TRANSFORM-HF:

SOLVING THE DIURETIC MYSTERY WITH

A TWIST OF VINTAGE VS MODERN

Dr. Keshab Raj Neupane

FCPS Resident, Cardiology
SGNHC, Bansbari
DISCLOSURE
 No Conflict of Interest
JAMA JAN 17;329(3):214-223.
DOI: 10.1001/JAMA.2022.23924.
 Effect of Torsemide vs Furosemide After Discharge on All-Cause
Mortality in Patients Hospitalized With Heart Failure: The
TRANSFORM-HF Randomized Clinical Trial
 Robert J Mentz, Kevin J Anstrom, Eric L Eisenstein, Shelly Sapp,
Stephen J Greene, Shelby Morgan, Jeffrey M Testani,
Amanda H Harrington, Vandana Sachdev, Fassil Ketema,
Dong-Yun Kim, Patrice Desvigne-Nickens, Bertram Pitt,
Eric J Velazquez; TRANSFORM-HF Investigators
 PMID: 36648467
 BACKGROUND
LOOP DIURETICS are routinely used to manage congestion in patients with
heart failure (HF)

Both furosemide and torsemide are loop diuretics, which block sodium chloride
reabsorption in the thick ascending limb of the loop of Henle. This is achieved by
inhibiting the Na-K-2Cl symporter in the luminal membrane.
COMPARISON
 BACKGROUND
FUROSEMIDE is the most commonly used loop diuretic
TORSEMIDE may offer advantages over furosemide
 More consistent oral bioavailability and longer duration of action
 Anti-aldosterone effects and anti-fibrotic myocardial effects
 Prior observational studies have suggested potential outcome benefits

Whether torsemide improves clinical outcomes compared with

furosemide in patients with HF is unknown.
Murray MD, et al. Am J Med 2001;111(7):513-20.
Cosin J, et al. Eur J Heart Fail 2002;4(4):507-13.
Buggey J, et al. Am Heart J 2015; 169(3):323-33.
Potential Advantages of Torsemide Over Furosemide for Treatment of Heart Failure

Pharmacologic Properties Better Suited for Managing Congestion

•More predictable and reliable diuretic effect
•  Near 100% bioavailability compared with variable furosemide bioavailability (i.e., 10%–
100%)
•  Absorption not affected by food
•  2–4 times more potent than furosemide
•  May be less vulnerable to diuretic resistance
•Longer half-life (3.5 h vs. 2.0 h) and duration of effect (6–16 h vs. 6–8 h) than furosemide

•Less prone to hypokalemia

Favorable Effects on Neurohormones
•Renin-angiotensin-aldosterone system inhibition
•  Decrease aldosterone secretion from adrenal cells
•  Aldosterone antagonist-like blockade of aldosterone receptors
•  Inhibition of downstream effects of angiotensin II

•Decreased sympathetic activation

Favorable Effects on Cardiac Remodeling
•Slows or reverses development of myocardial fibrosis
•Attenuates progressive ventricular dilation and hypertrophy
PREVIOUS TRIALS
 In two unblinded, comparative effectiveness trials from the early 2000s,
Murray et al in the US, and Muller et al in Switzerland, compared
torsemide and furosemide and showed no significant difference in
mortality in patients with heart failure.
 Murray's study showed a reduction in HF and cardiovascular hospital
readmissions, while Muller’s study showed improved quality of life for
torsemide patients.
 The TORasemide In Congestive Heart Failure (TORIC) study, the
largest previous trial, reported an improvement in NYHA functional
class, a 59.7% relative risk reduction in cardiovascular mortality, and a
51.5% relative risk reduction in overall mortality in the torsemide
group. However, the study was conducted primarily in rural Spain, and
results may not be globally generalizable.
 The recent TORNADO study, with a small sample size and limited
geographic scope, showed a statistically significant improvement in a
composite outcome of NYHA class, a 6-minute walk test, and decrease
in fluid retention.
METHODS
 TRANSFORM-HF was a pragmatic, open-label, randomized trial that
aims to compare the efficacy of furosemide and torsemide in treating
HF.
 The pre-specified hypothesis was that torsemide would reduce all-cause
mortality by 20% compared to furosemide. 
POPULATION
 This trial included the whole spectrum of HF.
 To be eligible for the trial, patients had to
 have been hospitalized for at least 24 hours due to worsening of chronic
heart failure or
 a new diagnosis of heart failure and

 meet one of two criteria

 a LVEF of ≤40% within 24 months prior to the hospitalization or
 elevated natriuretic peptide levels during the hospitalization
 DESIGN
Primary Objective: Compare the treatment strategy of
torsemide vs. furosemide on long-term clinical outcomes
among patients hospitalized with HF through a pragmatic trial
Regardless of EF
Hospitalized Patients with HF Long-term plan for loop diuretic
(60 US Sites)
1:1 Randomization

Open-Label
Torsemide Furosemide Dosing per Clinician

Routine Clinical Follow-up DCRI Call Center (30 d, 6 m, 12 m)

No in-person study visits National Death Index

Primary Endpoint:
Primary Hypothesis: Event-Driven
Torsemide reduces mortality All-Cause Mortality 721 Death Events
by 20% vs. furosemide (85% power)
Secondary Endpoints:
All-cause Mortality + All-cause Hospitalization
Total Hospitalizations
Health-related Quality of Life (KCCQ)
Symptoms of Depression (PHQ-2)
 STUDY EXECUTION
Consented
N = 2973
ENROLLMENT BEGAN
June 2018 Excluded (N = 112, 3.8%)
Did not meet eligibility (N=33)
1,000 Patients – Aug 2019 Discharged (N=30)
2,000 Patients – Oct 2020 PI decision (N=27)
Randomized*
2,800 Patients – Jan 2022 Patient decision (N=19)
N = 2859
Feb 2022 DSMB Meeting Death (N=3)
Recommend Ending Recruitment
Sufficient Sample Size
RECRUITMENT ENDS
March 4, 2022 Torsemide Furosemide
FOLLOW-UP ENDS N = 1431 N = 1428
July 29, 2022
Withdrawal of Withdrawal of
Consent Consent
N = 53 (3.8%) N = 60 (4.2%)
All-Cause Mortality
All-cause Mortality + All-cause Hospitalization
Total Hospitalizations
*Excludes 2 patients randomized twice (first randomization used)
 BASELINE CHARACTERISTICS
Torsemide Furosemide
Characteristics (N=1431) (N=1428)
Age (yr) 64±14 65±14
Women 35% 39%
White race 58% 59%
Black race 33% 35%

Newly diagnosed HF 30% 29%

EF ≥50% 22% 23%
41-49% 6% 5% LVEF≤40%
≤40% 65% 63% (N=1836)
NT-proBNP (pg/mL) 3994 (1938, 8850) 3833 (1936, 7807)
HFrEF Therapy
Ischemic etiology 30% 27%
Beta-blocker 82%
Systolic blood pressure (mmHg) 118±19 119±21 ACE/ARB/
Body mass index (kg/m2) 32±10 32±9 (ARNI) 68% (25%)
MRA 44%
eGFR (ml/min/1.73 m2) 59±25 60±26 SGLT2i 8%
Presented as %, Mean ± SD or median (IQR)
LOOP DIURETIC & DOSING
Torsemide Furosemide
Baseline Characteristics (N=1431) (N=1428)
Loop diuretic prior to admission 964 (67%) 956 (67%)

Furosemide 78% 81%

Torsemide 15% 12%

Bumetanide 7% 7%

Total daily dose* (mg) 66 ± 65 66 ± 58

Torsemide Furosemide
Randomized Loop Diuretic (N=1431) (N=1428)
Discharge total daily dose* (mg) 80 ± 70 79 ± 56

*Furosemide equivalents (1 mg bumetanide = 20 mg torsemide = 40 mg furosemide)

Primary Results
PRIMARY ENDPOINT: ALL-
CAUSE MORTALITY
HR 1.02 (95% CI, 0.89 to 1.18); P-value 0.77
Furosemide:
374 events (26.2%);
17.0 per 100 pt-yr

Torsemide:
373 events (26.1%);
17.0 per 100 pt-yr

Consistent across all pre-specified subgroups including Age, Gender, Race, EF, HF chronicity, GFR

Median follow-up: 17.4 months (IQR: 8.0 to 29.0)

ALL-CAUSE MORTALITY OR HOSPITALIZATION (12 MOS)
HR 0.92 (95% CI, 0.83 to 1.02); P-value 0.11
Furosemide:
704 events (49.3%);
107.6 per 100 pt-yr

Torsemide:
677 events (47.3%);
99.2 per 100 pt-yr
TOTAL HOSPITALIZATIONS
(12 MOS)
RR 0.94 (95% CI, 0.84 to 1.07)
1200

1000
987 940

800 Furosemide Torsemide

600

400
Among Among
200 577 (40.4%) 536 (37.5%)
Participants Participants
0
Total Hospitalizations (N)
ON-TREATMENT ANALYSIS (PRE-
SPECIFIED)
Known diuretic status Torsemide Furosemide
On randomized therapy N = 1431 N = 1428
Unknown Loop Status (N=40)
Unknown Loop Status (N=57) Death (N=4)
Death (N=3) 5.4% Cross-over Known Loop Status (N=1384)
Known Loop Status (N=1371) 2.8% No Loop Different Loop (N=75)
Different Loop (N=112) Crossover (N=53) – 3.8%
Crossover (N=96) – 7.0% On-Treatment at Discharge On-Treatment at Discharge No Loop (N=41) – 3.0%
No Loop (N=36) – 2.6% N = 1223 N = 1268

Unknown Loop Status (N=351) Unknown Loop Status (N=325)

Death (N=56) 6.7% Cross-over Death (N=63)
Known Loop Status (N=1016) 7.0% No Loop Known Loop Status (N=1031)
Different Loop (N=92) Different Loop (N=102)
Crossover (N=81) – 8.0% On-Treatment at 30 Days On-Treatment at 30 Days Crossover (N=57) – 5.5%
No Loop (N=76) – 7.5% N = 848 N = 862 No Loop (N=67) – 6.5%

ITT Analysis On-Treatment On-Treatment

  at Discharge at 30 Days
All-cause mortality 1.02 (0.89, 1.18) 0.99 (0.85, 1.15) 0.96 (0.78, 1.18)
P=0.76 P=0.86 P=0.69
All-cause mortality 0.92 (0.83, 1.02) 0.91 (0.81, 1.01) 0.89 (0.78, 1.02)
or all-cause hospitalization P=0.11
P=0.082 P=0.10
 LIMITATIONS AND FUTURE
OPPORTUNITIES
 Cross-overs and diuretic discontinuation would bias toward neutral results
 Dose was left to clinician discretion which may have influenced results
 All-cause outcomes may have been too imprecise for measuring differences
especially during the COVID-19 pandemic
 Assumed treatment effect was large (especially with evolution of GDMT)
 No assessment of other adverse events (e.g., worsening renal function,
electrolyte abnormalities or non-hospitalization events)
 Future work will characterize how non-adherence and dose may have affected
these findings
 PRAGMATIC TRIAL INSIGHTS
 Broad eligibility criteria and streamlined study protocol embedded within
routine care supported the inclusion of diverse participants
 Pragmatic elements lowered traditional barriers for patient and site
participation supported robust enrollment rates (even during the COVID-19
pandemic)
 Opportunities to enhance patient adherence and engagement at follow-up
 In this context, this real-world comparative-effectiveness study provides results
that are generalizable to routine clinical practice
 STUDY CONCLUSIONS AND
IMPLICATIONS
 A strategy of torsemide had similar effectiveness compared with a strategy of
furosemide for the clinical outcomes of mortality and hospitalization in patients
hospitalized with heart failure.
 Clinical time should be spent focusing on appropriate diuretic dosing and
prioritizing guideline-directed medical therapy (GDMT) initiation / titration.
 Insights from the pragmatic trial design and execution inform future studies
aiming to assess real-world comparative effectiveness.
COMMENTS
 The TRANSFORM-HF trial made us realize that we are stuck in a loop
with loop diuretics, doggedly expecting different results despite the
same outcome.
 It's a never-ending cycle that we need to break out of and look for drugs
that provide real CV benefits and truly transform the lives of our
patients.
CONCLUSION
 The results of the comparison between torsemide and furosemide in
post-hospitalization heart failure patients were underwhelming, with no
significant difference in all-cause mortality observed over the course of
12 months.
 However, the validity of these conclusions is hampered by the issues of
participant dropout, crossover, and medication non-adherence.
 Thus, a more definitive answer to the question of the efficacy of these
drugs remains elusive.