Regulatory Decision Summary for ZONTIVITY

Zontivity (vorapaxar) is a competitive and selective antagonist of the protease-activated receptor-1 (PAR-1) that potently inhibits thrombin-induced platelet aggregation. The efficacy and safety of Zontivity for the reduction of atherothrombotic events was assessed in 17,779 patients with a history of myocardial infarction (MI) and 3,787 patients with peripheral artery disease (PAD) in the randomized, double-blind, placebo-controlled TRAP 20P-TIMI 50 trial.

In the pivotal TRAP 20P-TIMI 50 trial, in patients with a history of MI, Zontivity 2.5 mg (n=8,898) once daily added to standard of care which included acetylsalicylic acid (ASA), with or without clopidogrel, significantly reduced the primary (cardiovascular death [CV] death, MI, stroke and urgent coronary revascularization [UCR], hazard ratio [HR] 0.82; 95% CI 0.74-0.90; p <0.001) and key secondary (CV death, MI and stroke, HR 0.78; 95%CI 0.70-0.88; p <0.001) efficacy composite endpoints compared to those in the placebo group (n = 8,881). These reductions were mostly driven by a reduction in the rates of MI. These effects were similar regardless of the time from qualifying MI to the start of therapy with Zontivity, and were maintained for the duration of the study. However, there was an attenuation of the effect of Zontivity from year 2 to 3, while bleeding risk measured with GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded arteries) scale remained and even increased over time with patient age and co-morbidities. Therefore, based on insufficient evidence to support long-term treatment, the use of Zontivity should be reassessed after 2 years of therapy.

In patients with PAD, there was no statistically significant difference between the Zontivity and placebo groups in the primary and key secondary efficacy composite endpoints, although the numbers of events (CV death, MI, stroke and UCR) were lower in the Zontivity group compared to the placebo group. Therefore, Zontivity has not been indicated for the treatment of PAD.

In patients with a history of MI, bleeding risk was greater for subjects on Zontivity compared to placebo. In particular, patients with a history of stroke or transient ischemic attack (TIA) had an increased risk of intracranial hemorrhage (ICH). The use of Zontivity in these patients has therefore been contraindicated.

Patients weighing <60 kg and patients with severe renal impairment, end-stage renal disease or severe hepatic impairment were also at increased risk of bleeding. The increased risks with these co-morbidities have been included as Warnings and Precautions in the Product Monograph.
 
Compared to placebo, Zontivity prevented 71 CV death, non-fatal MI or ischemic stroke per 10,000 patient-years, while causing 31 additional GUSTO moderate bleeding events, one additional GUSTO severe non-fatal non-ICH event and 0 fatal bleedings. From a number-needed-to-treat (NNT) or number-needed-to-harm (NNH) perspective, 140 patients would need to be treated for one year with Zontivity to prevent one CV death, MI or stroke event, while one in every 7,488 patients and one in every 325 patients treated for one year with Zontivity would have a GUSTO severe non-fatal non-ICH event and a GUSTO moderate bleeding event, respectively.

Based on the information submitted for review, the benefit/risk ratio of Zontivity, co-administered with acetylsalicylic acid (ASA) with or without clopidogrel, for the reduction of atherothrombotic events in adult high-risk patients with a history of myocardial infarction (MI) is considered to be favorable.