS-AMI was a prospective, open-label, randomised trial undertaken at 123 institutions in 11 countries. Patients aged 18 years or older were eligible for enrolment if they had ST-segment elevation myocardial infarction (STEMI), presented within 12 h after onset of symptoms, and were undergoing primary percutaneous coronary intervention. By use of a computerised interactive voice response system, we randomly allocated patients 1:1 to receive bivalirudin or heparin plus a glycoprotein IIb/IIIa inhibitor (GPI; pharmacological randomisation; stratifi ed by previous and expected drug use and study site) and, if eligible, randomly allocated 3:1 to receive a paclitaxel-eluting stent or a bare metal stent (stent randomisation; stratifi ed by pharmacological group assignment, diabetes mellitus status, lesion length, and study site). We produced Kaplan-Meier estimates of major adverse cardiovascular events at 3 years by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00433966.

Findings Compared with 1802 patients allocated to receive heparin plus a GPI, 1800 patients allocated to bivalirudin monotherapy had lower rates of all-cause mortality (5·9% vs 7·7%, diff erence –1·9% [–3·5 to –0·2], HR 0·75 [0·58–0·97]; p=0·03), cardiac mortality (2·9% vs 5·1%, –2·2% [–3·5 to –0·9], 0·56 [0·40–0·80]; p=0·001), reinfarction (6·2% vs 8·2%, –1·9% [–3·7 to –0·2], 0·76 [0·59–0·99]; p=0·04), and major bleeding not related to bypass graft surgery (6·9% vs 10·5%, –3·6% [–5·5 to –1·7], 0·64 [0·51–0·80]; p=0·0001) at 3 years, with no signifi cant diff erences in ischaemia-driven target vessel revascularisation, stent thrombosis, or composite adverse events. Compared with 749 patients who received a bare-metal stent, 2257 patients who received a paclitaxel-eluting stent had lower rates of ischaemia-driven target lesion revascularisation (9·4% vs 15·1%, –5·7% [–8·6 to –2·7], 0·60 [0·48–0·76]; p<0·0001) after 3 years, with no signifi cant diff erences in the rates of death, reinfarction, stroke or stent thrombosis. Stent thrombosis was high (≥4·5%) in both groups.

Interpretation The eff ectiveness and safety of bivalirudin monotherapy and paclitaxel-eluting stenting are sustained at 3 years for patients with STEMI undergoing primary percutaneous coronary intervention.

Funding Boston Scientifi c and The Medicines Company.

IntroductionAcute myocardial infarction occurs in about 1·5 million people in the USA and Europe every year, and is the leading cause of death in men and women.1,2 Primary percutaneous coronary intervention is the preferred reperfusion technique for patients with evolving ST-segment elevation myocardial infarction (STEMI), and reduces the rate of death, reinfarction, and stroke compared with fi brinolytic therapy.3–5 Therefore, outcomes for patients with STEMI might be improved by selection of the optimal antithrombotic regimen and stent type for intervention. Bleeding complications and transfusions have emerged as major independent predictors of subsequent mortality in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention,6–8 and drugs that

minimise bleeding while eff ectively suppressing ischaemia might improve early and midterm survival.9,10 Whether these benefi ts are sustained is unknown. Moreover, in patients with STEMI undergoing primary percutaneous coronary intervention, bare-metal stents reduce recurrent ischaemia, restenosis, and the need for repeat revascularisation procedures compared with balloon angioplasty alone.11,12 Whether drug-eluting stents can be safely implanted in patients with a STEMI without an excessive risk of stent thrombosis, and whether they are more eff ective than bare-metal stents is controversial.

The prospective, factorial, randomised HORIZONS-AMI trial was an investigator-sponsored study designed to establish the optimum antithrombotic regimen and stent type for patients with STEMI undergoing

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2194 www.thelancet.com Vol 377 June 25, 2011

Correspondence to:Dr Gregg W Stone, Columbia

University Medical Center, The Cardiovascular Research

Foundation, 111 East 59th Street, 11th Floor,

New York, NY 10022, [email protected]

percutaneous coronary intervention. Findings from this trial showed that a primary percutaneous coronary intervention with the direct thrombin inhibitor bivalirudin reduced the 30-day rates of major bleeding, cardiac mortality, and all-cause mortality, and enhanced event-free survival compared with an intervention with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (GPI);13 these results were sustained to 1 year.14 The trial also showed that placement of a paclitaxel-eluting stent rather than a bare-metal stent reduced the 1-year rates of recurrent ischaemia necessitating repeat target lesion revascularisation procedures, with non-signifi cantly diff erent rates of stent thrombosis and other adverse ischaemic events;15 these results were sustained to 2 years.16 Whether the benefi ts noted with bivalirudin and paclitaxel-eluting stents in this trial are sustained with longer-term follow-up has not been reported. In this fi nal main report from the HORIZONS-AMI trial, we aimed to establish the 3-year outcomes for patients randomly allocated to the diff erent pharmacological and stent-type groups.

MethodsStudy design and participantsThe study design of the HORIZONS-AMI trial has been reported elsewhere.16 Briefl y, HORIZONS-AMI was a prospective, open-label, factorial, randomised, multicentre trial comparing bivalirudin monotherapy with heparin plus a GPI and paclitaxel-eluting stents with bare-metal stents in patients with STEMI undergoing a primary percutaneous coronary intervention management strategy. Consecutive patients aged 18 years or older with a symptom duration of 20–720 min and ST-segment elevation of 1 mm or more in two or more contiguous leads, new left bundle branch block, or true posterior myocardial infarction were eligible for enrolment. The main exclusion criteria were contraindications to study drugs; previous administration of thrombolytic therapy, bivalirudin, GPI, low-molecular-weight heparin, or fondaparinux for the present admission (previous unfractionated heparin was allowed); present use of warfarin; history of bleeding diathesis, coagulopathy, heparin-induced thrombo cytopenia, intracerebral mass, aneurysm, arteriovenous malformation, or previous haemorrhagic stroke; stroke or transient ischaemic attack within 6 months or any permanent neurological defi cit; refusal to receive blood transfusions; gastrointestinal or genitourinary bleeding within 2 months; major surgery within 6 weeks; known platelet count of fewer than 100 000 cells per mm³ or haemoglobin of lower than 100 g/L; planned elective surgical procedure that would necessitate interruption of thienopyridines during the fi rst 6 months after enrolment; coronary stent implantation within 30 days; and non-cardiac comorbid conditions with life expectancy of less than 1 year or that might interfere with protocol compliance. The study was approved by the institutional review board or ethics

committee at every participating centre, and all patients provided signed informed consent.

Randomisation and maskingPatients were randomly assigned in a one-to-one and open-label manner to receive bivalirudin (Angiomax, The Medicines Company, Parsippany, NJ, USA) alone or unfractionated heparin (control group). Patients in the heparin group were routinely given a GPI before percutaneous coronary intervention, but such inhibitors were only given to patients in the bivalirudin group who had refractory no refl ow or giant thrombus after percutaneous coronary intervention. We allocated patients through use of a computerised interactive voice response system (E-trials, Morrisville, NC, USA), stratifi ed by administration of prerandomisation heparin, administration of clopidogrel 300 mg or 600 mg or ticlopidine 500 mg before catheterisation, planned administration of abciximab versus eptifi batide if randomised to the control group, and US study site versus non-US study site. Following coronary angiography the patient received percutaneous coronary intervention, coronary artery bypass graft (CABG) surgery, or medical management at the doctor’s discretion, as previously described.17 For eligible patients undergoing percutaneous coronary intervention, after patency was restored in the infarct vessel, we undertook a second telephone-based randomisation in a 3:1 ratio to allocate patients to receive a TAXUS Express paclitaxel-eluting stent (Boston Scientifi c, Natick, MA, USA) or otherwise identical uncoated Express bare-metal stent (Boston Scientifi c), stratifi ed by the fi rst randomisation (pharmacological assignment), diabetes mellitus status, lesion length of more than 26 mm (which required overlapping stents), and US study site versus non-US study site.

ProceduresPatients in the intervention group were fi rst given an intravenous bivalirudin bolus of 0·75 mg/kg and infusion of 1·75 mg/kg per h. Controls were given an intravenous heparin bolus of 60 IU/kg with subsequent boluses targeted to an activated clotting time of 200–250 s. Bivalirudin and heparin were discontinued per protocol after completion of angiography or percutaneous coronary intervention but could be continued at low doses if clinically indicated. Either abciximab or double-bolus eptifi batide were permitted at the investigator’s discretion, adjusted for renal impairment, and continued for 12 h (for abciximab) or 12–18 h (for eptifi batide). Aspirin 324 mg (oral) or 500 mg (intravenous) was given in the emergency room, followed by 300–325 mg orally per day during the hospital stay and 75–81 mg per day indefi nitely thereafter. Patients were given a clopidogrel loading dose of either 300 mg or 600 mg at the investigator’s discretion before catheterisation, followed-up by 75 mg orally per day for at least 6 months (1 year or more was recommended).

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Clinical follow-up was done at 30 days, 6 months, 1 year, 2 years, and 3 years. Routine angiographic follow-up at 13 months was planned for 1800 consecutively randomised patients in the stenting group in whom acute stent implantation was successful (diameter stenosis <10% with Thrombolysis In Myocardial Infarction [TIMI]-3 fl ow with US National Heart, Lung and Blood Institute type A or no peristent dissection) and in whom neither stent thrombosis occurred nor bypass graft surgery was undertaken within 30 days, as previously described.15 Clinical follow-up was planned to 5 years, but after patients reached 3 years’ follow-up, suffi cient funding was not available to continue to 5 years. Therefore, this report is the fi nal follow-up from the HORIZONS-AMI trial.

Prespecifi ed endpoints for the pharmacological randomisation at 3 years included death, reinfarction, ischaemia-driven target vessel revascularisation, stroke, and the composite of these events (major adverse

cardiac events); protocol-defi ned major bleeding not related to CABG; and the composite of major adverse cardiac events or major bleeding not related to CABG (net adverse clinical events). Prespecifi ed endpoints for the stent randomisation at 3 years included ischaemia-driven target lesion revascularisation and the composite and component measures of safety major adverse cardiac events (death, reinfarction, stroke, or stent thrombosis). Protocol-defi ned major bleeding was defi ned as intracranial or intraocular haemorrhage; access site bleeding with a haematoma diameter of 5 cm or more or requiring intervention; haemoglobin decrease of 40 g/L or more without an overt bleeding source or 30 g/L or more with an overt bleeding source; reoperation for bleeding; or blood product transfusion. Bleeding was also adjudicated according to the TIMI and Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO) scales, and defi nite or probable stent thrombosis according to the Academic

3602 patients enrolled and included in pharmacological randomisation

1802 randomly allocated to receive heparinplus a glycoprotein IIb/IIIa inhibitor

1802 with emergent angiography 1591 primary PCI with stent

75 primary PCI without stent0 deferred PCI

38 primary CABG98 medical therapy

1800 with emergent angiography 1611 primary PCI with stent

68 primary PCI without stent2 deferred PCI

24 primary CABG95 medical therapy

1800 randomly allocated to receive bivalirudin monotherapy

28 excluded as not truemyocardial infarction

1774 eligible for 3-year analysis

26 withdrew46 lost to follow-up


1628 available for3-year follow-up


23 withdrew60 lost to

follow-up


follow-up


follow-up


follow-up





2103 available for 3-year follow-up


2257 randomly allocatedto receive apaclitaxel-elutingstent

2103 available for 3-year follow-up


749 randomly allocatedto receive a bare- metal stent

3006 eligible for stent randomisation

29 excluded as not truemyocardial infarction

1771 eligible for 3-year analysis

Figure 1: Study profi le3545 (98%) of 3602 enrolled patients had a true myocardial infarction and were eligible for long-term follow-up. 3-year follow-up was completed in 3262 (92%) of 3545 patients with true myocardial infarction who were randomly allocated to drug treatment groups and 2790 (93%) of 3006 patients who were randomly allocated to receive stents.

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Research Consortium (ARC) criteria.17 The com-prehensive defi nitions for the other endpoints have been previously detailed.13,15,17 An independent clinical events committee (Cardiovascular Research Foundation,

NY, USA) that was masked to treatment assign-ment adjudicated all adverse ischaemic and bleeding events from original source documents and proced ural angiograms.

Pharmacological randomisation (n=3602) Stent randomisation (n=3006)

Heparin plus a GPI(n=1802)

Bivalirudin monotherapy (n=1800)

Paclitaxel-eluting stent (n=2257)

Bare-metal stent(n=749)

Baseline characteristics

Age (years) 60·7 (52·9–70·1) 59·8 (51·9–69·5) 59·9 (52·4–69·4) 59·3 (51·8–69·2)

Male 1372/1802 (76%) 1388/1800 (77%) 1738/2257 (77%) 569/749 (76%)

Diabetes 312/1800 (17%) 281/1799 (16%) 364/2256 (16%) 114/749 (15%)

Insulin requiring 87/1800 (5%) 72/1799 (4%) 98/2256 (4%) 31/749 (4%)

Hypertension 993/1800 (55%) 931/1799 (52%)* 1155/2256 (51%) 389/749 (52%)

Hyperlipidaemia 769/1800 (43%) 781/1798 (43%) 953/2256 (42%) 308/749 (41%)

Current smoker 807/1792 (45%) 845/1789 (47%) 1041/2246 (46%) 388/748 (52%)†

Previous myocardial infarction 205/1800 (11%) 187/1799 (10%) 206/2256 (9%) 82/749 (11%)

Symptom onset to balloon (h) 3·7 (2·7–5·6) 3·7 (2·7–5·6) 3·7 (2·7–5·55) 3·8 (2·7–5·8)

Body-mass index (kg/m²) 27·0 (24·6–30·1) 27·1 (24·5–30·2) 27·1 (24·6–30·1) 27·0 (24·6–30·4)

Killip class 2–4 152/1797 (8%) 153/1795 (9%) 199/2254 (9%) 60/748 (8%)

Baseline laboratory results

Renal insuffi ciency‡ 292/1676 (17%) 262/1661 (16%) 328/2102 (16%) 107/696 (15%)

Anaemia§ 181/1692 (11%) 175/1693 (10%) 235/2130 (11%) 54/715 (8%)†

Thrombocytopenia¶ 80/1733 (5%) 64/1729 (4%) 91/2186 (4%) 30/733 (4%)

Drug use at discharge

β blockers 1575/1747 (90%) 1598/1763 (91%) 2048/2213 (93%) 680/738 (92%)

ACEI or ARB 1437/1749 (82%) 1402/1763 (80%) 1840/2212 (83%) 614/738 (83%)

Statins 1641/1749 (94%) 1652/1763 (94%) 2123/2212 (96%) 708/738 (96%)

Aspirin use||

At discharge 1697/1748 (97%) 1729/1762 (98%) 2192/2213 (99%) 728/738 (99%)

At 30 days 1634/1690 (97%) 1648/1694 (97%) 2115/2148 (98%) 700/712 (98%)

At 6 months 1570/1631 (96%) 1591/1641 (97%) 2042/2096 (97%) 682/694 (98%)

At 1 year 1537/1606 (96%) 1562/1624 (96%) 2019/2080 (97%) 662/679 (97%)

At 2 years 1500/1572 (95%) 1545/1621 (95%) 1980/2057 (96%) 651/668 (97%)

At 3 years 1440/1532 (94%) 1488/1568 (95%) 1919/2006 (96%) 621/648 (96%)

Thienopyridine use||

At discharge 1621/1748 (93%) 1652/1764 (94%) 2200/2213 (99%) 730/738 (99%)

At 30 days 1573/1695 (93%) 1585/1698 (93%) 2127/2154 (99%) 696/712 (98%)

At 6 months 1424/1634 (87%) 1442/1644 (88%) 1987/2100 (95%) 607/694 (87%)**

At 1 year 1056/1609 (66%) 1100/1626 (68%) 1517/2084 (73%) 431/678 (64%)**

At 2 years 515/1577 (33%) 578/1626 (36%) 755/2060 (37%) 205/672 (31%)†

At 3 years 393/1535 (26%) 432/1574 (27%) 570/2011 (28%) 146/650 (22%)†

Aspirin and thienopyridine use||

At discharge 1595/1748 (91%) 1639/1762 (93%) 2180/2213 (98·5%) 723/738 (98%)

At 30 days 1540/1690 (91%) 1560/1694 (92%) 2094/2148 (97·5%) 685/712 (96%)

At 6 months 1390/1631 (85%) 1416/1641 (86%) 1946/2096 (93%) 601/694 (87%)**

At 1 year 1036/1606 (65%) 1078/1624 (66%) 1488/2080 (72%) 427/678 (63%)**

At 2 years 492/1571 (31%) 556/1621 (34%) 724/2056 (35%) 201/668 (30%)*

At 3 years 365/1531 (24%) 406/1568 (26%) 533/2005 (27%) 139/648 (21%)†

Data are median (IQR) or number/number of patients tested (%). p values were non-signifi cant unless otherwise stated. ACEI=angiotensin-converting-enzyme inhibitor. GPI=glycoprotein IIb/IIIa inhibitor. ARB=angiotensin receptor blocker. *p<0·05. †p<0·01. ‡Baseline creatinine clearance calculated with the Cockcroft-Gault equation18 of <60 mL/min. §Defi ned from World Health Organization criteria.19 of a baseline haematocrit of lower than 39% for men and lower than 36% for women. ¶Fewer than 150 000 cells per mm³ at baseline. ||Taken on more than 50% of days since the previous visit. **p<0·0001.

Table 1: Baseline characteristics of patients and drug use during the study

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Statistical analysisWe did all analyses by intention to treat. We compared categorical outcomes with the χ² test or Fisher’s exact test and continuous variables with the Wilcoxon rank sum test. We did the 3-year event analyses with time-to-event data (for which patients were censored at the time of withdrawal from the study or at last follow-up), which are shown as Kaplan-Meier plots and were compared with the log-rank test. We calculated hazard ratios (HRs) and 95% CI from a

Cox regression model that was unadjusted for other covariates. The study sample size was established to aff ord sequential non-inferiority and superiority testing for the primary endpoints for the pharmacological randomisation group at 30 days and the stent randomisation group at 1 year, as previously described.13,15,17 Specifi c hypothesis testing was not prespecifi ed for longer-term follow-up.

This study is registered with ClinicalTrials.gov, number NCT00433966.

Pharmacological randomisation (n=3602) Stent randomisation (n=3006)

Heparin plus a GPI (n=1802)

Bivalirudin monotherapy (n=1800)

p value Number needed to treat

Paclitaxel-eluting stent (n=2257)

Bare-metal stents (n=749)

p value Number needed to treat

Death (all-cause) 134 (7·7%) 102 (5·9%) 0·03 54 123 (5·6%) 48 (6·6%) 0·31 ··

Cardiac 88 (5·1%) 50 (2·9%) 0·001 45 71 (3·2%) 28 (3·8%) 0·42 ··

Non-cardiac 46 (2·8%) 52 (3·1%) 0·62 ·· 52 (2·4%) 20 (2·9%) 0·53 ··

<1 year 86 (4·8%) 61 (3·5%) 0·04 71 78 (3·5%) 26 (3·5%) 0·98 ··

1–3 years 48 (3·0%) 41 (2·5%) 0·38 ·· 45 (2·2%) 22 (3·2%) 0·11 ··

Reinfarction 135 (8·2%) 105 (6·2%) 0·04 52 150 (7·0%) 47 (6·6%) 0·77 ··

Q wave 63 (3·8%) 58 (3·4%) 0·61 ·· 75 (3·5%) 20 (2·8%) 0·39 ··

Non-Q wave 80 (4·9%) 52 (3·2%) 0·009 58 84 (4·0%) 27 (3·8%) 0·94 ··

Death or reinfarction 251 (14·5%) 196 (11·3%) 0·005 31 260 (11·8%) 84 (11·5%) 0·88 ··

Stroke 34 (2·0%) 29 (1·7%) 0·50 ·· 35 (1·6%) 10 (1·4%) 0·70 ··

Ischaemia-driven TVR 200 (12·1%) 239 (14·2%) 0·06 ·· 265 (12·4%) 125 (17·6%) 0·0003 19

Ischaemia-driven TLR 160 (9·7%) 190 (11·3%) 0·11 ·· 202 (9·4%) 107 (15·1%) <0·0001 18

Ischaemia-driven TVR, non-TLR 68 (4·1%) 86 (5·2%) 0·17 ·· 96 (4·5%) 37 (5·3%) 0·39 ··

Bleeding endpoints ··

Major bleeding (protocol), non-CABG 185 (10·5%) 121 (6·9%) 0·0001 28 188 (8·4%) 54 (7·3%) 0·34 ··

Major bleeding (protocol), including CABG 227 (12·8%) 156 (8·9%) <0·0001 25 205 (9·2%) 56 (7·6%) 0·19 ··

Blood transfusion 89 (5·1%) 60 (3·5%) 0·01 61 90 (4·1%) 28 (3·8%) 0·78 ··

TIMI major or minor 193 (10·9%) 124 (7·0%) <0·0001 26 164 (7·4%) 44 (6·0%) 0·20 ··

TIMI major 107 (6·1%) 72 (4·1%) 0·007 51 82 (3·7%) 23 (3·1%) 0·48 ··

TIMI minor 89 (5·0%) 57 (3·2%) 0·007 56 85 (3·8%) 23 (3·1%) 0·37 ··

GUSTO (any) 224 (12·7%) 154 (8·8%) 0·0001 26 202 (9·1%) 56 (7·6%) 0·23 ··

GUSTO life-threatening or severe 15 (0·9%) 17 (1·0%) 0·74 ·· 17 (0·8%) 3 (0·4%) 0·31 ··

GUSTO moderate 110 (6·3%) 81 (4·7%) 0·03 63 94 (4·3%) 28 (3·8%) 0·63 ··

GUSTO mild 110 (6·2%) 71 (4·0%) 0·003 ·· 106 (4·7%) 27 (3·6%) 0·21 ··

Stent thrombosis endpoints, ARC

Defi nite 62 (4·1%) 65 (4·2%) 0·87 ·· 91 (4·2%) 27 (3·7%) 0·61 ··

Probable 15 (1·0%) 5 (0·3%) 0·02 ·· 12 (0·6%) 4 (0·6%) 0·99 ··

Defi nite or probable 77 (5·1%) 70 (4·5%) 0·49 ·· 103 (4·8%) 31 (4·3%) 0·63 ··

Early (<30 days) 33 (2·1%) 42 (2·6%) 0·31 ·· 50 (2·3%) 20 (2·7%) 0·50 ··

Late (30 days to 1 year) 15 (1·0%) 13 (0·9%) 0·64 ·· 21 (1·0%) 5 (0·7%) 0·51 ··

Very late (>1 year) 31 (2·2%) 16 (1·1%) 0·02 ·· 36 (1·7%) 6 (0·9%) 0·12 ··

Composite endpoints

MACE* 377 (21·8%) 379 (21·9%) 0·95 ·· 441 (20·0%) 175 (24·0%) 0·02 ··

Safety MACE† 276 (16·0%) 232 (13·4%) 0·04 ·· 300 (13·6%) 94 (12·9%) 0·66 ··

NACE‡ 483 (27·6%) 444 (25·5%) 0·09 ·· 544 (24·5%) 205 (28·0%) 0·08 ··

Data are number of events (rate [%], expressed as Kaplan-Meier estimate). GPI=glycoprotein IIb/IIIa inhibitors. TVR=target vessel revascularisation. TLR=target lesion revascularisation. CABG=coronary artery bypass graft. TIMI=thrombolysis in myocardial infarction. GUSTO=global utilisation of streptokinase and tissue plasminogen activator for occluded coronary arteries. ARC=academic research consortium. MACE=major adverse cardiac events. *Composite of death, reinfarction, ischaemia-driven TVR, or stroke. †Composite of death, reinfarction, stroke, or stent thrombosis. ‡Composite of death, reinfarction, ischaemia-driven TVR, stroke, or major bleeding not related to CABG.

Table 2: Clinical outcomes at 3 years

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Role of the funding sourceThis study was sponsored by The Cardiovascular Research Foundation, under an Investigational Device Exemption from the US Food and Drug Administration, with funding from Boston Scientifi c (Natick, MA, USA) and The Medicines Company (Parsippany, NJ, USA). The sponsor designed and undertook the study, including site management, data collection and management, safety reporting, and data analysis and interpretation. The corresponding author had full access to all the data in the study, had fi nal responsibility for the decision to submit for publication, and takes responsibility for the integrity of the data and the accuracy of the data analysis. The funding sources did not participate in the decision to submit for publication, but did have the right to a non-binding review of the

manuscript. Approval of the funding sources was not required before submission.

ResultsBetween March 25, 2005, and May 7, 2007, we enrolled 3602 patients with STEMI undergoing primary percutaneous coronary intervention at 123 academic or community-based medical centres in 11 countries (fi gure 1). After emergent angiography, the primary management strategy was primary percutaneous coronary intervention in 3345 (93%) patients, deferred percutaneous coronary intervention in two (<1%) patients, primary CABG in 62 (2%) patients, and medical management in 193 (5%) patients. Primary stenting was undertaken in 3202 patients, of whom 3006 (93%) were randomly allocated to receive either a

Number at riskHeparin plus a GPI

Bivalirudin

0

18021800

3 6

15341601

9 12

15091572

15 18

14651544

21 24

14421523

27 30

14021485

33 36

9571039

0

2

4

6

8

10

12

Maj

or b

leed

ing

(%)

A

0

18021800

3 6

16701689

9 12

16431660

15 18

15931633

21 24

15681611

27 30

15251574

33 36

10431098

0

1

2

3

4

5

6

1

2

3

4

5

6

Card

iac m

orta

lity

(%)

B

Number at riskHeparin plus a GPI

Bivalirudin

0

18021800

3 6

16231643

9 12

15811605

15 18

15131560

21 24

14741536

27 30

14251494

33 36

9651032

Time (months)

0

1

2

3

4

5

6

7

8

9

10

Rein

farc

tion

(%)

C

0

15911611

3 6

14841509

9 12

14561478

15 18

14011453

21 24

13731432

27 30

13351398

33 36

906971

Time (months)

0

Sten

t thr

ombo

sis (%

)

D

Heparin plus a GPI (n=1802)Bivalirudin monotherapy (n=1800)




6·0%

9·4%

3·8%

3·5%

3·0%

2·1%

10·5%5·1%

5·1%

4·5%

2·9%

6·9%

HR at 3 years 0·64, 95% CI 0·51–0·80;p=0·0001

HR at 3 years 0·76, 95% CI 0·59–0·99;p=0·04

HR at 3 years 0·89, 95% CI 0·65–1·23;p=0·49

HR at 3 years 0·56, 95% CI 0·40–0·80;p=0·001

4·4%

8·2%

6·2%

3·6%

Figure 2: Time-to-event curves to 3 years for major bleeding not related to coronary artery bypass graft surgery (A), cardiac mortality (B), reinfarction (C), and defi nite or probable stent thrombosis (D) in patients randomised to heparin plus a GPI or bivalirudin monotherapyGPI=glycoprotein IIb/IIIa inhibitor. HR=hazard ratio. Vertical dotted line shows the 1-year event rate.

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paclitaxel-eluting stent (2257 [75%] patients) or a bare-metal stent (749 [25%]).

Table 1 shows baseline demographic, angiographic, and procedural characteristics of the population of patients.12,14 The median age was 60·2 years (IQR 52·4–69·9) and 2760 (77%) of 3602 enrolled patients were men. The infarct vessel was the left anterior descending artery in 1447 (41%) of 3559 patients undergoing percutaneous coronary intervention and the median door-to-balloon time was 99 min (IQR 73–135). Aspirin was taken by most patients throughout the duration of follow-up in all treatment groups. Thienopyridine use fell rapidly after 1 year, and was taken by only about 25% of patients at 3 years. Thienopyridine agents were prescribed equally in the bivalirudin and heparin plus GPI groups at all time points, but were used slightly more frequently in patients who were randomly assigned to paclitaxel-eluting stents compared with bare-metal stents from 6 months to 3 years (table 1).

Compared with heparin plus a GPI, at 3 years bivalirudin reduced rates of all-cause mortality (diff erence –1·9% [95% CI –0·2 to –3·5], HR 0·75 [95% CI 0·58–0·97]), cardiac mortality (–2·2% [–0·9 to –3·5], 0·56 [0·40–0·80]), reinfarction (–1·9% [–0·2 to –3·7], 0·76 [0·59–0·99]), and non-CABG-related major bleeding (–3·6% [–1·7 to –5·5], 0·64 [0·51–0·80]; table 2). Diff erences in major bleeding favoured

bivalirudin at 30 days, after which major bleeding events accrued at the same rate in both groups (fi gure 2). By contrast, the diff erences in cardiac mortality and reinfarction that favoured bivalirudin continued to increase throughout the 3 years of follow-up (fi gure 2). Between 30 days and 3 years, patients treated with bivalirudin had lower rates of cardiac mortality, reinfarction, and all-cause mortality or reinfarction than did those treated with heparin plus a GPI (fi gure 3).

The incidence of ischaemia-driven target vessel revascu-lari sation, stroke, and net adverse clinical events at 3 years did not diff er signifi cantly between patients treated with bivalirudin and those treated with heparin plus a GPI (table 2).

As previously reported,12 the rate of stent thrombosis within the fi rst 24 h was signifi cantly increased in patients treated with bivalirudin compared with heparin plus a GPI (1·5% vs 0·3%, HR 5·94 [95% CI 2·06–17·13]; p=0·0002). By contrast, between 24 h and 3 years, stent thrombosis occurred less frequently in patients treated with bivalirudin compared with heparin plus a GPI (3·1% vs 4·8%, 0·64 [0·44–0·92], p=0·01), such that by the end of the 3-year follow-up rates of stent thrombosis did not diff er between the two groups (4·5% vs 5·1%, 0·89 [0·65–1·23], p=0·49; table 2 and fi gure 2).

Use of paclitaxel-eluting stents signifi cantly reduced the 3-year rates of ischaemia-driven target lesion

Time (months)

0

1

2

3

4

5

Card

iac m

orta

lity

(%)

AHeparin plus a GPI (n=1802)Bivalirudin monotherapy (n=1800)

2·2%

6·5%

4·4%

1·1%

10·6%

7·8%

HR at day 30 0·62,95% CI 0·40–0·96;p=0·03

HR at day 30 1·07,95% CI 0·66–1·73;p=0·79

HR at 3 years 0·49,95% CI 0·28–0·86;p=0·01

HR at 3 years 0·66,95% CI 0·49–0·90;p=0·007

0 3 6 9 12 15 18 21 24 27 30 33 360

1

2

3

4

5

6

7

8

9

10

Rein

farc

tion

(%)

B

2·9%

1·8%

4·5%3·8%

0 3 6 9 12 15 18Time (months)

21 24 27 30 33 360

3

6

9

12

15

All-c

ause

mor

talit

y or r

einf

arct

ion

(%)

CHR at day 30 0·84,95% CI 0·61–1·16;p=0·30

HR at 3 years 0·72,95% CI 0·58–0·91;p=0·005

1·9%1·8%

Figure 3: Time-to-event curves with landmark analysis showing the 0–30 day and 30 day to 3 year rates for cardiac mortality (A), reinfarction (B), and all-cause mortality or reinfarction (C) in patients randomly allocated to receive heparin plus a GPI or bivalirudin monotherapyGPI=glycoprotein IIb/IIIa inhibitor. HR=hazard ratio.

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revascularisation by 5·7% (95% CI 2·7–8·6) compared with bare-metal stents (table 2 and fi gure 4). However, a marked increase in target lesion revascularisation procedures occurred in the 1006 patients who underwent protocol-specifi ed routine follow-up angiography at 13 months. For 2000 patients in whom 13-month routine protocol follow-up angiography was not undertaken, the absolute risk reduction in target lesion revascularisation at 3 years with a paclitaxel-eluting stent compared with a bare-metal stent was 4·6% (number needed to treat 22; fi gure 4).

Patients who received a paclitaxel-eluting stent did not have diff erent 3-year rates of safety major adverse cardiac events (HR 1·05, 95% CI 0·84–1·33), reinfarction (1·05, 0·76–1·46), or mortality (0·84, 0·60–1·17)

compared with those who received a bare-metal stent (table 2 and fi gure 4). Similarly, rates of stent thrombosis did not diff er between paclitaxel-eluting stents and bare-metal stents at the end of the 3-year follow-up (1·10, 0·74–1·65) or at any other time (table 2 and fi gure 4). Major bleeding unrelated to CABG surgery at 3 years occurred with much the same frequency (7·3–8·4%) in patients who received either stent type (HR 1·16, 95% CI 0·85–1·57; table 2).

DiscussionIn this fi nal 3-year report from the HORIZONS-AMI trial, we show that after primary percutaneous coronary intervention in patients with STEMI, initial treatment with bivalirudin alone results in a signifi cant reduction

Number at riskBare-metal stent

Paclitaxel-elutingstent

0

7492257

3 6

6762104

9 12

6552042

15 18

5981942

21 24

5871902

27 30

5671846

33 36

3721277

0

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Ischa

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et le

sion

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scul

arisa

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(%)

ABare-metal stent (n=749)Paclitaxel-eluting stent (n=2257)

0

5121488

3 6

4411336

9 12

4201275

15 18

3981217

21 24

3891193

27 30

3731151

33 36

241756

BBare-metal stent (n=512)Paclitaxel-eluting stent (n=1488)

Number at riskBare-metal stent

Paclitaxel-elutingstent

0

7492257

3 6

7132170

9 12

7022138

15 18

6832097

21 24

6742072

27 30

6572026

33 36

4431409

0

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All-c

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mor

talit

y (%

)

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6

Sten

t thr

ombo

sis (%

)

CBare-metal stent (n=744)Paclitaxel-eluting stent (n=2238)

0

7442238

3 6

6952108

9 12

6832066

15 18Time (months) Time (months)

6642013

21 24

6541980

27 30

6371932

33 36

4251341

DBare-metal stent (n=744)Paclitaxel-eluting stent (n=2238)

HR at 3 years 0·60,95% CI 0·48–0·76;p<0·0001

HR at 3 years 0·84,95% CI 0·60–1·17;p=0·31

HR at 3 years 1·10,95% CI 0·74–1·65;p=0·63

HR at 3 years 0·67,95% CI 0·51–0·90;p=0·006

15·1%

9·4%

6·6%

5·6%

7·4%

4·6%

14·8%

10·2%

4·8%

4·3%

10·6%

3·4%

3·1%

6·9%

3·5%

3·5%

Ischa

emic

targ

et le

sion

reva

scul

arisa

tion

(%)

Figure 4: Time-to-event curves to 3 years for ischaemia-driven target lesion revascularisation in all patients (A) and in those not undergoing routine 13-month angiographic follow-up (B), all-cause mortality (C), and defi nite or probable stent thrombosis (D) in patients randomly allocated to receive paclitaxel-eluting stents or bare-metal stentsHR=hazard ratio.

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in non-CABG-related major bleeding, reinfarction, and all-cause mortality compared with treatment with heparin plus a GPI; however, rates of stent thrombosis, target vessel revascularisation, stroke, and net adverse clinical events did not diff er between groups. The reported reduction in all-cause mortality equates to 18 lives saved per 1000 patients treated with bivalirudin compared with heparin plus a GPI. Furthermore, implantation of a paclitaxel-eluting stent can result in a signifi cant relative reduction in ischaemia-driven target lesion revascular isation at 3 years compared with implantation of a bare-metal stent (with no evidence of late catch-up), with rates of all-cause and cardiac mortality, reinfarction, and stent thrombosis that did not diff er between groups. The rate of stent thrombosis was notably high (nearly 5% at 3 years) with both stent types, however, with no plateau evident.

Previous studies have identifi ed major bleeding to be a powerful independent predictor of subsequent mortality in patients with acute coronary syndromes and after percutaneous coronary intervention (panel).6–8 In the OASIS-5 trial,9 patients with acute coronary syndromes who were managed conservatively with fondaparinux rather than enoxaparin had signifi cant reductions in early major bleeding and mortality, with similar rates of other adverse ischaemic events. In early reports from HORIZONS-AMI,13 bivalirudin mono therapy compared with heparin plus a GPI in patients with STEMI undergoing primary percutaneous coronary intervention markedly reduced major bleeding with identical rates of reinfarction at 30 days; the reduction in haemorrhagic complications directly correlated with reduced cardiac and all-cause mortality at 30 days. Consistent with these studies, a report10 from a prospective database in 127 185 patients undergoing percutaneous coronary intervention between 2003 and 2006 (representing about a sixth of all hospitals in the USA, with bivalirudin used in 26% of cases) documented a 33% reduction in transfusion requirements and a 49% reduction in adjusted mortality with bivalirudin (adjusted HR 0·51, 95% CI 0·44–0·60). Our report extends these fi ndings by showing that the absolute reduction in mortality with bivalirudin (especially cardiac mortality) in STEMI not only persists with long-term follow-up, but continues to increase with time, which is consistent with delayed benefi ts from prevention of major bleeding.

The mechanisms through which major bleeding might increase mortality in patients at high-risk with cardiovascular disease are numerous, including (uncommonly) fatal haemorrhage, such as intracranial bleeding; direct eff ects from volume depletion resulting in hypotension, ischaemia, arrhythmia, heart failure, and shock; transfusion of aged red-blood cells resulting in systemic vasoconstriction, infl ammation, and apoptosis, which are eff ects that might be extended;29–33 and the necessity after bleeding to discontinue drugs otherwise known to prolong survival (eg, antiplatelet agents,

β blockers, and angiotensin-converting-enzyme inhibitors), which often are never restarted because of fear of rebleeding or persistent clinical instability.34,35 Thus, although the present studies do not prove causality, the fi nding that treatment with drugs with no known benefi cial eff ects other than reduction of major bleeding resulted in robust improvements in survival9,14 suggests that prevention of major haemorrhagic complications might enhance cardiac and all-cause survival. For individual patients, both those at low risk and high risk should benefi t from the prevention of bleeding, so long as ischaemia is also eff ectively suppressed.36

During 3-year follow-up, a signifi cant reduction in the incidence of reinfarction and late stent thrombosis

Panel: Research in context

Systematic reviewWe searched the PubMed database for complete reports of studies in which patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention were prospectively randomised to use of diff erent procedural anticoagulation regimens or to drug-eluting stents or bare-metal stents, and in each case had follow-up for at least 3 years. We identifi ed two primary percutaneous coronary intervention studies of unfractionated heparin versus heparin plus a GPI with long-term follow-up: the ADMIRAL trial20 (3 years’ follow-up) and the ISAR-2 trial21 (5 years’ follow-up). We identifi ed seven primary percutaneous coronary intervention studies with long-term follow-up in which various drug-eluting stents were compared with a bare-metal stent: MULTISTRATEGY (5 years’ follow-up),22 PASSION (5 years’ follow-up),23 TYPHOON (4 years’ follow-up),24 SESAMI (3 years’ follow-up),25 PASEO (5 years’ follow-up),26 MISSION (3 years’ follow-up),27 and DEDICATION (3 years’ follow-up).28

InterpretationAlthough both the ISAR-2 and ADMIRAL trials showed early benefi ts of addition of abciximab to unfractionated heparin, rates of death or reinfarction between the groups at late follow-up did not diff er signifi cantly in either study. However, caution is required in interpretation of these results, because both studies were quite small by contemporary standards (401 patients in ISAR-2 and 300 in ADMIRAL). In our trial of 3602 patients, bivalirudin compared with heparin plus a GPI (either abciximab or eptifi batide) showed sustained benefi ts in terms of reduction of late mortality and reinfarction, thus showing a signifi cant advance compared with the previous standard of care.

The seven studies that assessed drug-eluting stents versus bare-metal stents were all modest in size (175–626 patients), and used diff erent drug-eluting stents (paclitaxel-eluting, sirolimus-eluting, and zotarolimus-eluting stents). Nonetheless, for the most part the results were consistent, suggesting a sustained reduction in either target lesion or target vessel revascularisation during 3–5 years’ follow-up, with non-signifi cantly diff erent rates of death, reinfarction, or stent thrombosis between groups. The one notable exception was the DEDICATION trial, in which cardiac mortality at 3 years was increased with a drug-eluting stent compared with a bare-metal stent, raising concerns about late safety with these stents. Our trial randomly allocated 3006 patients with STEMI to drug-eluting or bare-metal stents—thereby nearly doubling in size the previous collective experience—and after follow-up to 3 years showed a sustained benefi t of paclitaxel-eluting stents in terms of reduction of recurrent ischaemia necessitating repeat percutaneous coronary intervention or coronary artery bypass grafting (ie, less target lesion revascularisation), without signifi cant diff erences in rates of death, cardiac death, reinfarction and stent thrombosis between groups, thus suggesting long-term safety.

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emerged with bivalirudin compared with heparin plus a GPI, more than off setting the initial increase in stent thrombosis within the fi rst 24 h with bivalirudin that we reported previously.13 Our trial of bivalirudin with follow-up beyond 1 year, and as such the reduction in late reinfarction and stent thrombosis are new fi ndings; whether these fi ndings are reproducible and attributable to late benefi ts from reducing bleeding is unknown. Conversely, a non-signifi cant diff erence favouring heparin plus GPI compared with bivalirudin was present at 3 years for reduced target vessel revascular-isation. However, in 1203 stented patients undergoing routine angiographic follow-up in HORIZONS-AMI, restenosis occurred in 12·8% and 12·9% of lesions treated with bivalirudin and heparin plus GPI respectively (p=0·98),15 suggesting that this fi nding is probably attributable to chance.

For the 3006 patients who received stents, those randomly allocated to receive a paclitaxel-eluting stent had a 39% (95% CI 15–56) reduction in relative risk of ischaemia-driven target lesion revascularisation by 1 year and 40% (24–52) by 3 years compared with those given a bare-metal stent. However, routine angiographic follow-up, undertaken solely for protocol reasons in about a third of patients at 13 months, led to unplanned revascularisation procedures that potentially exaggerated the late absolute clinical benefi ts of paclitaxel-eluting stents.16 Thus, we believe that the 4·6% absolute reduction in ischaemia-driven target lesion revascularisation at 3 years in those patients not undergoing routine angiographic follow-up is a more accurate estimate of the true long-term clinical benefi t of paclitaxel-eluting stents compared with bare-metal stents in STEMI. The eff ect of routine angiographic follow-up in infl ating event rates probably explains why the absolute magnitude of benefi t of drug-eluting stents compared with bare-metal stents in STEMI was greater in previous smaller trials in which protocol-specifi c routine angiographic follow-up was even more frequent than it was in our study.37

Previous randomised studies in which patients were followed-up beyond 1 year have reported confl icting data for the late safety profi le of drug-eluting stents in STEMI.22–28 However, all of these studies were underpowered to examine low frequency adverse event rates, so increasing the likelihood for false-negative (or false-positive) fi ndings. No signifi cant diff erences in cardiac death or stent thrombosis were noted between paclitaxel-eluting stents and bare-metal stents at 5 years in 619 patients in the PASSION trial,23 or between sirolimus-eluting stents and bare-metal stents at 4 years in 501 patients in the TYPHOON trial.24 By contrast, cardiac mortality was increased at 3 years in patients assigned to one of several drug-eluting stents rather than bare-metal stents in the 626 patients in the DEDICATION trial,28 despite non-signifi cant diff erences in stent thrombosis and total mortality, and a robust reduction in late target lesion revascularisation with

drug-eluting stents. It is therefore reassuring that after 3 years’ follow-up in our study, paclitaxel-eluting stents did not have signifi cantly higher rates of safety major adverse cardiac events,15 death, reinfarction, or stent thrombosis than did bare-metal stents, despite the infrequent use of dual antiplatelet therapy beyond 1 year. However, between 1 and 3 years, a non-signifi cant increase in very late stent thrombosis was noted between stent types. Although our trial was not adequately powered to exclude a small increase in very late stent thrombosis with paclitaxel-eluting stents compared with bare-metal stents, concerns about the clinical signifi cance of this fi nding might be tempered by the non-signifi cant decrease in mortality during the same 1–3 years.

Thus, paclitaxel-eluting stents can be safely used in STEMI to reduce clinical and angiographic restenosis (so long as antiplatelet therapy discontinuation before 1 year is unlikely).35,38 In this regard, the cost-to-benefi t ratio of drug-eluting stents should be considered, although patients at high risk for restenosis after bare-metal stenting might be identifi ed in whom drug-eluting-stent use in STEMI is likely to be most benefi cial.16 Of importance, however, is that stent thrombosis with both stent types was documented to occur in nearly 5% of patients at 3-year follow-up (more than 80% of which was ARC defi nite), irrespective of stent type, and probably due to arrested vascular healing after device placement in a ruptured fi broatheroma.39 This rate is higher than has been reported in previous series, and is perhaps attributable to the few exclusion criteria for clinical enrolment in our trial, and careful follow-up with close monitoring. These data represent contemporary outcomes after stenting in STEMI from a large, diverse, global study, and as such emphasise the need for more thromboresistant stents40,41 and appropriate use of more potent antiplatelet agents42,43 if outcomes are to be further improved in STEMI.

Limitations of the HORIZONS-AMI trial have been discussed previously.13–15 The open-label design was mitigated by the high compliance with proscribed study processes, and use of masked core laboratories and adjudication committees. Although the study’s fi ndings are applicable only to the patients and lesion types enrolled, the trial had few exclusion criteria. Furthermore, the pharmacological randomisation occurred before the coronary anatomy was known, and 93·2% of all enrolled patients undergoing primary stenting were randomised. There were slight imbalances between the study groups in a few baseline measures and out-patient thienopyridine prescription. However, none of the salient results of the study varied after multivariable adjustment for these small diff erences (data not shown). Results were not adjusted for multiple comparisons, and thus should be regarded as hypothesis-generating, especially when marginally signifi cant. Furthermore, 8·0% and 7·2% of patients from the pharmacological and stent randomisations were

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unavailable for 3-year follow-up. Although these percentages are low, this factor adds some additional uncertainty to the point estimates. Heparin plus a GPI was used in more than 90% of patients undergoing primary percutaneous coronary intervention in the USA before the HORIZONS-AMI trial, and in most patients in Europe.44,45 Whether anticoagulation with unfractionated heparin alone after adequate thienopyridine preloading without a GPI is safe and eff ective in patients undergoing primary percutaneous coronary intervention has not been examined in a randomised trial powered for clinical endpoints. Furthermore, radial access was used in only 6% of cases in our trial. Whether the benefi ts of bivalirudin would be as marked if the radial approach was used routinely in STEMI is not known. Whether next generation stent designs might further improve clinical outcomes in STEMI is also unknown and can only be addressed in appropriately sized randomised trials. Finally, longer-term follow-up (beyond 3 years) is needed to establish whether very late adverse events might emerge in any of the study groups.

ContributorsGWS, SJP, and RM participated in design of the trial. GWS, SJP, MF,

HP, and RM participated in data analysis. GWS wrote the report, which

was revised after review by the co-authors, all of whom provided critical

review of the manuscript.

Confl icts of interestGWS has been a consultant for Osprey, Reva, Merck, CoreValve,

Boston Scientifi c, Abbott Vascular, Xtent, Edwards, BTI, Asten

Biopharma, ATI, SB Medical, Evalve, AstraZeneca, Prescient, Eli Lilly,

Bristol-Myers-Squibb, Biosensors, Otsuka, The Medicines Company,

Ortho-McNeil, and Gilead; received research grants from TherOx, The

Medicines Company, Abbott Vascular, Atrium, Boston Scientifi c,

Volcano, and InfraReDx; received honoraria from Edwards and Vascular

Solutions; and has equity in CoreValve, Savacor, Biostar I and II funds,

Caliber, FlowCardia, MedFocus I, II, and Accelerator funds, Ovalum,

MediGuide, Guided Delivery Systems, Arstasis, Micardia, and

AccessClosure. BW has received lecture honoraria from The Medicines

Company and Boston Scientifi c and travel expenses from Abbott

Vascular. GG has served on a board for Boston Scientifi c and as a

consultant for Boston Scientifi c and Volcano; received research grants

from Medtronic, Boston Scientifi c, Abbott Vascular, and LightLab

Imaging; and received speaking honoraria from The Medicines

Company. BRB has received lecture honoraria from The Medicines

Company. DD has received research grants or served as consultant or

advisory board member for Abbott, Adamed, Biotronik, Balton, Bayer,

BBraun, BioMatrix, Boston Scientifi c, Boehringer Ingleheim,

Bristol-Myers Squibb, Cordis, Cook, Eli Lilly, EuroCor, GlaxoSmithKline,

Invatec, Medtronic, The Medicines Company, Merck, Nycomed,

Orbus-Neich, Pfi zer, Possis, Promed, Sanofi -Aventis, Siemens, Solvay,

Terumo, and Tyco. FH reports that his institution received research

grants from The Medicines Company and Boston Scientifi c, and that he

received travel expenses from Nycomed, lecture honoraria from

AstraZeneca, Merck, Sharpe and Dohme, Novartis, Daiichi-Sankyo, and

Berlin Chemie, and that he has received manuscript preparation fees

and royalties for serving as a co-editor and author from Elsevier, Urban,

and Fischer. BJG has served as a consultant for Ortho-McNeil Janssen

Scientifi c Aff airs, Amorcyte, Merck Sharp & Dohme, GE Healthcare,

St Jude Medical Center, Medispec, Merck, and Boston Scientifi c. SJP has

served as a consultant to Boston Scientifi c and The Medicines Company,

and that his institution has received research grants from Boston

Scientifi c and The Medicines Company. GD has served as a consultant to

AstraZeneca, Datascope, Gilead, Guerbet, St Jude, Cordis; has provided

expert legal testimony; and has received a research grant from

Accumetrics. MF and HF are full-time employees of The Cardiovascular

Research Foundation. RM has served as a consultant for Abbott, Cardiva,

Cordis, The Medicines Company, AstraZeneca, Ortho-McNeil, Regado,

Abiomed, Accumetrics, Daichii-Sankyo, Eli Lilly, Gilead, Guerbet, and

TherOx, and has received research grants from Bristol-Myers Squibb

and Sanofi . JZP, RK, and SCW declare no confl icts of interest.

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Documents

Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI):