Pragmatic Design of Randomized Clinical Trials for Heart Failure: Rationale and Design of the TRANSFORM-HF Trial

Abstract

Randomized clinical trials are the foundation of evidence-based medicine and central to practice guidelines and patient care decisions. Nonetheless, randomized trials in heart failure (HF) populations have become increasingly difficult to conduct and are frequently associated with slow patient enrollment, highly selected populations, extensive data collection, and high costs. The traditional model for HF trials has become particularly difficult to execute in the United States, where challenges to site-based research have frequently led to modest U.S. representation in global trials. In this context, the TRANSFORM-HF (Torsemide Comparison with Furosemide for Management of Heart Failure) trial aims to overcome traditional trial challenges and compare the effects of torsemide versus furosemide among patients with HF in the United States. Loop diuretic agents are regularly used by most patients with HF and practice guidelines recommend optimal use of diuretic agents as key to a successful treatment strategy. Long-time clinical experience has contributed to dominant use of furosemide for loop diuretic therapy, although preclinical and small clinical studies suggest potential advantages of torsemide. However, due to the lack of appropriately powered clinical outcome studies, there is insufficient evidence to conclude that torsemide should be routinely recommended over furosemide. Given this gap in knowledge and the fundamental role of loop diuretic agents in HF care, the TRANSFORM-HF trial was designed as a prospective, randomized, event-driven, pragmatic, comparative-effectiveness study to definitively compare the effect of a treatment strategy of torsemide versus furosemide on long-term mortality, hospitalization, and patient-reported outcomes among patients with HF. (TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure [TRANSFORM-HF]; NCT03296813).

Keywords: clinical trial; diuretic; furosemide; heart failure; pragmatic; torsemide.

Figure 1.. Timeline for the TRANSFORM-HF Trial.

TRANSFORM-HF trial time lines are shown beginning from the first patient randomized. COVID-19, Coronavirus Disease 2019; DSMB, data safety and monitoring board.

Figure 2.. Cumulative and Monthly Randomization in the TRANSFORM-HF Trial.

Cumulative and monthly randomization in the TRANSFORM-HF trial are shown in the context of timing of the 1^st case of COVID-19 in the United States. COVID-19, Coronavirus Disease 2019

Central Illustration.. Study Design and Conceptual Framework of the TRANSFORM-HF Trial.

(A) TRANSFORM-HF is a prospective, randomized, comparative effectiveness trial designed to definitively compare the effect of a treatment strategy of torsemide versus furosemide on long-term mortality. (B) TRANSFORM-HF was designed to lower the traditional barriers for patient and site participation in HF trials and support a robust enrollment rate several fold higher than seen in prior studies. These collective strategies are intended to produce trial results widely applicable to routine US clinical practice at substantially lower cost and over a shorter timeline than traditional large HF programs. BNP, B-type natriuretic peptide; DCRI, Duke Clinical Research Institute; KCCQ, Kansas City Cardiomyopathy Questionnaire; NT-proBNP, N-terminal pro-B-type natriuretic peptide; Patient Health Questionnaire-2, PHQ-2. *Patients enrolled early in the trial will have additional phone interviews at 6-month intervals.