Abstract

Selecting patients of appropriate risk is a seminal element of any clinical trial methodology. However, inappropriate risk markers may result in selecting patients with unintended risk levels. We aimed to review systematically the outcomes of randomized clinical trials of antithrombotics in acute coronary syndromes (ACS) in relation to the inclusion risk markers, dividing them into groups reflecting increased hemodynamic (for example Killip>1, ejection fraction<40%) or bleeding risks (for example renal failure, elderly age). According to our analysis, the trials including increased bleeding risk selection criteria were significantly related to the trial outcome of increased bleeding. Conclusions: Results of antithrombotic trials in ACS may be related to the kind of patients’ selection criteria rather than the drug efficacy/safety. We also provide a conceptual basis for avoiding the pitfalls, which will help future researchers to design and carry out robust studies. Implications for clinical practice, sponsors and regulators are highlighted.

Highlights

  • There are a growing proportion of antithrombotic clinical trials in acute coronary syndromes (ACS), which by so called “enrichment” design include patients with higher baseline risk for primary outcomes

  • The enrichment ensures increased number of relevant events within a smaller population. In practice it is attained by adding various combinations of higher risk entry criteria, including: acute heart failure, lower ejection fraction, diabetes, elderly age, impaired renal function, TIMI or GRACE risk scores, etc, according to the classic concept of risk

  • We identified randomized multicenter cardiovascular clinical trials reflecting the contemporary practice of care in acute coronary syndromes, i.e. double antiplatelet therapy, and intended invasive management of the majority of patients, percutaneous intervention with routine stenting, fulfilling additional criteria – (1) primary efficacy endpoints based on “hard” clinical events including: death, myocardial infarction, revascularization, heart failure, objective ischemia, re-hospitalization for ischemia, or combination thereof, (2) predefined primary safety endpoints, (3) in the case of mixed population the majority of patients with acute coronary syndromes

Read more

Summary

Introduction

There are a growing proportion of antithrombotic clinical trials in acute coronary syndromes (ACS), which by so called “enrichment” design include patients with higher baseline risk for primary outcomes This is one of the critical aspects of any trial design, regulated by Food and Drug Administration draft guidance [1]. The selection of patients with large hemodynamic threat but low risk for bleeding (right lower quadrant of Figure 1) may “inflate” the efficacy and conceal complications of the therapy tested. These scenarios suggest that uncontrolled choice of the trial selection criteria may influence the study outcomes rather than the drug action, creating opportunities for either intentional or unintentional trial misconduct

Objectives
Methods
Results
Discussion
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.