title: Vorapaxar and diplopia: Possible off-target PAR-receptor mismodulation.
abstract: 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.
authors.affiliation: Dr. Serebruany, HeartDrug™ Research Laboratories, Johns Hopkins University, Osler Medical Building, 7600 Osler Drive, Suite 307, Towson, MD 21204, USA, E-mail: vserebr1@jhmi.edu.
authors.forename: Victor L
authors.initials: VL
authors.lastname: Serebruany
authors.forename: Seth D
authors.initials: SD
authors.lastname: Fortmann
authors.forename: Sunil V
authors.initials: SV
authors.lastname: Rao
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Tanguay
authors.forename: Marie
authors.initials: M
authors.lastname: Lordkipanidze
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hanley
authors.forename: Mehmet
authors.initials: M
authors.lastname: Can
authors.forename: Moo Hyun
authors.initials: MH
authors.lastname: Kim
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Marciniak
mesh_terms: D000818:Animals; D001241:Aspirin / Q000008:administration & dosage; D000077144:Clopidogrel; D004172:Diplopia / Q000139:chemically induced*; D017277:Drug Approval; D005123:Eye / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects*; D058729:Peripheral Arterial Disease / Q000188:drug therapy; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D044462:Receptors, Proteinase-Activated / Q000187:drug effects* / Q000378:metabolism; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D044462:Receptors, Proteinase-Activated; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin; C530299:vorapaxar
keywords: PAR receptor; Vorapaxar; adverse events; clinical trials; diplopia; safety