Clarity on Loop Diuretic Choice in HF: TRANSFORM-HF Published

Survival and readmission risk were similar whether patients hospitalized with heart failure (HF) were discharged on furosemide or torsemide in a randomized trial entering the literature this week.

The study, TRANSFORM-HF, helps fill a major gap in the sparse evidence base guiding diuretic therapy in patients with a history of HF hospitalization. In that setting, for example, results suggest that discharge on any appropriate loop diuretic is more important than which loop diuretic is chosen.

TRANSFORM-HF is no ordinary randomized trial. Designed as a pragmatic comparative effectiveness study, it featured a streamlined protocol and other adaptations that made it easier and cheaper to conduct, but that have complicated its interpretation, the trialists and some observers acknowledge.

Perceived Torsemide Advantages

Furosemide may be the most-prescribed loop diuretic in HF, but in practice —based on some limited evidence — clinicians often prefer torsemide for its perceived advantages that include greater bioavailability, potassium sparing, and potentially helpful pleiotropic effects.

TRANSFORM-HF, however, provides no evidence to support such a preference. The primary endpoint of all-cause mortality was about 26% over a median 17 months whether patients were assigned to an initial furosemide or torsemide-first strategy, regardless of ejection fraction. Composite rates of death or hospitalization at 12 months also weren't significantly different, at about 49% and 47%, respectively.

The findings suggest that clinicians may safely continue to prescribe either loop diuretic at their discretion, now with the support of data from a randomized trial.

TRANSFORM-HF was published January 17 in the Journal of the American Medical Association, with lead author Robert J. Mentz, MD, Duke University School of Medicine, Durham, North Carolina.

Mentz had also presented the trial's preliminary results at the November American Heart Association (AHA) Scientific Sessions in Chicago. The findings unveiled at the meeting and those published in the journal are essentially the same.

Reflections of Standard Practice

With its pragmatic design, TRANSFORM-HF entered a diverse HF population broadly representative of actual clinical practice. Patients were managed with few restrictions in a protocol that allowed, for example, loop-diuretic crossovers and other discretionary diuretic changes.

Diuretic dosing also varied significantly between the groups, and there was an unexpectedly high prevalence of diuretic withdrawal, the published report notes. Those factors, it states, may have "diminished" the trial's ability "to distinguish the hypothesized between-group differences."

Still, the trial "should be celebrated for dispelling a long-standing myth, based on surrogate markers and small trials, of the superiority of torsemide over furosemide," writes Michelle M. Kittleson, MD, PhD, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, in an accompanying editorial.

Now, she continues, "when faced with a patient with heart failure and congestive symptoms, clinicians can focus their energy on what really matters: not the relative merits of different loop diuretics, but rather the initiation and optimization of evidence and guideline-based therapies to help their patients feel better and live longer."

Trial Design Caveats

But that pragmatic design raises cautions, the editorial notes. "Pragmatic trials are more flexible and nimbler in design and execution, but this agility comes at a cost. An overly heterogeneous patient population can impact the trial's ability to assess efficacy of therapies while minimally intensive follow-up precludes comprehensive outcome assessment."

The study's 2859 patients hospitalized with HF were assigned to open-label treatment with furosemide or torsemide at more than 60 US centers. Of the 1428 and 1431 patients, respectively, about 37% were women and 34% were African American.

The hazard ratio (HR) for all cause mortality across the 17.4-month follow-up, torsemide vs furosemide, was 1.02 (95% CI, 0.89 - 1.18). The HR for death or hospitalization for any cause at 12 months was 0.92 (95% CI, 0.83 - 1.02). And the rate ratio (RR) for 12-month all-cause hospitalization was 0.94 (95% CI, 0.84 - 1.07).

"TRANSFORM-HF joins a catalog of cautionary tales in cardiology, whereby carefully executed negative trials have refuted the misleading promise of plausible surrogate end points and preliminary data," Kittleson writes.

"The lesson: clinicians should have a healthy suspicion for plausible pathophysiology, surrogate end points, and nonrandomized data as the sole basis of defining superiority of an intervention."

TRANSFORM-HF was funded by the National Institutes of Health. Mentz reports receiving grants from American Regent and Novartis; personal fees from AstraZeneca, Boehringer Ingelheim/Eli Lilly, Cytokinetics, Bayer, Merck, and Pharmacosmos; and research support from Abbott, Amgen, Bayer, Boston Scientific, Fast BioMedical, Gilead, Innolife, Medtronic, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Disclosures for the other authors can be found with the original article. Kittleson reports no relevant financial relationships.

JAMA. Published online January 17, 2023. Full Text, Editorial

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