Real-world effectiveness and safety of torsemide and spironolactone fixed dose combination in Indian heart failure patients (RESTORE-HF study): a prospective,multicenter,observational study

Abstract

Background:

Heart failure (HF) remains a major public health challenge in India, with a need for effective and well-tolerated therapeutic strategies.

Objective:

The RESTORE-HF study evaluated the real-world effectiveness and safety of torsemide-spironolactone fixed-dose combination (FDC) in Indian patients with HF.

Design:

Prospective, multicenter, observational study.

Methods:

This study was conducted across 101 sites in India. Patients aged 18–75 years with HF with reduced ejection fraction and signs of congestion were enrolled and initiated on the torsemide-spironolactone FDC. Participants were followed over 3 weeks from baseline. The primary objective was the change in body weight. Secondary endpoints included changes in New York Heart Association (NYHA) functional class, edema, occurrence of adverse events (AEs), and physician and patient assessments of efficacy and tolerability.

Results:

Of the 1841 patients screened, 1752 were enrolled, and 1520 completed the study. The mean (SD) age of participants was 58.61 (9.45) years, of whom 61.05% were male. The study showed a significant reduction in mean body weight was observed from 75.54 kg at baseline to 73.13 kg at week 3 (mean difference: 2.41 kg; p < 0.0001). Additionally, an improvement in NYHA functional class and edema was observed over 3 weeks from baseline. Overall, 22.11% patients achieved no-edema stage. Only three mild AEs related to loose stools were reported, and no serious AEs or deaths occurred. Over 98% of physicians and patients rated the therapy favorably.

Conclusion:

The RESTORE-HF study demonstrated that the torsemide-spironolactone FDC may be associated with a mean body weight reduction of 2.41 kg and may be generally well-tolerated in Indian heart failure patients. Furthermore, the FDC may be linked to significant symptomatic improvement over 3 weeks in real-world clinical practice.

Graphical Abstract

Plain language summary

Combined torsemide-spironolactone tablet shows benefits for heart failure patients in India

The RESTORE-HF study evaluated the effectiveness of a tablet that combines torsemide and spironolactone in treating heart failure in people in India. Around 1752 patients took the medicine for 3 weeks. On average, they lost about 2.41 kg, their breathing and activity improved, and their swelling went down. About 22.11% patients had no swelling by the end. Side effects were very mild and uncommon. Most doctors and patients reported that the treatment was effective and easy to tolerate.

Keywords

diuretic therapy fixed dose combination heart failure Indian population NYHA functional class short-term outcomes

Introduction

Heart failure (HF) is a serious and multifactorial clinical condition associated with high rates of morbidity and mortality, reduced functional capacity and quality of life, and substantial healthcare costs.¹ In India, the burden of HF has been increasing due to the rising prevalence of risk factors such as coronary artery disease, hypertension, diabetes mellitus, obesity, and rheumatic heart disease.² Despite the availability of guideline-directed medical therapies (GDMTs), including beta-blockers, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists (MRAs), and sodium glucose cotransporter 2 inhibitors, optimal volume management remains a cornerstone for symptom relief and the prevention of acute decompensation.³

Loop diuretics are a mainstay of HF management, primarily due to their ability to relieve congestive symptoms by promoting the excretion of sodium, chloride, and potassium, thereby reducing fluid overload.⁴ Torsemide, a potent loop diuretic, plays a vital role in HF treatment by inhibiting sodium reabsorption in the renal tubules, which promotes diuresis and alleviates volume overload in conditions such as edema and hypertension.⁵ Compared to furosemide, torsemide has a longer half-life, greater bioavailability, and more predictable pharmacokinetics,⁶ making it a favorable choice in chronic HF management. Spironolactone, an MRA, has demonstrated efficacy in reducing mortality and hospitalizations in patients with severe HF, as shown in large randomized trials such as RALES,⁷ by antagonizing aldosterone, a key driver of myocardial fibrosis and fluid retention.

Despite their complementary mechanisms of action, real-world data on the combined use of torsemide and spironolactone in a fixed dose formulation are sparse, particularly in the Indian context. Fixed dose combinations (FDCs) may offer benefits in terms of simplifying treatment regimens, improving medication adherence, and ensuring consistent pharmacological synergy. In India, torsemide and spironolactone are widely co-prescribed in routine clinical practice, and fixed-dose formulations combining these agents are commercially available; however, their use has largely been guided by clinical experience rather than robust prospective real-world evidence.⁵ Consequently, systematic evaluation of their effectiveness and safety across diverse clinical settings and patient populations is warranted to support broader clinical adoption.

To address this knowledge gap, the RESTORE-HF (Real-world Effectiveness and Safety of Torsemide and Spironolactone FDC in Indian Heart Failure Patients) study was designed as a prospective, multicenter, observational investigation across multiple centers in India. The rationale, methodology, and baseline characteristics of the enrolled population have been previously reported and highlight a representative sample of Indian HF patients with varied demographic and clinical profiles.^8,9

The current manuscript presents the real-world effectiveness and safety outcomes of the torsemide-spironolactone FDC based on follow-up data from the RESTORE-HF study.

Methods

Details of the design and methodology of the RESTORE-HF study were published earlier⁸ followed by baseline characteristics,⁹ and are briefly summarized in this article. This study was designed and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines for cohort studies, as recommended by the EQUATOR Network (Supplemental Material) .¹⁰

Study design and participants

The RESTORE-HF study was a multicenter, prospective, observational study conducted across 101 sites in India from October 2023 to July 2024. The study was conducted in accordance with applicable national regulatory requirements, the Declaration of Helsinki, and Good Clinical Practice guidelines.

No identifiable information was collected during data collection, ensuring the privacy of all participants. Eligible participants were adults aged 18–75 years with established or de novo HF with reduced ejection fraction (HFrEF; EF ⩽40%) and elevated N-terminal pro–B-type natriuretic peptide levels (>450 pg/mL for age <50 years and >900 pg/mL for age 50–75 years). Patients were required to be in New York Heart Association (NYHA) Class II or III. For NYHA Class II patients, at least one of the objective signs of fluid retention was required, such as pedal edema, elevated jugular venous pressure, basal rales, dilated plethoric inferior vena cava on ultrasound, or evidence of lung congestion on chest X-ray. The patient deemed suitable for initiation of a FDC of torsemide and spironolactone (10/25 mg or 10/50 mg) was included. Key exclusion criteria included NYHA Class IV, recent use (<8 weeks) of loop diuretics or MRA, significant renal dysfunction (estimated glomerular filtration rate <30 mL/min/1.73 m²), hyperkalemia (K⁺ >5.0 mmol/L), concomitant nonsteroidal anti-inflammatory drug use (except aspirin 75–300 mg/day), hypersensitivity to study drugs, Addison’s disease, participation in another clinical study, and other conditions considered unsuitable by the treating physician.

Data collection

The study spanned 3 weeks following the initiation of the FDC therapy. Participants attended two scheduled visits: Visit 1 at baseline and Visit 2 at the end of the study period. The primary objective was to assess the change in body weight, while secondary endpoints included evaluating the change in NYHA functional class, documenting the occurrence of adverse events (AEs), and serious AEs.

Treating physicians assessed treatment efficacy and tolerability at follow-up visits based on their overall clinical judgment during routine care. These assessments were recorded using a categorical physician global impression, classified as strongly agree, agree, neutral, and disagree. No formal scoring scale or validated questionnaire was mandated, reflecting the real-world observational nature of the study.

Patient-reported assessment of treatment was collected during follow-up visits as part of routine clinical care. Patients were asked to provide an overall assessment of their experience with the study medication, focusing on perceived symptom relief and treatment acceptability. Responses were recorded using a simple categorical scale (extremely satisfied, satisfied, and neutral).

Safety monitoring

Participant safety was closely monitored by investigators throughout the study, with particular attention to adverse drug reactions associated with the FDC treatment. Any adverse reactions were followed until resolution or stabilization of the patient’s clinical condition and laboratory findings. Serious AEs that met expedited reporting criteria were promptly reported by the sponsor to the relevant institutional ethics committees or review boards.

Sample size calculation

A total of 3000 eligible HF patients will be enrolled across approximately 150 sites. The sample size was estimated using an HF prevalence of 1.0% in the Indian adult population as the population proportion (P^).¹¹ With a 95% confidence level and a 0.36% margin of error (Є) applied in the formula:

Sample size : N = Z^{2} \times P^(1 - P^) / Є^{2}

where

z = is the z - score

The required sample size was calculated to be N = 2934. Therefore, the planned enrollment of 3000 patients comfortably meets the sample size requirement.

Statistical analysis

Demographic data, such as age and weight, were summarized using sample size “n,” mean, standard deviation (SD), range, and confidence intervals, while categorical data, like gender, are presented as numbers and percentages. In terms of efficacy analysis, parameters like weight changes are categorized as mean, SD, range, and mean change from baseline. To determine the statistical significance of the mean change from baseline, a paired T test is applied. Changes in the NYHA class, comorbidities, and concomitant medications are summarized as numbers and percentages. A p-value <0.05 is considered statistically significant within the analysis. The incidences of AE are summarized with count (%).

Results

Patient disposition

Of the 1841 participants recruited, 1752 met the eligibility criteria and were enrolled in the study. A total of 232 participants were lost to follow-up. Overall, 1520 participants completed the 3-week study period (Figure 1). Of these subjects, 1251 (82.30%) were prescribed torsemide + spironolactone [10 + 50] mg FDC, and 269 (17.70%) were prescribed torsemide + spironolactone [10 + 25] mg FDC.

Figure 1.

Patient disposition.

Demographic characteristics

The mean (SD) age of the patients was 58.49 (9.53) years. The majority of patients were male (61.36%). The mean (SD) body weight was 75.44 (9.39) kg, height was 167.39 (10.37) cm, and body mass index was 27.12 (4.08) kg/m². The mean (SD) systolic blood pressure and diastolic blood pressure were 133.41 (3.21) mmHg and 87.02 (4.10) mmHg, respectively. The pulse rate was 80.41 (11.98) bpm, and the respiratory rate was 14 (1.4) bpm. The majority of patients had NYHA Class II (70.15%), followed by NYHA Class III (29.85%). Edema Grade 2 was the most commonly seen in 35.56% of patients, followed by Grade 3 (29.28%), Grade 1 (21.92%), and Grade 4 (13.24%). Type 2 diabetes mellitus (30.88%) was the most common comorbid condition, and metformin (29.05%) was the most common concomitant medication used in these patients.

Primary endpoint

The mean (SD) body weight of participants decreased significantly from 75.54 (9.47) kg at baseline to 73.13 (9.37) kg at week 3, reflecting a mean reduction of 2.41 kg (p < 0.0001; Figure 2).

Figure 2.

Change in body weight (primary endpoint).

Secondary endpoint

At baseline, out of 1520 participants, 451 patients were in NYHA Class III and 1069 patients were in NYHA Class II. By the end of the 3 weeks, among those initially in NYHA Class III, 77.16% (n = 348) improved to Class II, and 8.65% (n = 39) improved further to Class I. Only 14.19% (n = 64) remained in Class III. Among those initially in NYHA Class II, 85.41% (n = 913) improved to Class I and 14.59% (n = 156) remained in Class II (Table 1).

Table 1.

Change in NYHA functional class from baseline to 3 weeks.

NYHA classBaseline visit (N = 1520)	Week 3 visit
NYHA classBaseline visit (N = 1520)	NYHA Class III	NYHA Class II	NYHA Class I
NYHA class 3 (N = 451)	64 (14.19)	348 (77.16)	39 (8.65)
NYHA class 2 (N = 1069)	—	156 (14.59)	913 (85.41)

Data presented as n (%).

NYHA, New York Heart Association.

Over the 3-week treatment period, patients with Grade 4 edema (n = 204) at baseline, 65.20% (n = 133) improved to Grade 3, and 1.96% to Grade 2 (n = 4), while 32.84% (n = 67) remained at Grade 4. Similarly, among the patients with Grade 3 edema (n = 445) at baseline, edema grade in 82.02% (n = 365) of patients improved to Grade 2, and a small proportion (0.45% (n = 2)) improved to Grade 1. Furthermore, among those with Grade 2 edema (n = 531), 91.34% (n = 485) showed improvement to Grade 1, and 8.66% (n = 46) remained with Grade 2 edema. Nearly all patients with Grade 1 edema (n = 340) at baseline improved to no edema (98.82% (n = 336)) by the end of follow-up. Overall, at the end of follow-up, 22.11% of all participants had no detectable edema, and 32.30% had only Grade 1 edema (Table 2).

Table 2.

Change in edema grades from baseline to week 3.

Baseline visit (N = 1520)	Edema Grades				No edema
Baseline visit (N = 1520)	Grade 4	Grade 3	Grade 2	Grade 1	No edema
Grade 4 (N = 204)	67 (32.84)	133 (65.20)	4 (1.96)	—	—
Grade 3 (N = 445)	—	78 (17.53)	365 (82.02)	2 (0.45)	—
Grade 2 (N = 531)	—	—	46 (8.66)	485 (91.34)	—
Grade 1 (N = 340)	—	—	—	4 (1.18)	336 (98.82)
Week 3 visit N = 1520	67 (4.41)	211 (13.88)	415 (27.30)	491 (32.30)	336 (22.11)

Data presented as n (%).

At baseline, the mean (SD) serum creatinine level was 1.19 m (0.15) g/dL, which decreased to 0.97 (0.17) mg/dL at week 3, with a mean difference of −0.22 mg/dL. The mean (SD) serum sodium level was 140.01 (3.17) mg/dL at baseline and slightly decreased to 139.62 (3.04) mg/dL at week 3, showing a mean difference of −0.36 mg/dL. The mean (SD) serum potassium level increased from 4.07 (0.47) mEq/L at baseline to 4.59 (0.59) mEq/L at week 3, with a mean difference of 0.51 mEq/L.

The majority of physicians either strongly agreed or agreed in their overall assessment of the efficacy and tolerability of the FDC of torsemide and spironolactone (98.35% for each; Figure 3(a)). The patients’ overall assessment showed that the majority were either extremely satisfied or satisfied with the treatment (98.75%; Figure 3(b)).

Figure 3.

Overall efficacy assessment. (a) Physician’s overall assessment of evaluable patients on efficacy and tolerability; (b) Patient’s overall assessment on treatment.

Safety endpoint

A total of three AEs were reported in three patients (n = 3) by the end of the study. All reported AEs were related to loose stools and were mild in nature. No serious AEs or deaths were reported during the study period.

Discussion

The current study evaluated the efficacy and safety of a FDC of Torsemide and Spironolactone in Indian patients with HFrEF over a 3-week follow-up. The use of GDMT for the treatment of HFrEF remains suboptimal, despite notable progress.¹² For instance, the Trivandrum Heart Failure Registry reported that only 25% of HFrEF patients received GDMT at discharge, with nearly 60% mortality within 5 years, underscoring the need for improved adherence to evidence-based therapies.¹³ Similarly, the TRANSFORM-HF trial found no mortality difference between torsemide and furosemide in hospitalized HF patients,¹⁴ highlighting the ongoing need to optimize both efficacy and patient-centered outcomes in routine practice.

As per the recent guidelines, loop diuretics like torsemide are the principal pharmacologic therapy for reducing congestion in HF.¹⁵ The MRAs, such as Spironolactone or Eplerenone, are recommended by the European Society of Cardiology and the American College of Cardiology guidelines (Class I-A) for managing HFrEF.¹⁶

The real-world data collected over a 3-week follow-up period in this RESTORE-HF study, which evaluated a large cohort of Indian HF patients (1520 participants with HFrEF and a high prevalence of comorbidities such as diabetes and CAD), has provided valuable insights into short-term clinical outcomes, symptom improvement, and the safety profile of the torsemide-spironolactone FDC. The study highlights significant reductions in body weight, reflecting effective decongestion and volume management, key therapeutic goals in HF care, and was accompanied by improvement in NYHA functional class, and high physician and patient satisfaction, reinforcing the potential role of this FDC in routine HF management.

Diuretics have long served as the cornerstone of symptom relief in HF, with loop diuretics receiving a Class I recommendation in clinical guidelines for alleviating congestion.^17,18 Although loop diuretics are routinely used in nearly all patients with acute decompensated HF, clinical evidence guiding their optimal use in real-world settings remains limited. In the present study, torsemide, as the loop diuretic component of the FDC, may have played a key role in the observed weight reduction through its diuretic effect.

In addition, an improvement in NYHA functional class was observed, with a majority of patients shifting to lower classes by the end of the study. Torsemide promotes the excretion of sodium and water, thereby reducing pulmonary congestion and peripheral edema.¹⁹ While spironolactone complements this effect by blocking aldosterone, reducing sodium retention, and preventing potassium loss. It also contributes to symptomatic improvement in HF patients, as reflected by favorable changes in the NYHA functional class.²⁰ Together, the combination may work complementary to control symptoms more effectively than either drug alone. In the present study, this combination was associated with a marked improvement in NYHA classification, with many patients shifting from Class III to Class II or even Class I. These findings suggest that the FDC contributes to rapid symptomatic relief and better functional capacity in a real-world clinical setting. Moreover, the progressive and substantial reduction in edema severity observed over the study period further reinforces the clinical utility of the torsemide-spironolactone FDC in achieving effective volume management in HF patients.

In terms of safety, the treatment was well-tolerated. Only three mild AE, all related to loose stools, were reported, and no serious AE or deaths occurred during the 3-week study period. While this short-term data suggests a favorable safety profile, it is important to consider previously reported adverse effects associated with the individual components of the FDC. Spironolactone has been linked to hyperkalemia and gynecomastia, whereas torsemide has been reported to cause excessive urination, as noted in FDA safety communications.^21,22 Rare but serious adverse reactions have also been documented, including severe skin reactions such as Stevens-Johnson syndrome²³ and toxic epidermal necrolysis,²⁴ as well as rare neurological complications like quadriparesis.²⁵ Although such events were not observed in our study, these known risks highlight the importance of ongoing monitoring, especially in longer-term use or in patients with additional risk factors. Biochemical parameters, including serum creatinine, sodium, and potassium, remained within acceptable ranges, with no clinically alarming trends, although the rise in serum potassium warrants continued monitoring in longer-term use.

Beyond symptom relief, the complementary effects of torsemide and spironolactone may also contribute to blood pressure control in hypertensive patients, and their combination as a single regimen could reduce pill burden, potentially improving medication adherence.^5,26 High agreement rates on efficacy and tolerability (over 98%) indicate a favorable perception from both clinicians and patients, supporting its acceptability and integration into routine care.

Our findings reinforce the utility of torsemide-spironolactone FDC in achieving rapid symptomatic relief and effective volume management in real-world HFrEF patients. While real-world data on spironolactone use in Indian populations are limited, our study provides evidence of favorable efficacy, tolerability, and high patient- and physician-reported satisfaction over short-term follow-up. While SGLT2 inhibitors, such as dapagliflozin and empagliflozin, have demonstrated reductions in cardiovascular and all-cause mortality, HF hospitalizations, and renal events in the pooled analyses of DAPA-HF and EMPEROR-Reduced trials, these therapies complement rather than replace the role of diuretics and MRAs in managing congestion and fluid balance.²⁷

However, this study is not without limitations. The observational nature of the study limits causal interpretation, and the absence of a control group prevents direct comparison with other diuretic regimens. This design also increases the potential for systematic errors, including selection bias, which should be taken into account when interpreting the findings. Although a sample size calculation was performed, the final enrolled population was smaller than the planned target, which may limit the study’s statistical power. Additionally, the short 3-week follow-up period does not capture long-term clinical outcomes such as hospitalizations, mortality, or sustained renal and electrolyte effects.

Also, the study has potential biases from sponsorship and the absence of blinding, which may have influenced the outcomes. Additionally, the findings are based on an Indian population and may not be generalizable to other settings.

Despite these limitations, the study offers robust real-world insights into the short-term clinical benefits and safety of torsemide-spironolactone FDC therapy in Indian HF patients. The high levels of clinical and patient-reported satisfaction further support its potential utility in everyday practice, especially in resource-constrained settings. Future studies with longer follow-up RCTs and comparative arms are warranted to confirm and extend these findings.

Conclusion

The RESTORE-HF study demonstrates that the torsemide-spironolactone FDC may be effective and well-tolerated in real-world settings. Over 3 weeks, patients showed significant weight reduction, improvement in NYHA functional class, and edema grade improvement, and minimal AEs. These findings indicate that the torsemide-spironolactone FDC may offer a practical and clinically beneficial option for managing symptoms and improving functional outcomes in routine HF care.

Supplemental Material

sj-docx-1-tak-10.1177_17539447261430243 – Supplemental material for Real-world effectiveness and safety of torsemide and spironolactone fixed dose combination in Indian heart failure patients (RESTORE-HF study): a prospective, multicenter, observational study

Supplemental material, sj-docx-1-tak-10.1177_17539447261430243 for Real-world effectiveness and safety of torsemide and spironolactone fixed dose combination in Indian heart failure patients (RESTORE-HF study): a prospective, multicenter, observational study by Chandrashekhar K. Ponde, Devanu Ghosh Roy, Uday Jadav, Arun Mohanty, Karan Dang, Febin Francis, Nitin Zalte, Amarnath Sugumaran, Sandesh Sawant and Senthilnathan Mohanasundaram in Therapeutic Advances in Cardiovascular Disease

Footnotes

Acknowledgements

The medical writing support was provided by Snehal Khanolkar (Sqarona Medical Communications LLP, Pune).

Declarations

ORCID iD

Amarnath Sugumaran

Supplemental material

Supplemental material for this article is available online.

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