INtraveNous and Oral administration of elinogrel to eVAluate Tolerability and Efficacy in nonurgent PCI patients - INNOVATE PCI

Jun 20, 2012
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Christopher P. Cannon, MD, FACC
Trial Sponsor:
Portola Pharmaceuticals
Date Presented:
01/01/2010
Date Published:
01/01/2012
Date Updated:
06/20/2012
Original Posted Date:
06/20/2012
References

Description:

The goal of the trial was to evaluate treatment with the intravenous (IV) and oral P2Y12 receptor inhibitor (elinogrel) compared with clopidogrel during nonurgent percutaneous coronary intervention (PCI). Elinogrel is a direct acting reversible agent, which competitively binds to the P2Y12 receptor. This is a phase 2b dose-finding study for elinogrel.

Hypothesis:

IV and oral elinogrel will result in faster and greater platelet inhibition at the time of PCI.

Study Design

  • Parallel
  • Randomized
  • Blinded

Patient Populations:

  • Patients 18-75 years of age undergoing nonurgent PCI of at least one coronary lesion

    Number of enrollees: 652
    Duration of follow-up: 4 months
    Mean patient age: median 61 years
    Percentage female: 23%

Exclusions:

  • Anemia/thrombocytopenia
  • Recent trauma/bleeding
  • Stroke or transient ischemic attack within the last 5 years
  • Clopidogrel load (≥300 mg) within the last 7 days
  • Use of thrombolytics, anticoagulates, or fondaparinux
  • Age >75 years
  • Weight <55 kg
  • Creatinine clearance <45 cc/min
  • Allergy to study medication
  •  Acute coronary syndrome within the last 7 days
  • Planned staged PCI
  • Planned use of glycoprotein IIb/IIIa inhibitor
  • Planned surgery within the study period

Primary Endpoints:

  • TIMI major/minor bleeding
  • Bleeding requiring medical attention
  • Clinically relevant major/minor/nuisance bleeding

Secondary Endpoints:

  • Troponin elevation >2 x upper limit of normal at 24 hours
  • Death, MI, stroke, revascularization, bailout glycoprotein IIb/IIIa inhibitor use, or stent thrombosis at 24 hours
  • Death, MI, stroke, or revascularization at 4 months
  • Death, MI, stroke, revascularization, or stent thrombosis at 4 months

Drug/Procedures Used:

Patients undergoing nonurgent PCI were randomized to one of four groups prior to PCI: 1) elinogrel 80 mg IV, then 50 mg oral twice daily; 2) elinogrel 80 mg IV, then 100 mg oral twice daily; 3) elinogrel 80 mg IV, then 150 mg oral twice daily; or 4) clopidogrel 300-600 mg, then 75 mg daily.

After the trial began, the Data Safety and Monitoring Board recommended increasing the IV dose of elinogrel from 80 mg to 120 mg and discontinuing the 50 mg twice daily arm. The chronic phase was also extended from 2 to 4 months.

Principal Findings:

Overall, 652 patients were randomized. In the pooled elinogrel 100/150 mg group, the median age was 61 years, 23% were women, body mass index was 29 kg/m2, 36% had diabetes, 46% were on chronic clopidogrel therapy, and femoral access was used in 76%.

Inhibition of platelet aggregation was greater with elinogrel versus clopidogrel.

There were no TIMI major bleeds in any group. TIMI major/minor or bleeding requiring medical attention occurred in 8.8% of the pooled 100/150 mg elinogrel group and 3.8% of the clopidogrel group.

Ischemic outcomes are similar across the study groups. Death, MI, stroke, or revascularization occurred in 7.7% of the pooled elinogrel 100/150 mg group, versus 4.8% of the clopidogrel group (p = NS).

At least one adverse event occurred in 69.9% of the pooled elinogrel 100/150 mg group, and 61.5% of the clopidogrel group. Dyspnea occurred in 12.3%, versus 3.8%, whereas alanine aminotransferase (ALT)/aspartate aminotransferase (AST) >3 x upper limit of normal occurred in 4.4%, versus 1.0%, respectively.

Interpretation:

Among patients undergoing nonurgent PCI, elinogrel did not increase TIMI major bleeds; however, access site bleeds that required medical attention were numerically higher with elinogrel. Similar to ticagrelor, dyspnea was more common with the study drug. Certain properties of elinogrel are attractive such as the IV and oral formulations, which can be used for acute and chronic settings; however, the increase in liver enzymes will need to be carefully monitored during future phase III studies.

References:

Welsh RC, Rao SV, Zeymer U, et al., on behalf of the INNOVATE PCI Investigators. A Randomized, Double-Blind, Active-Controlled Phase 2 Trial to Evaluate a Novel Selective and Reversible Intravenous and Oral P2Y12 Inhibitor Elinogrel Versus Clopidogrel in Patients Undergoing Nonurgent Percutaneous Coronary Intervention: The INNOVATE PCI Trial. Circ Cardiovasc Interv 2012;5:336-346.

Presented by Dr. Sunil Rao at the European Society of Cardiology Congress, Stockholm, Sweden, August 2010.

Keywords: Stroke, Follow-Up Studies, Body Mass Index, Platelet Aggregation Inhibitors, Coronary Disease, Ticlopidine, Dyspnea, Angioplasty, Balloon, Coronary, Diabetes Mellitus


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