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Comparison of Outcome Adjudication by Investigators and by a Central End Point Committee in Heart Failure Trials:
Benoît Tyl1, José Lopez Sendon2, Jeffrey S Borer3,4
1CardioVascular & Metabolic Disease Center for Therapeutic Innovation (B.T., C.V.), Institut de Recherches Internationales Servier, Suresnes, France.
Insights
Central end point committees (CECs) confirmed most events in heart failure (HF) trials, with minimal impact on ivabradine
Area of Science:
- Cardiology
- Clinical Trials
- Heart Failure Research
Background:
- The role of central end point committees (CECs) in heart failure (HF) trials is not well-established.
- Assessing the impact of CEC adjudication on trial outcomes is crucial for improving trial methodology.
Purpose of the Study:
- To evaluate the effect of central adjudication by CECs on the outcomes of the Systolic HF Treatment With the If Inhibitor Ivabradine Trial (SHIFT).
- To compare endpoint assessments made by investigators versus a CEC in a large HF clinical trial.
Main Methods:
- The SHIFT trial was a randomized, placebo-controlled study involving 6505 HF patients with reduced ejection fraction.
- Prespecified endpoints, including deaths and hospitalizations, were reported by investigators and adjudicated by a CEC.
- A comparison was made between investigator-adjudicated endpoints and CEC-adjudicated endpoints.
Main Results:
- The CEC confirmed the majority of endpoints assessed by investigators, including 98.1% of cardiovascular deaths and 84.4% of hospitalizations for worsening HF.
- Differences in adjudication between investigators and the CEC did not significantly alter the study's primary composite endpoint results.
- Hazard ratios for the primary endpoint and its components remained consistent between investigator and CEC assessments.
Conclusions:
- Central adjudication by CECs in the SHIFT trial largely confirmed investigator assessments without significantly changing the overall study results.
- The findings suggest that the benefits of CECs in blinded HF trials warrant reconsideration.
- Further evaluation is needed to determine the optimal role of CECs in HF clinical trials.
Background:
The usefulness of adjudication by central end point committees (CECs) is poorly assessed in heart failure (HF) trials. We aimed to assess its impact on the outcome of the SHIFT trial (Systolic HF Treatment With the If Inhibitor Ivabradine Trial).
Methods:
SHIFT was a randomized placebo-controlled trial investigating the effect of ivabradine in 6505 HF patients with reduced ejection fraction. Prespecified end points, reported by investigators (all cardiologists) using specific case report form pages, included all-cause and specific causes of deaths and hospitalizations. The primary end point was a composite of cardiovascular deaths or hospitalizations for worsening HF. We compared the adjudication of prespecified end points made by investigators and by the CEC.
Results:
Investigators identified 7529 prespecified end points, 6793 of which were confirmed by the CEC: 98.1% of cardiovascular deaths, 88.6% of all hospitalizations, and 84.4% of hospitalizations for worsening HF. These differences had no meaningful impact on the study results; hazard ratio for the primary composite end point: investigators, 0.83 (95% CI, 0.76-0.91) versus CEC, 0.82 (95% CI, 0.75-0.90), with similar results for each component of the primary end point (hazard ratio of 0.92 versus 0.91 for cardiovascular death and 0.78 versus 0.74 for hospitalization for worsening HF).
Conclusions:
Central adjudication by a CEC in the SHIFT study confirmed most of cardiovascular deaths and worsening HF hospitalizations assessed by cardiologists and did not result in a significant change of the final result as compared to investigator judgment. In this context, the benefits of CEC in blinded HF trials should be reconsidered. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02441218. URL: http://www.isrctn.com/ISRCTN70429960; Unique identifier: ISRCTN70429960.
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