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Novel antithrombotic approaches to coronary artery disease
1Department of Cardiology, Cleveland Clinic Foundation, Ohio 44195.
Abstract:
Current prevention or treatment of coronary thrombosis relies on antiplatelet agents (aspirin), antithrombin agents (heparin), and plasminogen activators (t-PA). The purpose of this review is to describe novel antithrombotic agents in each of these classes and to discuss recent and future clinical trials with the new agents. Whereas aspirin is a cyclo-oxygenase inhibitor, the most promising new antiplatelets are directed at an integrin cell surface receptor--glycoprotein (GP) IIb/IIIa--which represents the final common pathway for platelet aggregation. The monoclonal F(ab) antibody c7E3, a chimeric murine-human immunoglobulin G (IgG) fragment, is the most intensively studied to date. c7E3 was assessed by the Evaluation of Platelet Monoclonal Antibody to Prevent Ischemic Complications (EPIC) trial in which 2,099 high-risk angioplasty patients were randomized to bolus (placebo) plus infusion (placebo), bolus (c7E3, 0.25 mg/kg) plus infusion (placebo), and bolus (c7E3, 0.25 mg/kg) plus infusion (c7E3, 10 micrograms/min; 12 hours). The overall event rate at 30 days was significantly decreased from 12.8% (placebo) to 8.3% (c7E3), a 36% relative reduction (p = 0.009). Integrelin is a cyclic heptapeptide with marked specificity for GP IIb/IIIa integrin. It was studied during the Integrelin to Manage Platelet Aggregation to Prevent Coronary Thrombosis (IMPACT) trial, which enrolled 150 routine coronary intervention patients. At endpoint, overall event rate was reduced from 11.9% (placebo) to 5.6% (integrelin). The much larger (4,010 patients) IMPACT-II trial has just completed enrollment to confirm and extend these encouraging results. Hirudin is the prototype of the direct antithrombins; it binds to the active catalytic site and the substrate recognition site (exosite) of thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Novel antiplatelet agents targeting glycoprotein (GP) IIb/IIIa show promise in preventing coronary thrombosis. Trials like EPIC and IMPACT demonstrate significant reductions in event rates for patients receiving these new antithrombotic therapies.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Hematology
Background:
- Current coronary thrombosis prevention utilizes aspirin, heparin, and t-PA.
- Emerging antithrombotic agents offer targeted mechanisms beyond traditional therapies.
- Glycoprotein (GP) IIb/IIIa inhibitors represent a novel class targeting platelet aggregation.
Purpose of the Study:
- To review novel antithrombotic agents across established classes.
- To discuss recent and future clinical trials involving these new agents.
- To highlight advancements in antiplatelet, antithrombin, and plasminogen activator therapies.
Main Methods:
- Review of clinical trials for new antiplatelet agents, including c7E3 (monoclonal antibody) and Integrelin (cyclic heptapeptide).
- Analysis of the EPIC trial (2,099 high-risk angioplasty patients) evaluating c7E3 efficacy.
- Assessment of IMPACT and IMPACT-II trials (150 and 4,010 patients, respectively) for Integrelin.
Main Results:
- The EPIC trial showed a 36% relative reduction in 30-day event rates with c7E3 compared to placebo (8.3% vs. 12.8%).
- The IMPACT trial demonstrated a reduction in overall event rates from 11.9% (placebo) to 5.6% (Integrelin).
- New agents like c7E3 and Integrelin show significant potential in reducing thrombotic events.
Conclusions:
- Novel antiplatelet agents targeting GP IIb/IIIa integrin receptor are effective in reducing thrombotic events.
- Clinical trials confirm the efficacy of agents like c7E3 and Integrelin in high-risk cardiovascular patients.
- Further research and trials are ongoing to establish the role of these advanced antithrombotic therapies.