Original Article
Safety of the Novel Protease-Activated Receptor-1 Antagonist Vorapaxar in Japanese Patients with a History of Ischemic Stroke

https://doi.org/10.1016/j.jstrokecerebrovasdis.2010.09.005Get rights and content

Background

Vorapaxar, formerly SCH 530348, is a novel, orally active, potent thrombin receptor inhibitor selective for the protease-activated receptor-1 (PAR-1). Previous phase II studies of patients undergoing urgent or scheduled percutaneous coronary intervention treated with vorapaxar plus aspirin and clopidogrel or ticlopidine showed a trend toward reducing major adverse cardiac events, particularly myocardial infarction, without increasing bleeding risk. The present study evaluated the safety of vorapaxar in Japanese patients with a history of ischemic stroke receiving aspirin.

Methods

Ninety patients with previous ischemic stroke (≥14 days to <1 year before randomization) were randomized to receive vorapaxar (1 or 2.5 mg) or placebo once daily for 60 days. All patients received aspirin (75-150 mg/day). The primary endpoint was overall incidence of adverse events during the protocol-defined treatment phase (60 days).

Results

Addition of vorapaxar to aspirin did not significantly increase the overall incidence of adverse events, including serious adverse events. None of the patients treated with vorapaxar plus aspirin experienced thrombolysis in myocardial infarction major or minor bleeding versus 1 patient treated with placebo. Nonfatal stroke occurred in 1 patient allocated to placebo and 1 patient allocated to vorapaxar.

Conclusions

Vorapaxar used in combination with standard doses of aspirin was safe and well tolerated in Japanese subjects with a history of ischemic stroke.

Introduction

Stroke is a major cause of long-term disability and the third leading cause of death in both Japan and the United States.1, 2, 3 The incidence of stroke in Japan remains high, as shown by age-adjusted incidences of 311.5 and 221.0 per 100,000 person-years in men and women, respectively.4 In Japanese men, approximately 70% of all strokes are ischemic, compared with approximately 60% in Japanese women.4 Furthermore, in a report from 2005, first-year mortality from stroke in Japanese individuals was 7%.1

The primary pathophysiologic mechanism of acute ischemic manifestations of atherothrombotic disease (such as stroke, transient ischemic attacks [TIAs] and acute coronary syndrome [ACS]) involves platelet-mediated thrombosis in response to rupture or erosion of atherosclerotic lesions, which results in occlusion of blood flow and ischemia.5, 6 Antiplatelet therapy reduces the incidence of stroke in patients at high risk for atherothrombotic disease.7, 8 However, the secondary prevention benefit of current antiplatelet therapy in patients with previous stroke or TIA is low, and the number needed-to-treat patients (NNT) is 28 over a period of 29 months, leaving a significant unmet medical need in this population.8 Joint guidelines from the American Heart Association (AHA) and American Stroke Association (ASA) recommend aspirin monotherapy or in combination with other antiplatelet agents for secondary prevention of ischemic events in patients with a history of ischemic stroke or TIA.9 Japanese guidelines for management of stroke recommend aspirin at doses ranging between 75 and 150 mg per day for the secondary prevention of noncardioembolic stroke.10, 11 Thienopyridine is recommended as an alternative to aspirin, and cilostazol is recommended in patients with lacunar infarction. Clopidogrel, another thienopyridine, was approved in Japan in 2004 and is now recommended in the new stroke treatment guidelines.12 Other antiplatelet therapies (e.g., dipyridamole) are not commonly used in Japan in patients with stroke.10, 11

A metaanalysis of 31 clinical trials with a total of 192,036 patients with ischemic disease analyzed the rates of bleeding in patients treated with aspirin, stratified by dose. Dose-dependent increases in total and major bleeding events were observed in patients treated with aspirin, with a significantly elevated bleeding risk at doses ≥200 mg.13 There is an urgent medical need to develop novel and more effective oral antiplatelet agents in order to reduce the residual risk for thrombotic events in patients with a history of ischemic disease without incremental bleeding risk.

Vorapaxar, formerly SCH 530348, is a novel, potent, orally bioavailable thrombin receptor inhibitor selective for protease-activated receptor-1 (PAR-1), the primary receptor for thrombin on human platelets.14 The present study was undertaken to evaluate the safety of vorapaxar in Japanese patients with a history of ischemic cerebral infarction receiving aspirin.

Section snippets

Subjects

Subjects were men and women aged ≥18 years with stable ischemic stroke occurring ≥14 days to <1 year before randomization with stable neurologic symptoms for at least 24 hours. Major exclusion criteria included the following: Cardiogenic cerebral embolism, bleeding diathesis or abnormal bleeding episode within 30 days, platelet count <100,000/mm3, major surgery within 2 weeks, systolic blood pressure (BP) >200 mm Hg or diastolic BP >110 mm Hg, history of cerebral bleeding or evidence of

Patient Characteristics

Ninety patients were randomized from 19 sites (Table 1). The baseline characteristics across treatment groups were shown in Table 2. For each treatment group, the majority of subjects were male (Table 2). All subjects received the protocol-specified regimen of aspirin. The majority of patients in each treatment group had experienced a previous lacunar stroke (66% in the active treatment groups and 75% in the placebo group; Table 3). The mean (standard deviation) time interval from the most

Discussion

An important platelet activation pathway contributing to thrombosis involves the binding of thrombin to PAR-1.15 Thrombin contributes both to platelet activation and the coagulation cascade.5 Importantly, thrombin-mediated cleavage of fibrinogen into fibrin may be more critical for hemostasis than platelet activation induced by thrombin through PAR-1.15 Preclinical studies have shown that PAR-1 inhibition prevents thrombin-stimulated platelet aggregation and pathogenic thrombus growth without

Acknowledgments

This study and editorial support for the manuscript was funded by Schering-Plough Corporation. We thank Bo Yang for performing the statistical analyses and Joshua Barbach and Sean Gregory for editorial support on the manuscript. We also thank the following investigators as part of the Japanese Stroke Study Group: Akifumi Suzuki (Research Institute for Brain and Blood Vessels Akita), Ban Mihara (Mihara Memorial Hospital), Junichi Maruyama (Asahikawa Rehabilitation Hospital), Jyoji Nakagawara

References (21)

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    Sixteen of these retrieved studies, however, were excluded because they were health technology assessment studies [10] or reviews [11–18], were for nonhuman subjects [19,20], investigated in vitro effect [21], carried out testing in healthy volunteers [22,23], or focused on pharmacokinetics only [24,25], leaving 8 randomized controlled trials (RCTs) as potentially eligible. Furthermore, because one study was dedicated to investigate the therapeutic effect of vorapaxar for patients with a history of ischemia stroke [26], it was excluded eventually. In all, seven RCTs were finally included in our meta-analysis [27–33].

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    This is supported by the results of the TRA-CER trial showing that the rate of bleeding continued to increase over time in patients receiving vorapaxar therapy in conjunction with dual antiplatelet therapy [58]. Accordingly, several trials have also shown excessive bleeding with prolonged dual antiplatelet therapy [67–69]. The effect of the duration of therapy with vorapaxar either as monotherapy or in combination with aspirin and/or a P2Y12 antagonist, on the patients' hemorrhagic risk deserves further investigation.

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    The first potent PAR1 antagonists were SFLLRN-based peptidomimetic ureas, represented by the optimized antagonist RWJ-58259 (Fig. 1) [29], where an indazole ring is used as scaffold to assemble three key pharmacophoric groups (an aromatic and two amines). Later, several laboratories have reported a few series of antagonists obtained from HTS of diverse libraries of non-peptide small molecules, followed by optimization [20,30], such SCH-530348 (named vorapaxar, Fig. 1) [31], currently in Phase III clinical trials [32–34]. Mutagenesis, X-ray, and NMR studies have shown that the first thrombin/PAR1 interaction is produced between the exosite I of thrombin and the hirudin-like sequence of PAR1 (K51YEPF55), and that this first interaction is essential and determinant for high thrombin/PAR1 affinity [35–46].

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Supported by Schering-Plough Corporation.

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