The clinical evidence for the effectiveness of ZONTIVITY is supported by TRA 2°P - TIMI 50. TRA 2°P was a multicenter, randomized, double-blind, placebo-controlled study conducted in patients who had evidence or a history of atherosclerosis involving the coronary (spontaneous MI ≥2 weeks but ≤12 months prior), cerebral (ischemic stroke), or peripheral vascular (documented peripheral arterial disease [PAD]) systems. Patients were randomized to receive daily treatment with ZONTIVITY (n=13,225) or placebo (n=13,224) in addition to standard of care. The study's primary endpoint was the composite of cardiovascular death, MI, stroke, and urgent coronary revascularization (UCR). The composite of cardiovascular death, MI, and stroke was assessed as key secondary endpoint. The median follow-up was 2.5 years (up to 4 years).

The findings in all randomized patients for the primary efficacy composite endpoint show a 3-year K-M event rate of 11.2% in the ZONTIVITY group compared to 12.4% in the placebo group (hazard ratio [HR]: 0.88; 95% confidence interval [CI], 0.82 to 0.95; p=0.001).

The findings for the key secondary efficacy endpoint show a 3-year Kaplan-Meier (K-M) event rate of 9.3% in the ZONTIVITY group compared to 10.5% in placebo group (HR 0.87; 95% CI, 0.80 to 0.94; p<0.001).

Although TRA 2°P was not designed to evaluate the relative benefits and risks of ZONTIVITY in individual patient subgroups, patients with a history of stroke or TIA showed an increased risk of ICH. Of the patients who comprised the post-MI and PAD strata and had no baseline history of stroke or TIA,10,080 were randomized to treatment with ZONTIVITY and 10,090 to placebo. These patients were 89% Caucasian, 22% female, and 33% ≥65 years of age, with a median age of 60 years. The population included patients with diabetes (24%) and patients with hypertension (65%). Of the patients who qualified for the trial with MI without a history of stroke or TIA, 98% were receiving aspirin, 78% were receiving a thienopyridine, and 77% were receiving both aspirin and a thienopyridine when they enrolled in the trial. Of the patients who qualified for the trial with PAD without a history of stroke or TIA, 88% were receiving aspirin, 35% were receiving a thienopyridine, and 27% were receiving both aspirin and a thienopyridine when they enrolled.

In post-MI or PAD patients without a history of stroke or TIA the 3-year K-M event rate for the primary efficacy endpoint (composite of time to first CV death, MI, stroke, or UCR) was 10.1% in the ZONTIVITY group compared to 11.8% in the placebo group (HR 0.83; 95% CI, 0.76 to 0.90; p<0.001) (see Figure 5 and Table 3). 

The results for the key secondary efficacy endpoint (composite of time to first CV death, MI, or stroke) show a 3-year K-M event rate of 7.9% in the ZONTIVITY group compared to 9.5% in the placebo group (HR 0.80; 95% CI, 0.73 to 0.89; p<0.001) (see Table 3). 

The effect of chronic dosing with ZONTIVITY on the primary and key secondary endpoints was maintained for the duration of the trial (median follow up 2.5 years, up to 4 years).

In post-MI or PAD patients who survived an on-study efficacy event, the incidence of subsequent events was lower with ZONTIVITY.

The time from the prior MI to randomization had no relationship to the treatment benefit for the primary study outcome.

A range of demographic, concurrent baseline medications, and other treatment differences were examined for their influence on outcomes as shown in Figure 6. Such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.