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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
1   Johns Hopkins University, Department of Neurology, Baltimore, Maryland, USA
2   HeartDrug Research Laboratories, Towson, Maryland, USA
,
Seth D. Fortmann
2   HeartDrug Research Laboratories, Towson, Maryland, USA
,
Sunil V. Rao
3   Duke University, Department of Medicine, Durham, North Carolina, USA
,
Jean-Francois Tanguay
4   Montreal Heart Institute, Montreal, Quebec, Canada
,
Marie Lordkipanidze
4   Montreal Heart Institute, Montreal, Quebec, Canada
,
Daniel F. Hanley
1   Johns Hopkins University, Department of Neurology, Baltimore, Maryland, USA
,
Mehmet Can
5   Haseki Research and Education Hospital, Cardiology Department, Istanbul, Turkey
,
Moo Hyun Kim
6   Dong-A University Hospital, Department of Cardiology, Busan, South Korea
,
Thomas A. Marciniak
7   Bethesda, Maryland, USA
› Author Affiliations
Further Information

Publication History

Received: 17 November 2015

Accepted after major revision: 05 January 2016

Publication Date:
06 December 2017 (online)

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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
 

  • References

  • 1 Storey RF, Kotha J, Smyth SS. et al. Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy. Thromb Haemost 2014; 111: 883-891.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Tricoci P, Huang Z, Held C. et al. the TRACER Investigators. Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes. N Engl J Med 2012; 366: 20-33.
    CrossrefPubMedGoogle Scholar
  • 3 Morrow DA, Braunwald E, Bonaca MP. et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: 1404-1413.
    CrossrefPubMedGoogle Scholar
  • 4 NDA 294–886. Medical reviews on Vorapaxar. June 18th, 2014 Available at www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000MedR.pdf Accessed May 15, 2015.
    PubMedGoogle Scholar
  • 5 NDA 294–886. Cross-discipline Team Leader review on Vorapaxar. April 18th, 2014 Available at: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204886Orig1s000SumR.pdf Accessed May 15, 2015.
    PubMed
  • 6 Sowka J. Neurogenic diplopia: paralysis of cranial nerves III, IV, and VI. Optom Clin 1996; 5: 53-76.
    PubMedGoogle Scholar
  • 7 Dinkin M. Diagnostic approach to diplopia. Continuum 2014; 20: 942-965.
    PubMedGoogle Scholar
  • 8 Fraine L. Nonsurgical management of diplopia. Am Orthopt J 2012; 62: 13-18.
    CrossrefPubMedGoogle Scholar
  • 9 Chhabra MS, Golnik KC. Recovery of ocular motor cranial nerve palsy after herpes zoster ophthalmicus. J Neuroophthalmol 2014; 34: 20-22.
    CrossrefPubMedGoogle Scholar
  • 10 Schmidt RF, Yick F, Boghani Z. et al. Malignant peripheral nerve sheath tumors of the trigeminal nerve: a systematic review of 36 cases. Neurosurg Focus 2013; 34: E5.
    PubMedGoogle Scholar
  • 11 Fraser CL, Skalicky SE, Gurbaxani A. et al. Ocular myositis. Curr Allergy Asthma Rep 2013; 13: 315-321.
    CrossrefPubMedGoogle Scholar
  • 12 Penedones A, Mendes D, Alves C. et al. Drug-induced ocular adverse reactions: review of the safety alerts issued during the last decade. J Ocul Pharmacol Ther 2015; 31: 258-268.
    CrossrefPubMedGoogle Scholar
  • 13 Lucca JM, Ramesh M, Parthasarathi G. et al. Lorazepam-induced diplopia. Indian J Pharmacol 2014; 46: 228-229.
    CrossrefPubMedGoogle Scholar
  • 14 Karadag H, Acar M, özdel K. Aripiprazole Induced Acute Transient Bilateral Myopia: A Case Report. Balkan Med J 2015; 32: 230-232.
    CrossrefPubMedGoogle Scholar
  • 15 Mellon G, Stitou H, Aoun O. et al. Lateral rectus muscle paralysis induced by ribavirin and pegylated interferon-β2a in a patient with HIV/HCV co-infection. J Infect Chemother 2012; 18: 937-938.
    CrossrefPubMedGoogle Scholar
  • 16 Fraunfelder FW, Fraunfelder FT. Diplopia and fluoroquinolones. Ophthalmology 2009; 116: 1814-1817.
    CrossrefPubMedGoogle Scholar
  • 17 Fraunfelder FW, Richards AB. Diplopia, blepharoptosis, and ophthalmoplegia and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitor use. Ophthalmology 2008; 115: 2282-2285.
    CrossrefPubMedGoogle Scholar
  • 18 Mowla A, Ghanizadeh A, Ashkani H. Diplopia with citalopram: a case report. J Clin Psychopharmacol 2005; 25: 623-624.
    CrossrefPubMedGoogle Scholar
  • 19 Kalis MM, Huff NA. Oxcarbazepine, an antiepileptic agent. Clin Ther 2001; 23: 680-700.
    CrossrefPubMedGoogle Scholar
  • 20 Openshaw H, Slatkin NE, Smith E. Eye movement disorders in bone marrow transplant patients on cyclosporin and ganciclovir. Bone Marrow Transplant 1997; 19: 503-505.
    CrossrefPubMedGoogle Scholar
  • 21 Wutthiphan S, Kowal L, O’Day J. et al. Diplopia following subcutaneous injections of botulinum A toxin for facial spasms. J Pediatr Ophthalmol Strabismus 1997; 34: 229-234.
    PubMedGoogle Scholar
  • 22 Digre KB, Varner MW, Schiffman JS. Neuroophthalmologic effects of intravenous magnesium sulfate. Am J Obstet Gynecol 1990; 163: 1848-1852.
    CrossrefPubMedGoogle Scholar
  • 23 Rubin ML, Thomas Jr WC. Diplopia and loss of accommodation due to chloroquine. Arthritis Rheum 1970; 13: 75-82.
    CrossrefPubMedGoogle Scholar
  • 24 Luo W, Wang Y, Reiser G. Two types of protease-activated receptors (PAR-1 and PAR-2) mediate calcium signaling in rat retinal ganglion cells RGC-5. Brain Res 2005; 1047: 159-167.
    CrossrefPubMedGoogle Scholar
  • 25 Rohatgi T, Sedehizade F, Sabel BA. et al. Protease-activated receptor subtype expression in developing eye and adult retina of the rat after optic nerve crush. J Neurosci Res 2003; 73: 246-254.
    CrossrefPubMedGoogle Scholar
  • 26 Joyal JS, Nim S, Zhu T. et al. Subcellular localisation of coagulation factor II receptor- like 1 in neurons governs angiogenesis. Nat Med 2014; 20: 1165-1173.
    CrossrefPubMedGoogle Scholar
  • 27 Cowan C, Muraleedharan CK, O’Donnell JJ 3rd. et al. MicroRNA-146 inhibits thrombin-induced NF-ETSB activation and subsequent inflammatory responses in human retinal endothelial cells. Invest Ophthalmol Vis Sci 2014; 55: 4944-4951.
    CrossrefPubMedGoogle Scholar
  • 28 Bastiaans J, van Meurs JC, van Holten-Neelen C. et al. Factor Xa and thrombin stimulate proinflammatory and profibrotic mediator production by retinal pigment epithelial cells: a role in vitreoretinal disorders?. Graefes Arch Clin Exp Ophthalmol 2013; 251: 1723-1733.
    CrossrefPubMedGoogle Scholar
  • 29 Peng Y, Zhang J, Xu H. et al. Neuroprotective effect of protease-activated receptor- 2 in the hypoxia-induced apoptosis of rat RGC-5 cells. J Mol Neurosci 2013; 50: 98-108.
    CrossrefPubMedGoogle Scholar
  • 30 Narayan S, Prasanna G, Tchedre K. et al. Thrombin-induced endothelin-1 synthesis and secretion in retinal pigment epithelial cells is rho kinase dependent. J Ocul Pharmacol Ther 2010; 26: 389-397.
    CrossrefPubMedGoogle Scholar
  • 31 James C, Collison DJ, Duncan G. Characterisation and functional activity of thrombin receptors in the human lens. Invest Ophthalmol Vis Sci 2005; 46: 925-932.
    CrossrefPubMedGoogle Scholar
  • 32 Lang R, Song PI, Legat FJ. et al. Human corneal epithelial cells express functional PAR-1 and PAR-2. Invest Ophthalmol Vis Sci 2003; 44: 99-105.
    CrossrefPubMedGoogle Scholar
  • 33 Tripathi T, Abdi M, Alizadeh H. Protease-activated receptor 2 (PAR2) is upregulated by Acanthamoeba plasminogen activator (aPA) and induces proinflammatory cytokine in human corneal epithelial cells. Invest Ophthalmol Vis Sci 2014; 55: 3912-3921.
    CrossrefPubMedGoogle Scholar
  • 34 Satpathy M, Gallagher P, Jin Y. et al. Extracellular ATP opposes thrombin-induced myosin light chain phosphorylation and loss of barrier integrity in corneal endothelial cells. Exp Eye Res 2005; 81: 183-192.
    CrossrefPubMedGoogle Scholar
  • 35 Yeoh S, Church M, Lackie P. et al. Increased conjunctival expression of protease activated receptor 2 (PAR-2) in seasonal allergic conjunctivitis: a role for abnormal conjunctival epithelial permeability in disease pathogenesis?. Br J Ophthalmol 2011; 95: 1304-1308.
    CrossrefPubMedGoogle Scholar
  • 36 Nickel TJ, Kabir MH, Talreja J. et al. Constitutive expression of functionally active protease-activated receptors 1 and 2 in human conjunctival epithelial cells. Mediators Inflamm 2006; 3: 61359.
    PubMedGoogle Scholar
  • 37 Asano-Kato N, Fukagawa K, Okada N. et al. Tryptase increases proliferative activity of human conjunctival fibroblasts through protease-activated receptor-2. Invest Ophthalmol Vis Sci 2005; 46: 4622-4626.
    CrossrefPubMedGoogle Scholar
  • 38 Oikawa M, Saino T, Kimura K. et al. Effects of protease-activated receptors (PARs) on intracellular calcium dynamics of acinar cells in rat lacrimal glands. Histochem Cell Biol 2013; 140: 463-476.
    CrossrefPubMedGoogle Scholar
  • 39 Oh SJ, Han KS, Park H. et al. Protease activated receptor 1-induced glutamate release in cultured astrocytes is mediated by Bestrophin-1 channel but not by vesicular exocytosis. Mol Brain 2012; 5: 38.
    CrossrefPubMedGoogle Scholar
  • 40 Huang H, Vasilakis P, Zhong X. et al. Parstatin suppresses ocular neovascularisation and inflammation. Invest Ophthalmol Vis Sci 2010; 51: 5825-5832.
    CrossrefPubMedGoogle Scholar
  • 41 Serebruany VL. Redesigning TRACER after TRITON. Intern J Cardiol 2015; 197: 44-47.
    CrossrefPubMedGoogle Scholar
  • 42 Vries MJ, van der Meijden PE, Henskens YM. et al. Assessment of bleeding risk in patients with coronary artery disease on dual antiplatelet therapy. A systematic review.Thromb Haemost 2016; 115: 7-24.
    PubMedGoogle Scholar
  • 43 Serebruany VL, Cherepanov V, Cabrera-Fuentes HA. et al. Solid cancers after antiplatelet therapy: Confirmations, controversies, and challenges. Thromb Haemost 2015; 114: 1104-1112.
    Article in Thieme ConnectPubMedGoogle Scholar