The head-to-head battle of loop diuretics indicates that correct dosing rather than drug choice should be the focus of clinicians.
CHICAGO, IL—The choice of loop diuretic makes no difference in how patients hospitalized for heart failure fare, at least in terms of risk of death or readmission, the TRANSFORM-HF trial shows.
A decongestion strategy using torsemide was no better than one using furosemide for the risk of all-cause mortality (the primary endpoint) or a combination 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’s 2022 Scientific Sessions.
This contrasts with some previous observational research that suggested that torsemide might have an advantage over the more commonly used furosemide.
“While we were disappointed that we didn’t show that torsemide was better, I think we answered the question,” Mentz told TCTMD, noting that issues related to crossovers, treatment interruptions, and the COVID- 19 could have influenced the results.
The takeaway, he said, is that doctors should focus on getting patients on the right dose of loop diuretic rather than which agent to choose or whether to switch from one to the other. And also, he added, “for those other therapies for heart failure that have been shown to improve outcomes, we really need to start them and evaluate them.”
The TRANSFORM-HF test
In practice, furosemide is more commonly used than torsemide, probably because it has been available for a long time and doctors are used to looking to it to decongest their patients with heart failure.
Previous preclinical and clinical research, however, has indicated that torsemide may have some advantages over furosemide, such as more consistent bioavailability, a longer-lasting diuretic effect, and also antialdosterone and antifibrotic effects not seen with furosemide. The idea that these differences could translate into better clinical outcomes, including reduced mortality, has been supported by both previous observational studies and clinical experience that leads many clinicians to switch 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 at 60 US centers, was designed to address this need. The researchers randomized 2,859 patients (mean age 65 years; 37% women) who were hospitalized for heart failure to a loop diuretic strategy involving torsemide or furosemide, with dosing at the discretion of the treating physicians. About two-thirds of patients were receiving a loop diuretic before admission, with approximately 80% of them taking furosemide.
While we were disappointed that we didn’t prove that torsemide was better, I think we answered the question. Robert Mentz
There were no restrictions based on LVEF. Most patients (64%) had a reduced ejection fraction of 40% or less, and this group was well treated with other heart failure medications. Most were taking a beta-blocker (82%) and an ACE/ARA/ARNI inhibitor (68%), with 44% on a mineralocorticoid receptor antagonist and 8% on a sodium cotransporter inhibitor -glucose 2 (SGLT2).
The trial was designed to streamline processes for both patients and participating centers, and there were no mandatory face-to-face follow-up visits. Instead, patients were called at 30 days, 6 months, and 12 months. Mortality data were taken from the National Death Index.
With a median follow-up of 17.4 months, there was no difference in the all-cause mortality rate between the torsemide and furosemide groups (26.1% vs 26.2%; HR 1.02; CI 95% 0.89-1.18), with consistent subgroup results. Similarly, there was no difference between groups for all-cause mortality or all-cause hospitalization at 12 months (47.3% vs 49.3%; HR 0.92; CI 95 % 0.83-1.02) nor 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 among 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 pragmatically, respond in the long term. -standing question in the field and enrolled a diverse cohort of patients. “It’s important evidence that shows there’s not a big difference, at least in the hospitalized population, between these two drugs,” he said.
Walsh noted some limitations that the researchers also highlighted, including the potential impact of the COVID-19 pandemic and the evolution of guideline-directed medical therapy for heart failure that occurred during the trial, with a increasing the angiotensin-neprilysin receptor. sacubitril/valsartan inhibitor (Entresto; Novartis) and SGLT2 inhibitors.
Another key consideration when interpreting the findings, Walsh added, is that “we cannot extrapolate these data to patients treated outside the hospital.”
He said he was not surprised that no difference was seen between the agents in this trial because “using all-cause mortality as a primary endpoint is a high bar,” adding that questions about other important outcomes for the patients and/or health. Systems (eg, rapidity of decongestion, weight loss, and length of stay) were not addressed in TRANSFORM-HF.
For now, Walsh said, “as far as we can tell, it doesn’t matter which diuretic is used to decongest patients hospitalized for acute heart failure or acute-on-chronic heart failure, but we still need to understand the 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, noting the possibility that the differences between diuretics may have emerged for other outcomes such as successful decongestion, cardiovascular death, heart failure hospitalizations, and urgent care visits. If torsemide is more potent and efficient, there could also be cost implications, he said.
In addition, TRANSFORM-HF does not provide information on the use of torsemide among patients routinely treated with the agent, including those unresponsive to furosemide (considered diuretic resistant) and those with cardiorenal syndrome or chronic kidney disease, who are prone to diuretics. resistance, Bozkurt said.
But overall, despite some limitations, the trial shows that torsemide and furosemide have similar efficacy, “allowing clinicians to continue what they’re doing, which is treating according to the specific indications and phenotypes they anticipate,” he said. “So I don’t think the study changes our approach to which patients we treat with torsemide, which are usually diuretic-resistant individuals where we need bioavailability and efficacy.”
Pragmatic test lessons
Insights gained from TRANSFORM-HF’s pragmatic design will be used to inform future comparative effectiveness studies, Mentz said. On the one hand, the trial demonstrated that the use of broad eligibility criteria and streamlined protocols integrated into routine care lead to a more diverse participant population, with representation of women and black individuals exceeding many trials prior heart failure, and was driving robust recruitment, which was seen. even during the COVID-19 pandemic. The researchers also identified opportunities to improve patient adherence and engagement, he said, alluding to 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 reflecting what happens in routine practice that can be used to conduct future analyzes to answer important questions about diuretics and other medications. Of note, TRANSFORM-HF researchers 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 future trials need to consider this type of design”.