Stroke outcomes with vorapaxar versus placebo in patients with acute coronary syndromes: Insights from the TRACER trial

Leo Ungar; Robert M. Clare; Fatima Rodriguez; Bradley J. Kolls; Paul W. Armstrong; Philip Aylward; Claes Held; David J. Moliterno; John Strony; Frans Van de Werf; Lars Wallentin; Harvey D. White; Pierluigi Tricoci; Robert A. Harrington; Kenneth W. Mahaffey; Chiara Melloni

doi:10.1161/JAHA.118.009609

Stroke outcomes with vorapaxar versus placebo in patients with acute coronary syndromes: Insights from the TRACER trial

Leo Ungar, Robert M. Clare, Fatima Rodriguez, Bradley J. Kolls, Paul W. Armstrong, Philip Aylward, Claes Held, David J. Moliterno, John Strony, Frans Van de Werf, Lars Wallentin, Harvey D. White, Pierluigi Tricoci, Robert A. Harrington, Kenneth W. Mahaffey, Chiara Melloni

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

8 Scopus citations

Abstract

Background-Vorapaxar, a protease-activated receptor-1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. Methods and Results-TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow-up, 477 days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan-Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22-6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2 years [hazard ratio, 0.79; 95% confidence interval, 0.58-1.07]), and similar for stroke overall (1.93% versus 2.13% at 2 years [hazard ratio, 0.94; 95% confidence interval, 0.71-1.24]). Conclusions-Stroke occurred in <2% of patients. Vorapaxar-assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.

Original language	English
Article number	e009609
Journal	Journal of the American Heart Association
Volume	7
Issue number	24
DOIs	https://doi.org/10.1161/JAHA.118.009609
State	Published - Dec 1 2018

Bibliographical note

Funding Information:
research grants or contracts from Sanofi Aventis Recherche & Développement, Merck, Boehringer Ingelheim, Bayer, and CSL Limited; and consulting for AstraZeneca, Merck, Bayer, Novartis, and Boehringer Ingelheim. Aylward reports research grants from Merck & Co, AstraZeneca, Sanofi, and GSK; honoraria (speaker’s bureau and advisory board) from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Bayer J&J, Servier, and Bristol Myers Squibb. Held reports institutional research grants from AstraZeneca, GlaxoSmithKline, Pfizer/Bristol Myers Squibb, Roche, and Schering-Plough (now Merck); and consulting for AstraZeneca. Moliterno reports grants from Merck, Inc, during the conduct of the study. Strony is a former employee of Merck & Co and a current employee of Johnson & Johnson. Van de Werf reports research grants, honoraria for lectures, and advisory board membership for Merck. Wallentin reports grants from Merck & Co and Roche Diagnostics; grants and personal fees from Bristol-Myers Squibb/Pfizer, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim; and personal fees from Abbott. White reports grants from Sanofi Aventis, Eli Lilly and Company, National Institutes of Health (NIH), and DalGen Products and Services; personal fees and nonfinancial support from AstraZeneca; grants and personal fees from Omthera Pharmaceuticals, Pfizer, and Elsai Inc; and personal fees from Sirtex and Acetelion. Tricoci reports a consultant agreement and research grant from Merck. All disclosures are available at https://dcri.org/about-us/conflic t-of-interest/. Harrington reports consultant fees/honoraria from Adverse Events, Amgen Inc, Daiichi-Lilly, Gilead Sciences, Janssen Research and Development, Medtronic, Merck, Novartis Corporation, The Medicines Company, Vida Health, Vox Media, and WebMD; research/research grants from AstraZeneca, BMS, CSL Behring, GSK, Merck, Portola, Sanofi-Aventis, and The Medicines Company; ownership interest/partnership/principal from Element Science and MyoKardia; officer, director, trustee, or other fiduciary role for Evidint and Scanadu; Data Safety Monitoring Board for Regado; and other: American Heart Association. Mahaffey reports financial disclosures available at http://med.stanf ord.edu/profiles/kenneth-mahaffey; research grant or contract from Afferent, Amgen, Apple Inc, AstraZeneca, Cardiva Medical Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St Jude, and Tenax; consulting for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol Myers Squibb, Cardiometabolic Health Congress, Elsevier, GlaxoSmithKline, Johnson & Johnson, Medergy, Medscape, Merck, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Oculeve, Portola, Radiometer, Springer Publishing, Theravance, University of California, San Francisco, and WebMD; and equity in BioPrint Fitness. Melloni reports research grants or contracts from Abbott Laboratories, Amgen Inc, Duke Clinical Research Institute, Genzyme Corporation, Janssen Research & Development, Lundbeck Pharmaceuticals, Pfizer, and TESARO Inc; and consulting for Amgen Inc, Genetech, and Shire. A full list of disclosures for Dr Melloni is available at https://dcri. org/about-us/conflict-of-interest/. The remaining authors have no disclosures to report.

Funding Information:
The TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial was funded by Merck & Co.

Publisher Copyright:
© 2018 The Authors.

Keywords

Acute coronary syndrome
Stroke
Vorapaxar

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1161/JAHA.118.009609

Cite this

Ungar, L., Clare, R. M., Rodriguez, F., Kolls, B. J., Armstrong, P. W., Aylward, P., Held, C., Moliterno, D. J., Strony, J., Van de Werf, F., Wallentin, L., White, H. D., Tricoci, P., Harrington, R. A., Mahaffey, K. W., & Melloni, C. (2018). Stroke outcomes with vorapaxar versus placebo in patients with acute coronary syndromes: Insights from the TRACER trial. Journal of the American Heart Association, 7(24), [e009609]. https://doi.org/10.1161/JAHA.118.009609

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title = "Stroke outcomes with vorapaxar versus placebo in patients with acute coronary syndromes: Insights from the TRACER trial",

abstract = "Background-Vorapaxar, a protease-activated receptor-1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. Methods and Results-TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow-up, 477 days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan-Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22-6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2 years [hazard ratio, 0.79; 95% confidence interval, 0.58-1.07]), and similar for stroke overall (1.93% versus 2.13% at 2 years [hazard ratio, 0.94; 95% confidence interval, 0.71-1.24]). Conclusions-Stroke occurred in <2% of patients. Vorapaxar-assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.",

keywords = "Acute coronary syndrome, Stroke, Vorapaxar",

author = "Leo Ungar and Clare, {Robert M.} and Fatima Rodriguez and Kolls, {Bradley J.} and Armstrong, {Paul W.} and Philip Aylward and Claes Held and Moliterno, {David J.} and John Strony and {Van de Werf}, Frans and Lars Wallentin and White, {Harvey D.} and Pierluigi Tricoci and Harrington, {Robert A.} and Mahaffey, {Kenneth W.} and Chiara Melloni",

note = "Funding Information: research grants or contracts from Sanofi Aventis Recherche & D{\'e}veloppement, Merck, Boehringer Ingelheim, Bayer, and CSL Limited; and consulting for AstraZeneca, Merck, Bayer, Novartis, and Boehringer Ingelheim. Aylward reports research grants from Merck & Co, AstraZeneca, Sanofi, and GSK; honoraria (speaker{\textquoteright}s bureau and advisory board) from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Bayer J&J, Servier, and Bristol Myers Squibb. Held reports institutional research grants from AstraZeneca, GlaxoSmithKline, Pfizer/Bristol Myers Squibb, Roche, and Schering-Plough (now Merck); and consulting for AstraZeneca. Moliterno reports grants from Merck, Inc, during the conduct of the study. Strony is a former employee of Merck & Co and a current employee of Johnson & Johnson. Van de Werf reports research grants, honoraria for lectures, and advisory board membership for Merck. Wallentin reports grants from Merck & Co and Roche Diagnostics; grants and personal fees from Bristol-Myers Squibb/Pfizer, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim; and personal fees from Abbott. White reports grants from Sanofi Aventis, Eli Lilly and Company, National Institutes of Health (NIH), and DalGen Products and Services; personal fees and nonfinancial support from AstraZeneca; grants and personal fees from Omthera Pharmaceuticals, Pfizer, and Elsai Inc; and personal fees from Sirtex and Acetelion. Tricoci reports a consultant agreement and research grant from Merck. All disclosures are available at https://dcri.org/about-us/conflic t-of-interest/. Harrington reports consultant fees/honoraria from Adverse Events, Amgen Inc, Daiichi-Lilly, Gilead Sciences, Janssen Research and Development, Medtronic, Merck, Novartis Corporation, The Medicines Company, Vida Health, Vox Media, and WebMD; research/research grants from AstraZeneca, BMS, CSL Behring, GSK, Merck, Portola, Sanofi-Aventis, and The Medicines Company; ownership interest/partnership/principal from Element Science and MyoKardia; officer, director, trustee, or other fiduciary role for Evidint and Scanadu; Data Safety Monitoring Board for Regado; and other: American Heart Association. Mahaffey reports financial disclosures available at http://med.stanf ord.edu/profiles/kenneth-mahaffey; research grant or contract from Afferent, Amgen, Apple Inc, AstraZeneca, Cardiva Medical Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St Jude, and Tenax; consulting for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol Myers Squibb, Cardiometabolic Health Congress, Elsevier, GlaxoSmithKline, Johnson & Johnson, Medergy, Medscape, Merck, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Oculeve, Portola, Radiometer, Springer Publishing, Theravance, University of California, San Francisco, and WebMD; and equity in BioPrint Fitness. Melloni reports research grants or contracts from Abbott Laboratories, Amgen Inc, Duke Clinical Research Institute, Genzyme Corporation, Janssen Research & Development, Lundbeck Pharmaceuticals, Pfizer, and TESARO Inc; and consulting for Amgen Inc, Genetech, and Shire. A full list of disclosures for Dr Melloni is available at https://dcri. org/about-us/conflict-of-interest/. The remaining authors have no disclosures to report. Funding Information: The TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial was funded by Merck & Co. Publisher Copyright: {\textcopyright} 2018 The Authors.",

year = "2018",

month = dec,

day = "1",

doi = "10.1161/JAHA.118.009609",

language = "English",

volume = "7",

number = "24",

}

Ungar, L, Clare, RM, Rodriguez, F, Kolls, BJ, Armstrong, PW, Aylward, P, Held, C, Moliterno, DJ, Strony, J, Van de Werf, F, Wallentin, L, White, HD, Tricoci, P, Harrington, RA, Mahaffey, KW & Melloni, C 2018, 'Stroke outcomes with vorapaxar versus placebo in patients with acute coronary syndromes: Insights from the TRACER trial', Journal of the American Heart Association, vol. 7, no. 24, e009609. https://doi.org/10.1161/JAHA.118.009609

TY - JOUR

T1 - Stroke outcomes with vorapaxar versus placebo in patients with acute coronary syndromes

T2 - Insights from the TRACER trial

AU - Ungar, Leo

AU - Clare, Robert M.

AU - Rodriguez, Fatima

AU - Kolls, Bradley J.

AU - Armstrong, Paul W.

AU - Aylward, Philip

AU - Held, Claes

AU - Moliterno, David J.

AU - Strony, John

AU - Van de Werf, Frans

AU - Wallentin, Lars

AU - White, Harvey D.

AU - Tricoci, Pierluigi

AU - Harrington, Robert A.

AU - Mahaffey, Kenneth W.

AU - Melloni, Chiara

N1 - Funding Information: research grants or contracts from Sanofi Aventis Recherche & Développement, Merck, Boehringer Ingelheim, Bayer, and CSL Limited; and consulting for AstraZeneca, Merck, Bayer, Novartis, and Boehringer Ingelheim. Aylward reports research grants from Merck & Co, AstraZeneca, Sanofi, and GSK; honoraria (speaker’s bureau and advisory board) from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Bayer J&J, Servier, and Bristol Myers Squibb. Held reports institutional research grants from AstraZeneca, GlaxoSmithKline, Pfizer/Bristol Myers Squibb, Roche, and Schering-Plough (now Merck); and consulting for AstraZeneca. Moliterno reports grants from Merck, Inc, during the conduct of the study. Strony is a former employee of Merck & Co and a current employee of Johnson & Johnson. Van de Werf reports research grants, honoraria for lectures, and advisory board membership for Merck. Wallentin reports grants from Merck & Co and Roche Diagnostics; grants and personal fees from Bristol-Myers Squibb/Pfizer, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim; and personal fees from Abbott. White reports grants from Sanofi Aventis, Eli Lilly and Company, National Institutes of Health (NIH), and DalGen Products and Services; personal fees and nonfinancial support from AstraZeneca; grants and personal fees from Omthera Pharmaceuticals, Pfizer, and Elsai Inc; and personal fees from Sirtex and Acetelion. Tricoci reports a consultant agreement and research grant from Merck. All disclosures are available at https://dcri.org/about-us/conflic t-of-interest/. Harrington reports consultant fees/honoraria from Adverse Events, Amgen Inc, Daiichi-Lilly, Gilead Sciences, Janssen Research and Development, Medtronic, Merck, Novartis Corporation, The Medicines Company, Vida Health, Vox Media, and WebMD; research/research grants from AstraZeneca, BMS, CSL Behring, GSK, Merck, Portola, Sanofi-Aventis, and The Medicines Company; ownership interest/partnership/principal from Element Science and MyoKardia; officer, director, trustee, or other fiduciary role for Evidint and Scanadu; Data Safety Monitoring Board for Regado; and other: American Heart Association. Mahaffey reports financial disclosures available at http://med.stanf ord.edu/profiles/kenneth-mahaffey; research grant or contract from Afferent, Amgen, Apple Inc, AstraZeneca, Cardiva Medical Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St Jude, and Tenax; consulting for Abbott, Ablynx, AstraZeneca, Baim Institute, Boehringer Ingelheim, Bristol Myers Squibb, Cardiometabolic Health Congress, Elsevier, GlaxoSmithKline, Johnson & Johnson, Medergy, Medscape, Merck, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Oculeve, Portola, Radiometer, Springer Publishing, Theravance, University of California, San Francisco, and WebMD; and equity in BioPrint Fitness. Melloni reports research grants or contracts from Abbott Laboratories, Amgen Inc, Duke Clinical Research Institute, Genzyme Corporation, Janssen Research & Development, Lundbeck Pharmaceuticals, Pfizer, and TESARO Inc; and consulting for Amgen Inc, Genetech, and Shire. A full list of disclosures for Dr Melloni is available at https://dcri. org/about-us/conflict-of-interest/. The remaining authors have no disclosures to report. Funding Information: The TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial was funded by Merck & Co. Publisher Copyright: © 2018 The Authors.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Background-Vorapaxar, a protease-activated receptor-1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. Methods and Results-TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow-up, 477 days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan-Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22-6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2 years [hazard ratio, 0.79; 95% confidence interval, 0.58-1.07]), and similar for stroke overall (1.93% versus 2.13% at 2 years [hazard ratio, 0.94; 95% confidence interval, 0.71-1.24]). Conclusions-Stroke occurred in <2% of patients. Vorapaxar-assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.

AB - Background-Vorapaxar, a protease-activated receptor-1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. Methods and Results-TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12 944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow-up, 477 days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan-Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22-6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2 years [hazard ratio, 0.79; 95% confidence interval, 0.58-1.07]), and similar for stroke overall (1.93% versus 2.13% at 2 years [hazard ratio, 0.94; 95% confidence interval, 0.71-1.24]). Conclusions-Stroke occurred in <2% of patients. Vorapaxar-assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.

KW - Acute coronary syndrome

KW - Stroke

KW - Vorapaxar

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Stroke outcomes with vorapaxar versus placebo in patients with acute coronary syndromes: Insights from the TRACER trial

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