Safety and Tolerability of SCH 530348 in Patients Undergoing Non-Urgent Percutaneous Coronary Intervention - TRA-PCI

Mar 17, 2009
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Schering-Plough Research Institute
Date Published:
01/01/2009
Date Updated:
03/17/2009
Original Posted Date:
03/17/2009
References

Description:

The goal of the trial was to evaluate treatment with the platelet thrombin receptor (specifically the PAR-1 receptor) antagonist SCH 530348 compared with placebo in patients undergoing elective percutaneous coronary intervention (PCI).

Hypothesis:

SCH530348 would be more effective at reducing major and minor bleeding.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patients Enrolled: 1,030
Mean Follow Up: 4 months
Mean Patient Age: 63 years
Female: 30%

Patient Populations:

  • Patients at least 45 years of age undergoing elective PCI
  • No planned use of a glycoprotein IIb/IIIa inhibitor
  • Women of child-bearing age were eligible to participate if they used an acceptable form of contraception

Exclusions:

  • Pregnancy
  • Serious illness that would interfere with participation in the study
  • Hypersensitivity to any study medication
  • Enrollment in another investigation drug trial within the last 30 days
  • Ongoing chest pain prior to PCI
  • Bleeding disorder or active bleeding
  • Recent stroke or transient ischemic attack
  • History of hemorrhagic stroke
  • Uncontrolled hypertension (systolic >200 mm Hg or diastolic >110 mm Hg)
  • New York Heart Association class III or IV
  • Thrombocytopenia
  • Uncontrolled arrhythmia
  • Renal insufficiency, dysproteinemia, or nephrotic syndrome
  • Active liver disease
  • Elevated liver transaminases
  • Recent major surgery
  • Recent use of a glycoprotein IIb/IIIa inhibitor
  • Use of an investigational antiplatelet or antithrombin agent
  • Planned staged PCI
  • Expected use of warfarin
  • Expected use of brachytherapy

Primary Endpoints:

  • TIMI major or minor bleeding

Secondary Endpoints:

  • Overt and clinically important bleeding that did not meet the definition of TIMI major bleeding
  • Platelet aggregation
  • Composite of cardiovascular death, MI, or stroke
  • Individual components of the composite cardiovascular outcome

Drug/Procedures Used:

Patients with coronary artery disease undergoing elective coronary angiography or PCI were randomized to oral SCH 530348 (10 mg, n = 222; 20 mg, n = 238; 40 mg, n = 313) versus placebo (n = 257). Patients were also randomized to a maintenance dose of SCH 530348 (0.5 mg, 1 mg, or 2.5 mg daily). Patients who received a placebo loading dose were continued on daily placebo for maintenance. Study medications were continued for 60 days.

On the day of the procedure, patients received aspirin (orally or intravenously) and clopidogrel (300-600 mg) prior to PCI. Patients received unfractionated heparin, low molecular weight heparin, or bivalirudin according to operator discretion.

Concomitant Medications:

Concomitant medications at the time of catheterization in the SCH 530348 groups were: aspirin 94%, clopidogrel 67%, heparin 35%, bivalirudin 26%, and glycoprotein IIb/IIIa inhibitor 5.

Principal Findings:

Overall, 1,030 patients were randomized. The mean age was 63 years, 30% were women, body mass index was 30 kg/m2, 34% were diabetics, and 35% had a previous myocardial infarction (MI).

The primary outcome, Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding, occurred in 3% of the combined SCH 530348 group versus 3% of the placebo group (p = NS). By SCH 530348 loading dose, TIMI major or minor bleeding was 2% with 10 mg, 3% with 20 mg, and 4% with 40 mg. By SCH 530348 maintenance dose, TIMI major or minor bleeding was 2% with 0.5 mg daily, 4% with 1 mg daily, and 3% with 2.5 mg daily. Most bleeding was due to arterial access, epistaxis, or gingival bleeding, and most events occurred during the hospitalization.

Death, MI, or stroke occurred in 5% of the combined SCH 530348 group versus 7% of the placebo group (p = NS). There were no cerebrovascular events or deaths attributable to the study drug.

Interpretation:

Among patients undergoing elective PCI and treated with aspirin, clopidogrel, and an antithrombin agent, SCH 530348 appeared to be safe and well tolerated. This agent was associated with similar TIMI major and minor bleeding compared with placebo. Moreover, there appeared to be similar adverse cardiac events between the groups.

This is a novel platelet thrombin receptor inhibitor that acts complementary to aspirin and clopidogrel. Phase III trials are now required (and are ongoing) to more precisely determine the efficacy and safety of this agent. Studies are also needed to determine how this agent will fit into our current antiplatelet/antithrombin armamentarium.

References:

Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomized, double-blind, placebo-controlled phase II study. Lancet 2009;373:919-28.

Keywords: Myocardial Infarction, Stroke, Platelet Aggregation Inhibitors, Heparin, Low-Molecular-Weight, Receptors, Thrombin, Blood Platelets, Ticlopidine, Pyridines, Hirudins, Purinergic P2Y Receptor Antagonists, Epistaxis, Percutaneous Coronary Intervention, Receptor, PAR-1, Contraception, Body Mass Index, Coronary Angiography, Lactones, Peptide Fragments, Recombinant Proteins, Diabetes Mellitus


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