Cardiovascular Benefits of Spironolactone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction: Insights from a Win Ratio Analysis of the TOPCAT Trial

The universal definition and classification of heart failure (HF) divides it into three distinct categories based on left ventricular ejection fraction (LVEF): HF with reduced ejection fraction (HFrEF; LVEF ≤40%), HF with mildly reduced ejection fraction (HFmrEF; LVEF 41–49%) and HF with preserved ejection fraction (HFpEF; LVEF ≥50%).¹ In contrast to the well-established pharmacological therapies in HFrEF, supported by robust evidence from landmark trials, the medical treatment of HFmrEF and HFpEF remains limited.^2–5 Spironolactone, a well-established and widely accessible steroid mineralocorticoid receptor antagonist (MRA), was evaluated for its efficacy in improving cardiovascular (CV) outcomes in the TOPCAT trial.⁶ Although the original analysis of the TOPCAT trial demonstrated that spironolactone did not significantly reduce the primary outcome, which was a composite of CV death, aborted cardiac arrest and hospitalisation for HF, a subsequent post hoc analysis suggested potential benefits in patients enrolled from the Americas cohort. In that subgroup, spironolactone was associated with a statistically significant reduction in the primary outcome, with an HR of 0.82 (95% CI [0.69–0.98]; p=0.026).^6,7

However, previous analyses of the TOPCAT trial primarily used conventional statistical methods, such as Cox proportional hazards models and time-to-first-event analyses commonly used for composite outcomes in HF clinical trials. These approaches have notable limitations in accurately capturing the full spectrum of treatment benefits, particularly in complex and chronic conditions such as HFpEF/HFmrEF.^8,9 Combining multiple outcomes into a composite endpoint primarily aims to increase statistical power and improve efficiency in detecting treatment effects. However, this approach may obscure which individual outcomes are driving the overall result, particularly when less clinically meaningful components occur more frequently or disproportionately influence the composite measure.^8,9 Therefore, it is essential for readers to critically examine the results of the individual component outcomes because these provide important context and greater clarity regarding the true clinical impact of the intervention. For example, in TOPCAT, the primary composite outcome assigned equal statistical weight to non-fatal hospitalisations and CV death, despite the substantial differences in clinical severity and patient impact between these events. This introduces a mismatch between statistical representation and clinical reality.

To address these limitations, the win ratio method has been developed and has recently emerged as a robust statistical approach in HF-related trials.^8–10 This method enables a more comprehensive and clinically relevant assessment of treatment efficacy by incorporating hierarchical composite outcomes and integrating both event-based and non-event-based outcomes while prioritising them based on their clinical significance.^8–10 By accommodating both clinical endpoints and patient-reported outcomes, ranging from life-threatening events to measures of symptom burden, the win ratio offers a more nuanced and clinically meaningful representation of therapeutic efficacy.^8,9,11 This is particularly salient in chronic, heterogeneous conditions, such as HFpEF/HFmrEF, where improvements in patient experience and functional status and the prevention of recurrent, high-burden events are central goals of care, yet are frequently under-represented in conventional time-to-first-event analyses. As such, the win ratio provides a richer, more patient-centred interpretation of treatment effects.

Given these considerations, the aim of the present study was to provide a more comprehensive evaluation of the CV benefits of spironolactone in HFmrEF and HFpEF through the application of this novel statistical method in a post hoc analysis of TOPCAT trial.

Methods

Study Population

The design and primary results of the TOPCAT trial (NCT00094302) have been reported previously.⁶ Briefly, TOPCAT was a multicentre double-blind randomised controlled trial that evaluated the clinical benefit of spironolactone (15–45 mg daily) versus placebo in symptomatic HF patients with LVEF ≥45%, age >50 years, controlled systolic blood pressure, serum potassium <5.0 mmol/l and either a history of HF hospitalisation within the past 12 months or elevated natriuretic peptide levels within the past 60 days. The original primary outcome of the TOPCAT trial was a composite of death from CV causes, aborted cardiac arrest or HF hospitalisation.⁶ The mean follow-up duration was 3.3 years in each study group.⁶ A deidentified version of the TOPCAT trial database, obtained from the National Heart, Lung, and Blood Institute’s Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC), was used for this study. We restricted the present analysis to the subset of TOPCAT participants enrolled in the Americas (US, Canada, Argentina and Brazil), due to previously reported concerns regarding significantly lower adherence to study medication among participants enrolled in Russia and Georgia.^6,7,12

Primary Outcome

The primary outcome of this study is the clinically relevant CV benefit as assessed by the win ratio approach. Clinical CV benefit is defined as a hierarchical composite outcome of (ordered according to descending clinical significance): time to CV death, time to first aborted cardiac arrest, time to first HF hospitalisation, time to first hospitalisation for arrhythmias and the improvement of a patients’ symptoms, function and quality of life, assessed by changes from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score (OSS). The KCCQ-OSS ranges from 0 to 100, with higher scores indicating better health status and fewer HF symptoms.¹³ All component outcome definitions used in this study were consistent with those in the original study, which were adjudicated by the clinical endpoint committee of the TOPCAT trial.⁶

Statistical Analysis

Baseline characteristics are presented descriptively according to the treatment group, with continuous variables reported as the mean ± SD or median with interquartile range (IQR), as appropriate. Categorical variables are expressed as frequencies and percentages. The significance of between-group differences in continuous variables was assessed using either parametric or non-parametric tests. Categorical variables were compared using Pearson’s Chi-squared test.

The primary outcome was evaluated using the win ratio method, adhering to the intention-to-treat principle. The win ratio analysis compared each patient in the spironolactone group with each patient in the placebo group to determine a win, loss or tie within each pair across the hierarchical composite outcome.^9,11 The comparison followed a predefined hierarchy, prioritising the most clinically significant outcome (here, CV death) to the least important outcome (here, KCCQ-OSS). For time-to-event outcomes (CV death, aborted cardiac arrest, HF hospitalisation and arrhythmia hospitalisation), only events occurring within each pair’s shared follow-up period (defined as the minimum follow-up time within the pair) were considered. Within this interval, if one patient experienced an event while the other did not, the patient without an event was the ‘winner’. If both patients experienced an event, the patient with a longer event-free duration was considered the winner. A pairwise comparison was classified as a tie if both patients survived without experiencing an adverse event throughout their shared follow-up period. For quantitative outcomes (KCCQ-OSS), the winner in each patient pair was defined as the individual with a greater change from baseline to 36 months in KCCQ-OSS, indicating superior improvement in symptoms, functional status and quality of life. In cases where a patient’s KCCQ-OSS data were missing, all their paired comparisons were considered ties.

The unmatched win ratio was calculated by dividing the total number of wins by the total number of losses in the spironolactone group.⁹ To provide a more comprehensive assessment of absolute treatment effects, complementing the relative benefit of the win ratio and elucidating the contribution of each component to the overall win ratio, we also reported the win difference, commonly referred to as the net treatment benefit.⁹ The win difference was determined by calculating the difference between the proportion of wins and the proportion of losses in the spironolactone group.⁹ Estimates of win statistics (win ratio or win difference) are reported along with their corresponding 95% CIs.⁹ In addition, we performed subgroup analyses to evaluate the impact of selected baseline characteristics, including sex, age, race, LVEF and various clinical factors.^5,6,14–16

To assess the robustness of our findings, we conducted sensitivity analyses. First, we modified the primary hierarchical outcome in several ways: replacing CV death with all-cause mortality; excluding time to first hospitalisation for arrhythmias from the hierarchy; analysing the change in KCCQ-OSS at 12 or 24 months instead of 36 months; and using a threshold of a ≥5-point improvement in KCCQ-OSS, rather than any difference, to determine a win. Second, we performed a similar win ratio analysis in the full TOPCAT trial population.

All tests were 2-tailed and p<0.05 was considered statistically significant. Statistical analyses and plots were performed using Stata Version 18.0 (StataCorp) and R version 4.4.2 (R Foundation for Statistical Computing).

Results

Patient Characteristics

In all, 1,767 patients were included in this post hoc analysis: 886 (50.1%) patients in the spironolactone group and 881 (49.9%) patients in placebo group. There were no significant differences between the spironolactone and placebo groups in terms of age (71.8 ± 9.7 years versus 71.2 ± 9.6 years, respectively), female sex (49.9% versus 49.9%, respectively), body mass index (33.9 ± 8.1 kg/m² versus 33.7 ± 8.2 kg/m², respectively) and LVEF (58.3 ± 7.7% versus 58.0 ± 7.9%, respectively), or other baseline characteristics (p>0.05). Detailed baseline characteristics of the participants are presented in Table 1.

Follow-up

During a median follow-up of 35 months (IQR 23–50 months), 96 (10.8%) patients in the spironolactone group and 127 (14.5%) in the placebo group died from CV causes. Aborted cardiac arrest occurred in two patients in the spironolactone group and in four in the placebo group. In all, 184 (20.8%) patients in the spironolactone group and 216 (24.5%) in the placebo group experienced at least one hospitalisation for HF management. Hospitalisation for arrhythmias was reported in 14 (1.6%) and 18 (2.0%) patients in the spironolactone and placebo groups, respectively. From baseline to Month 36, the median improvement in the KCCQ-OSS was 5.6 points (IQR −8.3 to 21.4 points) in the spironolactone group and 5.2 points (IQR −7.4 to 18.8 points) in the placebo group.

Win Ratio Analysis

The win ratio analysis of the primary outcome involved a total of 780,566 patient pairs. Figure 1 presents the primary efficacy analysis of the hierarchical assessment of five components. Spironolactone won in 28.32% of paired comparisons and placebo won in 23.12%, with 48.54% of comparisons tied, yielding a win ratio of 1.22 in favour of spironolactone (95% CI [1.05–1.42]; p=0.008). The distribution of wins and ties (including numbers and proportions) for each paired comparison for all components of the hierarchical composite endpoint is shown in Figure 1. In addition, the overall win difference of 5.20% (95% CI [1.36–9.04]) illustrates the net clinical benefit of spironolactone. A detailed assessment of the win differences revealed a concordant positive benefit across all components of the outcome hierarchy (Figure 1).

The CV benefits of spironolactone were generally consistent across subgroups categorised by sex, age, ethnicity, BMI, LVEF, New York Heart Association class, AF, diabetes, hypertension, history of MI, systolic blood pressure, estimated glomerular filtration rate and the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (p for interaction >0.05; Figure 2). Furthermore, sensitivity analyses confirmed the robustness of the treatment effect, with win ratios favouring spironolactone across all analytical strategies, aligning with the primary analysis (Supplementary Table 1).

Discussion

By incorporating additional outcomes beyond those included in the original study’s primary endpoint (CV death, aborted cardiac arrest, and HF hospitalisation), the win ratio approach used in the present study enabled a more comprehensive assessment of the benefits of spironolactone. Our results revealed a significant advantage for spironolactone, with a win ratio of 1.22 (95% CI [1.05–1.42]; p=0.008). This can be interpreted as follows: for any randomly chosen pair of patients (one on spironolactone and the other on placebo) who are not tied, the estimated odds that the patient treated with spironolactone will experience a better outcome (win) are 1.22. Furthermore, for each untied pair, the probability that the patient in spironolactone group wins can also be estimated as 1.22/(1.22+1)=0.55.⁹

To examine the contribution of each component to the overall win ratio, a detailed analysis of the win difference is necessary. In this study, the win difference was 5.2%, indicating the net clinical benefit of spironolactone in this HFmrEF/HFpEF population.⁹ A detailed assessment of the win differences for each component revealed that although spironolactone therapy provided concordant positive benefits across all component outcomes (adverse CV events, patient symptoms, functional status and quality of life) with all win differences>0, notably most of the benefit was attributable to reductions in CV deaths (win difference=2.77%), followed by HF hospitalisations (win difference=1.61%). This highlights another advantage of the win ratio approach with hierarchical composite outcomes: it allows for a clear assessment of the impact of the most important outcomes, minimising the confounding influence of less important but earlier-occurring outcomes, as can be the case with conventional statistical methods and conventional composite endpoints. Conversely, subgroup analyses in our study did not reveal any significant differences in the treatment effect of spironolactone across subgroups defined by age, sex or LVEF. These results suggest that the efficacy of spironolactone was consistent across these subgroups.

Furthermore, sensitivity analyses yielded results consistent with the primary analysis, further demonstrating the robustness of the clinical CV benefits provided by spironolactone among this population of HFmrEF/HFpEF patients. Our findings provide additional evidence supporting the use of spironolactone, a well-established and widely accessible MRA, in clinical practice for HF patients with mildly reduced or preserved ejection fraction. This is particularly valuable in low- and middle-income countries, where novel MRAs, such as finerenone, may require considerable time to achieve widespread availability.

Among HF subtypes, HFpEF has historically been less studied than HFrEF.¹⁷ However, the incidence and prevalence of HFpEF are rising, with notable geographic variation, and are projected to exceed those of HFrEF in the near future.¹⁷ Although mortality and morbidity rates in HFpEF are somewhat lower than in HFrEF, they remain substantial, underscoring the growing burden of this condition and the urgent need for improved understanding and management strategies.¹⁷ However, a recent meta-analysis highlighted major gaps in knowledge regarding the clinical profile of patients with HFpEF, particularly the under-reporting of comorbidities, which appeared in only 27% of HFpEF trials compared with 51% of HFrEF trials and 48% of HF trials overall.¹⁸

Over time, the most prevalent comorbidities in HF populations include hypertension, AF, and chronic kidney disease.^17,18 Compared with HFrEF, patients with HFpEF are typically older, more often women, and have higher rates of hypertension, obesity, AF, anaemia, chronic kidney disease, chronic pulmonary disease and valvular heart disease.^17,18 In contrast, coronary artery disease, hyperlipidaemia, peripheral artery disease and cerebrovascular disease are less common in patients with HFpEF compared with HFrEF.¹⁷ Ethnic and regional differences have also been observed, such as a lower prevalence of HFpEF among black individuals and divergent associations with coronary artery disease in Chinese cohorts.¹⁷ Associations with diabetes remain inconsistent across studies.¹⁷ Notably, HFpEF patients generally exhibit lower serum natriuretic peptide levels than patients with HFrEF.¹⁷ The complexity and multimorbidity of HFpEF have led cardiologists to classify patients into distinct subgroups to improve diagnosis and guide treatment.¹⁹ Currently, three widely accepted clinical phenotypes have been proposed, each influenced by a combination of cardiac and non-cardiac comorbidities.¹⁹ These phenotypes exhibit a gradient in terms of age, systemic inflammation, diagnostic biomarkers and prognosis.¹⁹ The ‘older, vascular ageing’ phenotype is associated with the greatest inflammatory burden and poorest outcomes, whereas the ‘metabolic, obese’ phenotype demonstrates an intermediate profile and the ‘younger, low B-type natriuretic peptide’ phenotype is characterised by comparatively more favourable clinical features.¹⁹

In contrast to HFrEF, where the four therapeutic pillars (renin–angiotensin system inhibitors, β-blockers, MRAs and sodium–glucose cotransporter 2 inhibitors) are well-established and strongly recommended in contemporary guideline-directed management, treatment options for HFpEF remain limited.¹⁷ To date, only sodium–glucose cotransporter 2 inhibitors and MRAs have demonstrated consistent clinical benefits in large randomised controlled trials, whereas angiotensin receptor–neprilysin inhibitors have shown only potential benefits, supported primarily by post hoc analyses rather than definitive trial evidence.^17,19,20 MRAs, including spironolactone, have emerged as a cornerstone therapy in the management of HF.^21,22 They confer benefits in patients with HF through several distinct mechanisms. First, and of central importance, is their ability to limit excessive fibrosis and attenuate prohypertrophic signalling, thereby improving cardiac structural remodelling and mitigating dysfunction.^22,23 This effect is mediated through negative modulation of proinflammatory pathways and downregulation of pathways associated with collagen and extracellular matrix organisation, notably reducing collagen formation.^22,24,25

A further prominent contributing mechanism is the blockade of mineralocorticoid receptors within the heart and vasculature.^21,23 Under conditions of heightened physiological stress, particularly in the context of HF, elevated aldosterone levels precipitate overactivation of mineralocorticoid receptors.²² This, in turn, promotes myocardial fibrosis, adverse remodelling, cardiomyocyte apoptosis, endothelial dysfunction, perivascular fibrosis and vascular stiffening.²² Thus, by directly inhibiting mineralocorticoid receptors, MRAs can significantly mitigate these pathological processes. Another noteworthy mechanism is the capacity of spironolactone to reduce the risk of hypokalaemia and hypomagnesaemia in HF patients, especially those concurrently using loop or thiazide/thiazide-like diuretics.²² This has the potential to confer survival advantages, because hypokalaemia is strongly associated with an increased risk of adverse outcomes in HF, particularly critical arrhythmias.^22,26,27 Finally, some other mechanisms of action of spironolactone and MRAs, such as blocking the effects of norepinephrine from sympathetic nerve terminals and reducing the activation of inflammatory pathways and macrophage-to-myofibroblast transition, may also confer benefits in HF management.^22,27,28

The efficacy of MRAs in HFrEF has been investigated in numerous landmark trials, which have demonstrated significant reductions in CV mortality and hospitalisations for HF with MRA therapy.^29–31 These findings have led to strong recommendations in the current European Society of Cardiology and American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines for the use of MRAs, including spironolactone, in the management of HFrEF patients.^2,3 Conversely, the role of MRAs has also been investigated in HFmrEF and HFpEF. In the Aldo-DHF trial, spironolactone significantly improved diastolic function, as assessed by echocardiography, compared with placebo at 12 months in patients with HF and LVEF ≥50%.³²

The TOPCAT trial, which evaluated spironolactone versus placebo in symptomatic HF patients with LVEF ≥45%, did not demonstrate a significant reduction in the primary composite outcome of CV death, aborted cardiac arrest or hospitalisation for HF (HR 0.89; 95% CI [0.77–1.04]; p=0.14) over a median follow-up of 3.3 years.⁶ However, regional variation analyses suggested that spironolactone may be effective in the Americas cohort, with an HR for the primary composite endpoint of 0.82 (95% CI [0.69–0.98]; p=0.026).⁷ This observed regional difference may be attributed to the fact that a substantial proportion of patients enrolled in Russia and Georgia likely did not have true HF, demonstrated significantly lower adherence to study medication and experienced markedly lower event rates than participants from the Americas.⁷

More recently, the FINEARTS-HF trial, which included 6,001 patients with symptomatic HF and LVEF ≥40%, reported results similar to the post-hoc analysis of TOPCAT-Americas regarding the effect of MRA.^7,15 Specifically, finerenone significantly reduced the risk of a composite of total worsening HF events and death from CV causes compared with placebo (RR 0.84; 95% CI [0.74–0.95]; p=0.007).¹⁵ That trial also demonstrated more consistent benefits of finerenone, a non-steroidal MRA, across the spectrum of HF, diabetes and kidney disease compared with traditional steroidal MRAs.^15,20 These advantages may be explained by its higher potency and selectivity for the mineralocorticoid receptor, balanced distribution within both cardiac and renal tissues and favourable pharmacokinetic profile.²⁰ Unlike steroidal MRAs, finerenone has a shorter half-life, lacks active metabolites and exhibits superior receptor selectivity compared with spironolactone, along with greater binding affinity relative to eplerenone.²⁰ However, these studies used conventional statistical methods that inadequately capture the full spectrum of treatment effects in chronic conditions such as HFpEF/HFmrEF because they assign equal weight to clinically distinct events, such as hospitalisation and death, thereby limiting meaningful, patient-centred interpretation. Moreover, these methods often evaluate event-based and non-event-based outcomes separately, failing to provide an integrated assessment of overall therapeutic benefit.

To address the aforementioned limitations, the win ratio approach has gained increasing prominence in recent HF clinical trials, including DAPA-MI, EMPULSE, RELIEVE-HF and FINEARTS-HF.^33–38 Most of these trials incorporated all-cause or CV death and CV/HF hospitalisations as the highest-priority outcomes, with a quantitative outcome, such as change in patient-reported health status (e.g. KCCQ score), New York Heart Association class or physical function (e.g. 6-minute walk distance), as the lowest-priority outcome in the primary composite outcome. However, the number of components in the hierarchical composite outcomes varies considerably, ranging from two levels (ATTR-ACT trial) to seven levels (DAPA-MI trial).^35,36

In clinical trials with a high proportion of event-free patients, such as the TOPCAT trial, integrating patient-reported outcomes into the hierarchical composite outcome is recommended to enhance statistical power and facilitate the detection of clinical benefits more effectively.^9,11 However, additional components must be carefully selected to ensure a comprehensive assessment of treatment benefits while preserving interpretability for clinicians.^9,39 In the present post hoc analysis of the TOPCAT trial, we focused on the most clinically meaningful and well-established outcomes, comprising four CV adverse events and a patient-reported outcome (KCCQ score), which is qualified by the US Food and Drug Administration as a clinical outcome assessment and recommended as a performance measure for quantifying the quality of care.¹³ Using the KCCQ score to evaluate the treatment effectiveness of spironolactone may improve the patient-centredness of care by assessing patients’ symptoms, function and quality of life.¹³

The win ratio of 1.22 for spironolactone observed in our study likely represents a modest treatment effect. Unfortunately, to our knowledge, no absolute cut-off value of the win ratio has been established in the literature to define clinical meaningfulness. Nevertheless, the magnitude of benefit we report is consistent with findings from other landmark HFmrEF/HFpEF trials that also used hierarchical composite outcomes. Specifically, the FINEARTS-HF trial of finerenone reported a win ratio of 1.11 (95% CI [1.03–1.19]), the DELIVER trial of dapagliflozin reported a win ratio of 1.22 (95% CI [1.09–1.37]) and the EMPEROR-Preserved trial of empagliflozin reported a win ratio of 1.25 (95% CI [1.09–1.43]).^9,16,40

It is important to note that the win ratio reflects results derived from a hierarchical composite endpoint rather than a conventional time-to-first event composite. Unlike conventional composites, which may obscure the effect on mortality due to preceding non-fatal events (e.g. HF hospitalisation), the hierarchical approach prioritises clinically most important outcomes, such as CV death, thereby providing a clearer interpretation of treatment impact.^9,16 In addition, contemporary methodological literature has recommended reporting the win difference to clarify the contribution of each individual component to the overall win ratio.^9,11

In our study, the win difference analysis demonstrated that all component outcomes favoured spironolactone. For simplicity, the estimated win difference for CV death was 2.77%, indicating that, for any randomly selected pair of patients, those receiving spironolactone had a 2.77% higher probability of a longer survival time than those receiving placebo. If CV mortality benefit was not observed (a tie), spironolactone patients could still demonstrate benefit on aborted cardiac arrest (win difference 0.22%), and if both mortality and cardiac arrest were tied, benefit could still be observed at the level of HF hospitalisation (win difference 1.61%). Furthermore, if no benefit was seen for HF hospitalisation, patients could still potentially benefit in terms of arrhythmic events or improvement in quality of life, as assessed by the KCCQ-OSS.

Although the absolute win difference for CV death in our study (2.77%) was modest, it was numerically greater than that reported in other contemporary HFpEF/HFmrEF trials, namely 0.6% for finerenone in FINEARTS-HF, 1.0% for dapagliflozin in DELIVER and 0.4% for empagliflozin in EMPEROR-Preserved.^9,16,40 Taken together, and particularly in the context of the relatively lower event rates in HFmrEF/HFpEF trials compared with HFrEF populations, the benefits of spironolactone observed in our study may be considered clinically meaningful.

Study Limitations

This study has several limitations that warrant consideration. First, due to the inherent limitations of its post hoc nature, the present study was not based on prespecified hypotheses or analysis plans, which could introduce potential biases, even though each of the component outcomes used in our hierarchical composite outcome had been prespecified as an outcome of interest in the TOPCAT trial.⁹ Future clinical trials designed to use the win ratio method are needed to validate our findings.

Second, the prioritisation of component events in win ratio analysis is not always straightforward.⁴¹ Although we tried to construct a hierarchical composite outcome based on the most clinically meaningful outcomes commonly used in previous HF trials, the appropriateness of this composite endpoint may be subject to debate.⁸ However, sensitivity analyses using alternative hierarchical composite outcomes demonstrated the consistent efficacy of spironolactone.

Third, in the win ratio approach, symptomatic improvements assessed early in treatment and major clinical outcomes that occur later in the trial are combined within a single metric, which may obscure distinctions between short- and long-term efficacy.⁴¹ To mitigate this limitation, we assessed the KCCQ score at a later time point (36 months).

Fourth, although the inclusion of additional endpoints in the win ratio method can enhance statistical power by increasing the number of captured events, it also introduces the risk that the overall result may be disproportionately influenced by less clinically meaningful outcomes (e.g. KCCQ score), thereby diluting the clinical relevance of the findings.⁴¹ However, in our study, the KCCQ score contributed only minimally to the overall win ratio (win difference 0.30%).

Finally, as a relatively novel statistical approach, the win ratio method has only recently been applied in a limited number of clinical trials.¹¹ Consequently, interpreting the results from win ratio analyses may be challenging at present for many clinicians and researchers.^8,11 Nevertheless, by presenting a detailed description of the methodology used, as well as the individual components in the findings with both win ratios and win differences, we hope that the results of this study will be readily accessible and translatable to improved clinical practice.

Conclusion

The findings from this post hoc analysis, using the win ratio method, provide a comprehensive assessment of the CV benefits of spironolactone in patients with heart failure and an LVEF ≥45%. Notably, spironolactone yielded concordant positive benefits across all component outcomes, including reductions in the risk of CV death, aborted cardiac arrest, HF hospitalisation and arrhythmia hospitalisation, as well as improvements in KCCQ scores, compared with placebo. Furthermore, this efficacy was observed consistently across subgroups stratified by age, sex and LVEF. Given the post hoc nature of this analysis, further prospective trials explicitly designed to implement the win ratio approach are warranted to validate these findings.

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