Hierarchical End Points in Prior Heart Failure Trials and the HEART-FID Trial

Abstract

Background: Clinical trials in heart failure (HF) traditionally use time-to-event analyses focusing on death and hospitalization for HF. These time-to-first event analyses may have more limited abilities to assess the probability of benefiting from a therapy, especially if that benefit manifests as improved functional status rather than reduced risk of death or HF hospitalization. Hierarchical end points including clinical outcomes and patient status measures allow for ranked evaluation of outcomes in 1 metric assessing whether patients randomized to intervention or control are more likely to derive an overall benefit while also allowing more patients to contribute to the primary outcome.

Methods: We review the rationale for using hierarchical end points in HF trials, provide examples of HF trials that used this type of end point, and discuss its use in the HEART-FID trial (Randomized Placebo-Controlled Trial of Ferric Carboxymaltose as Treatment for Heart Failure With Iron Deficiency), the largest HF trial to date implementing a hierarchical end point analysis for the primary outcome.

Results: Using a hierarchical end point as the primary outcome allows for the inclusion of different types of outcomes in 1 ranked end point, making it possible to more holistically assess the potential utility of a new therapy on patient well-being and outcomes.

Conclusions: Hierarchical end points assess the potential utility of a new therapy on patient well-being and outcome more holistically than time-to-first event analysis. Trials that would not have been feasible due to decreasing rates of death and hospitalization in the HF population can use hierarchical end points to successfully power studies to identify promising HF therapies. The HEART-FID trial used hierarchical end points to better determine the role of intravenous ferric carboxymaltose in patients with HF.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Keywords: clinical trial; heart failure; iron.

Figure 1.

Results of the stratified win ratio from EMPULSE. CI indicates confidence interval; HFE, heart failure event; KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire Total Symptom Score.

Figure 2:

Win ratio: FCM vs. placebo. Each patient randomized to intervention (intravenous ferric carboxymaltose) is compared to each patient randomized to placebo (intravenous saline), from the first imputed dataset. If one patient dies, the one who survived “wins.” If both patients die, then the one who survived longest “wins.” If neither patient died, then whichever patients had the fewest number of hospitalizations for heart failure “wins.” If neither patient died or was hospitalized for heart failure, then the patient with the greatest improvement (or smallest worsening) in 6MWT distances wins. CI indicates confidence interval; FCM, ferric carboxymaltose; HF, heart failure; mos, months; 6MWD: 6-minute walk distance.