Win Ratio Research Articles

Analysis of the PARAGON-HF Study Results Using Win Ratio.

The PARAGON-HF study (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) investigated the effect of sacubitril-valsartan in heart failure (HF) with preserved ejection fraction. The results, which were analyzed using conventional statistical methods, did not find a significant reduction in the primary composite end point of cardiovascular death and total hospitalization for HF. Recent clinical trials used win ratio statistics that enable the incorporation of multiple outcome aspects into the primary end point and can detect positive outcomes with fewer patients. In this study, we assessed the effect of sacubitril-valsartan on outcomes using the win ratio to analyze results from patients included in the PARAGON-HF study. In the PARAGON-HF study, 4822 patients with HF with preserved ejection fraction were randomized either to sacubitril-valsartan or valsartan groups. In the present study, the primary outcome was a hierarchical composite of time to cardiovascular death, total number of hospitalization for HF, time to first hospitalization for HF, time to renal composite outcome, and change in the Kansas City Cardiomyopathy Questionnaire total symptom score at 8 months analyzed using a win ratio statistical model. Using this approach, we found that a greater number of patients who received sacubitril-valsartan experienced clinical benefits compared with those who received valsartan (win ratio, 1.13 [95% CI, 1.04-1.23]; P=0.005). This clinical advantage was evident in patients regardless of whether the left ventricular ejection fraction was above or below the median, that is, the left ventricular ejection fraction of 57%, and regardless of sex (Pinteraction=0.76 for the left ventricular ejection fraction and 0.73 for sex). Employing the innovative win ratio approach, sacubitril-valsartan demonstrated significant clinical benefits among patients with HF with preserved ejection fraction. Notably, this benefit was observed irrespective of left ventricular ejection fraction and sex. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Avoiding Treatment in Hospital With Subcutaneous Furosemide for Worsening Heart Failure: A Pilot Study (AT HOME-HF)

BackgroundTherapies are needed to address worsening congestion, without hospitalization, in patients with chronic heart failure (HF). ObjectivesThis pilot study assessed outcomes of a novel subcutaneous (SC) furosemide formulation compared to usual care in outpatients with worsening congestion. MethodsParticipants with chronic HF and worsening congestion were randomized open-label 2:1 to SC furosemide compared to usual care (UC). Decongestion was estimated by tracking body weight. The primary endpoint was a win ratio of a 30-day hierarchical composite of cardiovascular death, HF events, and change in N-terminal pro–B-type natriuretic peptide. Secondary endpoints included dyspnea severity, functional capacity, and quality of life. ResultsThirty-four participants were randomized to SC furosemide and 17 to UC. SC furosemide caused greater reduction in body weight: between-group difference in least square mean change was −2.02 kg at day 3 (95% CI: −3.9 to −0.14; P = 0.035). SC furosemide-to-UC win ratio was 1.11 (95% CI: 0.48-2.50; P = 0.806). Significant between-group least square mean differences favoring SC furosemide occurred in 7-point dyspnea score (P = 0.017) and 6-minute walk test (P = 0.032), with trend in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 Overall Summary Score of 9.15 (95% CI: 1.95-20.3; P = 0.106). The most common related adverse event with SC furosemide was mild infusion site pain (11.8%). ConclusionsSC furosemide augmented weight loss in patients with HF and worsening congestion. The composite primary endpoint was not statistically significant in this pilot investigation. However, findings of improved dyspnea scores and functional capacity, with favorable trend in KCCQ-12 score, warrant additional investigation to further document the clinical value of SC furosemide as an alternative to hospitalization (AT HOME-HF [Avoiding Treatment in the Hospital With Furoscix for the Management of Congestion in Heart Failure—A Pilot Study]; NCT04593823)

Components of the Atrial fibrillation Better Care pathway for holistic care of patients with atrial fibrillation: a win ratio analysis from the COOL-AF registry.

Compliance with integrated care based on the Atrial fibrillation Better Care (ABC) pathway has been associated with improved clinical outcomes. The primary objective of this study was to compare clinical outcomes of AF patients according to the compliant status of each component of the ABC pathway in a hierarchical win ratio approach. We studied AF patients in the COOL-AF registry. Each patient was followed every 6 months until 3 years. A win ratio analysis was performed, as not all clinical outcomes are equivalent. The hierarchical outcomes were (1) all-cause death, (2) intracranial haemorrhage (ICH), (3) ischaemic stroke/systemic embolism, (4) non-ICH major bleedings, and (5) acute myocardial infarction or heart failure. We also assessed win ratio and win proportion variance over the follow-up time, and the variations over time. A total of 3405 patients (mean age 67.8 ± 11.3; 41.8% female) were studied. Win ratio of ABC-compliant (all three components) vs. ABC-not-compliant was 1.57 (1.35-1.83), P < 0.001. When adding time in therapeutic range (TTR) data for compliant criteria for those who were on warfarin, the win ratio increased to 2.28 (1.89-2.75), P < 0.001. The A-compliant group (plus TTR data), B-compliant, and C-compliant had the win ratio of 1.81 (1.51-2.12), 1.82 (1.53-2.16), and 1.39 (1.18-1.62), all P < 0.001, compared to not compliant group. Management of AF patients according to each component of the ABC pathway is associated with better clinical outcomes compared to those non-compliant to ABC pathway. This finding underscores the importance of a holistic management approach strategy for AF patients.

Percutaneous coronary intervention plus medical therapy versus medical therapy alone in chronic coronary syndrome: a propensity score-matched analysis from the Swedish Coronary Angiography and Angioplasty Registry

BackgroundPercutaneous coronary intervention (PCI) is frequently used for patients with chronic coronary syndrome (CCS). However, the role of PCI beyond symptom relief in CCS remains controversial. The objective of this...

Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program

BackgroundObesity is a key factor in the development and progression of both heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). In the STEP-HFpEF Program (comprising the STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes] trials), once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations, and exercise function and reduced body weight in patients with obesity-related HFpEF. Whether the effects of semaglutide in this patient group differ in participants with and without AF (and across various AF types) has not been fully examined. ObjectivesThe goals of this study were: 1) to evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF with and without a history of AF; and 2) to determine if the efficacy of semaglutide across all key trial outcomes are influenced by baseline history of AF (and AF types) in the STEP-HFpEF Program. MethodsThis was a secondary analysis of pooled data from the STEP-HFpEF and STEP-HFpEF DM trials. Patients with heart failure, left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive once-weekly semaglutide 2.4 mg or matching placebo for 52 weeks. Dual primary endpoints (change in KCCQ-CSS and percent change in body weight), confirmatory secondary endpoints (change in 6-minute walk distance; hierarchical composite endpoint comprising all-cause death, HF events, thresholds of change in KCCQ-CSS, and 6-minute walk distance; and C-reactive protein [CRP]), and exploratory endpoint (change in N-terminal pro–B-type natriuretic peptide [NT-proBNP]) were examined according to investigator-reported history of AF (yes/no). Responder analyses examined the proportions of patients who experienced a ≥5-, ≥10, ≥15, and ≥20-point improvement in KCCQ-CSS per history of AF. ResultsOf the 1,145 participants, 518 (45%) had a history of AF (40% paroxysmal, 24% persistent AF, and 35% permanent AF) and 627 (55%) did not. Participants with (vs without) AF were older, more often male, had higher NT-proBNP levels, included a higher proportion of those with NYHA functional class III symptoms, and used more antithrombotic therapies, beta-blockers, and diuretics. Semaglutide led to larger improvements in KCCQ-CSS (11.5 points [95% CI: 8.3-14.8] vs 4.3 points [95% CI: 1.3-7.2]; P interaction = 0.001) and the hierarchal composite endpoint (win ratio of 2.25 [95% CI: 1.79-2.83] vs 1.30 [95% CI: 1.06-1.59]; P interaction < 0.001) in participants with AF vs without AF, respectively. The proportions of patients receiving semaglutide vs those receiving placebo experiencing ≥5-, ≥10-, ≥15-, and ≥20-point improvement in KCCQ-CSS were also higher in those with (vs without) AF (all P interaction values <0.05). Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status (all P interaction values not significant). There were fewer serious adverse events and serious cardiac disorders in participants treated with semaglutide vs placebo irrespective of AF history. ConclusionsIn the STEP-HFpEF Program, AF was observed in nearly one-half of patients with obesity-related HFpEF and was associated with several features of more advanced HF. Treatment with semaglutide led to significant improvements in HF-related symptoms, physical limitations, and exercise function, as well as reductions in weight, CRP, and NT-proBNP in people with and without AF and across AF types. The magnitude of semaglutide-mediated improvements in HF-related symptoms and physical limitations was more pronounced in those with AF vs without AF at baseline. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM; NCT04916470])

The Diagnosis and Treatment of Tricuspid Regurgitation.

It is estimated that 6% of persons over age 75 have clinically relevant tricuspid regurgitation (TR). This condition carries a high mortality and is of particular interest because of the recent development of new interventional treatments. This review is based on publications that were retrieved by a selective search in the PubMed database for randomized controlled trials (RCTs), observational studies, registry studies, expert recommendations, and current international guidelines. The evidence reveals that TR is an independent cause of mortality. Mortality is correlated with the severity of TR: approximately 35% of patients with severe TR and right heart failure die within 1 year, and about 60% within 3 years. The clinical course varies depending on the etiology (primary TR, atrial/ventricular secondary TR, association with pacemaker systems). In the outpatient setting, timely diagnosis by transthoracic echocardiography is crucial. The options for pharmacotherapy are essentially limited to diuretic treatment (grade 2a recommendation). Early referral to a specialized heart valve center is essential for the prevention of irreversible damage of the right heart and secondary end-organ damage, including cardiohepatic and cardiorenal syndromes. In the heart valve center, an extended diagnostic evaluation with multimodal imaging is followed by a case discussion by the interdisciplinary cardiac team, with individual evaluation of the treatment options. The first randomized controlled trial of treatment for TR yielded a win ratio of 1.48 (95% confidence interval, [1.06; 2.13]) for interventional treatment (edge-to-edge repair) compared to optimal medical therapy. As the understanding of tricuspid regurgitation improves, strategies for its interventional treatment are undergoing steady development, with the aim of lowering the mortality of this condition.

Expanding revascularization trials to women and underserved minorities and shifting to patient-centered outcomes: RECHARGE trials program.

We review the limited available evidence informing coronary revascularization decisions in women and minorities, and introduce the RECHARGE trial program, which consists of two separate but integrated parallel multicenter, randomized trials comparing coronary artery bypass grafting (CABG) to percutaneous coronary intervention (PCI), one exclusively enrolling women (RECHARGE:Women) and one exclusively enrolling Black or Hispanic patients (RECHARGE:Minorities). The extensive evidence base supporting coronary revascularization suffers from under-representation of women, minorities and minoritized populations, and the use of heterogeneous primary composite outcomes whose components have varying strengths of association with prognosis and quality-of-life (QOL). In RECHARGE, participants will be followed for up to 10 years, with QOL assessments at baseline, 30 days, 3 months, every 6 months for 3 years, and annually thereafter. The primary endpoint is the hierarchical composite of time to all-cause mortality, time-averaged change from baseline in the physical component of the SF-12v2 physical summary score, and time-averaged change from baseline in the mental component of the SF12v2 summary score, evaluated using a win ratio. Independently adjudicated major adverse cardiovascular and noncardiovascular events and disease-specific QoL will be secondary endpoints. The RECHARGE trials are the first revascularization trials to enroll exclusively women and minority patients and to use patient-centered outcomes as their primary outcome.

Randomization-based covariance adjustment of win ratios and win odds for randomized multi-visit studies with ordinal outcomes

In many randomized multi-visit studies, some response variables have an ordinal scale for outcomes. The win odds (accounts for ties) and the win ratio (ignores ties) are useful for treatment comparisons for ordinal outcomes. This paper discusses the application of randomization-based covariance and stratification adjustment of the win odds (and win ratio) to enable their more convenient use. Adjustment for strata is through the weighted average of within stratum two-sample U statistics for numerators and denominators for the stratified win odds (or win ratio). As randomization-based, invocation of covariance adjustment is through constraints to zeros for baseline covariate differences in the joint vector with logarithms of stratified win odds (or win ratios) for the respective visits. Such adjustment has no formal assumptions about the distributions of response variables or co-variates or the relationships of covariates to response variables; but the resulting adjusted stratified win odds (or win ratios) have narrower confidence intervals than their unadjusted counterparts when covariates have at least moderately strong associations with response variables. There is illustration of such results for the stratified win odds (and win ratio) for a randomized multi-visit clinical trial with an ordinal outcome for a chronic respiratory disorder. Journal of Statistical Research 2024, Vol. 58, No. 1, pp. 33-48

Far Cortical Locking Versus Standard Constructs for Locked Plate Fixation in the Treatment of Acute, Displaced Fractures of the Distal Femur

Background: Fixation of distal femoral fractures remains a challenge, and nonunions are common with standard constructs. Far cortical locking (FCL) constructs have been purported to lead to improved fracture-healing as compared with that achieved with traditional locking bridge plates. We sought to test this hypothesis in a comparative effectiveness clinical trial. Methods: This randomized trial was performed across 16 centers and included adult patients with an AO/OTA type 33A or 33C distal femoral fracture that was suitable for bridging fixation. We excluded patients with periprosthetic fractures. Participants were randomly assigned to either FCL fixation or standard locking plate fixation. The primary outcome was a hierarchical composite of radiographic and clinical fracture-healing at 3 months after fixation. We estimated between-group differences with use of the win ratio approach. Secondary outcomes included radiographic healing, clinical fracture-healing, complications, reoperations, and health-related quality of life (Short Form-36 Health Survey Version 2 [SF-36] Physical Component Summary and Mental Component Summary scores) at 3, 6, and 12 months after fixation. Results: We randomly assigned 193 patients to treatment with either FCL screws (96 patients) or standard screws (97 patients). The study population had a mean age of 63.4 years, consisted predominantly of women (68%), and was well-balanced between AO/OTA 33A and 33C fractures. Based on 4,355 pairwise comparisons, the calculated win ratio was 1.18 (95% confidence interval [CI], 0.77 to 1.79; p = 0.45), indicating that patients assigned to FCL screws had better outcomes in 51% of the comparisons. Radiographic healing did not differ significantly between the groups (odds ratio, 1.36; 95% CI, 0.69 to 2.72; p = 0.38), nor did Function IndeX for Trauma (FIX-IT) scores (p = 0.41). There were no significant differences between the groups in terms of SF-36 Physical Component Summary scores at 3 months or in the change in scores at 12 months after fixation. Conclusions: In this multicenter randomized trial of adult patients with an AO/OTA type 33A or 33C distal femoral fracture, similar clinical and radiographic healing outcomes were observed in the FCL and standard fixation groups. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

A three-level nested portfolio optimization model with position allocation

Existing portfolio optimization models cannot well capture the real position allocation requirement, leading to limited impact in practice. To overcome this challenge, we propose a three-level nested portfolio optimization model with position allocation. Within this model, the inner and middle levels collaboratively determine the optimal portfolio, while the outer level focuses on optimizing the holding proportion of each stock in the optimal portfolio. Compared with existing models with portfolio weights, the proposed model imposes the position allocation constraint that precisely characterizes the limitations on holding each stock. This constraint is crucial for investors to obey securities trading regulations involving position limitations and to mitigate the potential impact of market risks. To address the nonlinear and nonconvex nature of the novel model, we develop an intelligent optimization algorithm by effectively hybridizing the support vector regression and the enhanced grey wolf optimizer. We comprehensively evaluate its performance using eight metrics, including accumulative return, annual return, Sharpe ratio, maximum drawdown, absolute and relative win ratios, predictive precision and accuracy. The experimental results indicate that (i) the proposed model can achieve more excess returns than those stock selection models not considering position allocation, especially for the large-cap stocks; (ii) compared with other state-of-the-art meta-heuristics, the enhanced grey wolf optimizer can yield better portfolio in conjunction with the support vector regression; (iii) in the context of the Chinese A-share stock market, specific financial indicators such as return on equity, inventory turnover rate, net income growth rate, and debt-to-equity ratio should be given greater consideration compared to other financial metrics.

Defining estimand for the win ratio: Separate the true effect from censoring.

The win ratio has been increasingly used in trials with hierarchical composite endpoints. While the outcomes involved and the rule for their comparisons vary with the application, there is invariably little attention to the estimand of the resulting statistic, causing difficulties in interpretation and cross-trial comparison. We make the case for articulating the estimand as a first step to win ratio analysis and establish that the root cause for its elusiveness is its intrinsic dependency on the time frame of comparison, which, if left unspecified, is set haphazardly by trial-specific censoring. From the statistical literature, we summarize two general approaches to overcome this uncertainty-a nonparametric one that pre-specifies the time frame for all comparisons, and a semiparametric one that posits a constant win ratio across all times-each with publicly available software and real examples. Finally, we discuss unsolved challenges, such as estimand construction and inference in the presence of intercurrent events.

Win ratio analysis of short-term clinical outcomes of focal therapy and robot-assisted radical prostatectomy for the patients with localized prostate cancer

We compared the comprehensive clinical outcomes of focal therapy (FT) and robot-assisted radical prostatectomy (RARP) in patients with localized prostate cancer (PC) using a win ratio analysis. After propensity score matching, a win ratio analysis, in which the composite endpoints of failure-free survival (FFS) and the urinary domain of the Expanded Prostate Cancer Index Composite (EPIC) were analyzed, was used for the comparison of the clinical outcomes of FT and RARP for the patients with localized PC. Seventy-two patients were included in each group after propensity score matching. FFS was not significantly different between the groups (p = 0.5044) after 36 months of follow-up. In contrast, the score of the urinary domain of the EPIC in the FT group was significantly better than that in the RARP group (p < 0.0001). The win ratio of FT per RARP was 3.39 (p < 0.0001; 95% confidence interval 2.21–5.20), suggesting a higher comprehensive outcome in the FT group than in the RARP group during short-term follow-up in single institution. Although further randomized trial with long-term follow-up would be needed for the evaluation, the win ratio would be useful to analyze the efficacy of FT according to patient preferences comprehensively.

Trial Design with Win Statistics for Multiple Time-to-Event Endpoints with Hierarchy

The conventional approach to the analysis of composite endpoints is time-to-first event analysis. However, this approach has been criticized because it ignores the differences in clinical severity and may end up emphasizing the less severe time-to-event. To overcome this limitation, win statistics (win ratio, win odds, or net benefit) have become popular in analysis of hierarchical time to event endpoints. However, design of randomized clinical trials using the win statistics is lagging behind. In this article, we derive formulas for the win statistics and probability of ties under specific assumptions that can be useful in practice. We also address two design issues: the selection of meaningful and justifiable design parameters and power calculations, when the win statistics method is the primary analysis method for multiple time-to-event endpoints for a pre-specified hierarchy. Finally, we identify patterns where the win statistics approach would have greater statistical power than time-to-first event analysis. Several examples are used to illustrate the usefulness of the formula-based power calculations.

Time from admission to randomization and the effect of empagliflozin in acute heart failure: A post-hoc analysis from EMPULSE.

Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization. The EMPULSE population was dichotomized by median time from hospital admission to randomization (1-2 days vs. 3-5 days). The primary outcome was a hierarchical composite endpoint of time to all-cause death, number of HF events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3-5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1-2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3-5 days: WR 1.69, 95% confidence interval [CI] 1.26-2.25) but was attenuated in patients randomized earlier (1-2 days: WR 1.04, 95% CI 0.74-1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all-cause hospitalizations (interaction p < 0.1 for both). The reduction of N-terminal pro-B-type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004). Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3-5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1-2 days). These findings should be confirmed in future studies before clinical application.

Composite end points and competing risks analysis.

Composite end points are common primary outcomes in clinical trials. Their main benefit of utilizing a composite outcome is increasing the number of primary outcome events, meaning fewer participants are required to deliver an adequately powered trial. By combining multiple important end points in the primary outcome rather than having to select only 1, composite end points potentially make clinically meaningful benefits easier to detect and avoid ranking outcomes hierarchically. However, there are a number of important considerations when designing and interpreting clinical trials that utilize composite end points. In this Statistical Primer, issues with composite end points such as competing events, halo effect, risk of bias, time-to-event limitations and the win ratio are discussed in the context of real world clinical trials.

Results of the COMPASS Trial Analyzed Using Win Ratio Compared With Conventional Analytic Approaches

BackgroundWin ratio (WR) is a newer analytic approach for trials with composite end points that accounts for the relative importance of individual components. Our objective was to compare the results of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial analyzed using WR with those obtained using conventional statistical approaches. MethodsWe used an unmatched WR analysis for first and total (first plus recurrent) events to examine effects of rivaroxaban with aspirin and rivaroxaban alone vs aspirin alone on primary efficacy (cardiovascular death, stroke, myocardial infarction), safety (modified International Society on Thrombosis and Haemostasis major bleeding), and net clinical benefit (primary efficacy plus fatal or critical organ bleeding) end points. We compared the WR results with those obtained using the Cox proportional hazards regression model for first events and Anderson-Gill method for total events. We calculated the win difference to estimate absolute treatment effects. ResultsThe WR approach produced results consistent with those obtained using conventional statistical methods for the primary composite end point (first event: WR, 1.32 [95% confidence interval (CI), 1.14-1.52]; 1/Cox hazard ratio, 1.32 [95% CI, 1.16-1.52]; total [first plus recurrent] events: WR, 1.32 [95% CI, 1.14-1.52]; 1/Anderson-Gill hazard ratio, 1.32 [95% CI, 1.16-1.54]) as well as for main safety and net clinical benefit end points. The absolute benefits of the combination of rivaroxaban and aspirin compared with aspirin alone calculated using the win difference were greatest in those with multiple high-risk features. ConclusionsReanalysis of the COMPASS trial results using WR produced results that were consistent with those obtained using conventional statistical approaches. Clinical Trial RegistrationNCT01776424

2-Year Outcomes of an Atrial Shunt Device in HFpEF/HFmrEF: Results From REDUCE LAP-HF II

BackgroundThe REDUCE LAP-HF II (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II) trial found that, compared with a sham procedure, the Corvia Atrial Shunt did not improve outcomes in heart failure with preserved or mildly reduced ejection fraction. However, after 12-month follow-up, “responders” (peak-exercise pulmonary vascular resistance <1.74 WU and absence of a cardiac rhythm management device) were identified. ObjectivesThis study sought to determine: 1) the overall efficacy and safety of the atrial shunt vs sham control after 2 years of follow-up; and 2) whether the benefits of atrial shunting are sustained in responders during longer-term follow-up or are offset by adverse effects of the shunt. MethodsThe study analyzed 2-year outcomes in the overall REDUCE LAP-HF II trial, as well as in responder and nonresponder subgroups. The primary endpoint was a hierarchical composite of cardiovascular death or nonfatal ischemic/embolic stroke, total heart failure events, and change in health status. ResultsIn 621 randomized patients, there was no difference between the shunt (n = 309) and sham (n = 312) groups in the primary endpoint (win ratio: 1.01 [95% CI: 0.82-1.24]) or its individual components at 2 years. Shunt patency at 24 months was 98% in shunt-treated patients. Cardiovascular mortality and nonfatal ischemic stroke were not different between the groups; however, major adverse cardiac events were more common in those patients assigned to the shunt compared with sham (6.9% vs 2.7%; P = 0.018). More patients randomized to the shunt had an increase in right ventricular volume of ≥30% compared with the sham control (39% vs 28%, respectively; P < 0.001), but right ventricular dysfunction was uncommon and not different between the treatment groups. In responders (n = 313), the shunt was superior to sham (win ratio: 1.36 [95% CI: 1.02-1.83]; P = 0.037, with 51% fewer HF events [incidence rate ratio: 0.49 [95% CI: 0.25-0.95]; P = 0.034]). In nonresponders (n = 265), atrial shunting was inferior to sham (win ratio: 0.73 [95% CI: 0.54-0.98]). ConclusionsAt 2 years of follow-up in REDUCE LAP-HF II, there was no difference in efficacy between the atrial shunt and sham groups in the overall trial group. The potential clinical benefit identified in the responder group after 1 and 2 years of follow-up is currently being evaluated in the RESPONDER-HF (Re-Evaluation of the Corvia Atrial Shunt Device in a Precision Medicine Trial to Determine Efficacy in Mildly Reduced or Preserved Ejection Fraction Heart Failure) trial. (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure II [REDUCE LAP-HF II]; NCT03088033)

Dapagliflozin for Critically Ill Patients With Acute Organ Dysfunction

ImportanceSodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown.ObjectiveTo determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023.InterventionParticipants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first.Main Outcomes and MeasuresThe primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support–free days, ICU, and hospital stay, assessed using bayesian regression models.ResultsAmong 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group.Conclusion and RelevanceThe addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin.Trial RegistrationClinicalTrials.gov Identifier: NCT05558098

Application of the Win Ratio Method in the ENGAGE AF-TIMI 48 Trial Comparing Edoxaban With Warfarin in Patients With Atrial Fibrillation.

Cardiovascular trials often use a composite end point and a time-to-first event model. We sought to compare edoxaban versus warfarin using the win ratio, which offers data complementary to time-to-first event analysis, emphasizing the most severe clinical events. ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a double-blind, randomized trial in which patients with atrial fibrillation were assigned 1:1:1 to a higher dose edoxaban regimen (60/30 mg daily), a lower dose edoxaban regimen (30/15 mg daily), or warfarin. In an exploratory analysis, we analyzed the trial outcomes using an unmatched win ratio approach. The win ratio for each edoxaban regimen was the total number of edoxaban wins divided by the number of warfarin wins for the following ranked clinical outcomes: 1: death; 2: hemorrhagic stroke; 3: ischemic stroke/systemic embolic event/epidural or subdural bleeding; 4: noncerebral International Society on Thrombosis and Haemostasis major bleeding; and 5: cardiovascular hospitalization. 21 105 patients were randomized to higher dose edoxaban regimen (N=7035), lower dose edoxaban regimen (N=7034), or warfarin (N=7046), yielding >49 million pairs for each treatment comparison. The median age was 72 years, 38% were women, and 59% had prior vitamin K antagonist use. The win ratio was 1.11 (95% CI, 1.05-1.18) for higher dose edoxaban regimen versus warfarin and 1.11 (95% CI, 1.05-1.18) for lower dose edoxaban regimen versus warfarin. The favorable impacts of edoxaban on death (34% of wins) and cardiovascular hospitalization (41% of wins) were the major contributors to the win ratio. Results consistently favored edoxaban in subgroups based on creatine clearance and dose reduction at baseline, with heightened benefit among those without prior vitamin K antagonist use. In a win ratio analysis of the ENGAGE AF-TIMI 48 trial, both dose regimens of edoxaban were superior to warfarin for the net clinical outcome incorporating ischemic and bleeding events. As the win ratio emphasizes the most severe clinical events, this analysis supports the superiority of edoxaban over warfarin in patients with atrial fibrillation. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.

Win Statistics in Observational Cancer Research: Integrating Clinical and Quality-of-Life Outcomes.

Background: Quality-of-life metrics are increasingly important for oncological patients alongside traditional endpoints like mortality and disease progression. Statistical tools such as Win Ratio, Win Odds, and Net Benefit prioritize clinically significant outcomes using composite endpoints. In randomized trials, Win Statistics provide fair comparisons between treatment and control groups. However, their use in observational studies is complicated by confounding variables. Propensity score (PS) matching mitigates confounding variables but may reduce the sample size, affecting the power of win statistics analyses. Alternatively, PS matching can stratify samples, preserving the sample size. This study aims to assess the long-term impact of these methods on decision making, particularly in colorectal cancer patients. Methods: A motivating example involves a cohort of patients from the ReSARCh observational study (2016-2021) with locally advanced adenocarcinoma of the rectum, situated up to 12 cm from the anal verge. These patients underwent either a watch-and-wait approach (WW) or trans-anal local excision (LE). Win statistics compared the effects of WW and LE on a composite outcome (overall survival, recurrence, presence of ostomy, and rectum excision). For matched win statistics, we used robust inference techniques proposed by Matsouaka et al. (2022), and for stratified win statistics, we applied the method proposed by Dong et al. (2018). A simulation study assessed the coverage probability of matched and stratified win statistics in balanced and unbalanced groups, calculating how often the confidence intervals included the true values of WR, NB, and WO across 1000 simulations. Results: The results suggest a better efficacy of the LE approach when considering efficacy outcomes alone (WR: 0.47 (0.01 to 1.14); NB: -0.16 (-0.34 to 0.02); and WO: 0.73 (0.5 to 1.05)). However, when QoL outcomes are included in the analyses, the estimates are closer to 1 (WR: 0.87 (0.06 to 2.06); WO: 0.93 (0.61 to 1.4)) and to 0 (NB: -0.04 (-0.25 to 0.17)), indicating a negative impact of the treatment effect of LE regarding the presence of ostomy and the excision of the rectum. Moreover, based on the simulation study, our findings underscore the superior performance of matched compared to stratified win statistics in terms of coverage probability (matched WR: 97% vs. stratified WR: 33.3% in a high-imbalance setting; matched WR: 98% vs. stratified WR: 34.4% in a medium-imbalance setting; and matched WR: 99.2% vs. stratified WR: 37.4% in a low-imbalance setting). Conclusions: In conclusion, our study sheds light on the interpretation of the results of win statistics in terms of statistical significance, providing insights into the application of pairwise comparison in observational settings, promoting its use to improve outcomes for cancer patients.