Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)

David J. Whellan; Pierluigi Tricoci; Edmond Chen; Zhen Huang; David Leibowitz; Pascal Vranckx; Gregary D. Marhefka; Claes Held; Jose C. Nicolau; Robert F. Storey; Witold Ruzyllo; Kurt Huber; Peter Sinnaeve; A. Teddy Weiss; Jean Pierre Dery; David J. Moliterno; Frans Van De Werf; Philip E. Aylward; Harvey D. White; Paul W. Armstrong; Lars Wallentin; John Strony; Robert A. Harrington; Kenneth W. Mahaffey

doi:10.1016/j.jacc.2013.10.048

Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)

David J. Whellan, Pierluigi Tricoci, Edmond Chen, Zhen Huang, David Leibowitz, Pascal Vranckx, Gregary D. Marhefka, Claes Held, Jose C. Nicolau, Robert F. Storey, Witold Ruzyllo, Kurt Huber, Peter Sinnaeve, A. Teddy Weiss, Jean Pierre Dery, David J. Moliterno, Frans Van De Werf, Philip E. Aylward, Harvey D. White, Paul W. ArmstrongLars Wallentin, John Strony, Robert A. Harrington, Kenneth W. Mahaffey

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

Objectives This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Background Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Methods Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Results Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). Conclusions In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943)

Original language	English
Pages (from-to)	1048-1057
Number of pages	10
Journal	Journal of the American College of Cardiology
Volume	63
Issue number	11
DOIs	https://doi.org/10.1016/j.jacc.2013.10.048
State	Published - Mar 25 2014

Bibliographical note

Funding Information:
The TRACER trial was funded by Merck & Co., Inc . Dr. Whellan has received consultant honoraria from Novartis, POZEN, Terumo, and Medtronic; and he has received a research grant from Merck & Co., Inc., and Medtronic . Dr. Tricoci has received a consultant agreement and research grant from Merck & Co., Inc . Dr. Chen was an employee of Merck & Co., Inc. Dr. Held has received research support from Merck & Co., Inc., GlaxoSmithKline, AstraZeneca, and Bristol-Myers Squibb/Pfizer ; has received institutional research grants from Schering-Plough/Merck Sharp & Dohme and Roche ; has served on the advisory board for Pfizer and AstraZeneca; and has received lecture fees from AstraZeneca. Dr. Nicolau has received research grant support and consulting fees/honorarium from Merck & Co., Inc. ; has board membership with AstraZeneca; has received research grant support and lecture fees, including service on speakers’ bureaus from AstraZeneca and Eli Lilly ; and has received travel/accommodations/meeting expenses from AstraZeneca. Dr. Storey has received research grants from AstraZeneca, Eli Lilly/Daiichi Sankyo Alliance, Merck & Co., Inc., and Accumetrics ; has served as a consultant for AstraZeneca, Eli Lilly, Daiichi Sankyo, Novartis, Merck & Co., Inc., Eisai, Sanofi-Aventis/Regeneron, Bristol-Myers Squibb, Roche, and Accumetrics; and has received honorarium from AstraZeneca, Eli Lilly, Daiichi Sankyo, Merck & Co., Inc., Accumetrics, Medscape, and Iroko. Dr. Ruzyllo has received honoraria for lectures and clinical studies from Bayer, Bristol-Myers Squibb/Pfizer, Merck & Co., Inc., Daiichi Sankyo, Eli Lilly, and Sanofi-Aventis. Dr. Huber has received honoraria for lectures and expert rounds from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, Sanofi-Aventis, and The Medicines Company. Dr. Sinnaeve has received a research grant from AstraZeneca ; has received advisory/speakers fees from Merck Sharp & Dohme, Merck & Co., Inc., Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, Pfizer, and Bayer; and has served on the advisory board of Merck Sharp & Dohme. Dr. Moliterno has received research support and consulting fees/honoraria from Merck & Co., Inc . Dr. Van de Werf has received a research grant from Merck Sharp & Dohme ; has received research support from Merck & Co., Inc. and Boehringer Ingelheim; and has served as a consultant for and received lecture fees from AstraZeneca and Boehringer Ingelheim. Dr. Aylward has received research support from Merck & Co., Inc., AstraZeneca, Eli Lilly, and Bayer/Johnson & Johnson ; has served as a consultant for AstraZeneca, Boehringer Ingelheim, Pfizer, Sanofi-Aventis, and Eli Lilly; and has received lecture fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. Dr. White has received research support from Sanofi-Aventis, Eli Lilly, The Medicines Company, National Institutes of Health, Pfizer, Roche, Johnson & Johnson, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-Myers Squibb ; and has served on advisory boards for Merck Sharpe & Dohme, and Regado Biosciences. Dr. Armstrong has received research support and consulting fees/honoraria from Merck Sharp & Dohme ; has served as a consultant for Eli Lilly, Regado Biosciences, F. Hoffmann-La Roche Ltd., GlaxoSmithKline, Sanofi-Aventis, Takeda Pharmaceuticals, and Merck & Co., Inc.; has received a research grant from Schering-Plough Research Institute ; and has received research support from Boehringer Ingelheim, Sanofi-Aventis Canada, GlaxoSmithKline, AstraZeneca, Regado Biosciences, Amylin, and Novartis . Dr. Wallentin has received research support and consulting fees/honoraria from Merck & Co., Inc. ; has performed consultancy for Regado Biotechnologies, Portola, C.S.L. Behring, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, and Pfizer; has received research support and lecture fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, and Schering-Plough ; has received honoraria from Boehringer Ingelheim; and has received honoraria and travel support from AstraZeneca, Bristol-Myers Squibb, and Pfizer . Dr. Strony is an employee and stockholder of Merck & Co., Inc. Dr. Harrington’s disclosures are listed at: http://med.stanford.edu/profiles/medicine/frdActionServlet?choiceId=showCOIs&&fid=34240 . Dr. Mahaffey’s full disclosures prior to August 1, 2013 are available at www.dcri.org ; disclosures after August 1, 2013 are available at: http://med.stanford.edu/profiles/kenneth_mahaffey . All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Chen is currently affiliated with Global Clinical Development, Bayer HealthCare Pharmaceuticals Inc., Whippany, New Jersey.

Keywords

bypass
coronary disease
myocardial infarction
platelets
thrombin

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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Whellan, D. J., Tricoci, P., Chen, E., Huang, Z., Leibowitz, D., Vranckx, P., Marhefka, G. D., Held, C., Nicolau, J. C., Storey, R. F., Ruzyllo, W., Huber, K., Sinnaeve, P., Weiss, A. T., Dery, J. P., Moliterno, D. J., Van De Werf, F., Aylward, P. E., White, H. D., ... Mahaffey, K. W. (2014). Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). Journal of the American College of Cardiology, 63(11), 1048-1057. https://doi.org/10.1016/j.jacc.2013.10.048

Whellan, David J. ; Tricoci, Pierluigi ; Chen, Edmond et al. / Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery : Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). In: Journal of the American College of Cardiology. 2014 ; Vol. 63, No. 11. pp. 1048-1057.

@article{07ddc1daad1e4b4a8f511bd66cf4f9b8,

title = "Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)",

abstract = "Objectives This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Background Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Methods Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Results Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). Conclusions In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943)",

keywords = "bypass, coronary disease, myocardial infarction, platelets, thrombin",

author = "Whellan, {David J.} and Pierluigi Tricoci and Edmond Chen and Zhen Huang and David Leibowitz and Pascal Vranckx and Marhefka, {Gregary D.} and Claes Held and Nicolau, {Jose C.} and Storey, {Robert F.} and Witold Ruzyllo and Kurt Huber and Peter Sinnaeve and Weiss, {A. Teddy} and Dery, {Jean Pierre} and Moliterno, {David J.} and {Van De Werf}, Frans and Aylward, {Philip E.} and White, {Harvey D.} and Armstrong, {Paul W.} and Lars Wallentin and John Strony and Harrington, {Robert A.} and Mahaffey, {Kenneth W.}",

note = "Funding Information: The TRACER trial was funded by Merck & Co., Inc . Dr. Whellan has received consultant honoraria from Novartis, POZEN, Terumo, and Medtronic; and he has received a research grant from Merck & Co., Inc., and Medtronic . Dr. Tricoci has received a consultant agreement and research grant from Merck & Co., Inc . Dr. Chen was an employee of Merck & Co., Inc. Dr. Held has received research support from Merck & Co., Inc., GlaxoSmithKline, AstraZeneca, and Bristol-Myers Squibb/Pfizer ; has received institutional research grants from Schering-Plough/Merck Sharp & Dohme and Roche ; has served on the advisory board for Pfizer and AstraZeneca; and has received lecture fees from AstraZeneca. Dr. Nicolau has received research grant support and consulting fees/honorarium from Merck & Co., Inc. ; has board membership with AstraZeneca; has received research grant support and lecture fees, including service on speakers{\textquoteright} bureaus from AstraZeneca and Eli Lilly ; and has received travel/accommodations/meeting expenses from AstraZeneca. Dr. Storey has received research grants from AstraZeneca, Eli Lilly/Daiichi Sankyo Alliance, Merck & Co., Inc., and Accumetrics ; has served as a consultant for AstraZeneca, Eli Lilly, Daiichi Sankyo, Novartis, Merck & Co., Inc., Eisai, Sanofi-Aventis/Regeneron, Bristol-Myers Squibb, Roche, and Accumetrics; and has received honorarium from AstraZeneca, Eli Lilly, Daiichi Sankyo, Merck & Co., Inc., Accumetrics, Medscape, and Iroko. Dr. Ruzyllo has received honoraria for lectures and clinical studies from Bayer, Bristol-Myers Squibb/Pfizer, Merck & Co., Inc., Daiichi Sankyo, Eli Lilly, and Sanofi-Aventis. Dr. Huber has received honoraria for lectures and expert rounds from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, Sanofi-Aventis, and The Medicines Company. Dr. Sinnaeve has received a research grant from AstraZeneca ; has received advisory/speakers fees from Merck Sharp & Dohme, Merck & Co., Inc., Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, Pfizer, and Bayer; and has served on the advisory board of Merck Sharp & Dohme. Dr. Moliterno has received research support and consulting fees/honoraria from Merck & Co., Inc . Dr. Van de Werf has received a research grant from Merck Sharp & Dohme ; has received research support from Merck & Co., Inc. and Boehringer Ingelheim; and has served as a consultant for and received lecture fees from AstraZeneca and Boehringer Ingelheim. Dr. Aylward has received research support from Merck & Co., Inc., AstraZeneca, Eli Lilly, and Bayer/Johnson & Johnson ; has served as a consultant for AstraZeneca, Boehringer Ingelheim, Pfizer, Sanofi-Aventis, and Eli Lilly; and has received lecture fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. Dr. White has received research support from Sanofi-Aventis, Eli Lilly, The Medicines Company, National Institutes of Health, Pfizer, Roche, Johnson & Johnson, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-Myers Squibb ; and has served on advisory boards for Merck Sharpe & Dohme, and Regado Biosciences. Dr. Armstrong has received research support and consulting fees/honoraria from Merck Sharp & Dohme ; has served as a consultant for Eli Lilly, Regado Biosciences, F. Hoffmann-La Roche Ltd., GlaxoSmithKline, Sanofi-Aventis, Takeda Pharmaceuticals, and Merck & Co., Inc.; has received a research grant from Schering-Plough Research Institute ; and has received research support from Boehringer Ingelheim, Sanofi-Aventis Canada, GlaxoSmithKline, AstraZeneca, Regado Biosciences, Amylin, and Novartis . Dr. Wallentin has received research support and consulting fees/honoraria from Merck & Co., Inc. ; has performed consultancy for Regado Biotechnologies, Portola, C.S.L. Behring, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, and Pfizer; has received research support and lecture fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, and Schering-Plough ; has received honoraria from Boehringer Ingelheim; and has received honoraria and travel support from AstraZeneca, Bristol-Myers Squibb, and Pfizer . Dr. Strony is an employee and stockholder of Merck & Co., Inc. Dr. Harrington{\textquoteright}s disclosures are listed at: http://med.stanford.edu/profiles/medicine/frdActionServlet?choiceId=showCOIs&&fid=34240 . Dr. Mahaffey{\textquoteright}s full disclosures prior to August 1, 2013 are available at www.dcri.org ; disclosures after August 1, 2013 are available at: http://med.stanford.edu/profiles/kenneth_mahaffey . All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Chen is currently affiliated with Global Clinical Development, Bayer HealthCare Pharmaceuticals Inc., Whippany, New Jersey. ",

year = "2014",

month = mar,

day = "25",

doi = "10.1016/j.jacc.2013.10.048",

language = "English",

volume = "63",

pages = "1048--1057",

number = "11",

}

Whellan, DJ, Tricoci, P, Chen, E, Huang, Z, Leibowitz, D, Vranckx, P, Marhefka, GD, Held, C, Nicolau, JC, Storey, RF, Ruzyllo, W, Huber, K, Sinnaeve, P, Weiss, AT, Dery, JP, Moliterno, DJ, Van De Werf, F, Aylward, PE, White, HD, Armstrong, PW, Wallentin, L, Strony, J, Harrington, RA & Mahaffey, KW 2014, 'Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)', Journal of the American College of Cardiology, vol. 63, no. 11, pp. 1048-1057. https://doi.org/10.1016/j.jacc.2013.10.048

Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). / Whellan, David J.; Tricoci, Pierluigi; Chen, Edmond et al.
In: Journal of the American College of Cardiology, Vol. 63, No. 11, 25.03.2014, p. 1048-1057.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery

T2 - Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)

AU - Whellan, David J.

AU - Tricoci, Pierluigi

AU - Chen, Edmond

AU - Huang, Zhen

AU - Leibowitz, David

AU - Vranckx, Pascal

AU - Marhefka, Gregary D.

AU - Held, Claes

AU - Nicolau, Jose C.

AU - Storey, Robert F.

AU - Ruzyllo, Witold

AU - Huber, Kurt

AU - Sinnaeve, Peter

AU - Weiss, A. Teddy

AU - Dery, Jean Pierre

AU - Moliterno, David J.

AU - Van De Werf, Frans

AU - Aylward, Philip E.

AU - White, Harvey D.

AU - Armstrong, Paul W.

AU - Wallentin, Lars

AU - Strony, John

AU - Harrington, Robert A.

AU - Mahaffey, Kenneth W.

N1 - Funding Information: The TRACER trial was funded by Merck & Co., Inc . Dr. Whellan has received consultant honoraria from Novartis, POZEN, Terumo, and Medtronic; and he has received a research grant from Merck & Co., Inc., and Medtronic . Dr. Tricoci has received a consultant agreement and research grant from Merck & Co., Inc . Dr. Chen was an employee of Merck & Co., Inc. Dr. Held has received research support from Merck & Co., Inc., GlaxoSmithKline, AstraZeneca, and Bristol-Myers Squibb/Pfizer ; has received institutional research grants from Schering-Plough/Merck Sharp & Dohme and Roche ; has served on the advisory board for Pfizer and AstraZeneca; and has received lecture fees from AstraZeneca. Dr. Nicolau has received research grant support and consulting fees/honorarium from Merck & Co., Inc. ; has board membership with AstraZeneca; has received research grant support and lecture fees, including service on speakers’ bureaus from AstraZeneca and Eli Lilly ; and has received travel/accommodations/meeting expenses from AstraZeneca. Dr. Storey has received research grants from AstraZeneca, Eli Lilly/Daiichi Sankyo Alliance, Merck & Co., Inc., and Accumetrics ; has served as a consultant for AstraZeneca, Eli Lilly, Daiichi Sankyo, Novartis, Merck & Co., Inc., Eisai, Sanofi-Aventis/Regeneron, Bristol-Myers Squibb, Roche, and Accumetrics; and has received honorarium from AstraZeneca, Eli Lilly, Daiichi Sankyo, Merck & Co., Inc., Accumetrics, Medscape, and Iroko. Dr. Ruzyllo has received honoraria for lectures and clinical studies from Bayer, Bristol-Myers Squibb/Pfizer, Merck & Co., Inc., Daiichi Sankyo, Eli Lilly, and Sanofi-Aventis. Dr. Huber has received honoraria for lectures and expert rounds from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, Sanofi-Aventis, and The Medicines Company. Dr. Sinnaeve has received a research grant from AstraZeneca ; has received advisory/speakers fees from Merck Sharp & Dohme, Merck & Co., Inc., Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, Pfizer, and Bayer; and has served on the advisory board of Merck Sharp & Dohme. Dr. Moliterno has received research support and consulting fees/honoraria from Merck & Co., Inc . Dr. Van de Werf has received a research grant from Merck Sharp & Dohme ; has received research support from Merck & Co., Inc. and Boehringer Ingelheim; and has served as a consultant for and received lecture fees from AstraZeneca and Boehringer Ingelheim. Dr. Aylward has received research support from Merck & Co., Inc., AstraZeneca, Eli Lilly, and Bayer/Johnson & Johnson ; has served as a consultant for AstraZeneca, Boehringer Ingelheim, Pfizer, Sanofi-Aventis, and Eli Lilly; and has received lecture fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. Dr. White has received research support from Sanofi-Aventis, Eli Lilly, The Medicines Company, National Institutes of Health, Pfizer, Roche, Johnson & Johnson, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-Myers Squibb ; and has served on advisory boards for Merck Sharpe & Dohme, and Regado Biosciences. Dr. Armstrong has received research support and consulting fees/honoraria from Merck Sharp & Dohme ; has served as a consultant for Eli Lilly, Regado Biosciences, F. Hoffmann-La Roche Ltd., GlaxoSmithKline, Sanofi-Aventis, Takeda Pharmaceuticals, and Merck & Co., Inc.; has received a research grant from Schering-Plough Research Institute ; and has received research support from Boehringer Ingelheim, Sanofi-Aventis Canada, GlaxoSmithKline, AstraZeneca, Regado Biosciences, Amylin, and Novartis . Dr. Wallentin has received research support and consulting fees/honoraria from Merck & Co., Inc. ; has performed consultancy for Regado Biotechnologies, Portola, C.S.L. Behring, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, and Pfizer; has received research support and lecture fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, and Schering-Plough ; has received honoraria from Boehringer Ingelheim; and has received honoraria and travel support from AstraZeneca, Bristol-Myers Squibb, and Pfizer . Dr. Strony is an employee and stockholder of Merck & Co., Inc. Dr. Harrington’s disclosures are listed at: http://med.stanford.edu/profiles/medicine/frdActionServlet?choiceId=showCOIs&&fid=34240 . Dr. Mahaffey’s full disclosures prior to August 1, 2013 are available at www.dcri.org ; disclosures after August 1, 2013 are available at: http://med.stanford.edu/profiles/kenneth_mahaffey . All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Chen is currently affiliated with Global Clinical Development, Bayer HealthCare Pharmaceuticals Inc., Whippany, New Jersey.

PY - 2014/3/25

Y1 - 2014/3/25

N2 - Objectives This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Background Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Methods Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Results Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). Conclusions In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943)

AB - Objectives This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Background Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Methods Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Results Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). Conclusions In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943)

KW - bypass

KW - coronary disease

KW - myocardial infarction

KW - platelets

KW - thrombin

UR - http://www.scopus.com/inward/record.url?scp=84896532727&partnerID=8YFLogxK

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U2 - 10.1016/j.jacc.2013.10.048

DO - 10.1016/j.jacc.2013.10.048

M3 - Article

C2 - 24211500

AN - SCOPUS:84896532727

VL - 63

SP - 1048

EP - 1057

IS - 11

ER -

Whellan DJ, Tricoci P, Chen E, Huang Z, Leibowitz D, Vranckx P et al. Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). Journal of the American College of Cardiology. 2014 Mar 25;63(11):1048-1057. doi: 10.1016/j.jacc.2013.10.048

Vorapaxar in acute coronary syndrome patients undergoing coronary artery bypass graft surgery: Subgroup analysis from the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)

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