This editorial refers to ‘Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease’†, by S. Goto et al., on page 2601
Acute coronary syndromes (ACS), which comprise unstable angina (UA), non-ST-elevation acute myocardial infarction (NSTEMI), and ST-segment elevation acute myocardial infarction (STEMI), are a major public health problem. The primary pathophysiological mechanism responsible for the clinical manifestations of ACS involves the formation of platelet-rich thrombi that develop in response to vascular injury (atherosclerotic plaque rupture or erosion of endothelial monolayer). Current management of ACS consists of acute administration of antiplatelet and anticoagulant agents, revascularization procedures [plus reperfusion therapy with lytic agents or percutaneous coronary intervention (PCI) in the case of STEMI], and long-term treatment with antiplatelet agents as well as statins and agents inhibiting the angiotensin pathways. Despite the frequent use of these guidelines and recommended treatments, the residual acute and long-term morbidity and mortality associated with ACS remain high. In a paper presented at the Hotline Session of the ESC in Stockholm 2010 and published in the issue of this journal from the GRACE registry, long-term outcome data after ACS are reported.1 Mortality rates at 5 years of 19% in STEMI, 22% in NSTEMI, and, most astonishing, 17% in patients with UA were observed. More than 80% of the deaths in NSTEMI and UA patients occurred after initial hospital discharge. This high late residual mortality, despite guidelines and recommended treatments in most patients, can be partly attributed to suboptimal antithrombotic therapy and, more specifically, incomplete inhibition of platelet aggregation. New therapies that target pathways that are not affected by aspirin or P2Y12 ADP receptor antagonists could provide more comprehensive inhibition of platelet activation and contribute to greater inhibition of platelet-mediated thrombosis. Inhibition of PAR-1 (protease-activated receptor-1), a receptor for thrombin, is a new approach in the development of novel antiplatelet agents. PAR-1 inhibition, in combination with current dual antiplatelet therapy, could further reduce ischaemic events without significantly increasing bleeding risk. In the large phase II study with vorapaxar (the first PAR-1 inhibitor tested in patients) in 1030 patients with stable coronary artery disease, no increased TIMI bleeding rates were noted, even when given on top of aspirin and clopidogrel.2 Death and major adverse cardiac were numerically lower in the vorapaxar-treated patients.
The first results of the phase II programme with another PAR-1 inhibitor (E5555) have now been published.3 Results from two relatively small, double-blind, randomized, and placebo-controlled Japanese studies are presented: an ACS study in 241 patients and a study in 263 high risk patients with documented, stable coronary artery disease (CAD). Although statistically not significant, higher bleeding rates with E5555 were observed than with placebo in both studies with the higher doses (100 and 200 mg). However, no TIMI major bleedings were found in either study. As with vorapaxar, a numerically lower rate of major adverse cardiac events was also observed with E5555 in both studies. Of concern is the percentage of liver dysfunction observed with E5555 in both studies. With the 100 and 200 mg doses, ALT levels >3 times the upper limit of normal were reported in 6.2 and 14.8%, respectively, of the ACS patients (who also received an upfront bolus of 400 mg of E5555) and 1.5 and 7.2%, respectively, in the stable CAD patients who did not receive a bolus. It is not reported whether this increase in liver enzymes is transient and after how much time it disappears. No signal for possible liver toxicity has been reported so far with vorapaxar. Additionally, a modest but significant prolongation of the QTc interval was reported with the higher doses of E5555. Platelet inhibition of aggregation by thrombin receptor-activating peptide (TRAP) was >90% with the 100 and 200 mg doses but ∼50% with the 50 mg dose.
Overall, the key data obtained with E5555 are in line with those obtained with vorapaxar in that no statistically significant increase in clinically relevant bleeding complications was found and there was a trend towards fewer ischaemic events. It should be noted that, in contrast to the vorapaxar study in which study medication was given for 60 days, the duration of the study treatments was longer with E5555: 12 weeks in the ACS study and 24 weeks in the chronic CAD study. Thus, exposure to this PAR-1 antagonist was longer, which make comparisons of the rates of bleeding events with the two agents impossible. One might also wonder whether the results obtained with E5555 in Japanese patients are also relevant to Caucasian patients. In this regard, a short paper by the same first author with vorapaxar in Japanese ACS patients should be mentioned.4 Additionally, in this Japanese population with ACS, no significant increase in bleeding complications was reported and, surprisingly, a significant reduction in peri-procedural infarction rate was observed with vorapaxar. Thus, most probably the effects of PAR-1 inhibition observed in Japanese patients are also relevant for Caucasian patients.
Taken together, the available data with the two PAR-1 antagonists in patients with ACS and stable CAD suggest that additional platelet inhibition through the thrombin pathway is possible without a significant increase in clinically relevant bleeding complications and is probably associated with a further reduction in ischaemic events on top of that obtained with aspirin and a P2Y12 inhibitor. The future of this type of therapy will be determined by the outcome of phase III trials. Two very large trials with vorapaxar have recruited almost 40 000 patients (TRACER in ACS and TRA2P in chronic CAD).The results are expected in the course of 2011. Whether phase III trials with E5555 will take place is unknown at this moment and will certainly depend on, among other things, a careful analysis of the dose-related efficacy and adverse events observed in this and possibly other studies with this agent.
Adding a third antiplatelet agent to aspirin and a P2Y12 inhibitor for a prolonged period of time is not evident and surely will cause problems of compliance and cost. Even a slight increase in ‘nuisance’ bleedings may result in an interruption of all antithrombotic medications with subsequent recurrence of ischaemia. If the PAR-1 antagonists were to show favourable results in the phase III trials, combinations with aspirin or a P2Y12 antagonist alone should be considered. An alternative approach for obtaining better and longer antiplatelet protection after ACS would be a prolonged (>1 year) treatment with aspirin and a P2Y12 antagonist. This is currently being planned with ticagrelor post-myocardial infarction.
Conflict of interest: F.V.d.W. is a member of the executive committee of the TRACER study.