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Novel statistical methods have emerged in recent medical literature, which clinicians must understand to properly appraise and integrate evidence into their practice. Some of these key concepts include win ratios, restricted mean survival time, responder analyses, and standardized mean difference. This article offers guidance to busy clinicians on the comprehension and practical applicability of the results to patients. Win ratios provide an alternative method to analyze composite outcomes by prioritizing individual components of the composite; prioritization of the outcomes should be evidence-based, pre-specified, and patient-centered. Restricted mean survival time presents a method to analyze Kaplan-Meier curves when assumptions required for Cox proportional hazards analysis are not met. As it only considers outcomes that occur within a specific timeframe, the duration of follow-up must be appropriately defined and based on prior epidemiologic and mechanistic evidence. Researchers can analyze continuous outcomes with responder analyses, in which participants are dichotomized into \"responders\" or \"non-responders.\" While clinicians and patients may more easily grasp outcomes analyzed in this way, they should be aware of the loss of information and resulting imprecision, as well as potential to manipulate data presentation. When meta-analyzing continuous outcomes, point estimates can be converted to standardized mean differences to facilitate the combination of data utilizing various outcome measures. However, clinicians may find it challenging to grasp the clinical meaningfulness of a standardized mean difference, and may benefit from converting it to well-known outcomes. By providing the background knowledge of these statistical methods, along with practical applicability, benefits, and inevitable limitations, this article aims to provide clinicians with an approach to appraise the literature and apply the results in clinical practice.

•Effects of edoxaban versus VKAs on PROs were assessed using a WR approach•PACT-Q2 captured patient-perceived convenience/satisfaction with anticoagulants•WR adds interpretation of meaningfulness and drivers of satisfaction/convenience•Convenience/satisfaction was meaningfully better with edoxaban versus VKA•Key factors driving the favorable outcomes with edoxaban versus VKAs were identified The previous report on patient-reported outcome findings of the ENVISAGE-TAVI atrial fibrillation (AF) (NCT02943785) trial demonstrated improved patient experience for edoxaban versus vitamin K antagonists (VKAs). This post hoc analysis aimed to provide insights on the patient-reported outcome findings of ENVISAGE-TAVI AF using a win ratio (WR) approach to understand key drivers of treatment differences. This analysis included patients who received edoxaban or VKAs and had evaluable Perception of Anticoagulant Treatment Questionnaire 2 (PACT-Q2) assessments from ENVISAGE-TAVI AF. The PACT-Q2 assesses treatment convenience (13 items) and satisfaction (7 items). PACT-Q2 data at months 3 and 12 were analyzed using the WR. Patient-to-patient pairs (one from each group) were compared based on predefined outcome rules; a “win,” “loss,” or “tie” was determined for edoxaban in each pairwise comparison. The WR (95% confidence interval [CI]) for edoxaban was calculated as the total number of pairs with a win divided by that of pairs with a loss. WR >1 indicates a more favorable patient experience for edoxaban versus VKAs. Edoxaban was associated with a higher probability of improved overall treatment convenience and satisfaction compared with VKAs at months 3 (WR [95% CI], 1.87 [1.58 to 2.22]) and 12 (WR [95% CI], 2.01 [1.70 to 2.38]). This difference was driven by 18 of 20 PACT-Q2 items, showing a significantly higher probability of meaningfully better outcomes with edoxaban. In conclusion, this WR analysis demonstrated that meaningfully better treatment convenience and satisfaction were more likely with edoxaban than with VKAs in patients with AF after transcatheter aortic valve replacement.

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.

In order to investigate the optimal approach for synchronous colorectal liver metastases (sCRLM), we sought to use the “win ratio” (WR), a novel statistical approach, to assess the relative benefit of simultaneous versus staged surgical treatment. Patients who underwent hepatectomy for sCRLM between 2008 and 2020 were identified from a multi-institutional database. The WR approach was utilized to compare composite outcomes of patients undergoing simultaneous versus staged resection. Among 1116 patients, 642 (57.5%) presented with sCRLM; 290 (45.2%) underwent simultaneous resection, while 352 (54.8%) underwent staged resection. In assessing the composite outcome, staged resection yielded a WR of 1.59 (95%CI 1.47–1.71) over the simultaneous approach for sCRLM. The highest WR occurred among patients requiring major hepatectomy (WR = 1.93, 95%CI 1.77–2.10) compared with patients who required minor liver resection (WR = 1.55, 95%CI 1.44–1.70). Staged resection was superior to simultaneous resection for sCRLM based on a WR assessment. •The optimal strategy of synchronous colorectal liver metastases (sCRLM) is unsolved.•The win ratio (WR) is used to analyze the hierarchical composite endpoints.•The WR is increasingly utilized for more “patients-centric” viewpoints.•Staged resection was superior to simultaneous resection for sCRLM based on the WR.•The WR was higher when major hepatectomy was needed.

Background Win statistics offer an alternative approach to clinical trials that use survival analysis to analyze composite endpoints. Our objective was to re-analyze data from previously published registry-based randomized controlled trials that produced hazard ratios using win statistics to evaluate the correspondence between them. Good correspondence was defined as both results being positive, negative, or neutral. Win statistics were calculated for these trials to encourage transparency, scientific rigor, and possibly validate results. Methods The win ratio ordered events hierarchically by clinical importance for each trial, with all-cause death regarded as most severe, followed by acute myocardial infarction. Further components, i.e., other endpoints, were added subsequently to the hierarchy. Each patient in the treatment group was compared with each patient in the control arm in hierarchical order. The total number of wins for each category in the treatment group was added and divided by the total number of wins in the control group. Win odds were calculated as an extension, which incorporate ties into the calculation. Results The results using win statistics showed good correspondence to the previously reported hazard ratios with their composite endpoints: for the TASTE trial, the results were neutral for both the hazard ratio and win odds. The hazard ratio was 0.86 (0.67–1.10), and the win odds were 1.02 (0.99–1.04). Similar results were found for the iFR-SWEDEHEART, DETO2X-AMI, and VALIDATE trials. The IAMI trial showed better results for the vaccinated group compared to the placebo for both the hazard ratio and win odds. Conclusions Win statistics offer an alternative approach to traditional survival analysis by harnessing multiple events hierarchically by clinical importance. Win statistics also offer the potential to evaluate a broader range of clinical endpoints, providing a more rounded perspective of treatment efficacy, an important consideration when designing future randomized controlled trials. This is the first multi-registry-based controlled trial reanalysis using win statistics.

Introduction Despite its rising adoption, the use of minimally invasive (MIS) pancreaticoduodenectomy (PD) in the treatment of pancreatic cancer remains controversial. We sought to compare MIS and open PD for pancreatic cancer resection in terms of short-term, long-term, and oncologic outcomes using the win ratio, a novel statistical approach. Methods Patients undergoing PD for pancreatic adenocarcinoma 2010–2016 were identified from the National Cancer Database (NCDB). Patients were paired based on age, sex, race, tumor size, Charlson-Deyo score, and receipt of neoadjuvant chemotherapy. The win ratio was calculated based on 30-day and 3-year mortality, receipt of adjuvant chemotherapy, surgical margin status, examination of at least 11 lymph nodes, extended length of stay, and 30-day readmission. Results Among 18,936 patients, median age was 67 (IQR: 60–74); most patients had stage II disease at diagnosis ( n  = 16,530, 87.3%) and tumor size ≥ 2 cm ( n  = 15,880, 83.9%). The majority of patients underwent open PD ( n  = 16,409, 86.7%) versus MIS PD ( n  = 2527, 13.3%). For every matched patient-patient pair, the odds of the patient undergoing MIS PD “winning” were 1.14 (95%CI 1.13–1.15) higher versus open PD. The benefits of MIS PD were most pronounced among patients with tumor size < 2 cm (WR 1.21, 95%CI 1.13–1.30 versus  ≥ 2 cm, WR 1.13, 95%CI 1.12–1.14) and patients who received neoadjuvant chemotherapy prior to resection (WR 1.28, 95%CI 1.23–1.32 versus no neoadjuvant chemotherapy, WR 1.13, 95%CI 1.11–1.14). Conclusions MIS PD may be preferable to open PD based on a hierarchical composite outcome that considered short-term, long-term, and oncologic outcomes.

To reanalyze the results of the Balanced Solutions in Intensive Care Study (BaSICS) through hierarchical endpoint analysis with win ratio. All patients with full data in BaSICS trial were elected for the analysis. BaSICS compared balanced solutions (Plasma Lye 148) versus 0.9% saline in critically ill patients requiring fluid challenge. The win ratio was defined as a hierarchical endpoint of 90-day mortality, recepit of kidney replacement therapy, hospital length-of-stay (LOS), and intensive care unit (ICU) LOS. Both unstratified and stratified (by admission type: planned admission, unplanned admission with sepsis, and unplanned admission without sepsis) approaches were used. A subgroup analysis was performed in patients with traumatic brain injury. A total of 10,490 patients were included in the analysis, resulting in 27,587,566 unique combinations for unstratified WR. Unstratified Win ratio was 1.02 (95% confidence interval 0.97; 1.07), which was similar to stratified WR. No stratum in the stratified analysis resulted in significant results. Subgroup analysis confirmed the possible harm of balanced solutions in traumatic brain injury patients (WR 0.80; 95% confidence interval 0.64; 0.99). In this reanalysis of BaSICS, a win ratio analysis largely replicated the results of the main trial, yielding neutral results except for the subgroup of patients with traumatic brain injury where a signal of harm was found. •Hierarchical endpoint analysis using win ratio is a new method to evaluate outcomes in randomized controlled trials.•There are few trials in critical care medicine that have used this approach.•In a secondary analysis of the BaSICS trial, a win ratio approach provided similar results to the main analysis.

Background Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. Methods All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant’s response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses (“win ratio”), with ties excluded. Results In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30–4.29, p  = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13–3.62, p  = 0.018). Conclusion The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.

Pocock et al. (2012, European Heart Journal 33, 176–182) proposed a win ratio approach to analyzing composite endpoints comprised of outcomes with different clinical priorities. In this article, we establish a statistical framework for this approach. We derive the null hypothesis and propose a closed-form variance estimator for the win ratio statistic in all pairwise matching situation. Our simulation study shows that the proposed variance estimator performs well regardless of the magnitude of treatment effect size and the type of the joint distribution of the outcomes.

To perform a post-hoc reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) and the Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients (RENAL) trials through hierarchical composite endpoint analysis using win ratio (WR). All patients with complete information from the STARRT-AKI (which compared accelerated versus standard approaches for renal replacement therapy – RRT initiation) and RENAL (which compared two different RRT doses in critically ill patients) trials were selected. WR was defined as a hierarchical composite endpoint using 90-day mortality, RRT dependency at 90-days, intensive care unit (ICU) length-of-stay (LOS), and hospital LOS (primary analysis); values above the unit represent a benefit of the intervention for the hierarchical composite endpoint. A secondary analysis replacing LOS by days alive and free of RRT was performed. Stratified analyses were performed according to illness severity score, surgical status, and the presence of sepsis. The WR analysis produced 2,141,830 pairs for the STARRT-AKI trial and 536,446 pairs for the RENAL trial, respectively. The WR results for STARRT-AKI and RENAL were 1.04 (95% confidence interval [CI] 0.96–1.13; p = 0.33) and 1.02 (95% CI; 0.90–1.15; p = 0.75) for the primary analysis, and 0.88 (95% CI; 0.79–0.99; p = 0.03) and 1.02 (95% CI; 0.87–1.21; p = 0.77) for the secondary analysis, respectively. The stratified analysis of the primary suggested possible benefit of the accelerated-strategy in the STARRT-AKI trial for non-surgical patients with sepsis, while the secondary analysis suggested possible harm of the accelerated-strategy for surgical patients without sepsis. There was no evidence of heterogeneity in treatment effects in stratified analyses in the RENAL trial. WR approach using a hierarchical composite endpoint is feasible for trials in critical care nephrology. The primary re-analyses of the STARRT-AKI and RENAL trials both yielded neutral results; however, there was suggestion of heterogeneity in treatment effect in stratified analyses of the STARRT-AKI trial by surgical status and sepsis. Selection of the endpoints and hierarchical ordering before trial design using the WR approach can have important implications for trial interpretation. Trial Registry: ClinicalTrials.gov number NCT02568722 (STARRT-AKI) and NCT00076219 (RENAL). •Hierarchical endpoints can be assessed using win ratio (WR), which provides pairwise comparisons among trial participants according to a defined hierarchy.•WR is an alternative to endpoint assessment in trials with competing risks•In this post-hoc reanalysis of the STARRT-AKI and RENAL trials, WR showed overall neutral results for both trials; however, in the STARRT-AKI trial, there was evidence of heterogeneity in treatment effect according to surgical status and the presence of sepsis.