TRANSFORM-HF: Torsemide No Better Than Furosemide for Hospitalized HF

CHICAGO, IL—The choice of loop diuretic doesn’t make a difference in how patients hospitalized for heart failure fare, at least when it comes to their risk of dying or of being readmitted, the TRANSFORM-HF trial shows.

A decongestion strategy using torsemide was no better than one using furosemide for risk of all-cause mortality—the primary endpoint—or a composite of all-cause mortality and total hospitalizations, Robert Mentz, MD (Duke Clinical Research Institute, Durham, NC), one of the trial’s principal investigators, reported here at the American Heart Association 2022 Scientific Sessions.

That contrasts with some earlier observational research that suggested torsemide might have an edge over the more widely used furosemide.

“While we were disappointed that we didn’t show torsemide was better, I think we’ve answered the question,” Mentz told TCTMD, noting that issues around crossovers, treatment discontinuations, and the COVID-19 pandemic could have influenced the results.

What can be taken away, he said, is that clinicians should focus on getting patients on the right dose of loop diuretic rather than on which agent to choose or whether to switch from one to the other. And on top of that, he added, “for those other therapies for heart failure that have been shown to improve outcomes, we really need to be starting those and titrating those.”

The TRANSFORM-HF Trial

Out in practice, furosemide is more commonly used than torsemide, likely because it’s been available longer and clinicians are used to reaching for it for decongestion for their patients with heart failure.

Earlier preclinical and clinical research, however, has indicated that torsemide might have some advantages over furosemide, including more-consistent bioavailability, a longer-lasting diuretic effect, and also antialdosterone and antifibrotic effects that aren’t seen with furosemide. The idea that those differences might translate into better clinical outcomes, including reduced mortality, has been supported both by prior observational studies and by clinical experience that has many physicians switching patients to torsemide after they fail to respond to furosemide.

Still, there was a need for a large randomized trial to compare the two head-to-head.

TRANSFORM-HF, a pragmatic, open-label trial conducted across 60 US centers, was designed to address that need. Investigators randomized 2,859 patients (mean age 65 years; 37% women) who were hospitalized for heart failure to a loop-diuretic strategy involving either torsemide or furosemide, with dosing left to the discretion of the treating physicians. About two-thirds of patients were receiving a loop diuretic before admission, with roughly 80% of them taking furosemide.

While we were disappointed that we didn’t show torsemide was better, I think we’ve answered the question. Robert Mentz

There were no restrictions based on LVEF. Most patients (64%) had a reduced ejection fraction of 40% or lower, and this group was well treated with other heart failure medications. Most were taking a beta-blocker (82%) and an ACE inhibitor/ARB/ARNI (68%), with 44% on a mineralocorticoid receptor antagonist and 8% on a sodium-glucose cotransporter 2 (SGLT2) inhibitor.

The trial was designed to streamline processes for patients and participating centers alike, and there were no mandated in-person follow-up visits. Instead, patients were called at 30 days, 6 months, and 12 months. Mortality data were pulled from the National Death Index.

Through a median follow-up of 17.4 months, there was no difference in the rate of all-cause mortality between the torsemide and furosemide groups (26.1% vs 26.2%; HR 1.02; 95% CI 0.89-1.18), with findings consistent across subgroups. Similarly, there was no difference between groups for the composite of all-cause mortality or all-cause hospitalization at 12 months (47.3% vs 49.3%; HR 0.92; 95% CI 0.83-1.02) or for total hospitalizations (37.5% vs 40.4%; rate ratio 0.94; 95% CI 0.84-1.07).

The lack of a significant advantage for torsemide across endpoints was consistent in a prespecified on-treatment analysis.

Important Answers, but Questions Remain

Commenting for TCTMD, Mary Norine Walsh, MD (Ascension St. Vincent Heart Center, Indianapolis, IN), a past president of the American College of Cardiology, said TRANSFORM-HF is valuable because it was done in a pragmatic manner, answered a long-standing question in the field, and enrolled a diverse patient cohort. “It’s important evidence showing that there’s not a big difference, at least in the hospitalized population, between these two medications,” she said.

Walsh pointed out some limitations that were also highlighted by the investigators, including the possible impact of the COVID-19 pandemic and the evolution of guideline-directed medical therapy for heart failure that occurred during the trial, with increasing use of the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (Entresto; Novartis) and SGLT2 inhibitors.

Another key consideration when interpreting the findings, Walsh added, is that “we can’t extrapolate this data to patients treated outside the hospital.”

She said she isn’t surprised that there was no difference observed between the agents in this trial because “using all-cause mortality as a primary endpoint is a high bar,” and added that questions around other outcomes important to patients and/or health systems—eg, rapidity of decongestion, weight loss, and length of stay—were not answered in TRANSFORM-HF.

For now, Walsh said, “as best we can tell, it does not matter which diuretic is used to decongest patients who are hospitalized for acute heart failure or acute-on-chronic heart failure, but we have yet to understand differences for outpatients.”

Biykem Bozkurt, MD, PhD (Baylor College of Medicine, Houston, TX), discussing the results at a press conference, agreed that there are some issues that could not be addressed by the trial, pointing to the possibility that differences between the diuretics might have emerged for other outcomes like successful decongestion, cardiovascular death, heart failure hospitalizations, and urgent-care visits. If torsemide is more potent and efficient, there could be cost implications as well, she indicated.

Moreover, TRANSFORM-HF does not provide information on use of torsemide among patients typically treated with the agent, including those who are not responding to furosemide (deemed diuretic-resistant) and those with cardiorenal syndrome or chronic kidney disease, who are prone to diuretic resistance, Bozkurt said.

But overall, despite some limitations, the trial shows that torsemide and furosemide have similar effectiveness, “allowing the clinicians to continue what they do, meaning treat according to the indications and specific phenotypes that they envision,” she said. “So I don’t think the study’s going to change our approach to which patients we treat with torsemide, which tends to be individuals who are diuretic resistant where we need the bioavailability and the effectiveness.”

Pragmatic Trial Lessons

Insights gleaned from the pragmatic design of TRANSFORM-HF will be used to inform future comparative-effectiveness studies, Mentz said. For one, the trial showed that using broad eligibility criteria and streamlined protocols embedded within routine care lead to a more-diverse participant population—with representation of women and Black individuals that exceeded many prior heart failure trials—and spur robust recruitment, which was seen even during the COVID-19 pandemic. The investigators also identified opportunities to enhance adherence and patient engagement, he said, alluding to the crossovers and loss to follow-up.

“In this context, this real-world, comparative-effectiveness study provides generalizable results that are applicable to our patients,” Mentz said during the press conference.

In addition, he told TCTMD, there is now a rich database reflective of what’s happening in routine practice that can be used to perform future analyses to answer important questions around diuretics and other medications. Of note, the TRANSFORM-HF investigators collected data on quality of life and depression, which will be reported later.

Addressing the implications for future research, Walsh said, “This type of trial, which enrolled a real-world population in a very pragmatic way, is impressive, and trials going forward need to consider this type of design.”