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INNOVATE PCI: A Phase II Safety and Efficacy Study of PRT060128 (Elinogrel), a Novel Intravenous and Oral P2Y12 Inhibitor, in Non-Urgent PCI.

Invasive and Interventional Cardiology, Cardiovascular Surgery




Sunil Rao
  Presenter
Presenter | see Discussant report Webcasts become available 24h after the session
Rao, Sunil
(United States of America)
Open presentation slides

List of Authors:
Sunil V. Rao MD, Uwe Zeymer MD, Vivian Thompson MPH, Kurt Huber MD, Janusz Kochman MD, Matthew W. McClure MD, Daniel D. Gretler MD, Deepak L. Bhatt MD MPH, C. Michael Gibson MD, Mina Madan MD, Lisa Berdan, Gayle Paynter RN MBA MHA, Sergio Leonardi MD, Robert A. Harrington MD, Robert Welsh MD

Abstract:

Background:
Currently available options for oral antiplatelet therapy are limited by variability of response and/or increased risk for major bleeding. Elinogrel is a novel oral and intravenous (IV) P2Y12 inhibitor that does not require metabolic activation and provides rapid, intense, competitive and reversible platelet inhibition.

Methods:
We performed a randomized, double-blind, triple dummy, active-controlled, parallel-group, dose-ranging Phase 2 trial to evaluate the safety and tolerability of IV and oral elinogrel in 652 patients undergoing non-urgent percutaneous coronary intervention (PCI). Patients were assigned to receive pre-PCI clopidogrel 300 or 600 mg followed by 75mg once daily or elinogrel 80 mg IV bolus followed by 50 mg, 100 mg, or 150 mg of oral elinogrel twice daily. The trial was not powered for any specific endpoint, and a range of clinical and biological endpoints was examined. Efficacy measures included short- and intermediate-term death, myocardial infarction, ischemic stroke, urgent target vessel revascularization, stent thrombosis, or urgent GP IIb/IIIa bail out.
Biological efficacy endpoints included the proportion of patients experiencing any troponin elevation or troponin elevation 2 X the upper limit of normal after PCI. Safety measures consisted of short- and intermediate-term bleeding defined as Clinically Relevant Major, Minor, or Nuisance Bleeding as well as TIMI Major and Minor Bleeding and Bleeding Requiring Medical Attention (BRMA). Pharmacodynamic studies were performed on a subset of patients. Short-term outcomes were assessed at 24 hours post-PCI or at hospital discharge, whichever occurred first.
The patients were initially followed for 60 days, but the protocol was amended to extend follow-up to 120 days. In addition, the DSMC recommended to discontinue enrollment into the 50mg oral dose arm and increase the IV dose of elinogrel to 120mg as described in the protocol. Enrollment into the 50 mg oral dose arm of elinogrel was discontinued after 116 patients had been enrolled. The IV dose of elinogrel was increased to 120mg after 177 patients had been enrolled. 590 patients were followed for 60 days and 328 patients were followed for 120 days.

Results:
The median age of the patients was 61 years and 77% were male. Approximately 30-40% of the patients had diabetes mellitus and 46% were on maintenance clopidogrel at the time of enrollment. Pharmacodynamic data were available on 52 patients, 75% of whom were on maintenance clopidogrel at the time of enrollment. Using light transmittance aggregometry and 5 micromolar ADP, IV and oral elinogrel resulted in greater platelet inhibition than clopidogrel at the peri-PCI and 30-day timepoints. There was no excess of TIMI Major or Minor bleeding with elinogrel at either the 24-hour or 120-day timepoints. There was a dose-dependent increase in BRMA across the elinogrel arms, mostly occurring in the periprocedural period. There were no significant differences in efficacy measures at either the 24-hour or 120-day timepoints between elinogrel and clopidogrel. Adverse events were similar between elinogrel and clopidogrel, with the exception of dyspnea, which was more common among patients assigned to elinogrel. In addition, there were more cases of liver transaminase elevation, predominantly occurring within 60 days of enrollment, in the elinogrel arms with a possible dose-response, but no Hy’s Law cases.

Conclusions:
The results of the INNOVATE-PCI Phase 2 trial demonstrate that despite greater platelet inhibition with elinogrel compared with standard doses of clopidogrel, there was no increase in TIMI Major or Minor bleeding in the peri-PCI period or during follow-up. While the trial was not powered for efficacy, there were no significant differences in clinical or biological efficacy endpoints across the treatment arms. These data support the further investigation of this novel compound in patients with ischemic heart disease.



Steen Dalby Kristensen, FESC
  Discussant
Discussant | see Presenter abstract Webcasts become available 24h after the session
Kristensen, Steen Dalby
(Denmark)
Department of Cardiology, Aarhus University Hospital Skejby, Denmark. Open presentation slides

Report:

Inhibition of the platelet ADP P2Y12 receptor is a corner stone in anti-platelet therapy. The well established drug, clopidogrel, is now known to cause a great variation in the inhibition of platelet aggregation among patients, and a low platelet inhibitory response has been shown to be related to an increased clinical event rate. A low response is often caused by an inadequate generation of the active metabolite of clopidogrel, which in part is due to genetic induced changes in the CYP enzyme system.

New oral P2Y12 inhibitors, such as the irreversible inhibitor prasugrel and the reversible inhibitor ticagrelor have been shown to improve clinical outcome in patients with acute coronary syndromes. Immediate reversible blockade of the P2Y12 receptor is attractive in the acute setting and an intravenous direct acting reversible inhibitor cangrelor has been developed. Cangrelor has in large trials not been shown to be superior to clopidogrel, maybe because switching between cangrelor and clopidogrel causes a temporary insufficient inhibition of the P2Y12 receptor.

An interesting new direct acting reversible P2Y12 inhibitor elinogrel is available both in an i.v. formulation and also as an oral drug. The reversibility of the drugs makes it particularly attractive in a context where surgery might be necessary. Also this drug has advantages in case of severe bleeding.

The INNOVATE PCI study is a randomized double blind phase II study to assess different doses of elinogrel compared to conventional doses of clopidogrel in patients undergoing elective PCI. The aim of the study was to examine a number of clinical and biological end-points in order to evaluate the efficacy and safety of the new drug in different doses. The study was not statistically powered for any specific end-point. Furthermore pharmacokinetic and pharmacodynamic data were collected in a subset of trial participants.

The study showed that elinogrel given i.v. and followed by oral administration in different doses caused a faster onset and a stronger inhibition of platelet aggregation compared to clopidogrel 300-600 mg loading dose followed by 75 mg daily. There was no statistically significant difference in bleeding, although there was a trend towards a higher frequency of bleedings requiring medical attention in the high dose elinogrel group. Clinical efficacy evaluated by different combined ischaemic end-points showed no difference between the two drugs. In patients treated with elinogrel, dyspnoea and elevation of transaminases occurred more frequently.

In conclusion, this interesting phase II trial gives promises for elinogrel as a new intravenous and oral reversible P2Y12 receptor blocker. The drug should be tested in phase III trials and has potential advantages in particular in patients with acute coronary syndromes undergoing invasive therapy.

References


707001 - 707002

SessionTitle:

Hot Line II - Coronary artery disease
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.