Author + information
- Received October 7, 2010
- Revision received January 6, 2011
- Accepted January 18, 2011
- Published online June 7, 2011.
- George D. Dangas, MD, PhD⁎,‡,⁎ ( )(, )
- Roxana Mehran, MD⁎,‡,
- Eugenia Nikolsky, MD, PhD‡,
- Bimmer E. Claessen, MD‡,
- Alexandra J. Lansky, MD‡,§,
- Bruce R. Brodie, MD∥,
- Bernhard Witzenbichler, MD¶,
- Giulio Guagliumi, MD#,
- Jan Z. Peruga, MD††,
- Dariusz Dudek, MD‡‡,
- Martin Möckel, MD§§,
- Adriano Caixeta, MD, PhD‡,
- Helen Parise, ScD‡,
- Harvey White, MD⁎⁎,
- Gregg W. Stone, MD†,‡,
- HORIZONS-AMI Trial Investigators
- ↵⁎Reprint requests and correspondence:
Dr. George D. Dangas, Cardiovascular Institute, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, New York 10029
Objectives We investigated the outcomes of switching to bivalirudin after initial administration of heparin in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.
Background Unfractionated heparin (UFH) is frequently administered early in ST-segment elevation myocardial infarction. Whether the benefits of bivalirudin documented in the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial persist in patients previously administered UFH is unknown.
Methods We analyzed the outcomes of the 2,357 patients from HORIZONS-AMI treated with UFH before enrollment according to their subsequent randomization to bivalirudin (switch group, n = 1,178) or UFH plus a glycoprotein IIb/IIIa inhibitor (control group, n = 1,179).
Results At 30 days, major bleeding occurred in 7.6% of the switch group versus 12.3% of the control group (p = 0.0001). Switch patients had lower 30-day rates of cardiac mortality (1.6% vs. 2.9%, p = 0.04). At 2-year follow-up, switch patients experienced lower rates of major bleeding (8.4% vs. 13.0%, p = 0.0003), cardiac mortality (2.3% vs. 3.8%, p = 0.04), and reinfarction (4.0% vs. 7.1%, p = 0.0002). Two-year rates of definite/probable stent thrombosis were similar in switch and control patients (3.1% vs. 4.3%, p = 0.17).
Conclusions In ST-segment elevation myocardial infarction patients who receive early treatment with UFH, switching to bivalirudin before primary percutaneous coronary intervention results in reduced rates of major bleeding and improved early and late cardiac survival.
Primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI) is the standard of care, and current American College of Cardiology/American Heart Association guidelines recommend the use of an anticoagulant as soon as the diagnosis is made (Class I indication) (1,2). Unfractionated heparin (UFH) is typically initiated early in the emergency department or even before hospital arrival due to its availability and familiarity to all medical personnel.
The HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial demonstrated that the direct thrombin inhibitor bivalirudin (with glycoprotein IIb/IIIa inhibitor [GPI] use reserved for bail-out indications) rather than UFH plus routine GPI reduces major bleeding and mortality after primary PCI (3,4), resulting in a class I recommendation for bivalirudin in STEMI (1). However, whether bivalirudin is as beneficial in patients initially treated with UFH who are then switched to bivalirudin is unknown because previous experiences with switching antithrombin agents in non-STEMI have been disappointing (5,6).
In the HORIZONS-AMI trial, randomization was stratified according to pre-enrollment UFH administration. We therefore examined the outcomes of switching antithrombins after early UFH use before primary PCI.
The HORIZONS-AMI trial design and patient eligibility were previously described in detail (3,7). In brief, the HORIZONS-AMI trial was a prospective, open-label, randomized, multicenter trial in patients with STEMI presenting within 12 h of symptom onset managed by primary PCI. Patients were randomized 1:1 to UFH plus GPI (control) or bivalirudin monotherapy. Patients who received UFH before consent were actively recruited, with randomization stratified according to administration of pre-enrollment UFH, 300- versus 600-mg clopidogrel loading dose, abciximab versus eptifibatide if randomized to control, and location (United States vs. non-United States).
Control patients who did not receive pre-randomization UFH were administered a 60-IU/kg UFH bolus, with subsequent boluses targeted to an activated clotting time (ACT) of 200 to 250 s. If UFH was previously given, an ACT was measured to guide additional UFH by nomogram. Bivalirudin-assigned patients received a 0.75-mg/kg bolus followed by 1.75 mg/kg/h. If UFH was administered before randomization, bivalirudin was started 30 min after the last UFH bolus, but in all cases before PCI regardless of ACT. All antithrombin agents were discontinued at the completion of the index procedure but could be continued at low doses if clinically indicated. Weight-adjusted GPI was administered before PCI in all control patients, but only for refractory no-reflow or giant thrombus after PCI with bivalirudin, and were continued for 12 h (abciximab) or 12 to 18 h (eptifibatide).
After angiography, eligible patients then underwent a second randomization to TAXUS paclitaxel-eluting stents or bare-metal stents (both Boston Scientific, Natick, Massachusetts) (8). The study was approved by the institutional review board or ethics committee at each participating center, and all patients signed informed consent.
The present analysis is restricted to 2,357 patients who received UFH before study enrollment and were subsequently randomly assigned to bivalirudin (switch group, n = 1,178) or UFH plus GPI (control group, n = 1,179).
Principal endpoint definitions were previously detailed and included major adverse cardiac events (death, reinfarction, target vessel revascularization for ischemia, or stroke), major bleeding unrelated to coronary artery bypass graft (CABG) surgery, and net adverse clinical events (NACEs) (major adverse cardiac events or non-CABG surgery major bleeding) (3,7–9). Stent thrombosis was classified as definite or probable by Academic Research Consortium criteria (10). All adverse events were adjudicated by an independent clinical events committee blinded to randomization after review of original source documentation. An independent angiographic laboratory assessed all angiograms for baseline and final lesion and flow characteristics (Cardiovascular Research Foundation, New York, New York).
Categorical variables were compared by the Fisher exact test. Continuous variables are expressed as mean ± SD or median (interquartile range) and compared by unpaired t tests or Wilcoxon rank-sum test, respectively. Follow-up event rates and time-to-event curves were determined by Kaplan-Meier methodology, with comparisons made using the log-rank test. Landmark analysis was used to assess events occurring in different time periods. Cox proportional hazards was used to perform multivariable analysis via stepwise regression. All statistical tests were 2-tailed. Statistical significance was set at 0.05.
Pre-randomization UFH was administered in a transfer facility (n = 650), ambulance (n = 876), the enrolling hospital (n = 797), or multiple locations (n = 37); the location was unknown in 65 patients. Most patients (n = 1,934) received a UFH bolus only, whereas the remainder received a bolus plus infusion (n = 399) or infusion only (n = 22). The mean UFH bolus dose was 4,912 ± 1,684 IU and 4,892 ± 883 IU in the switch versus control groups (p = 0.72). After randomization, the study antithrombin was started in the catheterization laboratory in 85% and in the emergency department in 15% of patients in both groups. The duration from pre-randomization UFH bolus to study drug initiation was 64 ± 61 min versus 59 ± 55 min in the switch versus control groups (p = 0.05). The mean baseline ACT levels were 205 ± 95 s versus 183 ± 85 s in the switch versus control groups (p < 0.001).
Baseline characteristics, antiplatelet medication use, and angiographic and procedural variables were well matched between the groups, although switch patients were slightly more likely to be smokers and have undergone previous CABG surgery (Tables 1 and 2).⇓⇓ PCI was performed in 93% in both groups; 2% were referred for CABG surgery, and 5% were managed conservatively. The median ACT during PCI was significantly longer in switch versus control patients (369 s vs. 265.5 s, p < 0.0001).
Patients in the switch group compared with the control group had significantly lower rates of bleeding (by all classifications), thrombocytopenia, and blood product transfusions in-hospital and at 30 days (Table 3). Patients in the switch group compared with the control group had lower rates of NACEs at 30 days without significantly different rates of major adverse cardiac events (Table 4). Cardiac mortality was significantly lower (p = 0.04), and there was a trend toward lower all-cause mortality (p = 0.055) in the switch group compared with the control group at 30-day follow-up. Stent thrombosis was significantly more common in the switch group within the first 24 h, but significantly less common after the first 24 h, and thus occurred with comparable cumulative frequency at 30 days.
At 2 years, patients in the switch group compared with the control group had significantly lower rates of cardiac mortality, reinfarction, death or reinfarction, major bleeding, and NACEs, and similar rates of all-cause mortality and stent thrombosis (Table 4, Fig. 1).
Impact of baseline ACT before bivalirudin
Among switch patients, the ACT at the beginning of catheterization before bivalirudin administration was <200 s in 637 patients (63.8%) and ≥200 s in 362 patients (36.2%); a pre-procedure pre-bivalirudin ACT was not available in 179 patients. In these 2 subgroups, the median baseline ACT before bivalirudin was 158 and 257 s, respectively (p < 0.0001), and the median peak ACT after bivalirudin was 355 and 394 s, respectively (p < 0.0001). The rates of major bleeding and ischemic complications after switching from UFH to bivalirudin were not related to the pre-procedure ACT (Table 5).
Although there are no randomized trials demonstrating that administration of UFH before angiography in patients with STEMI undergoing primary PCI strategy is as safe and more effective than waiting until after arteriography, this practice is very common and is supported by guidelines (1,2). The ACT in such patients is often increased at the time of angiography, which may raise concerns about initiating bivalirudin in all cases before PCI, as performed in the HORIZONS-AMI trial.
In the HORIZONS-AMI trial, 65.4% of patients received UFH before randomization, reflecting the urgency with which this agent is started in clinical practice after STEMI diagnosis. Because randomization was stratified according to pre-randomization UFH administration, the present analysis reflects a stand-alone randomized comparison less subject to confounding than a nonrandomized subgroup analysis. The present study demonstrates that bivalirudin may be safely administered in STEMI even if the ACT from a previous UFH bolus is elevated, and results in reduced hemorrhagic complications, thrombocytopenia, and reinfarction, with improved early and late cardiac survival and freedom from NACEs compared with the alternative of continuing UFH and starting a GPI.
A previous analysis of patients with non-STEMI suggested that switching between UFH and low molecular weight heparin may result in excessive bleeding (5). In contrast, switching from UFH to bivalirudin in non-STEMI was safe (6), consistent with the results from the present trial. Another small trial (N = 90) also suggested that switching from enoxaparin to bivalirudin in acute coronary syndrome patients undergoing PCI is safe (11).
The present protocol for switching from UFH to bivalirudin demonstrates that bivalirudin may be safely started 30 min after the last UFH bolus, or in all cases before PCI, regardless of the ACT. Even with an initial ACT >200 s (present in 36.2% of patients), switching to bivalirudin was not associated with increased rates of major bleeding or blood transfusion compared with those who switched with a shorter initial ACT, despite a markedly higher peak ACT level. The lack of a relationship between the ACT level with bivalirudin and hemorrhagic complications is consistent with previous reports with this agent in STEMI (12).
The observations from this study may streamline and optimize care of the patient with STEMI undergoing primary PCI. Intravenous UFH is universally available and simpler to administer (typically as a bolus only) in the emergency setting than is obtaining bivalirudin from a pharmacy and administering a weight-adjusted bolus plus infusion (the latter also adjusted for renal insufficiency). There may even be a clinical benefit of UFH before bivalirudin compared with bivalirudin alone before primary PCI. In a post hoc analysis from the HORIZONS-AMI trial, this practice ameliorated the increased risk of acute stent thrombosis within the first 24 h in patients treated with a bivalirudin monotherapy regimen (13). In the present study, although there was a 0.7% increase in acute stent thrombosis in the switch group, subacute stent thrombosis was significantly less common by 1% with bivalirudin and even after including late plus very late stent thrombosis, the cumulative 2-year rates were 3.1% and 4.3% in the bivalirudin switch versus heparin plus GPI groups, respectively. Alteration in stent thrombosis timing with GPI has been previously reported (14).
Despite the randomized treatment assignment, this substudy of the HORIZONS-AMI trial should be considered exploratory and hypothesis-generating due to limited statistical power. We did not test a switch strategy from UFH to bivalirudin versus continuing UFH without a GPI. However, previous studies showed that adding a GPI to UFH reduces mortality and reinfarction after primary PCI (15), and thus before the HORIZONS-AMI trial, >90% of patients with STEMI undergoing primary PCI were treated with UFH plus GPI (16).
These limitations notwithstanding, the present study demonstrates that STEMI patients who receive early treatment with UFH may be safely switched to bivalirudin, a strategy that results in reduced hemorrhagic complications and cardiac mortality and enhanced event-free survival compared with UFH continuation and initiation of a GPI.
The HORIZONS-AMI trial was funded through research grants from The Medicines Company and Boston Scientific to the Cardiovascular Research Foundation, New York, New York. Drs. Dangas and Mehran have received speaker honoraria from AstraZeneca, Cordis, The Medicines Company, and National CME (funded by Sanofi and Bristol-Myers Squibb); have received consulting fees from Abbott Vascular, AstraZeneca, Cordiva, Cordis, The Medicines Co., and Regado Biosciences; and have received research support from Bristol-Myers Squibb/Sanofi-Aventis. Dr. Lansky has received research grants from The Medicines Company, Cordis, Boston Scientific, Medtronic, and Abbott. Dr. Brodie is on the Speakers' Bureau of The Medicines Company. Dr. Witzenbichler has received lecture honoraria from Boston Scientific and The Medicines Company. Dr. Guagliumi has served as a consultant to Boston Scientific and Volcano; has received lecture honoraria from Boston Scientific, Medtronic, Lightlab, and Labcoat; and is receiving grant support from Medtronic, Abbott Vascular, Lightlab Imaging, and Boston Scientific. Dr. Dudek has received lecture fees from Nycomed; and research grants or served as consultant/advisory board member for Abbott, Adamed, AstraZeneca, Biotronik, Balton, Bayer, BBraun, BioMatrix, Boston Scientific, Boehringer Ing., Bristol-Myers Squibb, Cordis, Cook, Eli Lilly, EuroCor, Glaxo, Invatec, Medtronic, the Medicines Company, MSD, Nycomed, Orbus-Neich, Pfizer, Possis, Promed, Sanofi-Aventis, Siemens, Sovay, Terumo, and Tyco. Dr. White has received research grants from Sanofi-Aventis, Eli Lilly, The Medicines Company, National Institutes of Health, Pfizer, Roche, Johnson & Johnson, Schering-Plough, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-Myers Squibb; and has received consultant fees from Regado Biosciences. Dr. Stone is on the scientific advisory boards of and has received honoraria from Abbott Vascular and Boston Scientific and has served as a consultant to The Medicines Company, Merck, Eli Lilly, Bristol-Myers Squibb/Sanofi, and AstraZeneca. All other authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- activated clotting time
- coronary artery bypass graft
- glycoprotein IIb/IIIa inhibitor
- net adverse clinical event
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- unfractionated heparin
- Received October 7, 2010.
- Revision received January 6, 2011.
- Accepted January 18, 2011.
- American College of Cardiology Foundation
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