Diplopia on vorapaxar: An unexpected side effect emerging only at second glance

http://dx.doi. org/10.1160/TH16-02-0124 Thromb Haemost 2016; 115: 911–912 Dual antiplatelet treatment (DAPT) with the cyclooxygenase inhibitor aspirin and an adenosine diphosphate (ADP) P2Y12 receptor inhibitor represents the mainstay of pharmacological treatment in both stable coronary artery disease and acute coronary syndromes patients undergoing an invasive management by percutaneous coronary intervention (PCI) (1). However, the residual risk of recurrent ischaemic complications especially among ACS patients undergoing PCI still remains high despite contemporary treatment strategies including DAPT. Keeping this is mind, the development of novel antiplatelet agents that target new and alternative platelet receptor pathways is still of great importance. Vorapaxar (SCH 530348, Merck) is a novel orally active competitive and selective antagonist of the platelet thrombin receptor PAR-1 that potently inhibits thrombin-induced platelet aggregation. For administration on top of standard antiplatelet therapy, the US Food and Drug Administration (FDA) approved vorapaxar for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease on May 8, 2014. On January 19, 2015, the European Medicines Agency (EMA) granted approval for the reduction of atherothrombotic events in patients with a history of MI. Of note, the two large phase III trials conducted on vorapaxar, the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) (2) and the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2P-TIMI 50) (3) trials showed a modest reduction in CV death, MI and stroke for the study drug groups during long-term follow-up. However, in both trials vorapaxar treatment was associated with a significant increase in severe bleeding events, including intracranial haemorrhage. Moreover, besides the observed but also expected increase in bleeding risk due to the coadministration of vorapaxar on top of standard antiplatelet therapy, there seem to be unexpected side effects to the drug as well that merit discussion and closer investigations. In a Viewpoint Article in this issue of Thrombosis and Haemostasis, Serebruany et al. turn our attention to excess diplopia rates associated with vorapaxar within both phase III trials (4). As pointed out by the authors, there is FDA-confirmed evidence for overall 34 vorapaxar diplopia cases in TRACER (2) (13 vorapaxar vs 2 placebo cases; p=0.010) and TRA 2P-TIMI 50 (3) (21 vs 8 cases; p = 0.018) versus overall 10 cases in the placebo arm of the respective trials (p=0.018) (5). However, both trial publications did not mention excess diplopia in their main publications or in their supplemental material. Interestingly, the very small – and most likely underpowered – ocular sub-study in 102 TRA 2P-TIMI 50 subjects, featuring spectral domain optical coherence tomography, visual acuity, retraction and fundus photography, was neutral in this respect (6). Because of the low incidence (1 case per 1,000 treated patients) and mostly transient nature of the events, FDA authorities did not recommend the addition of diplopia to the package insert yet. The authors of this Viewpoint paper suggest off-target PAR receptor mismodulation in the eye as a possible mechanism for excess diplopia associated with vorapaxar. However, no direct evidence for such a possible causal relationship is provided. Of note, Serebruany et al. have challenged the published data on vorapaxar and other novel antiplatelet agents several times so far (7–10). Encouraging such lively discussions is vital in modern days when numerous novel (antiplatelet) drugs enter the market. Thus, the authors are to be commended for this Viewpoint paper and for raising awareness for this important, so far underreported finding associated with vorapaxar. However, in interpreting the data, some issues and important aspects merit mentioning: First, patients included in both trials represent a high-risk atherosclerotic patient population with significant co-medication. For example, 62 % of TRACER patients had known hyperlipidaemia and 91 % of TRA 2P-TIMI patients were on (non-specified) lipid-lowering agents. In addition, 31.5 % of TRACER patients and 25.5 % of TRA 2P-TIMI patients were suffering from diabetes mellitus, without further specification of medication even in the supplemental appendices. Of note, there is a published association between diplopia and statin use, which was first described in 2008 after reviewing spontaneous reports from the National Registry of Drug-induced Ocular Side Effects (Casey Eye Institute, Oregon Health & Science University, Portland, Oregon), the WHO and the FDA between 1988 and 2008 (11). Also for antidiabetic glitazones (rosiglitazone, pioglitazone), and for ivabradine, blurred vision and excess diplopia have been described after reviewing safety alerts issued on ocular adverse events by four health authorities between January 2005 and December 2014 (12). Without detailed information on co-medication of the different study groups, a confounding impact of co-medication on diplopia rates in these trials cannot be excluded and the