Win Ratio Research Articles

Win Ratio Analyses Using a Modified Hierarchical Composite Outcome: Insights from PARAGLIDE-HF

The win ratio (WR) is an emerging alternative for reporting composite outcomes, prioritizing clinically significant events such as mortality while incorporating surrogate measures. However, its benefits should be weighed against limitations, particularly the influence of lower hierarchical outcomes. This secondary analysis of the PARAGLIDE-HF trial performed a WR sensitivity analysis using a modified hierarchical composite outcome to assess the utility of WR sensitivity analysis and the efficacy of sacubitril/valsartan versus valsartan. PARAGLIDE-HF compared sacubitril/valsartan with valsartan in heart failure (HF) patients with ejection fraction >40% (N=466). A hierarchical outcome in the primary analysis included cardiovascular death, HF hospitalizations, urgent HF visits, and change in N-terminal pro-B-type natriuretic peptide (NT-proBNP), with a 25% decrease considered a win. In the pre-specified subgroup with ejection fraction ≤60% (N=357), sacubitril/valsartan showed a treatment effect on the hierarchical outcome (WR, 1.46; 95% CI, 1.08-1.97). Sensitivity analyses for this subgroup included: 1) excluding NT-proBNP change, 2) substituting the 25% proportion change of NT-proBNP with 10% or 50%, and 3) including renal outcomes within the hierarchical outcome. In addition to the WR, the win odds (WO), in which 50% of the ties are allocated to both the numerator and denominator of the WR-a potentially more suitable modification of the WR that accounts for the presence of ties-were presented. Excluding NT-proBNP (WR, 1.49; 95% CI, 1.00-2.22; WO, 1.12; 95% CI, 1.00-1.26), adjusting the NT-proBNP threshold from 25% to 10% or 50% (WR, 1.41; 95% CI, 1.06-1.89; WO, 1.27; 95% CI, 1.04-1.56 for 10%; and WR, 1.54; 95% CI, 1.11-2.12; WO, 1.25; 95% CI, 1.06-1.48 for 50%), and incorporating renal outcomes (WR, 1.44; 95% CI, 1.07-1.94; WO, 1.28; 95% CI, 1.05-1.56) consistently favored sacubitril/valsartan. Multiple WR sensitivity analyses support a consistent treatment benefit of sacubitril/valsartan versus valsartan in patients with ejection fraction >40% to 60%. Future studies could consider prespecifying WR sensitivity analysis for comprehensive assessment of treatment effects. PARAGLIDE-HF; ClinicalTrials.gov ID, NCT03988634 (https://clinicaltrials.gov/study/NCT03988634).

Rationale and Design of the DEFIANCE Study: A Randomized Controlled Trial of Mechanical Thrombectomy Versus Anticoagulation Alone for Iliofemoral Deep Vein Thrombosis

BackgroundDeep vein thrombosis (DVT) is a common medical condition that is associated with clinically significant sequelae, including postthrombotic syndrome (PTS). Anticoagulation alone remains the guideline-recommended treatment for many patients with iliofemoral DVT. Recent technological advances have led to an increase in the use of mechanical thrombectomy for DVT, but mechanical thrombectomy-based procedures have not yet been compared with standard-of-care anticoagulation therapy in randomized studies. MethodsThe DEFIANCE study (ClinicalTrials.gov: NCT05701917) is an international and actively enrolling randomized controlled trial (RCT) in lower extremity DVT assessing an interventional strategy that includes mechanical thrombectomy with the ClotTriever System (Inari Medical, Irvine, CA) versus anticoagulation alone. Approximately 300 patients with unilateral iliofemoral DVT and symptom duration ≤12 weeks will be randomized 1:1. Study conduct includes an independent core laboratory for duplex ultrasound assessment, an independent medical monitor for safety adjudication, and evaluation of PTS severity on the Villalta scale using best clinical practices. The primary endpoint is a composite outcome structured as a hierarchal win ratio of 1) the occurrence of treatment failure or therapy escalation as adjudicated by the medical monitor, with failure defined as amputation or gangrene of the target leg or venous thromboembolism-related mortality, and 2) the assessment of PTS severity at the 6-month follow-up visit. In addition to being a component of the primary endpoint, the severity of PTS at 6 months is also evaluated as a stand-alone secondary endpoint. An additional secondary endpoint is a composite of outcomes at the 10-day visit and is structured as a hierarchal win ratio of 1) vessel compressibility on duplex ultrasound, 2) patient-reported pain, and 3) improvement of edema. The safety endpoints are access site complications requiring endovascular or surgical repair and the occurrence through the 30-day visit of mortality, major bleeding, or new symptomatic pulmonary embolism. ConclusionsDEFIANCE will be the first RCT to evaluate a mechanical thrombectomy-based interventional approach versus anticoagulation therapy alone for DVT. The results will inform the treatment of patients with iliofemoral DVT and the prevention of PTS-associated morbidity. Trial RegistrationDEFIANCE: RCT of ClotTriever System Versus Anticoagulation In Deep Vein Thrombosis (DEFIANCE), ClinicalTrials.gov: NCT05701917, URL: https://clinicaltrials.gov/study/NCT05701917?cond=Deep%20Vein%20Thrombosis&term=defiance&rank=1

Sex differences in cardiovascular outcomes in patients with acute pancreatitis.

The risk of cardiovascular disease increases in patients with acute pancreatitis. However, it remains unknown whether this increase varies between males and females. To assess sex differences in cardiovascular outcomes among acute pancreatitis patients during long-term follow-up. Participants were recruited from the UK-biobank, which is a population-based cohort study consisting of 502 368 individuals aged 40-69 years old. Cardiovascular outcomes were defined as major cardiovascular and cerebrovascular adverse events (MACCE), encompassing all-cause death, myocardial infarction, and stroke. We compared sex difference in MACCE incidence using incidence rate per 1,000 person-years. The association between sex and MACCE risk was assessed using Cox proportional hazards models and win-ratio method, adjusted for demographic, lifestyle, metabolic factors and medication use. A total of 1371 participants with acute pancreatitis were included, 42.5% were male. Over a median follow-up of 13.9 years, 226 MACCE cases occurred. The incidence rate of MACCE for male was 16.44, compared to 9.80 in female. Multivariate Cox regression analysis indicated a higher risk of MACCE in male compared to female (HR 1.80 [95% CI 1.36-2.38]). Adjusted HR for all-cause mortality, myocardial infarction, and stroke were 1.49, 2.75, and 1.67, respectively. The adjusted win ratio by inverse probability of treatment weighting was 0.55 (P <0.001), suggesting a worse outcome in male acute pancreatitis patients. Male experienced more adverse cardiovascular outcomes than female in the long follow-up after acute pancreatitis, suggesting a need for sex-specific management strategies in acute pancreatitis patients.

Transcatheter Valve Replacement in Severe Tricuspid Regurgitation.

Severe tricuspid regurgitation is associated with disabling symptoms and an increased risk of death. Data regarding outcomes after percutaneous transcatheter tricuspid-valve replacement are needed. In this international, multicenter trial, we randomly assigned 400 patients with severe symptomatic tricuspid regurgitation in a 2:1 ratio to undergo either transcatheter tricuspid-valve replacement and medical therapy (valve-replacement group) or medical therapy alone (control group). The hierarchical composite primary outcome was death from any cause, implantation of a right ventricular assist device or heart transplantation, postindex tricuspid-valve intervention, hospitalization for heart failure, an improvement of at least 10 points in the score on the Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS), an improvement of at least one New York Heart Association (NYHA) functional class, and an improvement of at least 30 m on the 6-minute walk distance. A win ratio was calculated for the primary outcome by comparing all possible patient pairs, starting with the first event in the hierarchy. A total of 267 patients were assigned to the valve-replacement group and 133 to the control group. At 1 year, the win ratio favoring valve replacement was 2.02 (95% confidence interval [CI], 1.56 to 2.62; P<0.001). In comparisons of patient pairs, those in the valve-replacement group had more wins than the control group with respect to death from any cause (14.8% vs. 12.5%), postindex tricuspid-valve intervention (3.2% vs. 0.6%), and improvement in the KCCQ-OS score (23.1% vs. 6.0%), NYHA class (10.2% vs. 0.8%), and 6-minute walk distance (1.1% vs. 0.9%). The valve-replacement group had fewer wins than the control group with respect to the annualized rate of hospitalization for heart failure (9.7% vs. 10.0%). Severe bleeding occurred in 15.4% of the valve-replacement group and in 5.3% of the control group (P = 0.003); new permanent pacemakers were implanted in 17.4% and 2.3%, respectively (P<0.001). For patients with severe tricuspid regurgitation, transcatheter tricuspid-valve replacement was superior to medical therapy alone for the primary composite outcome, driven primarily by improvements in symptoms and quality of life. (Funded by Edwards Lifesciences; TRISCEND II ClinicalTrials.gov number, NCT04482062.).

Large-bore Mechanical Thrombectomy Versus Catheter-directed Thrombolysis in the Management of Intermediate-risk Pulmonary Embolism: Primary Results of the PEERLESS Randomized Controlled Trial.

There is a lack of randomized controlled trial (RCT) data comparing outcomes of different catheter-based interventions for intermediate-risk pulmonary embolism (PE). PEERLESS is a prospective, multicenter, RCT that enrolled 550 intermediate-risk PE patients with right ventricular dilatation and additional clinical risk factors randomized 1:1 to treatment with large-bore mechanical thrombectomy (LBMT) or catheter-directed thrombolysis (CDT). The primary endpoint was a hierarchal win ratio (WR) composite of the following: 1) all-cause mortality, 2) intracranial hemorrhage, 3) major bleeding, 4) clinical deterioration and/or escalation to bailout, and 5) postprocedural intensive care unit (ICU) admission and length of stay, assessed at the sooner of hospital discharge or 7 days post-procedure. Assessments at the 24-hour visit included respiratory rate, mMRC dyspnea score, NYHA classification, right ventricle (RV)/left ventricle (LV) ratio reduction, and RV function. Endpoints through 30 days included total hospital stay, all-cause readmission, and all-cause mortality. The primary endpoint occurred significantly less frequently with LBMT vs CDT (WR 5.01 [95% CI: 3.68-6.97]; P<0.001). There were significantly fewer episodes of clinical deterioration and/or bailout (1.8% vs 5.4%; P=0.04) with LBMT vs CDT and less postprocedural ICU utilization (P<0.001), including admissions (41.6% vs 98.6%) and stays >24 hours (19.3% vs 64.5%). There was no significant difference in mortality, intracranial hemorrhage, or major bleeding between strategies, nor in a secondary WR endpoint including the first 4 components (WR 1.34 [95% CI: 0.78-2.35]; P=0.30). At the 24-hour visit, respiratory rate was lower for LBMT patients (18.3±3.3 vs 20.1±5.1; P<0.001) and fewer had moderate to severe mMRC dyspnea scores (13.5% vs 26.4%; P<0.001), NYHA classifications (16.3% vs 27.4%; P=0.002), and RV dysfunction (42.1% vs 57.9%; P=0.004). RV/LV ratio reduction was similar (0.32±0.24 vs 0.30±0.26; P=0.55). LBMT patients had shorter total hospital stays (4.5±2.8 vs 5.3±3.9 overnights; P=0.002) and fewer all-cause readmissions (3.2% vs 7.9%; P=0.03), while 30-day mortality was similar (0.4% vs 0.8%; P=0.62). PEERLESS met its primary endpoint in favor of LBMT vs CDT in treatment of intermediate-risk PE. LBMT had lower rates of clinical deterioration and/or bailout and postprocedural ICU utilization compared with CDT, with no difference in mortality or bleeding.

Impact of dapagliflozin on cardiometabolic outcomes after myocardial infarction according to baseline left ventricular ejection fraction: a DAPA-MI substudy

Abstract Background Dapagliflozin improved cardiometabolic outcomes compared with placebo following acute myocardial infarction (MI) in participants without prior diabetes mellitus (DM) or chronic heart failure (HF) in the DAPA-MI trial. Purpose Cardiometabolic outcomes were assessed in the DAPA-MI trial according to left ventricular ejection fraction (EF) at randomisation. Methods Participants were categorised according to whether baseline EF was ≥50 or &amp;lt;50%. Those without a baseline EF result and those who did not receive a dose of study drug were excluded. The primary objective was to determine the clinical effect of dapagliflozin 10 mg versus placebo assessed using a hierarchical composite outcome and analysed by the win ratio method. The primary outcome was the hierarchical composite, by order of perceived clinical importance, of death, hospitalization for HF (HHF), nonfatal MI, atrial fibrillation/flutter event, new diagnosis of type 2 DM, NYHA functional class at the last trial visit, and body weight decrease of ≥5% from baseline to the last trial visit. Time to first event of NYHA class II-IV or HHF and time to first event of NYHA class III-IV or HHF were assessed as endpoints of special interest. Hazard ratios (HR) with 95% confidence intervals (CI) were determined using Cox proportional hazards models. The main subgroup variable (baseline EF ≥50 or &amp;lt;50) and its interaction with treatment (P int) were included. Results 838 participants had EF≥50 and 2913 had EF&amp;lt;50 at baseline. The primary hierarchical composite outcome resulted in a win ratio for those with EF≥50 of 1.32 (CI 1.00-1.73) and 1.38 for those with EF&amp;lt;50 (CI 1.21-1.57; P int 0.8) (Figures). There were no significant interactions by EF for any of the secondary outcomes. In those with EF&amp;lt;50, a first event of NYHA class II-IV or HHF occurred in 435 (29.4%) participants in the dapagliflozin group and 485 (33.8%) in the placebo group (absolute risk difference [ARD] 4.4%; HR 0.83, CI 0.73-0.94, P&amp;lt;0.01). In those with EF≥50, this occurred in 81 (19.7%) and 93 (21.8%), respectively (ARD 2.1%; HR 0.96, CI 0.65-1.41, P=0.7; P int 0.47). In those with EF&amp;lt;50, a first event of NYHA class III-IV or HHF occurred in 77 (5.2%) in the dapagliflozin and 115 (8.0%) in the placebo groups (ARD 2.2%; HR 0.64, CI 0.48-0.85, P&amp;lt;0.01). In those with EF≥50, this occurred in 14 (3.4%) and 19 (4.4%), respectively (ARD 1.0%; HR 0.80, CI 0.40-1.60, P=0.5; P int 0.55). There was no significant effect of dapagliflozin on death/MI/stroke in either subgroup (EF&amp;lt;50: HR 0.96, CI 0.65-1.41; EF≥50: HR 0.83, CI 0.38-1.84; P int 0.75). Dapagliflozin increased the incidence of 5% weight loss in both of the EF subgroups with no significant interaction. Conclusions Dapagliflozin resulted in significant benefit in cardiometabolic outcomes compared with placebo regardless of baseline EF. The absolute reduction in HF symptoms or HHF with dapagliflozin, compared with placebo, was greatest in those with baseline EF&amp;lt;50.Figures

GenePHIT phase 2 study design: a double blind, placebo-controlled trial to assess efficacy, safety, and tolerability of AB-1002 gene therapy in adults with heart failure

Abstract Introduction Heart failure (HF) is associated with substantial morbidity and mortality, highlighting a critical need for novel therapies. AB-1002, an engineered adeno-associated virus (AAV) vector gene therapy candidate, delivers a constitutively active form of protein phosphatase inhibitor (I-1c) to restore cardiomyocyte intracellular calcium homeostasis. Preliminary results from an ongoing Phase (Ph) 1 trial (NCT04179643) of AB-1002 showed favourable safety and tolerability. Here we describe the design of AB-1002 Ph 2 trial (GenePHIT; NCT05598333) to evaluate efficacy, safety, and tolerability. Methods This phase 2 adaptive, double-blind, placebo-controlled, randomised, multi-centre trial (currently United States; European sites planned) includes a 52-week observation and 4-year follow-up period. Eligible patients are ≥18 years of age with non-ischaemic cardiomyopathy and New York Health Association (NYHA) Class III heart failure symptoms (Figure). Patients will be randomised 1:1:1 (n=30–50/treatment arm), including a single dose of AB-1002 administered via antegrade intracoronary infusion at 1 of 2 different doses, or placebo, all in addition to standard of care. The primary endpoint will evaluate efficacy at 52 weeks based on the composite endpoint by modified win ratio, which includes cardiovascular-related death, change in NYHA classification, and for the responders, improvements in left ventricular ejection fraction (LVEF) (≥5%), peak oxygen uptake (pVO2) ≥1.5 mL/kg/min, and 6-min walk test (6MWT) &amp;gt;30 metres. Key secondary efficacy endpoints include functional status and hospitalisations at 24 and 52 weeks, by assessing changes over time in NYHA classification, LVEF, pVO2, 6MWT, biomarkers (N-terminal pro-hormone b-type natriuretic peptide and troponin), quality of life questionnaires (Minnesota Living with Heart Failure, Kansas City Cardiomyopathy), and physiological assessments. Key safety endpoints will be assessed through 52 weeks and include treatment-emergent adverse events (AEs) and serious AEs (SAEs). Exploratory endpoints will evaluate AAV2i8 antibody titres, T-cell response to AAV2i8 capsid and I-1c, and optional right ventricular biopsy testing. Long-term follow-up will assess treatment-emergent AEs and SAEs, and number of HF hospitalisations. Data safety monitoring board assessment will occur every 3 months. Primary efficacy endpoint will compare both active dose groups combined versus placebo using the joint rank test (1). Key secondary endpoints will be analysed using Analysis of Covariance with baseline as a continuous covariate. Multiple imputations will be used to address missing data. Interim efficacy analysis will be performed using a Bayesian adaptive sample size algorithm. Conclusions GenePHIT is currently recruiting and will evaluate the efficacy, safety, and tolerability of intracoronary infusion of AB-1002, an innovative gene therapy targeting ventricular dysfunction in HF.

Win ratio analysis of transvenous phrenic nerve stimulation to treat central sleep apnoea in heart failure.

Central sleep apnoea (CSA) is present in 20-40% of heart failure (HF) patients and is associated with poor clinical outcomes and health status. Transvenous phrenic nerve stimulation (TPNS) is an available treatment for CSA in HF patients. The impact on HF outcomes is incompletely understood. The win ratio (WR) allows inclusion of multiple endpoint components, considers the relative severity of each component, and permits assessment of recurrent events in evaluation of clinical benefit. A WR hierarchy was pre-defined for analysis of the HF subgroup of the remedē® System Pivotal Trial. The analysis used three hierarchical components to compare all treated to all control subjects: longest survival, lowest HF hospitalization rate, and ≥2-category difference in Patient Global Assessment at 6months. Sensitivity analyses were performed substituting Epworth Sleepiness Scale and 4% oxygen desaturation index for the third component, and a 4-component WR hierarchy was also evaluated. Ninety-one HF subjects, 43 receiving TPNS and 48 in the control group, provided 2064 pairwise comparisons. More patients treated with TPNS experienced clinical benefit compared with control (WR 4.92, 95% confidence interval 2.27-10.63, P<0.0001). There were 1111 (53.83%) winning pairwise comparisons for the treatment group and 226 (10.95%) for the control group. Similarly, large WRs were observed for all additional WR hierarchies. This WR analysis of the remedē® System Pivotal Trial suggests that TPNS may be superior to untreated CSA in HF patients with CSA using a hierarchical clinical benefit endpoint composed of mortality, HF hospitalization, and health status.

The win ratio in cardiology trials: lessons learnt, new developments, and wise future use.

The win ratio method for analysing a composite clinical hierarchy of outcomes is growing in popularity especially in cardiovascular trials. This article gives a perspective on its use so far and the issues derived from that experience. Specifically, it focuses on the limitations of a conventional composite outcome; how does the win ratio work, what does it mean, and how to display its findings; guidance on choosing an appropriate clinical hierarchy of outcomes including clinical events, quantitative outcomes, and other options; the additional value of the win difference as a measure of absolute benefit: extension to stratified win ratio, subgroup analysis, matched win ratio, and covariate adjustment; determining trial size for a win ratio outcome; specific insights such as adaptive designs, use of repeat events, and use of margins and time averages for quantitative outcomes; a critique of potential misuses; availability of statistical software; and a statistical appendix on the methodological details. Throughout, each principle is illustrated by examples from specific cardiology trials. The article concludes with a set of recommendations for future use of the win ratio.

On approximate equality of Z-values of the statistical tests for win statistics (win ratio, win odds, and net benefit)

ABSTRACT Dong et al. (2023) showed that the win statistics (win ratio, win odds, and net benefit) can complement each another to demonstrate the strength of treatment effects in randomized trials with prioritized multiple outcomes. This result was built on the connections among the point and variance estimates of the three statistics, and the approximate equality of Z-values in their statistical tests. However, the impact of this approximation was not clear. This Discussion refines this approach and shows that the approximate equality of Z-values for the win statistics holds more generally. Thus, the three win statistics consistently yield closely similar p-values. In addition, our simulations show an example that the naive approach without adjustment for censoring bias may produce a completely opposite conclusion from the true results, whereas the IPCW (inverse-probability-of-censoring weighting) approach can effectively adjust the win statistics to the corresponding true values (i.e. IPCW-adjusted win statistics are unbiased estimators of treatment effect).

Exploring desirability of outcome ranking and generalised pairwise comparisons as endpoints in serious infections: Post hoc application with the MERINO trial

ObjectivesRandomised controlled trials in serious infections typically use a single primary endpoint such as mortality. Ordinal or rank-based composite endpoints that evaluate mortality and other measures are a novel approach in clinical trials. Desirability of outcome ranking (DOOR) has been increasingly used in infectious disease trials and generalised pairwise comparisons (GPC) in cardiovascular trials. MethodsWe undertook a post hoc analysis of the MERINO trial, comparing piperacillin-tazobactam (PTZ) with meropenem in bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp. to demonstrate and compare the DOOR and GPC approaches. The primary composite endpoint included mortality, microbiological relapse and secondary infection. A further analysis was performed by adding length of stay as a tiebreaker. We applied DOOR to evaluate the DOOR distribution, probability and conducted partial credit analyses. We applied GPC to estimate the win statistics: win ratio, win odds and net benefit. A secondary analysis with both approaches was conducted with trial participants with PTZ susceptible isolates only as recorded by a central laboratory. ResultsThe DOOR probability was 44.3 % (95 % CI: 40.8 %, 47.9 %), indicating superiority of meropenem. Partial credit analyses demonstrated similar conclusions across different patient preferences. The win ratio, win odds and net benefit were 0.40 (95 % CI: 0.23, 0.70; p = 0.001), 0.80 (95 % CI: 0.69, 0.92; p = 0.002) and −11.3 % (95 % CI:18.7 %, −4.0 %; p = 0.003), also indicating superiority of meropenem. With the addition of length of stay, the DOOR probability was 43.7 % (95 % CI: 37.9 %, 49.6 %) and the win ratio, win odds and net benefit were 0.77 (95 % CI: 0.60, 0.99; p = 0.04), 0.78 (95 % CI: 0.62, 0.99; p = 0.04), −12.1 % (95 % CI:23.8 %, −0.3 %; p = 0.04). Superiority of meropenem was not able to be demonstrated in the secondary analysis where only patients with PTZ susceptible isolates were assessed. ConclusionsThough the functionality and interpretation of DOOR and GPC differ, both approaches can enhance the overall understanding of treatment effect in survivors beyond a single endpoint such as mortality.

Use of the Win Ratio for Analysis of Stroke Trials: Description, Illustration, and Planned Use in the Second European Carotid Surgery Trial (ECST-2).

Randomized trials in stroke often focus on outcomes beyond a single clinical event. Trials of stroke prevention commonly use composite outcomes that include multiple components (eg, death, stroke, or myocardial infarction). A major limitation is that all events count equally but may differ markedly in terms of clinical severity. Trials in acute stroke often use ordinal outcomes or scale scores. Limitations include the requirement for statistical assumptions and the difficulty of handling the competing risk of death. We introduce the win ratio as an alternative method. It works by placing components of a composite into a hierarchy, whereby clinically more important outcomes take priority over less important ones. We illustrate how it works using data from 2 major stroke trials: the ICSS (International Carotid Stenting Study, a trial in stroke prevention) and the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Potential benefits of the win ratio approach include the possibility to (1) emphasize the clinically most important outcomes, (2) combine components of different outcome types into a composite (eg, a mixture of time-to-event, continuous, and categorical), and (3) naturally handle the competing risk of death in analyses of quantitative outcomes. The win ratio will be used in the upcoming analysis of the ECST-2 (Second European Carotid Surgery Trial), which has a hierarchical primary outcome of (1) time to perioperative death, fatal stroke, or fatal myocardial infarction (most important); (2) time to nonfatal stroke; (3) time to nonfatal myocardial infarction (excluding silent infarcts); and (4) new silent cerebral infarct on brain imaging (least important). The win ratio provides a useful clinically relevant method for analyzing trial outcomes. It has some advantages over conventional methods, and we recommend its wider application in future stroke trials.

A multiparametric heart failure score at baseline is associated with long-term outcome in patients with remotely monitored implantable cardioverter-defibrillators: A pooled analysis of 9 clinical trials

BackgroundTo predict worsening heart failure hospitalizations (WHFHs), the HeartInsight multiparametric algorithm calculates a heart failure (HF) score based on temporal trends of physiologic parameters obtained through automatic daily remote monitoring of implantable cardioverter-defibrillators (ICDs). ObjectiveWe studied the association of the baseline HF score, determined at algorithm activation, with long-term patient outcomes. MethodsData from 9 clinical trials were pooled, including 1841 ICD patients with a preimplantation ejection fraction ≤35%, New York Heart Association class II/III, and no long-standing atrial fibrillation. The primary end point was a composite of death or WHFH. ResultsAfter a median follow-up of 631 days (interquartile range, 385–865 days), there were 243 WHFHs in 173 patients (9.4%) and 122 deaths (6.6%), 52 of which (42.6%) were cardiovascular. The primary end point occurred in 265 patients (14.4%). A multivariable time-to-first-event analysis showed that a high baseline HF score (>23, as determined by a time-dependent receiver operating characteristics curve analysis) was significantly associated with the occurrence of the primary end point (adjusted hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.54–2.71; P < .0001), all-cause death (HR, 2.37; CI, 1.56–3.58; P < .0001), cardiovascular death (HR, 2.19; CI, 1.14–4.22; P = .019), and WHFH (HR, 1.91; CI, 1.35–2.71; P = .0003). In a hierarchical event analysis of all-cause death as the outcome with highest priority and WHFHs as repeated event outcomes, the win ratio was 2.47 (CI, 1.89–3.24; P < .0001). ConclusionBased on a retrospective analysis of clinical trial data with adjudicated events, baseline HF score derived from device-monitored variables was able to stratify patients at higher long-term risk of death or WHFH.

Transcatheter Aortic Valve Replacement in Patients With Systolic HeartFailure and Moderate Aortic Stenosis: TAVR UNLOAD.

Neurohormonal modulation and afterload reduction are key for treatment of heart failure with reduced ejection fraction (HFrEF). In HFrEF patients with concomitant moderate aortic stenosis (AS), treatment with transcatheter aortic valve replacement (TAVR) may be complementary to guideline-directed medical therapy (GDMT). This study sought to determine whether TAVR for moderate AS provides clinical benefit in patients with HFrEF on top of GDMT. We performed an investigator-initiated, international, randomized controlled trial in patients with HFrEF on GDMT with moderate AS who were suitable for transfemoral TAVR with a balloon-expandable valve. Patients were randomized 1:1 to TAVR or clinical aortic stenosis surveillance (CASS) with aortic valve replacement upon progression to severe AS. The primary endpoint was the hierarchical occurrence of: 1) all-cause death; 2) disabling stroke; 3) disease-related hospitalizations and heart failure equivalents; and 4) change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score analyzed using the win ratio. From January 2017 to December 2022, 178 patients were randomized to TAVR (n=89) or AS surveillance (n=89). The mean age was 77 years, 20.8% were female, and 55.6% were in NYHA functional class III or IV. The median follow-up duration was 23months (Q1-Q3: 12-33months). A total of 38 (43%) patients in the CASS group (of whom 35had progressed to severe AS) underwent TAVR at a median of 12months postrandomization. TAVR was associated with wins in 47.6% of pairs, compared with 36.6% in the CASS group, resulting in a win ratio of 1.31 (95%CI: 0.91-1.88; P=0.14). At 1 year, TAVR resulted in a greater improvement in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared with the CASS group (12.8 ± 21.9 points vs 3.2 ± 22.8 points; P=0.018). TAVR was not superior to AS surveillance for the primary hierarchical composite endpoint in patients with moderate AS and HFrEF on GDMT. Preemptive TAVR for moderate AS was safe and may provide clinically meaningful quality-of-life benefits.

Tricuspid transcatheter edge-to-edge repair for severe tricuspid regurgitation: 1-year outcomes from the TRILUMINATE randomized cohort.

Tricuspid regurgitation (TR) is a right-sided valvular disease independently associated with morbidity and mortality. The TRILUMINATE Pivotal trial is the first randomized, controlled trial assessing the impact of TR reduction with tricuspid transcatheter edge-to-edge repair (T-TEER). Outcomes from the full randomized cohort of the TRILUMINATE Pivotal trial have not been previously reported, and the additional enrollment may further support the safety and effectiveness of T-TEER through 1 year. The TRILUMINATE Pivotal trial is an international RCT of T-TEER with the TriClip device in patients with symptomatic, severe TR. Adaptive trial design allowed enrollment past the primary analysis population. The primary outcome was a hierarchical composite of all-cause mortality or tricuspid valve surgery, heart failure hospitalizations (HFH), and quality-of-life improvement measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) at 1 year. Between August 21, 2019 and June 29, 2022, 572 subjects were randomized, including the primary cohort (n=350) and subsequent enrollment (n=222). Subjects were elderly (78.1±7.8 years) and predominantly female (58.9%), with atrial fibrillation (87.8%) and prior HFH (23.8%). The primary endpoint was met for the full cohort (win ratio=1.84, p<0.0001). Freedom from all-cause mortality and tricuspid valve surgery through 12 months was 90.6% and 89.9% for the device and control groups, respectively (p=0.82). Annualized HFH rate was comparable between device and control subjects (0.17 vs 0.20 events/patient-year, p=0.40). A significant treatment effect was observed for change in quality of life with 49.5% of device subjects achieving a ≥15-point KCCQ score improvement (compared to 25.6% of control subjects, p<0.0001). All secondary endpoints favored T-TEER: moderate or less TR at 30 days (88.9% vs 5.3%, p<0.0001), KCCQ change at 1 year (13.0±1.4 vs -0.5±1.4 points, p<0.0001), and six-minute walk distance change at 1 year (1.7±7.5 vs -27.4±7.4 meters, p<0.0001). Freedom from major adverse events was 98.9% for T-TEER (vs. performance goal: 90%, p<0.0001). TriClip was safe and effective in the full randomized cohort of TRILUMINATE Pivotal with significant TR reduction and improvements in six-minute walk distance and health status. Rates of all-cause mortality or TV surgery and HFH through 1 year were not reduced by T-TEER.

Design and Rationale of a Pragmatic Randomized Clinical Trial of Early Dronedarone versus Usual Care to Change and Improve Outcomes in Persons with First-Detected Atrial Fibrillation – The CHANGE AFIB Study

BackgroundWhile there are several completed clinical trials that address treatment strategies in patients with symptomatic and recurrent atrial fibrillation (AF), there are no randomized clinical trials that address first-line rhythm control of new-onset AF. Recent data suggest that early initiation of rhythm control within 1 year can improve outcomes. MethodsIn this open-label pragmatic clinical trial nested within the Get With The Guidelines Atrial Fibrillation registry, approximately 3,000 patients with first-detected AF will be enrolled at approximately 200 sites. Participants will be randomized (1:1) to treatment with dronedarone in addition to usual care versus usual care alone. The primary endpoint will be time to first cardiovascular (CV) hospitalization or death from any cause through 12 months from randomization. Secondary endpoints will include a WIN ratio (all-cause death, ischemic stroke or systemic embolism, heart failure hospitalization, acute coronary hospitalization), CV hospitalization, and all-cause mortality. Patient reported outcomes will be analyzed based on change in Atrial Fibrillation Effect on Quality of Life (AFEQT) and change in Mayo AF-Specific Symptom Inventory (MAFSI) from baseline to 12 months. ConclusionCHANGE AFIB will determine if treatment with dronedarone in addition to usual care is superior to usual care alone for the prevention of CV hospitalization or death from any cause in patients with first-detected AF. The trial will also determine whether initiation of rhythm control at the time of first-detected AF affects CV events or improves patient reported outcomes. ClinicalTrials.gov #- NCT05130268

Exploration of different statistical approaches in the comparison of dopamine and norepinephrine in the treatment of shock: SOAP II

BackgroundExploring clinical trial data using alternative methods may enhance original study’s findings and provide new insights. The SOAP II trial has been published more than 10 years ago; but there is still some speculation that some patients may benefit from dopamine administration for shock management. We aimed to reanalyse the trial under different approaches and evaluate for heterogeneity in treatment effect (HTE).MethodsAll patients enrolled in SOAP II were eligible for reanalysis. We used a variety of methods including the win-ratio (WR), a Bayesian reanalysis stratified according to shock type, and both a risk-based and effect-based explorations for HTE. The methods were applied to different endpoints, including a hierarchy of death, new use of renal-replacement therapy (RRT), and new-onset arrhythmia; 28-day mortality; a composite endpoint (mortality, new use of RRT, and new-onset arrhythmia), and days alive and free of ICU at 28-days (DAFICU28).ResultsA total of 1679 patients were included (average age was 64.9 years, 57% male, 62% with septic and 17% with cardiogenic shock). All analysis favoured norepinephrine over dopamine. Under the WR approach, dopamine had fewer wins compared to norepinephrine (WR 0.79; 95% confidence intervals [CI] 0.68–0.92; p = 0.003), evident in both cardiogenic and septic shock subgroups. The Bayesian reanalysis for type of shock showed, for dopamine, a probability of harm of 0.95 for mortality, > 0.99 probability of harm for composite endpoint, and 0.91 probability of harm for DAFICU28. The fewer DAFICU28 with dopamine was more apparent in those with cardiogenic shock (0.92). Under the risk-based HTE, there was a high probability that dopamine resulted fewer DAFICU28 in the highest quartile of predicted mortality risk. The effect-based HTE assessment model did not recommended dopamine over norepinephrine for any combination of possible modifiers including age, type of shock, presence of cardiomyopathy, and SOFA score. Receiving dopamine when the effect-based model recommended norepinephrine was associated with an absolute increase in composite endpoint of 6%.ConclusionThe harm associated with the use of dopamine for the management of shock appears to be present in both septic and cardiogenic shock patients. There was no suggestion of any subgroup in which dopamine was found to be favourable over norepinephrine.

On the intransitivity of the win ratio

The win-ratio analysis of controlled clinical trials uses pairwise comparisons between patients in the treatment and control group based on a primary outcome, say time to death, with indeterminacies resolved where possible by a secondary outcome, say time to hospitalization. The resulting preferences may not be transitive. Intransitivity occurs when potential follow-up times vary between patients and rankings from the primary events differ from those from secondary events. We characterize the structure of closed loops, derive some general properties of win-ratio preferences and provide simple numerical illustrations. Under realistic assumptions, unless all potential follow-up times are equal, intransitivities are certain to occur in sufficiently large samples, but their overall frequency is low.

Long term safety and outcomes after atrial shunting for heart failure with preserved or mildly reduced ejection fraction: 5-year and 3-year follow-up in the REDUCE LAP-HF I and II trials

BackgroundThere is a little evidence regarding long-term safety and efficacy for atrial shunt devices in heart failure (HF). MethodsThe REDUCE LAP-HF I (n=44) and II (n=621) trials (RCT-I and -II) were multicenter, randomized, sham-controlled trials of patients with HF and ejection fraction >40%. Outcome data were analyzed from RCT-I, a mechanistic trial with 5-year follow-up, and RCT-II, a pivotal trial identifying a responder group (n=313) defined by exercise PVR <1.74 WU and no cardiac rhythm management device with 3-year follow-up. ResultsAt 5 years in RCT I, there were no differences in cardiovascular (CV) mortality, HF events, embolic stroke, or new-onset atrial fibrillation between groups. After 3 years in RCT II, there was no difference in the primary outcome (hierarchical composite of CV mortality, stroke, HF events, and KCCQ) between shunt and sham in the overall trial. Compared to sham, those with responder characteristics in RCT-II had a better outcome with shunt (win ratio 1.6 [95% CI 1.2-2.2], P=0.006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P=0.005; and greater improvement in KCCQ overall summary score [+17.9±20.0 vs. +7.6±20.4], P<0.001), while non-responders had significantly more HF events. Shunt treatment at 3 years was associated with a higher rate of ischemic stroke (3.2% vs. 0%, 95% CI 2% - 6.1%, p=0.032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, p=0.041). ConclusionsWith up to 5 years of follow up, adverse events were low in patients receiving atrial shunts. In the responder group, atrial shunt treatment was associated with a significantly lower HF event rate and improved KCCQ compared to sham through 3 years of follow-up.Clinicaltrials.gov registration: NCT02600234, NCT03088033

Comparing Analytical Methods for Composite End Points in Clinical Trials: Insights from the Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction Trial

In VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), participants with heart failure (HF) and reduced ejection fraction, vericiguat decreased the primary composite outcome (time to first HF hospitalization [HFH] or cardiovascular death [CVD]) (897 events) compared with placebo (972 events) (hazard ratio, 0.90; 95% confidence interval [CI], 0.82-0.98; P = .02). In this prespecified secondary analysis, we applied the weighted composite end point (WCE) and the win ratio (WR) methods to provide complementary assessments of treatment effect. The WCE method estimated the mean HFH-adjusted survival based on prespecified weights from a Delphi panel of the VICTORIA executive committee and national leaders: mild (weight per event, 0.39), moderate (0.5), or severe (0.67) HFH, and CVD (1.0). The unmatched WR was estimated for the descending hierarchy of CVD, then recurrent HFH. The WCE used all 3412 primary clinical events: 875 severe HFH (vericiguat, 416/ placebo, 459), 1614 moderate HFH (767/847), 68 mild HFH (38/30), and 855 CVD (414/441). Improved HFH-adjusted survival occurred with vericiguat (mean 78.2% vs 75.6%, difference 2.4%, 95% CI, 1.7%-3.2%, P < .0001). Based on a comparison of 6,375,624 pairs, the WR of 1.13 (95% CI 1.03-1.24, P = .01) also indicated improved clinical outcomes with vericiguat. The results of the WCE and WR methods were consistent with the primary analysis of the time to first HFH or CVD. Although both WCE and WR assessed recurrent events, the WCE allowed inclusion of all recurrent events, insights on the severity of HFH events, and an absolute measure of the participant-treatment experience. This approach complements conventional assessment, better informing consumers of new therapeutics and future trial designs.