Adjudication Of Cause-specific Endpoints In Heart Failure Trials

Abstract

Introduction Clinical endpoints are standard outcomes measures used to prove treatment effect in clinical trials. Differences in endpoint definitions and ascertainment of cause-specific clinical events influence the validity of heart failure (HF) trials. Cause-specific clinical events have become preferred endpoints because they separate signals of efficacy from noise (non-related events). Clinical endpoints could be ascertained through case report forms (CRFs) by investigators or through a central adjudication method by a Clinical Endpoint Committee (CEC). Investigator reporting is more efficient and inexpensive but is affected by inaccuracy, geographic variability, and complexity of endpoint definitions. CEC adjudication is a standardized, blind and independent ascertainment process but may be limited by high costs. Aims To analyze cause-specific endpoints, and the need for CEC adjudication in HF trials, comparing HF with reduced versus preserved ejection fraction (EF). Methods We analyzed 10 HF with reduced EF (HFrEF) trials and five HF with preserved EF (HFpEF) trials. For each trial we described and compared the prevalence of all-cause and cause-specific mortality. Results A comparison between all-cause mortality and cardiovascular mortality in 9 selected HFrEF and HFpEF clinical trials is presented in Figure 1. The relative proportion of CV death was significantly lower in HFpEF compared with HFrEF trials. Additionally, in HFrEF, the relative proportion of CV death was significantly lower in recent trials compared with early trials. CV specific endpoints were the primary cause of death in HF trials. Conclusions There are more CV deaths in HFrEF trials, although it is the primary mode of death in both populations. CEC adjudication may be more beneficial in HFpEF vs. HFrEF trials, and in recent HFrEF trials due to the increase in non-CV events which may attenuate the treatment effect.