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Shift from surrogate end point to outcome trials: implications for cardiovascular safety assessment in development

J F Marcinak1, P Viswanathan, V Arora

  • 1Takeda Global Research & Development Center, Inc., Deerfield, Illinois, USA. john.marcinak@tgrd.com

Clinical Pharmacology and Therapeutics
|November 25, 2011
PubMed

Insights

Adding extended cardiovascular endpoints, including hospitalization for unstable angina or coronary revascularization, to clinical trials for type 2 diabetes may improve trial feasibility. This broader definition (Extended MACE) can enhance the detection of treatment effects compared to standard endpoints (Core MACE).

Area of Science:

  • Cardiology
  • Clinical Trials
  • Diabetes Mellitus

Background:

  • Cardiovascular (CV) outcome trials are crucial for evaluating antidiabetic medications.
  • Standard composite endpoints (Core MACE) include CV death, stroke, and myocardial infarction.
  • Low event rates in recent trials necessitate longer study durations.

Purpose of the Study:

  • To assess the impact of including hospitalization for unstable angina and coronary revascularization (Extended MACE) on CV outcome trials.
  • To evaluate if Extended MACE criteria improve the feasibility of CV outcome trials in patients with type 2 diabetes.
  • To model the required duration for CV outcome trials based on different endpoint definitions.

Main Methods:

  • Analysis of clinical trials with ≥1 year duration and >1,000 subjects.
  • Estimation of Annual Event Rates (AERs) for Core MACE in type 2 diabetes patients.
  • Modeling of trial duration needed to exclude an 80% risk increase using Core MACE and Extended MACE.

Main Results:

  • Hazard ratios for Core MACE were consistently ≤1.0 across studies.
  • In 21% of studies, Extended MACE showed hazard ratios >1, indicating discordance with Core MACE.
  • AERs for Core MACE varied from 0.5% to 6%, with lower rates in recent programs increasing required trial duration.

Conclusions:

  • Extending MACE criteria to include hospitalization for unstable angina or revascularization is unlikely to obscure CV risk.
  • The addition of Extended MACE endpoints may enhance the feasibility of CV outcome trials.
  • Broader endpoint definitions can potentially shorten the required duration for clinical trials in type 2 diabetes.

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