STOCKHOLM – The selective and reversible platelet inhibitor elinogrel will advance to a 24,000-patient, phase III megatrial on the strength of its encouraging performance in the phase II trial INNOVATE-PCI and other studies.

The phase III trial, due to start in the first quarter of 2011, will focus on patients with chronic coronary heart disease who are on background aspirin after an acute MI that occurred 6 months to 5 years before enrollment. They will be randomized to low- or high-dose oral elinogrel or placebo for roughly 29 months, with a primary efficacy end point comprising cardiovascular death, MI, or stroke, Dr. Sunil Rao announced while presenting the INNOVATE-PCI results at the annual congress of the European Society of Cardiology.

Elinogrel is the only competitive and reversible P2Y12 receptor antagonist. It has a 12-hour half-life. Other available P2Y12 inhibitors include clopidogrel – the standard workhorse in dual antiplatelet therapy – as well as prasugrel and ticlopidine. (Ticagrelor, an investigational oral antiplatelet that is also reversible and has a 12-hour half-life, is under review by the Food and Drug Administration, with a decision expected by the end of the year.)

A major potential advantage for elinogrel is that it can be used in both intravenous and oral preparations. The intravenous form provides near-maximal platelet inhibition within 15 minutes – hours faster than oral antiplatelet drugs – which would be of great benefit in acute coronary syndromes and for percutaneous coronary interventions. The patient could then be smoothly transferred to the oral version of the same platelet inhibitor for long-term therapy, explained Dr. Rao of Duke University, Durham, N.C.

Clopidogrel elicits highly variable patient responses and is ineffective in some patients. That’s not the case for elinogrel. And unlike clopidogrel, elinogrel is reversible, so it may reduce PCI-associated bleeding problems, although this has yet to be established, added Dr. Rao, coprincipal investigator of INNOVATE-PCI.

INNOVATE-PCI was a randomized, double-blind trial in which 652 patients who were undergoing nonurgent PCI were assigned to elinogrel or clopidogrel and followed for 120 days. The main elinogrel regimen consisted of a 120-mg intravenous bolus dose that was administered immediately before balloon inflation, followed by 100 mg or 150 mg of oral elinogrel twice daily for the remainder of the 4-month study. The clopidogrel regimen consisted of a 300-mg or 600-mg oral loading dose that was given up to 12 hours prior to PCI, followed by 75 mg/day.

Both intravenous and oral elinogrel resulted in faster and stronger platelet inhibition than did clopidogrel during acute and chronic therapy. There was no difference between the elinogrel and clopidogrel groups in rates of TIMI (Thrombolysis in Myocardial Infarction) major or minor bleeding or clinically relevant bleeding at either the 24-hour or 120-day assessments.

The elinogrel group did show a dose-dependent increase in less-severe bleeding requiring medical attention. These events mainly consisted of periprocedural hematomas at the vascular access site. But only about one-quarter of study participants underwent PCI using the radial approach, which is known to greatly reduce the frequency of such bleeding. As the radial approach grows in popularity – it was utilized in a clear majority of PCI patients in several other studies presented at the Stockholm congress – mild bleeding problems at the vascular access site will arise markedly less often than when femoral access was the rule, the cardiologist predicted.

Dyspnea occurred in 4.3% of the clopidogrel group during 120 days of follow-up, and was roughly threefold more common with elinogrel. The dyspnea was generally mild and transient, and seldom led to treatment discontinuation.

Elevated liver enzymes (greater than three times the upper limit of normal) occurred in 1% of the clopidogrel group and in 4.0% and 4.8% of the elinogrel 100-mg and 150-mg twice daily arms, respectively. Most cases occurred within the first 60 days, none involved serious hepatotoxicity, and all resolved even though treatment continued.

INNOVATE-PCI was not sufficiently powered to look at efficacy end points. This will happen in future studies of elinogrel in the setting of acute coronary syndrome and PCI. But the first phase III clinical trial of elinogrel will focus on chronic coronary heart disease patients because they are a population with a very high event rate and few treatment options.

“This is an indication that sorely needs new agents,” Dr. Rao emphasized.

Discussant Dr. Steen Dalby Kristensen said INNOVATE-PCI showed “quite convincingly” that elinogrel works faster and is a more efficient platelet inhibitor than clopidogrel, a drug with known disadvantages.

The elinogrel-induced liver enzyme elevations could be a matter of concern, however. Only further studies can resolve this issue, added Dr. Kristensen of Aarhus (Denmark) University.

Dr. Rao is a consultant to Novartis, which is developing elinogrel. Dr. Kristensen disclosed that he has received research grants from and serves as a consultant to numerous pharmaceutical companies that have an interest in platelet-inhibiting drugs.

Novel Antiplatelet Drug Elinogrel Moves Into Phase III Testing