Vorapaxar and diplopia: Possible off-target PAR-receptor mismodulation

Victor L. Serebruany; Seth D. Fortmann; Sunil V. Rao; Jean-Francois Tanguay; Marie Lordkipanidze; Daniel F. Hanley; Mehmet Can; Moo Hyun Kim; Thomas A. Marciniak

doi:10.1160/TH15-11-0882

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(05): 905-910
DOI: 10.1160/TH15-11-0882

Current Controversies

Schattauer GmbH

Vorapaxar and diplopia: Possible off-target PAR-receptor mismodulation

Victor L. Serebruany

¹Johns Hopkins University, Department of Neurology, Baltimore, Maryland, USA

²HeartDrug Research Laboratories, Towson, Maryland, USA

,

Seth D. Fortmann

²HeartDrug Research Laboratories, Towson, Maryland, USA

,

Sunil V. Rao

³Duke University, Department of Medicine, Durham, North Carolina, USA

,

Jean-Francois Tanguay

⁴Montreal Heart Institute, Montreal, Quebec, Canada

,

Marie Lordkipanidze

⁴Montreal Heart Institute, Montreal, Quebec, Canada

,

Daniel F. Hanley

¹Johns Hopkins University, Department of Neurology, Baltimore, Maryland, USA

,

Mehmet Can

⁵Haseki Research and Education Hospital, Cardiology Department, Istanbul, Turkey

,

Moo Hyun Kim

⁶Dong-A University Hospital, Department of Cardiology, Busan, South Korea

,

Thomas A. Marciniak

⁷Bethesda, Maryland, USA

› Author Affiliations

Abstract

Summary

Vorapaxar, a novel antiplatelet thrombin PAR-1 inhibitor, has been evaluated in the successful TRA2P trial and the failed TRACER trial. The drug is currently approved for post myocardial infarction and peripheral artery disease indications with concomitant use of clopidogrel and/or aspirin. The FDA ruled that the vorapaxar safety profile is acceptable. However, both trials revealed excess diplopia (double vision) usually reversible after vorapaxar. The diplopia risk appears to be small (about 1 extra case per 1,000 treated subjects), but real. Overall, there were 10 placebo and 34 vorapaxar diplopia cases (p=0.018) consistent for TRACER (2 vs 13 cases; p=0.010) and for TRA2P (8 vs 21 cases; p=0.018). Hence, we review the FDA-confirmed evidence and discuss potential causes and implications of such a surprising adverse association, which may be related to off-target PAR receptor mismodulation in the eye.

Keywords

Vorapaxar - PAR receptor - diplopia - adverse events - safety - clinical trials

Full Text

References

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