Vorapaxar monotherapy for secondary stroke prevention: A call for randomized trial

Introduction

Development of novel antiplatelet agents has been generally established for the management of patients with clinically evident coronary atherothrombosis. In contrast, these agents have shown limited (if any) efficacy in the prevention of cerebrovascular occlusions, and consistent harm in patients with a history of stroke or transient ischemic attack with regard to elevated bleeding risk including excess of deadly intracranial hemorrhages.^1,2 Vorapaxar is a selective, orally active, potent, and competitive protease-activated receptor 1 (PAR-1) antagonist that potently inhibits thrombin-induced platelet activation. ³ The drug Phase III program included two large outcome trials in patients with acute and chronic coronary atherothrombosis, namely thrombin-receptor antagonist vorapaxar in acute coronary syndromes (TRACER), ⁴ and trial to assess the effects of SCH 530348 in preventing heart attack and stroke in patients with arteriosclerosis (TRA 2P-TIMI 50). ⁵

Methods

Herein, the efficacy and safety of vorapaxar related to stroke are briefly reviewed with a focus on the perspectives and obstacles for an outcome-driven stroke prevention trial. We critically assessed the stroke data from vorapaxar trials, and affiliated Food and Drug Administration (FDA) reviews.

Results

The FDA reviews

The FDA conducted the detailed review of both vorapaxar trials.^9,10 Overall, the agency confirmed definite harm of vorapaxar addition to the conventional dual antiplatelet therapy for second stroke prevention. The harm is especially evident for the hemorrhagic stroke, and these subgroup findings were most relevant to labeling. In fact, the risk of intracranial hemorrhage was substantially increased in vorapaxar arm subjects with a prior history of stroke coupled with no observed benefit of vorapaxar for the primary endpoint in that same subgroup. The analyses that the FDA consider most relevant are the associations of bleeding and primary efficacy endpoint rates by dichotomizing indication subgroup and thienopyridine use (the original strata except including all patients with a prior history of stroke/TIA in the stroke subgroup.) Critically, just by removal of clopidogrel, the post-stroke patients experienced much less bleeding events (from 5.4% to 3.9%), but most importantly, solid two-fold reduction of the primary endpoint (17.9% to 8.9%). ¹⁰ These FDA-generated data clearly suggest that patients in vorapaxar trials were severely “overtreated,” and removal of just one antiplatelet agent (thienopyridine) substantially improve benefit/risk profile of vorapaxar. Overall, the FDA-confirmed evidence strongly suggests that unique vorapaxar pharmakynetics, and very mild antiplatelet profile makes it a good candidate for better secondary stroke prevention (SSP).^9,10 The outcome-driven trial should test head-to-head monotherapy with vorapaxar (Zontivity®), versus clopidogrel (Plavix®), and versus twice daily dipyridamole with very low dose aspirin (Aggrenox®). The summary of considerations is provided in Table 1.

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Table 1.

Advantages and obstacles for vorapaxar stroke prevention trial

Fact on vorapaxar	Impact	Comment
First-in-class	Pro	Never been tested for SSP indication
Excellent pharmacokinetics	Pro	Consistent exposure after once daily intake
99.8% serum albumin binding	Pro	Excellent bioavailability
10 days half-life elimination	Pro	Steady state over platelet life span
GI and biliary excretion	Pro	Suitable for patients with renal impairment
Delicate platelet inhibition	Pro	Maintaining the “comfort zone”, CABG advantage
Low molecular weight	Pro	No known renal or hepatic toxicity issues
First stroke prevention	Pro	Surprise finding from TRA2P
Low clinical utilization	Con	Despite approval in May 2014, no sales reported
SSP trial costs	Con	Very high, >20,000 sample size, low event rate

SSP: secondary stroke prevention; GI: gastrointestinal; CABG: coronary artery bypass grafting.

Discussion

In addition, to the facts outlined in Table 1, negative findings in TRACER and TRA2P with regard to stroke are predominantly related to overtreatment and are not applicable to per se vorapaxar antiplatelet properties. Applying the proposed vorapaxar monotherapy will ultimately yield much milder platelet inhibition, and most likely be superior to clopidogrel and dipyridamole with regard to bleeding risks in general, and hopefully intracranial hemorrhages in particular in stroke victims. On the other hand, borderline efficacy results of the latest SSP trials, high failure rates, and limited commercial success for the sponsors may represent the array of substantial obstacles for the new trial implementation. Indeed, the impact of event incidence miscalculations, heterogeneous population, different level of general health, concomitant comorbidities or/and medications in violation of protocol, and unwillingness to perform and accept subgroup analysis based on geographic regions somewhat clouded recent worldwide SSP mega trials.^11–13 By initially aggressive unreasonable design, TRA2P and TRACER were prone to fail for stroke prevention and cause more intracranial bleedings. The “good news” is that vorapaxar per se can be most definitely exonerated from the harm observed for stroke prevention, and especially from alarming ICH numbers. ¹⁴ The bad news is that vorapaxar has been approved in May 2014, but it’s clinical utilization is still very low, or even not existing in many remote from US markets. It seems that despite the heavy expense of investing in two mega trials, it is challenging to test vorapaxar as a monotherapy in another head-to-head stroke prevention study against clopidogrel and extended-released dipyridamole. Hopefully, future development of PAR1/PAR4 agents will learn from the pitfalls from the initial experience with vorapaxar, and will apply way more delicate strategies, especially relevant for stroke victims.