Author + information
- Received September 9, 2014
- Accepted September 10, 2014
- Published online March 1, 2015.
- Harvey D. White, DSc∗∗ (, )
- Deepak L. Bhatt, MD, MPH†,
- C. Michael Gibson, MD‡,
- Christian W. Hamm, MD§,
- Kenneth W. Mahaffey, MD‖,
- Matthew J. Price, MD¶,
- Ph. Gabriel Steg, MD#∗∗,††,‡‡,
- Gregg W. Stone, MD§§,
- Bernardo Cortese, MD‖‖,
- Michael Wilensky, MD¶¶,
- Efthymios N. Deliargyris, MD##,
- Tiepu Liu, MD, PhD##,
- Jayne Prats, PhD## and
- Robert A. Harrington, MD‖
- ∗Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
- †Brigham and Women's Hospital, Heart & Vascular Center, and Harvard Medical School, Boston, Massachusetts
- ‡Beth Israel Hospital, Boston, Massachusetts
- §University of Giessen and Kerckhoff Heart Center, Bad Nauheim, Germany
- ‖Department of Medicine, Stanford University School of Medicine, Stanford, California
- ¶Scripps Clinic and Scripps Translational Science Institute, La Jolla, California
- #Institut National de la Santé et de la Recherche Médicale–Unité 114, Paris, France
- ∗∗Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France
- ††Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France
- ‡‡Royal Brompton Hospital, London, United Kingdom
- §§Columbia University Medical Center and The Cardiovascular Research Foundation, New York, New York
- ‖‖Interventional Cardiology, A.O. Fatebenefratelli, Bastioni di Porta Nuova, Milan, Italy
- ¶¶Cardiology PC, Birmingham, Alabama
- ##The Medicines Company, Parsippany, New Jersey
- ↵∗Reprint requests and correspondence:
Dr. Harvey D. White, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, Victoria Street West, Auckland 1142, New Zealand.
Objectives The aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin.
Background Cangrelor is a potent intravenous P2Y12 inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis.
Methods In the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm.
Results At 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non–ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29).
Conclusions Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin.
Cangrelor is an intravenous P2Y12 receptor antagonist that acts immediately and was shown in CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) to reduce the rate of ischemic events at 48 h in patients undergoing urgent or elective percutaneous coronary intervention (PCI) (1). Cangrelor did not increase GUSTO (Global Use of Strategies to Open Occluded Arteries) severe or moderate bleeding, Thrombolysis In Myocardial Infarction (TIMI) major/minor bleeding or transfusion, although there was an increase in ACUITY (Acute Catheterization and Urgent Intervention Triage strategy) bleeding associated with access site hematoma.
Bivalirudin has demonstrated similar ischemic outcomes and lower bleeding risk as heparin with or without glycoprotein IIb/IIIa inhibition in patients undergoing PCI, including primary PCI for ST-segment elevation myocardial infarction (STEMI) (2–6). Bivalirudin may mitigate any increase in bleeding seen with cangrelor.
The HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial with bivalirudin compared with unfractionated heparin plus glycoprotein IIb/IIIa inhibitors in patients with STEMI showed a reduction in major bleeding, thrombocytopenia, and mortality (4–6). The European Society of Cardiology guidelines state that in patients undergoing primary angioplasty for STEMI that the direct thrombin inhibitor bivalirudin is recommended over unfractionated heparin and glycoprotein IIb/IIIa inhibitors (7). The American College of Cardiology Foundation/American Heart Association guidelines recommend that either bivalirudin or unfractionated heparin may be used in patients undergoing primary angioplasty (8).
The HORIZONS-AMI reported a 1.3% increase in stent thrombosis occurring within the first 24 h with bivalirudin compared with heparin plus a glycoprotein IIb/IIIa inhibitor, with similar rates thereafter (4). Strategies that have been suggested that might decrease this early hazard include a longer infusion of bivalirudin or the use of the newer P2Y12 receptor antagonists prasugrel and ticagrelor (9–12). However, in the recent EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial (13) in patients undergoing primary angioplasty in which ticagrelor or prasugrel was administered to 60.4% of patients and a low-dose bivalirudin infusion for at least 4 h was recommended, definite stent thrombosis in ≤24 h was increased with bivalirudin compared with unfractionated heparin (1.1% vs. 0.2%, p = 0.007).
The recent single-center HEAT-PPCI (How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention) trial compared bivalirudin infused to the end of the case with unfractionated heparin with selective use of glycoprotein IIb/IIIa inhibitors in patients undergoing primary PCI (PPCI). The rate of glycoprotein IIb/IIIa inhibitors was 13% in the bivalirudin group and 15% in the heparin group. The use of prasugrel or ticagrelor was 89% (14). Definite stent thrombosis at 28 days occurred in 3.4% of patients randomized to receive bivalirudin and 0.9% of patients randomized to receive unfractionated heparin (p = 0.001).
In the CHAMPION PHOENIX, early stent thrombosis (<48 h) was reduced by 38% with cangrelor compared with clopidogrel administered with either a 600-mg or 300-mg loading dose (1). In the CHAMPION PHOENIX, 2,059 (18.8%) randomized patients received bivalirudin. We therefore assessed the effects of cangrelor with background bivalirudin therapy in the CHAMPION PHOENIX (15).
The design and primary results of the CHAMPION PHOENIX were published previously (1,15). In brief, patients 18 years of age or older who required PCI for stable angina, non–ST-segment elevation acute coronary syndrome (NSTE-ACS), or STEMI and who had not received P2Y12 or glycoprotein IIb/IIIa inhibitors were eligible for inclusion.
The trial randomized 10,942 patients in the modified intention-to-treat (mITT) population, which comprised patients who actually underwent PCI and received the study drug. In the present analysis, we evaluated the primary and secondary endpoints in the 2,059 patients who received bivalirudin as their procedural anticoagulant.
Patients were randomly assigned in a double-dummy, double-blind manner to receive cangrelor or clopidogrel before PCI. Randomization was stratified according to site, baseline status (normal or abnormal, as defined by a combination of biomarker levels, electrocardiographic changes, and symptoms), and intended loading dose of clopidogrel (600 mg or 300 mg). After randomization, patients received an infusion of cangrelor or matching placebo with the first set of capsules containing either 600 mg or 300 mg of clopidogrel (with the dose determined at the discretion of the site investigator) or matching placebo. At the end of the infusion, patients received a second set of capsules containing either 600 mg of clopidogrel (cangrelor group) or matching placebo (clopidogrel group).
Cangrelor or matching placebo was administered as a bolus of 30 μg/kg followed by an infusion of 4 μg/kg/min for at least 2 h or the duration of the procedure, whichever was longer. Aspirin (75 to 325 mg) was to be administered to all patients. Clopidogrel (75 mg) was to be administered during the first 48 h; thereafter, clopidogrel or another P2Y12 inhibitor could be administered at the discretion of the investigator, according to local guidelines. The choice of a periprocedural anticoagulant (bivalirudin, unfractionated heparin, low molecular weight heparin, or fondaparinux) was also at the discretion of the investigator. Glycoprotein IIb/IIIa inhibitors were permitted only as rescue therapy during PCI to treat new or persistent thrombus formation, slow or no reflow, side-branch compromise, dissection, or distal embolization. The investigator at the site determined the protocol for management of the arterial sheath.
The primary efficacy endpoint was the composite rate of death from any cause, myocardial infarction (MI), ischemia-driven revascularization (IDR), or stent thrombosis in the 48 h after randomization.
The key secondary endpoint was the incidence of stent thrombosis at 48 h comprising both Academic Research Consortium–defined (16) and intraprocedural stent thrombosis defined as any new or worsened thrombus related to the stent procedure during the index procedure as assessed by a blinded angiographic core laboratory (17). Events of death, MI, IDR, or stent thrombosis that occurred during the first 30 days after randomization were all adjudicated by an independent and blinded Clinical Events Committee.
The primary safety endpoint was severe bleeding not related to coronary artery bypass grafting, according to the GUSTO criteria, at 48 h. For systematic evaluation, several other bleeding definitions were also applied.
Analyses were performed with data from the mITT cohort, which comprised patients who underwent PCI and received the study drug. Continuous variables are summarized as median and quartile or as mean ± SD, as appropriate, and compared using the Student t test or Wilcoxon rank sum test accordingly. Categorical variables are presented as rate (%) and compared by the chi-square or Fisher exact test as appropriate. Interaction between the treatment and different subgroups on endpoint events was tested using the Breslow-Day method. Time-to-event curves were constructed using the Kaplan-Meier method and compared with the log-rank test. No adjustment was made for multiple comparisons.
All calculations and statistical analyses were performed with the use of SAS software, version 9.2 (SAS Institute, Cary, North Carolina).
Of the 11,145 patients randomized in the CHAMPION PHOENIX, 203 did not undergo PCI or receive the study drug, resulting in an mITT study population of 10,942 patients. Bivalirudin was used during PCI in 2,059 of these patients (18.8%), comprising the present analysis cohort.
Baseline characteristics are shown in Table 1. Overall, the groups were well balanced. There were slightly fewer patients with increased biomarkers in the cangrelor group. PCI was most commonly performed in patients with stable angina (66.3%), 22.6% of patients had NSTE-ACS, and 11.1% presented with STEMI. The median duration of PCI was 20 min (interquartile range: 12 to 33 min) and the infusion of cangrelor was given for a median of 128 min (interquartile range: 121 to 144 min).
The main outcomes of the comparison between cangrelor- and clopidogrel-treated patients are shown in Table 2. Of the patients treated with bivalirudin, the use of cangrelor was associated with a significant (32%) reduction in the risk of primary efficacy endpoint of death, MI, IDR, or stent thrombosis at 48 h compared with clopidogrel (4.7% vs. 6.7%, odds ratio [OR]: 0.68 [95% confidence interval (CI): 0.47 to 0.99], p = 0.047). Figure 1 shows the Kaplan-Meier estimates of the time-to-event for the primary endpoint. The number needed to treat with cangrelor to prevent 1 primary endpoint was 50. The need for rescue glycoprotein IIb/IIIa inhibitors was also lower with cangrelor compared with clopidogrel (1.4% vs. 3.1%, OR: 0.44 [95% CI: 0.24 to 0.84]; p = 0.010).
The rate of stent thrombosis at 48 h was nonsignificantly lower in the cangrelor group than in the clopidogrel group (0.7% vs. 1.4%, OR: 0.48, 95% CI: 0.19 to 1.18; p = 0.10) (Table 2, Figure 2). There was also a trend for stent thrombosis to be lower with cangrelor in the first 2 h compared with clopidogrel (Figure 3) (0.59% cangrelor vs. 1.44% clopidogrel; log-rank p = 0.057).
Figure 4 shows a subgroup analysis of the primary efficacy endpoint. The reduction of the primary efficacy endpoint was consistent across multiple subgroups, including patient groups with stable angina, NSTE-ACS, and STEMI (p value for interaction = 0.62). There was an interaction with the infusion duration of cangrelor, with borderline significance (p = 0.048), given the lack of adjustment for multiple comparisons.
MI was also reduced with cangrelor compared with clopidogrel (3.6% vs. 5.6%, OR: 0.63, 95% CI: 0.42 to 0.96; p = 0.032). The composites of death or MI (p = 0.036) and death, MI, or stent thrombosis (p = 0.039) were also significantly reduced.
There were no significant differences in GUSTO severe or moderate bleeding, TIMI major or minor bleeding, ACUITY major bleeding, or the need for blood transfusions in patients treated with cangrelor compared with clopidogrel. Figure 5 shows a subgroup analysis of GUSTO severe/moderate bleeding.
Consistent with the overall findings from the CHAMPION PHOENIX in this pre-specified subgroup analysis of patients receiving bivalirudin, cangrelor compared with clopidogrel significantly reduced the primary composite outcomes of death, MI, IDR, or stent thrombosis at 48 h after randomization. There was a significant reduction in MI and the composite of death and MI. Although not statistically significant due to the low frequency of stent thrombosis, there was a reduction of ∼50% in the number of cases of stent thrombosis with cangrelor. This effect was especially prominent in the first few hours. The reduction in the primary endpoint with cangrelor was consistent across the different clinical subgroups of patients undergoing PCI. There was no significant difference in GUSTO- or TIMI-defined bleeding or in ACUITY-defined major bleeding between the 2 randomized groups.
In the HORIZONS-AMI trial (17) in STEMI patients undergoing primary PCI, bivalirudin use compared with heparin plus glycoprotein IIb/IIIa inhibitors resulted in similar ischemic events, significantly less bleeding and thrombocytopenia, and lower mortality rates at 30 days and 3 years (6). However, patients treated with bivalirudin also had a higher rate of acute stent thrombosis. In the HORIZONS-AMI trial, bivalirudin was given as a short infusion and clopidogrel as a loading dose of 600 mg was only given in ∼60% of patients.
One mechanism possibly related to the increase in acute stent thrombosis with bivalirudin in primary PCI may be the rapid clearance of the drug after discontinuation. In the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial, ∼78% of patients received the recommended dose of 0.25 mg/kg/h for the extended infusion, whereas in the remainder, the infusion was maintained at the PCI recommended dose of 1.75 mg/kg/h. The lower dose was not protective for acute stent thrombosis but in a post-hoc analysis of patients who received an extended PCI dose infusion, there was a similar rate of stent thrombosis for patients treated with unfractionated heparin (0.5% vs. 0.2%; p = 0.45) (18).
A second possible mechanism relating to an increase in acute stent thrombosis in STEMI patients is inadequate platelet inhibition. In the EUROMAX trial, which compared bivalirudin with unfractionated heparin with optional glycoprotein IIb/IIIa inhibitors in patients being transported for primary PCI, bivalirudin reduced major bleeding, transfusions, and thrombocytopenia, and there were no significant differences in the rates of death or reinfarction (13). In the EUROMAX trial, the newer P2Y12 inhibitors ticagrelor and prasugrel, which act earlier and have greater inhibition of platelet activity, were used in 60.4% of patients, and yet definite stent thrombosis still occurred at <24 h more frequently in patients randomized to receive bivalirudin. Also in the single-center HEAT-PPCI (How Effective Are Antithrombotic Therapies in Primary PCI) trial in which patients underwent primary angioplasty, despite the use of prasugrel or ticagrelor in 89% of patients, increased stent thrombosis occurred in patients randomized to receive bivalirudin. These findings may relate to the delayed onset of action of these agents in patients with STEMI who have increased platelet activity and delayed absorption and metabolism of an oral drug (19,20). The present study suggests that the potent and rapidly acting intravenous agent cangrelor in patients with stable angina, NSTE-ACS and STEMI patients may overcome this limitation and result in a decreased rate of acute stent thrombosis and MI in bivalirudin-treated patients, without an increase in bleeding.
The HEAT-PPCI trial showed in patients undergoing primary PCI that heparin reduced major ischemic events and did not increase bleeding complications compared with bivalirudin (14). The HEAT-PPCI trial raises the important question of whether the use of the new antiplatelet agents (prasugrel and ticagrelor) and reduced use of glycoprotein IIb/IIIa antagonists in the unfractionated heparin arm may have mitigated the bleeding advantage of bivalirudin over unfractionated heparin. A comparison of bivalirudin plus cangrelor versus unfractionated heparin plus cangrelor with the newer antiplatelet agents and reduced use of glycoprotein IIb/IIIa antagonists would address whether bivalirudin possesses a bleeding advantage over unfractionated heparin against the background of cangrelor. The current analysis addresses the comparison of cangrelor with clopidogrel on a background of bivalirudin therapy, which according to National Cardiovascular data from the overall PCI population in the United States, is used in a majority of patients (21).
This is a pre-specified subgroup analysis of a randomized trial, and bivalirudin was not randomized; as such, our findings should be considered hypothesis generating. It is possible that the lack of significantly increased bleeding with cangrelor may relate to a type II error due to the small number of patients treated with bivalirudin. The newer P2Y12 inhibitors ticagrelor and prasugrel were not used in the CHAMPION PHOENIX.
In patients receiving bivalirudin, cangrelor resulted in a lower frequency of MI and acute stent thrombosis compared with clopidogrel, without apparently increasing major bleeding or blood transfusions.
The authors thank Lanyu Lei and Yuyin Liu, biostatisticians from Harvard Clinical Research Institute, who were funded by The Medicines Company, for providing independent validation of data analysis. They also thank Charlene Nell, Desktop Support Administrator, Green Lane Cardiovascular Services/Cardiology Department, for excellent secretarial assistance.
The CHAMPION PHOENIX trial was funded by The Medicines Company. Dr. White has received research grants from Sanofi, Eli Lilly, The Medicines Company, NIH, Pfizer, Roche, Johnson & Johnson, Schering Plough, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Pharma Development, and Bristol-Myers Squibb; and has served on the advisory boards of Merck Sharpe & Dohme, Roche, and Regado Biosciences. Dr. Bhatt has served on the advisory boards of Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; has served on the Board of Directors of Boston VA Research Institute, Society of Cardiovascular Patient Care; has served as Chair of the American Heart Association Get With The Guidelines Steering Committee; has served on the Data Monitoring Committees of Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and the Population Health Research Institute; has received honoraria from the American College of Cardiology (Editor, Clinical Trials, Cardiosource), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), WebMD (CME steering committees), Clinical Cardiology (Associate Editor), and the Journal of the American College of Cardiology (Section Editor, Pharmacology); has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche, Sanofi, The Medicines Company; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. Dr. Gibson has received funding from or has been a consultant for Angel Medical Corporation, AstraZeneca, Atrium Medical Systems, Baxter Healthcare, Bayer, Cardiovascular Research Foundation, Consensus Medical Communications, CSL Behring, Cytori Therapeutics, Daiichi Sankyo, Eli Lilly, Exeter Group, Genentech, GlaxoSmithKline, Ikaria, Janssen Pharmaceuticals, Johnson & Johnson, Lantheus Medical Imaging, Merck, Ortho-McNeil, Portola Pharmaceuticals, Roche Diagnostics, Sanofi, Stealth Peptides, St. Jude Medical, The Medicines Company, UpToDate in Cardiovascular Medicine, Volcano Corp, and Walk Vascular. Dr. Hamm has received honoraria from Abbott, AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Merck Sharpe & Dohme, Bristol-Myers Squibb, BRAHMS, Daiichi Sankyo, Essex, GlaxoSmithKline, Medtronic, Lilly, Sanofi, Correvio, Pfizer, Roche, The Medicines Company, Boston Scientific, and Gilead. Dr. Mahaffey has received research grants from Medtronic and St. Jude; and has been a consultant for Cubist, Eli Lilly, GlaxoSmithKline, Johnson and Johnson, and The Medicines Company. Dr. Price has received consulting honoraria from Daiichi Sankyo/Eli Lilly, AstraZeneca, The Medicines Company, Accumetrics, Medtronic, St. Jude Medical, and Boston Scientific; and speaker honoraria from Daiichi Sankyo/Eli Lilly and AstraZeneca. Dr. Steg has received personal fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Lilly, Merck Sharpe & Dohme, Novartis, Otsuka, Pfizer, Roche, Sanofi, Servier, The Medicines Company, and Vivus. Dr. Stone has been a consultant for Abbott Vascular, Boston Scientific, Bristol-Myers Squibb–Sanofi partnership, Eli Lilly, Daiichi Sankyo, AstraZeneca, and The Medicines Company. Dr. Cortese has received personal fees from AstraZeneca, The Medicines Company, Hexacath, and Movi. Dr. Harrington has received research grants from AstraZeneca, Bristol-Myers Squibb, Sanofi, The Medicines Company, Eli Lilly, Daiichi Sankyo, GlaxoSmithKline, Johnson & Johnson, Portola, Merck, and Regado; and has been a consultant for Sanofi, Bristol-Myers Squibb, Merck, Johnson & Johnson, and Gilead.
- Abbreviations and Acronyms
- confidence interval
- Global Use of Strategies to Open Occluded Arteries
- ischemia-driven revascularization
- myocardial infarction
- modified intention-to-treat
- non–ST-segment elevation acute coronary syndrome
- odds ratio
- percutaneous coronary intervention
- ST-segment elevation myocardial infarction
- Thrombolysis In Myocardial Infarction
- Received September 9, 2014.
- Accepted September 10, 2014.
- 2015 American College of Cardiology Foundation
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