Author + information
- Tannas Jatene, MD,
- Robert A. Harrington, MD,
- Gregg W. Stone, MD,
- Ph. Gabriel Steg, MD,
- C. Michael Gibson, MS, MD,
- Christian W. Hamm, MD,
- Matthew J. Price, MD,
- Jayne Prats, PhD,
- Efthymios N. Deliargyris, MD,
- Kenneth W. Mahaffey, MD,
- Harvey D. White, DSc,
- Deepak L. Bhatt, MD, MPH∗ (, )
- CHAMPION PHOENIX Investigators
- ↵∗Brigham and Women’s Hospital Heart and Vascular Center, 75 Francis Street, Boston, Massachusetts 02115
Cangrelor, a potent intravenous, reversible, platelet P2Y12 inhibitor, was recently approved by both the U.S. Food and Drug Administration and the European Medicines Agency as an adjunct for percutaneous coronary intervention. The approval was based on CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) (1), a multicenter, double-dummy, double-blind trial, which randomized 11,145 patients with stable angina, non–ST-segment elevation acute coronary syndrome or ST-segment elevation myocardial infarction to receive cangrelor or clopidogrel at the time of percutaneous coronary intervention.
CHAMPION PHOENIX (1) demonstrated that cangrelor significantly reduced the rate of ischemic events without increasing severe bleeding. In the original analysis, bleeding was site-reported by the blinded investigators according to pre-specified definitions and was not adjudicated. Although the European Medicines Agency accepted this approach, during U.S. Food and Drug Administration review, the sponsor and the Food and Drug Administration independently re-evaluated bleeding in a post hoc, nonblinded manner. This evaluation included potential bleeding data that the investigator did not necessarily capture on the bleeding case report form, and findings were categorized and interpreted according to jointly agreed criteria based on previously published bleeding classifications. For example, there was a field in the case report form called “drop in hemoglobin or hematocrit”; the review rechecked the laboratory dataset for hemoglobin values. These data were included in the U.S. drug label for cangrelor. Here, we examine these post hoc analyses to compare them with the pre-specified bleeding results.
Table 1 illustrates the rates of investigator-reported bleeding events and bleeding events according to the post hoc review. This re-evaluation led to a numerical increase in bleeding events in both the cangrelor and clopidogrel arms and therefore provided more statistical power to detect differences between study groups. In the new analysis, the primary safety endpoint of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)–defined severe bleeding demonstrated no statistically significant difference between cangrelor and clopidogrel (0.2% vs. 0.1%; odds ratio [OR]: 1.83; 95% confidence interval [CI]: 0.68 to 4.96; p = 0.23), which is consistent with the investigator-reported event rates (1). ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) major or minor and GUSTO mild bleeding had previously been noted to be increased by cangrelor in the original analysis; blood transfusions, TIMI (Thrombolysis In Myocardial Infarction) major bleeding, and GUSTO moderate or severe bleeding continued to show no statistically significant differences after the review. Although most of the original conclusions were unaffected in the new analysis, the numerical increase in TIMI minor bleeding with cangrelor became statistically significant but the odds ratio did not change (Table 1).
Several issues explain differences between the pre-specified analysis and post hoc review. First, the computer algorithm used in CHAMPION PHOENIX to determine bleeding events did not account for data not reconciled properly (e.g., laboratory data that were not correctly recorded on the bleeding case report form; bleeds only recorded as serious adverse events; important details captured only in comments). Second, in some instances, pre-specified criteria were inconsistent with what was done in the review (e.g., the investigators’ bleeding definition attempted to assign a severity, while the review defined overt or clinically overt bleeding as any sign of bleeding, including if only seen on imaging). Third, observation bias could not be excluded as the adjudication was unblinded. The post hoc review suggests that minor bleeding may be more likely to be under-reported with lack of adjudication, whereas major bleeding and transfusions seem to be adequately captured regardless of adjudication.
The role of adjudication in clinical trials, especially blinded ones, remains controversial (2). Although adjudication could change results in terms of myocardial infarction endpoints in individual studies (3), a meta-analysis of trials with cardiovascular outcomes failed to detect any effect of event adjudication on study conclusions (4). An analysis of the PROTECT (Prophylaxis for Thromboembolism in Critical Care Trial) showed that bleeding adjudication did not significantly change the overall trial results and led to a significant increment in study cost (5). Nonetheless, if bleeding is considered an important endpoint in a clinical trial, we recommend that it be adjudicated using pre-specified definitions and original source documents for verification.
In conclusion, the pre-specified CHAMPION PHOENIX bleeding results and the post hoc unblinded review were qualitatively similar, confirming cangrelor’s safety profile. Whereas lack of adjudication of bleeding in a blinded trial should not affect the relative hazards of bleeding, it may lead to a lower number of events reported, mostly consisting of milder forms of bleeding. When possible, adjudication of bleeding events prior to unblinding would be expected to provide the most accurate assessment of bleeding, although this needs to be weighed against the financial costs and the burden of adjudication for clinical trial sites.
Please note: The CHAMPION-PHOENIX trial was funded by The Medicines Company. Dr. Harrington has served on the advisory boards of Evidint, Regado Biosciences, and Scanadu; has received honoraria from Amgen, Daiichi-Sankyo/Lilly, Gilead Sciences, Janssen Research and Development, Medtronic, Merck, Novartis Corporation, The Medicines Company, Vida Health, Vox Media, and WebMD; is affiliated with the American Heart Association; has received research funding from AstraZeneca, Bristol-Myers Squibb, CSL Behring, GlaxoSmithKline, Merck, Portola Pharmaceuticals, Sanofi, The Medicines Company; and has ownership interest in Element Science and MyoKardia. Dr. Steg has received research grants (to INSERM U1148) from Sanofi and Servier; has received speaking or consulting fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers-Squibb, CSL Behring, Daiichi-Sankyo, GlaxoSmithKline, Janssen Research and Development, Lilly, Novartis, Pfizer, Regeneron, Roche, Sanofi, Servier, and The Medicines Company; and is a stockholder in Aterovax. Dr. Gibson has received research support from Johnson & Johnson, Janssen Research and Development, Bayer, and Portola Pharmaceuticals; and has received consulting fees from The Medicines Company. Dr. Hamm has served as an advisor to The Medicines Company; has received honoraria from AstraZeneca, Sanofi, and Lilly; and has received research funding from AstraZeneca and The Medicines Company. Dr. Price has received honoraria from AstraZeneca, Boston Scientific, Medtronic, Merck, St. Jude Medical, Terumo, and The Medicines Company. Dr. Prats is an employee of The Medicines Company. Dr. Deliagyris is an employee of The Medicines Company. Dr. Mahaffey has received honoraria from American College of Cardiology, Amgen, AstraZeneca, Bayer, BioPrint Fitness, Boehringer Ingelheim, Bristol-Myers-Squibb, Cubist, Eli Lilly, Elsevier, Epson, Forest Laboratories, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Mt. Sinai, MyoKardia, Omthera Pharmaceuticals, Portola Pharmaceuticals, Purdue Pharma, Spring Publishing, The Medicines Company, Vindico, and WebMD; and has received research funding from Daiichi-Sankyo, Johnson & Johnson, Medtronic, St. Jude Medical, and Tenax. Dr. White has received honoraria from AstraZeneca; and has received research funding from Sanofi, Eli Lilly, National Institutes of Health, GlaxoSmithKline, Merck Sharpe & Dohme, AstraZeneca, and Daiichi-Sankyo. Dr. Bhatt has served on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; has served on the board of directors of Boston VA Research Institute and Society of Cardiovascular Patient Care; has served as chair of 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 Population Health Research Institute; has received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), 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), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), and WebMD (CME steering committees); has served as the Deputy Editor for Clinical Cardiology; has received research funding from Amarin, AstraZeneca, Bristol-Myers-Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company (including for his role as co-chair of CHAMPION PHOENIX); has served as site co-investigator for Biotronik and St. Jude Medical; is a trustee of the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. We would like to thank Steven E. Elkin, MS, and Debra Bernstein, PhD, of The Medicines Company for their statistical support, along with Yuyin Liu, MS, and Lanyu Lei, MS, of the Harvard Clinical Research Institute for their independent verification of the analyses. Harvard Clinical Research Institute received funding from The Medicines Company for these analyses. A full list of the investigators can be found in Bhatt et al. (1). (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [CHAMPION PHOENIX]; NCT01156571).
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