By Paul A. Gurbel, MD, and Udaya S. Tantry, PhD

Dual antiplatelet therapy (DAPT) with aspirin, a platelet cyclooxygenase (COX)-1 inhibitor, and P2Y₁₂ receptor blockers remains the major drug strategy to prevent ischemic event occurrence in patients with acute coronary syndrome (ACS) and patients undergoing coronary stenting. Although the new P2Y₁₂ inhibitors prasugrel and ticagrelor are associated with lower ischemic event occurrence compared with clopidogrel in patients with ACS, events are reduced by only ~20%, and absolute risk by only ~2%. These sobering observations suggest that, since the level of P2Y₁₂ blockade is uniformly high with newer agents, there is a ceiling effect with the current DAPT strategy. Perhaps residual ischemic event occurrence is mediated by platelet-signaling pathways that are unblocked by DAPT or by non-platelet mechanisms.

On May 8, 2014, the Food and Drug Administration approved vorapaxar, a first-in-class novel protease-activated receptor 1 (PAR-1) antagonist, to reduce the risk of myocardial infarction (MI), stroke, cardiovascular death, and revascularization in patients with a previous MI or peripheral arterial disease (PAD).

Ups and Downs on the Road to Approval
In phase I and II studies, vorapaxar markedly inhibited the platelet PAR-1 receptor without affecting the response to other platelet agonists or coagulation parameters. After a single loading dose, platelet function was inhibited for up to 3 weeks (with a plasma half-life of 5-11 days).¹ Vorapaxar's safety and efficacy were evaluated in two major phase III trials: TRACER and TRA 2°P TIMI-50.

TRACER tested whether vorapaxar plus standard therapy was superior to placebo in reducing ischemic cardiovascular event occurrence, as well as whether the PAR-1 inhibitor was safe in 12,944 patients with non-ST-elevation ACS. Vorapaxar (40 mg loading dose, 2.5 mg daily maintenance) led to significantly higher rates of intracranial hemorrhage (ICH) than placebo, resulting in premature termination of the study.

When added to aspirin and a P2Y₁₂ inhibitor, vorapaxar did not significantly reduce any of the primary endpoints (composite of cardiovascular death, MI, stroke, hospitalization for ischemia, or urgent revascularization; 2-year definite or probable stent thrombosis; or cardiovascular death). Further, moderate and severe bleeding were increased 1.35-fold and ICH 3.39-fold.²

TRA2°P-TIMI 50 tested a broader hypothesis: is the intensification of antiplatelet therapy by adding an agent with a different pharmacologic target beneficial for secondary prevention in patients with stable disease and a history of MI, ischemic stroke, or PAD? More than 24,000 patients with a history of spontaneous MI or ischemic stroke within 2 weeks to 12 months or PAD were treated with 2.5 mg/day vorapaxar therapy or placebo in addition to standard care. When investigators noted an alarming rate of ICH among patients with prior stroke, the DSMB recommended the PAR-1 inhibitor be discontinued in these patients, as well as those who suffered a stroke during the study. Other amendments were also made during the study period, including a reversal in the primary and secondary endpoints (based on the TRACER results) and an increase in sample size.

Overall, vorapaxar was associated with a significantly lower rate of the primary composite endpoint of 3-year cardiovascular death, MI, or stroke, but with an increase in the primary safety endpoint of GUSTO moderate or severe bleeding and ICH.³

The FDA based its approval of vorapaxar on the post-hoc analysis of "the proposed label population"—the 64% of patients in the post-MI group with no history of stroke or TIA. In this group, vorapaxar versus placebo significantly reduced ischemic events:

• composite of cardiovascular death, MI, and stroke: 7.4% vs. 9.0% (HR = 0.78; p < 0.001)
• MI: 4.6 vs. 5.7% (HR = 0.80; p < 0.001)
• composite of cardiovascular death, MI, stroke, and urgent coronary revascularization: 9.8% vs. 11.4% (HR = 0.82; p < 0.001)

In terms of safety, vorapaxar significantly increased GUSTO moderate/severe and major/minor TIMI bleeding versus placebo, and nonsignificantly increased ICH. The net clinical outcome favored vorapaxar therapy in the proposed population with five fewer fatal events, 45 fewer nonfatal serious events, but 33 additional GUSTO moderate bleeding events.

Examining the Evidence
There are some issues worth mentioning. First, the exclusion of patients with acute symptoms appears inconsistent with the pathophysiology of coronary ischemic event occurrence. Early after ACS or PCI, clinical vascular disease activity is at its zenith and thrombin generation is high—as is platelet reactivity and activation. Inhibition of the PAR-1 receptor, in addition to the inhibition of COX-1 enzyme and P2Y₁₂ receptor, may provide additional protection against ischemic event occurrence in selected patients.

Next, the proposed 2-week wait time after MI for the initiation of vorapaxar may be a less-than-optimal strategy in patients with heightened thrombin generation and response to thrombin. It remains unclear, though, how important the "platelet thrombin receptor pathway" is in the genesis of in vivo thrombus compared to the "ADP receptor pathway." Vorapaxar may exert its therapeutic benefit through non-platelet effects, particularly for select patients with heightened platelet reactivity and hypercoagulability who may have a lower risk for bleeding.

It is also important to note that experience with vorapaxar in combination with the new P2Y₁₂ receptor blockers is essentially nonexistent. Vorapaxar with ticagrelor or prasugrel may more significantly increase bleeding than when used with clopidogrel. Moreover, the estimated number to treat and number needed to harm may favor DAPT with more potent P2Y₁₂ receptor blockade versus triple therapy with vorapaxar plus clopidogrel. Finally, there was no benefit of vorapaxar regarding the hardest efficacy endpoint: cardiovascular mortality.

In summary, vorapaxar provides an additional therapeutic option that is associated with an anti-ischemic benefit at an acceptable bleeding risk for a selected patient population. Although the benefits of vorapaxar have been explained largely by inhibition of platelet PAR-1, PAR-1 blockade elsewhere in the vasculature may also play a role.

References

1. Gurbel PA, et al. Expert Opin Investig Drugs. 2011;20:1445-53.
2. Tricoci P, et al. N Engl J Med. 2012;366:20-33.
3. Morrow DA, et al. N Engl J Med. 2012;366:1404-13.