Endpoint Definitions Research Articles

What is confirmed in the treatment of metabolic acidosis in chronic kidney disease?

Precise regulation of the acid-base balance is essential for the functioning of various organs and physiological processes. Acid retention and metabolic acidosis (MA) are frequent complications of chronic kidney disease (CKD) and can also occur following kidney transplantation. In addition to dietary modifications, pharmacological interventions, most notably sodium bicarbonate, are employed to correct MA. While several studies have reported abeneficial effect of MA correction on the progression of CKD, the results remain inconsistent and the magnitude of the treatment effect may be limited. Importantly, no beneficial effect on graft function has been demonstrated after kidney transplantation. The MA is associated with impaired bone quality and although alkali treatment has generally shown positive effects on markers of bone metabolism, consistent changes in bone density have not been observed. Additionally, MA is linked to an increased incidence of cardiovascular events but so far there is alack of interventional studies with definitive cardiovascular endpoints. Sodium bicarbonate may lead to sodium retention, potentially increasing blood pressure, although the data on this are inconclusive. One interventional study with notable limitations reported apositive effect of alkali treatment on mortality. Correction of MA has been suggested to positively impact protein and muscle catabolism, although no improvement in physical performance was observed in ageriatric population. Limited studies exist on the endocrinological effects of alkali treatment but these indicate afavorable impact on glucose metabolism and potential benefits for thyroid function in predialysis CKD patients. Given the overall low to moderate level of evidence supporting the benefits of alkali treatment, the current guidelines from Kidney Disease: Improving Global Outcomes (KDIGO) propose alkali treatment to prevent serum bicarbonate levels < 18 mmol/l (prior < 22 mmol/l) in adults and the resulting complications.

Incidence and predictors of 2-year mortality following percutaneous left atrial appendage occlusion in the EWOLUTION tria

Abstract Background and aims Sufficient survival time following left atrial appendage occlusion (LAAO) is essential for ensuring the efficacy and cost-effectiveness of this strategy for stroke prevention. Understanding prognostic factors for early mortality after LAAO could optimize patient selection. In the current study we perform an in-depth analysis of 2-year mortality after LAAO, focusing particularly on potential predictors. Methods The EWOLUTION registry is a real-world cohort comprising 1020 patients that underwent LAAO. Endpoint definitions were prespecified and death was categorized as cardiovascular, non-cardiovascular, or of unknown origin. Mortality rates were calculated from Kaplan-Meier estimates. Patient characteristics and event rates were compared between deceased and alive patients by unpaired T-tests or Chi-squared test, as appropriate. Baseline characteristics significantly associated with death in univariate Cox regression analysis were incorporated into the multivariate analysis. All multivariate predictors were included in a risk model. Results 2-year mortality rate was 16.4% (CI: 14.0-18.7%), with 50% of patients dying from a noncardiovascular cause. Deceased patients had more comorbities and more often had a major bleeding after LAAO (20.6% vs 3.3%, p&amp;lt;0.001). Multivariate baseline predictors of 2-year mortality included age (HR 1.05, CI: 1.03-1.08, per year increase), heart failure (HR 1.73, CI: 1.24-2.41), vascular disease(HR 1.47, CI: 1.05-2.05), valvular disease (HR 1.63 CI: 1.15-2.33), abnormal liver function (HR 1.80 CI: 1.02-3.17) and abnormal renal function (HR 1.58, CI: 1.10-2.27). Mortality rate exhibited a gradual rise as the number of risk factors increased, reaching 46.1% in patients presenting with five or six risk factors. Conclusion One in six patients died within 2 years after LAAO. We were able to identify six independent predictors of mortality. When combined, this model showed a gradual increase in mortality rate with a growing number of risk factors, which may guide appropriate patient selection for LAAO.

Safety and efficacy of transcatheter aortic valve implantation (TAVI) for pure aortic regurgitation; a systematic review and meta-analysis

Abstract Background Although Transcatheter Aortic Valve Implantation (TAVI) has gained ground in the management of severe aortic stenosis (AS), evidence about its safety and efficacy for patients with pure native aortic regurgitation (AR) remains limited. Purpose The aim of the study is to systematically review and summarize available data regarding the safety and the outcomes of TAVI in pure AR. Methods This study was conducted according to the PRISMA guidelines. We systematically searched PubMed, SCOPUS, and Cochrane databases from their inception to February 1, 2024, for studies assessing the characteristics and outcomes of patients undergoing TAVI for pure AR. Primary endpoint of our systematic review and meta-analysis is the in-hospital, 30-days and 1-year mortality rates. Secondary endpoints comprised in-hospital stroke, major bleeding, and permanent pacemaker implantation (PPM) implantation. Endpoint definitions followed the Valve Academic Research Consortium 2 criteria. The cumulative incidence of primary and secondary endpoints and the corresponding 95% confidence intervals (CI) were estimated. A random effects model (DerSimonian-Laird) was used to account for heterogeneity among the included studies. Results Our meta-analysis included a total of 22 studies and 6,710 patients undergoing TAVI for pure-AR. Our analysis showed that patients undergoing TAVI for pure AR had 3.4% (95% CI: 2%-4.7%), 7.9% (95% CI: 5.2%-10.6%) and 15.5% (95% CI: 9.9%-21.2%) in-hospital, 30-days and 1-year all-cause mortality. In-hospital stroke occurred in 1.9% (95% CI: 1.5%-2.2%) of the patients, while 4.9% (95% CI: 3.3%-6.6%) of the patients suffered from major bleeding events. Finally, considering the PPM implantation rates, patients had a 10.7% (95% CI: 7.4%-13.9%) in-hospital incidence. Conclusion Our systematic review and meta-analysis shows a promising safety profile for TAVI treating pure AR. It demonstrated relatively low in-hospital, 30-days and 1-year mortality incidence, comparable to the TAVI treating severe AS, according to the existing literature. Taking into consideration that TAVI for pure-AR might be the only therapeutic option for an increasing number of patients, further studies are needed to further assess the safety and efficacy of the procedure.TAVI for pure AR mortality rates

Safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with previous TAVI; a systematic review and meta-analysis

Abstract Background Transcatheter Aortic Valve Implantation (TAVI) has gained ground in the management of severe aortic stenosis, even in low-surgical risk patients. However, TAVI prostheses, like bioprostheses, have a finite lifetime; thus, TAVI in patients with previous TAVI (TAVI-in-TAVI) rates are radically increased. Although data regarding TAVI indicate low mortality and stroke rates within the first year, TAVI-in-TAVI is less studied. Purpose The aim of the study is to systematically review and summarize available data regarding the safety and the outcomes of TAVI-in-TAVI. Methods This study was conducted according to the PRISMA guidelines. We systematically searched PubMed, SCOPUS, and Cochrane databases from their inception to February 10, 2024, for studies assessing the characteristics and outcomes of patients undergoing TAVI-in-TAVI. Primary endpoint of our systematic review and meta-analysis is the in-hospital, 30-days and 1-year mortality rates. Secondary endpoints comprised in-hospital, 30-days and 1-year stroke rates, in-hospital vascular complications, conversion to surgery, coronary compression or obstruction, and perforation with or without tamponade, and in-hospital and 30-days permanent pacemaker implantation (PPM) implantation. Endpoint definitions followed the Valve Academic Research Consortium 3 criteria. The cumulative incidence of primary and secondary endpoints and the corresponding 95% confidence intervals (CI) were estimated. A random effects model (DerSimonian-Laird) was used to account for heterogeneity among the included studies. Results Our meta-analysis included a total of 5 studies and 2,145 patients undergoing TAVI-in-TAVI, 72.9% (N=1,564) of whom were treated with a balloon-expandable valve. Our analysis showed that patients undergoing TAVI-in-TAVI had 3.7% (95% CI: 1.6%-5.9%), 3.9% (95% CI: 3%-4.7%) and 12.5% (95% CI: 11%-14%) in-hospital, 30-days and 1-year all-cause mortality, while stroke occurred in 1.8% (95% CI: 1.2%-2.4%), 2.1% (95% CI: 1.4%-2.9%) and 3% (95% CI: 2.3%-3.8%) of the patients in-hospital, 30-days and 1-year, respectively. Notalby, conversion to surgery, coronary compression/obstruction and perforation with or without tamponade occurred in &amp;lt;1% of the patients, while 6.1% (95% CI: 2.2%-9.9%) of the patients had vascular complications during the procedure. Considering the PPM implantation rates, patients had a 1.8% (95% CI: 1.2%-2.4%) for in-hospital and a 6.8% (95% CI: 5.2%-8.3%) for 30-days incidence. Conclusion Our systematic review and meta-analysis is the first to present that TAVI-in-TAVI has an acceptable safety profile with relatively low in-hospital, 30-days and 1-year mortality and stroke rates, comparable to the native-valve-TAVI. Taking into consideration that TAVI-in-TAVI might be the only therapeutic approach for an increasing number of patients, further studies are warranted to further assess its safety and efficacy and to provide additional procedural techniques.TAVI-in-TAVI mortality rates

Clinical, echocardiographic and haemodynamic predictors of morbidity and mortality in pulmonary hypertension: a nation-wide registry

Abstract Background and aims In this retrospective analysis of a nation-wide registry on pulmonary arterial hypertension (PAH), group IV and V, we aimed to evaluate the clinical, echocardiographic,haemodynamic and neurohumoral predictors of morbidity and mortality. Methods This study included 903 patients enrolled from 24 cardiology centers participating in the RegiStry on clInical outcoMe and sUrvival in pulmonaRy hypertension Groups (SIMURG II). ESC/ERS 2022 risk scoring model was used for risk predictions at baseline assessment. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Results Age was 51.27 + 21.37 years, and 72 % of patients were female. Incident cases were noted in 65.9 % of overall group. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), porto-PAH, Group IV and V pulmonary hypertension (PH) were documented in 33 %, 33.5 %, 12 %, 1.6 %, 20 % and 1.7 % of overall patients, respectively. Background mono and dual targeted combinations, and sequential dual or triple combinations were noted in 17 %, 57 % and 26 % of patients, respectively. Baseline low-, intermediate- and high-risk were noted in 1.2 %, 14.1 %, and 84.7 %, respectively. Median follow-up time was 867 (412-1667) days. Overall rates of mortality and CEP were 26 % and 39%, respectively. Prevalent versus incident cases were associated signifinatly lower mortality and CEP rates (p=0.028 and p=0.024, respectively). Mortality and CEP rates were 31 % and 44 % in IPAH, 20 % and 39 % in CHD-PAH, 31 % and 43 % in CTD-PAH, and 25 % and 30 % in group IV patients, respectively. CHD-PAH compared with other groups was associated with a higher Kaplan-Meier (K-M) survival and CEP-free survival (p&amp;lt; 0.0001 and p=0.00023, respectively). Survival was associated with prevalent versus incident status, baseline functional class (FC) and six-minute walk distance (6MWD) in all subgroups (p&amp;lt;0.0001 for all), NT-brain natriuretic peptide and right atrial area in IPAH,CHD-PAH and CTD-PAH, and mixed venous O2 saturation % in IPAH and CHD-PAH (p varying from &amp;lt;0.0001 to 0.027). But, TAPSE / systolic pulmonary artery pressure ratio, right atrial-pulmonary capillary wedge pressure difference, pulmonary vascular resistance and its ratio to systemic vascular resistance, cardiac index were not related with survival. Baseline high versus intermediate /low risk was associated with a lower overall survival and CEP-free survival ( p=0.03 and p=0.003, respectively). Male sex [hazard ratio(HR):1.73;1.2-2,51,p = 0.004], 6MWD (p&amp;lt;0.001), FC III/IV (HR: 2.52;1.47-4.32, p&amp;lt;0.001) and baseline low-risk (HR:0.37;0.21-0.65, p&amp;lt;0.001) were independent predictors of mortality. Conclusions Our nation-wide data revealed current insights regarding the clinical, echocardiographic,haemodynamic and neurohumoral predictors of morbidity and mortality in PAH and group IV PH.

Changing patterns in clinical, echocardiographic and haemodynamic characteristics, and management strategies that may be translated to improved survival in pulmonary hypertension

Abstract Background and aims In this retrospective analysis of a single-center series on pulmonary hypertension (PH), we aimed to evaluate clinical, echocardiographic, and hemodynamic characteristics, management strategies, morbidity, and mortality in PH subgroups across three consecutive periods. Methods The study included 1071 patients enrolled in the Evaluation of Pulmonary Hypertension Risk factors Associated with Survival study (EUPHRATES). In reference to enrollment time, patients were assessed in three periods ; before 2016, the era of primarily monotherapy or sequential combinations; between 2016 and 2019, post-approval and reimbursement of macitentan in our country, marking a shift towards more proactive sequential combinations; and after 2019, signifying the initiation of earlier sequential combinations with selexipag in pulmonary arterial hypertension (PAH). The ESC/ERS 2022 risk scoring, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Annual incidence curves for mortality and CEP were evaluated, but 2020 analysis was adjusted to account for the possible adverse effects of the COVID-19. Results During the 1st, 2nd and 3rd periods, 481, 352, and 238 patients with PH were diagnosed, respectively. Incident cases comprised 91% of them. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), group II, III, IV and V PH were documented in 24 %, 28 %, 4.6 %, 4.3 %, 11%, 27 % and 0.7 % of patients, respectively. Age and female dominance remained unchanged. Incidences of Group 1 PH and CHD-PAH decreased while IPAH, drug-associated PAH, and Group II and IV PH increased across three periods (p-values varying from &amp;lt;0.001 to 0.03). Although baseline functional class became worse (p=0.013), six-minute walk distance, N-terminal pro brain natriuretic peptide and risk scores showed no change (p=NS). Baseline echo and hemodynamic measures became better, and triple combinations increased after 2019 (p&amp;lt;0.001 for all). For overall PH, rates of all-cause mortality and CEPs at 1st, 2nd and 3rd periods were 52 % and 59 %, 30 % and 35 %, and 11 % and 13 %, respectively (p&amp;lt; 0.001, for all). Mortality rates for 1st, 2nd and 3rd periods were 36 %, 38 % and 26 % in IPAH, 60 %, 28 % and 13 % in CHD-PAH, 55 %, 22% and 22% in CTD-PAH, 38 %, 38% and 24 % in group IV PH, respectively (p&amp;lt; 0.001, for all). Mortality curves showed sudden increases in 2020, but excluding 2020, a steady improvement in the annual mortality was evident. Conclusions Our findings suggest a trend towards better clinical, echocardiographic, and hemodynamic presentations and improved survival in the PAH subgroups, and Group IV PH across the three periods that might be attributed to more proactive management strategies favouring earlier initiation of combinations.

Improving morbidity and mortality in patients with pulmonary hypertension: insights from a nation-wide registry

Abstract Background and aims In this retrospective analysis of a nation-wide registry on pulmonary arterial hypertension (PAH), group IV and V, we evaluated management strategies, morbidity and mortality across three consecutive time periods. Methods This study included 903 patients enrolled from 24 cardiology centers participating in the RegiStry on clInical outcoMe and sUrvival in pulmonaRy hypertension Groups (SIMURG II). Patients were divided into three enrollment periods: before 2016, the era of monotherapy or sequential combination therapies; between 2016 and 2019, post-approval and re-imbursement of macitentan in our country, marking a shift towards more proactive sequential combinations; and after 2019, signifying the initiation of earlier sequential combinations with selexipag in PAH. ESC/ERS 2022, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Results Age (mean +SD) was 51.27 + 21.37 years, and 72 % were female. Incident cases were noted in 65.9 % of patients. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), porto-PAH, Group IV and V pulmonary hypertension (PH) were documented in 33 %, 33.5 %, 12 %, 1.6 %, 20 % and 1.7 % of patients, respectively. Background mono and dual targeted combinations, and sequential triple combinations were noted in 17 %, 57 % and 26 % of patients, respectively. Baseline low-, intermediate-, and high-risk were noted in 1.2 %, 14.1 %, and 84.7 %, respectively. Median follow-up time (day) was 867 (412-1667). Overall rates of mortality and CEP were 26 % and 39%, respectively. There were increases in the % of PAH and group IV PH, and decreases in the % of CHD-PAH across the three periods. Prevalent versus incident cases were associated signifinatly lower mortality and CEP ( p=0.028 and p=0.024, respectively). Outcomes for mortality and CEP were predicted by three risk models (p&amp;lt;0.0001 for all). Mortality and CEP rates were 31 % and 44 % in IPAH, 20 % and 39 % in CHD-PAH, 31 % and 43 % in CTD-PAH, and 25 % and 30 % in group IV patients, respectively. In overall PH population, rates of mortality and CEP documented at 1st, 2nd and 3rd periods were 64 % and 67 %, 29 % and 31 %, and 3.5 % and 5.1 %, respectively (p&amp;lt; 0.001, for all). Mortality rates for 1st, 2nd and 3rd periods were 49 %, 39 % and 11 % in IPAH, 62 %, 33 % and 5.3 % in CHD-PAH, 47 %, 45 % and 7.7 in CTD-PAH, and 37 %, 52 % and 11 % in group IV, respectively (p&amp;lt; 0.001, for all). However, mortality curves showed sudden increases in 2020 that might be attributed to COVID-19. Conclusions Our nation-wide data revealed improving survival in the overall PH population, PAH and Group IV PH that might be associated with risk-based earlier targeted combination strategies. However, this trend seems to be counterbalanced with COVID-19 pandemic.

Multiparametric risk predictions for morbidity and mortality in patients with pulmonary arterial hypertension: insights from a nation-wide registry

Abstract Background and aims In this retrospective analysis of a nation-wide registry on pulmonary arterial hypertension (PAH), group IV and V, we aimed to evaluate risk predictions for morbidity and mortality. Methods This study included 903 patients enrolled from 24 cardiology centers participating in the RegiStry on clInical outcoMe and sUrvival in pulmonaRy hypertension Groups (SIMURG II). ESC/ERS 2022 risk scoring, COMPERA 2.0 and REVEAL lite 2 models were used for baseline risk predictions, and COMPERA 2.0 model was used for risk evaluation at follow-up. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Results Age (mean +SD) was 51.27 + 21.37 years, and 72 % of patients were female. Incident cases were noted in 65.9 % of overall study group. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), porto-PAH, Group IV and V pulmonary hypertension (PH) were documented in 33 %, 33.5 %, 12 %, 1.6 %, 20 % and 1.7 % of overall patients, respectively. Background mono and dual targeted combinations, and sequential dual or triple combinations were noted in 17 %, 57 % and 26 % of patients, respectively. According to the ESC/ERS 2022 baseline risk scoring, low-, intermediate-, and high-risk were noted in 1.2 %, 14.1 %, and 84.7 %, respectively. Median follow-up time was 867 (412-1667) days. Overall rates of mortality and CEP were 26 % and 39%, respectively. Prevalent versus incident cases were associated signifinatly lower mortality and CEP ( p=0.028 and p=0.024, respectively). Mortality and CEP rates were 31 % and 44 % in IPAH, 20 % and 39 % in CHD-PAH, 31 % and 43 % in CTD-PAH, and 25 % and 30 % in group IV patients, respectively. Baseline high versus intermediate /low risk status were associated with a lower survival estimates for mortality and CEP in patients with PAH ( p=0.03 and p=0.003, respectively). Baseline COMPERA 2.0 risk status revealed significant differences in overall survival and CEP-free survival among risk groups ( p&amp;lt;0.0001 for both), but 1st year COMPERA 2.0 score did not (p=0.39 and p=0.06, respectively) . As compared to baseline, 1st year COMPERA 2.0 score decreased in 31 %, and remained unchanged in 34 % of patients. Baseline REVEAL lite 2.0 score was associated with mortality (hazard ratio (HR): 1.14;1.08-1.2, p&amp;lt;0.0001) and CEP (HR:1.17;1.1-1.25, p&amp;lt;0.0001) risks. Male sex (HR: 1.73; 1.2-2.51, p = 0.004), six-minute walk distance (p&amp;lt;0.001), functional class III/IV (HR: 2.52;1.47-4.32, p&amp;lt;0.001) and baseline low-risk status (HR:0.37;0.21-0.65, p&amp;lt;0.001) were independent predictors of mortality. Conclusions Our nation-wide data revealed current insights concerning the multiparametric risk predictions for morbidity and mortality in PAH.

IPNA consensus definitions for clinical trial outcomes in steroid-resistant nephrotic syndrome.

Assessment of the true impact of therapeutic interventions is a challenge in the absence of universal, standardized definitions for clinical trial endpoints in children with kidney diseases. Steroid-resistant nephrotic syndrome (SRNS) is a difficult kidney disease to treat, with unremitting disease progressing to kidney failure. Currently, available therapies result in suboptimal cure rates. Clinical trials with innovative, targeted treatments will likely be conducted for this disease in the foreseeable future. An international consortium of the IPNA Best Practices and Standards Committee and the Pediatric Nephrology Expert Group of the conect4children (c4c) network developed through consensus, standardized, internationally acceptable definitions for trial outcomes for SRNS. The endpoint definitions were formulated for use with urine protein to creatinine ratios and estimated glomerular filtration rates. Definitions of complete remission, partial remission, non-remission of disease, reduction in proteinuria, kidney disease progression, kidney failure, and composite kidney outcome were refined using an iterative process until a consensus was achieved.

Expert opinion on design and endpoints for studies on catheter ablation of atrial fibrillation.

Catheter ablation of atrial fibrillation (AF) is frequently studied in randomized trials, observational and registry studies. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of future clinical studies on catheter ablation of AF, implement lessons learned from previous studies, and promote a higher degree of consistency across studies. Studies on catheter ablation of AF may benefit from well-described definitions of endpoints and consistent methodology and documentation of outcomes related to efficacy, safety and cost-effectiveness. The availably of new, innovative technologies warrants further consideration about their application and impact on study design and the choice of endpoints. Moreover, recent insights gained from AF ablation studies suggest a reconsideration of some methodological aspects. A panel of clinical experts on catheter ablation of AF and designing and conducting clinical studies developed an expert opinion on the design and endpoints for studies on catheter ablation of AF. Discussions within the expert panel with the aim to reach consensus on predefined topics were based on outcomes reported in the literature and experiences from recent clinical trials. A comprehensive set of recommendations is presented. Key elements include the documentation of clinical AF, medication during the study, repeated ablations and their effect on endpoint assessments, postablation blanking and the choice of rhythm-related and other endpoints. This expert opinion provides guidance and promotes consistency regarding design of AF catheter ablation studies and identified aspects requiring further research to optimize study design and methodology. Recent insights from studies on catheter ablation of atrial fibrillation (AF) and the availability of new innovative technologies warrant reconsideration of methodological aspects related to study design and the choice and assessment of endpoints. This expert opinion, developed by clinical experts on catheter ablation of AF provides a comprehensive set of recommendations related to these methodological aspects. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of clinical studies, implement lessons learned from previous studies, and promote a higher degree of consistency across studies.

Standardized Definitions for Efficacy End Points for Adjuvant Trials—The Updated STEEP Criteria

This Viewpoint discusses how the inclusion or exclusion of certain events in the standardization of clinical trial end points can affect the interpretation of results.

Heterogenous relapse and efficacy endpoint definitions for neuromyelitis optica spectrum disorder studies: A systematic review

BackgroundOver the last years, multiple studies have been dedicated to evaluate the efficacy of different treatment options for Neuromyelitis Optica Spectrum Disorder (NMOSD). However, there is a wide variety of endpoints employed across these studies. Our goal is to conduct a systematic review describing the endpoints utilized in studies related to NMOSD. MethodsMedline, Embase, and Cochrane were searched from inception to May 2023, to identify studies analyzing treatment options in patients with NMOSD. We collected data on baseline study characteristics and all efficacy outcomes available. ResultsWe included 127 studies and identified approximately 40 different efficacy endpoints, categorized into 1) relapse, 2) disability, 3) visual acuity, and 4) surrogate outcomes. Most studies were retrospective (54.3 %) and aimed at attack prevention (81.4 %). The most common relapse-related outcomes were annualized relapse rate (73.2 %), followed by relapse rate (50.4 %), and relapse-free rate (36.2 %). The relapse definition also varied widely among studies, with only 73 (57.4 %) studies explicitly addressing the definition used. The most common disability outcome was the Expanded Disability Scale (97.6 %), followed by the Modified Rankin Scale (7.9 %). Visual Acuity Score was employed in 14.2 % of studies, followed by Visual Evoked Potentials (6.3 %). Imaging was the most common surrogate (20.5 %), followed by the fraction of B cells (18.1 %). ConclusionPublications were heterogeneous in measuring efficacy, with different use of endpoints and relapse definitions. Standardization across studies would improve data analysis and application in clinical practice.

Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate the efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and end point definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on predefined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using the National Institutes of Health/National Institute of Neurological Disorders and Stroke common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.

Therapeutic Effects of Heart Failure Medical Therapies on Standardized Kidney Outcomes: Comprehensive Individual Participant-Level Analysis of 6 Randomized Clinical Trials.

Background: Kidney outcomes have been variably defined using non-standardized composite endpoints in key heart failure (HF) trials, thus introducing complexity in their interpretation and cross-trial comparability. We examined the effects of steroidal mineralocorticoid receptor antagonists (MRAs), the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, and sodium-glucose cotransporter-2 (SGLT2) inhibitors on composite kidney endpoints using uniform definitions in 6 contemporary HF trials. Methods: Individual participant-level data from trials of steroidal MRAs (EMPHASIS-HF, TOPCAT Americas), ARNI (PARADIGM-HF, PARAGON-HF), and SGLT2 inhibitors (DAPA-HF, DELIVER) were included. The standardized composite kidney endpoint was defined as a sustained decline (a reduction in estimated glomerular filtration rate (eGFR) confirmed by a subsequent measurement at least 30 days later) in eGFR by 40%, 50%, or 57%, end-stage kidney disease, or renal death. eGFR was recalculated in a standardized manner using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation. Results: Among 28,690 participants across the 6 trials (median age 69 years [IQR, 62-76]; 9,656 [33.7% ] women), the proportion experiencing the composite kidney endpoint with a more stringent definition of a sustained decline in kidney function (eGFR threshold of 57%) ranged from 0.3% to 3.3%. The proportion of patients experiencing this endpoint with a less stringent definition (eGFR threshold of 40%) ranged from 1.0% and 10.0%. The steroidal MRAs doubled the risk of the composite kidney endpoint when applying the least stringent definition compared with placebo, but these effects were less apparent and no longer significant with application of more stringent definitions. ARNI appeared to consistently reduce the occurrence of the composite kidney endpoints irrespective of specific eGFR threshold applied. The potential benefits of SGLT2-inhibitors on the composite kidney endpoints appeared more apparent when defined by more stringent eGFR thresholds, although none of these effects individually were statistically significant. Conclusions: When applying standardized stringent kidney endpoint definitions, steroidal MRAs, ARNI, and SGLT2-inhibitors have either neutral or beneficial effects on kidney outcomes in HF. Applying less stringent definitions increased event rates but included acute declines in eGFR that might not ultimately reflect long-term effects on kidney disease progression.

Assessing Severity and Need for Delivery in Early Onset Preeclampsia Before 32 Weeks of Gestation: a Delphi Consensus Procedure.

Preeclampsia is a potentially life-threatening hypertensive pregnancy disorder that carries an acute risk of an unfavorable outcome of the pregnancy but also has consequences for the long-term health of the mother. Women who develop the early form of pre-eclampsia before the 32nd week of pregnancy have the highest risk and are also the most difficult to treat. The severity of pre-eclampsia is not characterized uniformly in Germany, so that the indication for delivery is rather individualized. The aim of this study was to reach a consensus on parameters that could serve as criteria for describing the severity of pre-eclampsia based on the urgency of delivery. To this end, a Delphi procedure was used to present a scenario in which a woman was admitted for preeclampsia before 32 gestational weeks and after completion of antenatal steroid therapy. Clinicians specialized in maternal-fetal medicine from German-speaking countries completed five rounds of a modified Delphi questionnaire. Presented parameters were selected by the section "Hypertensive Pregnancy Diseases and Fetal Growth Restriction" of the German Society of Gynecology and Obstetrics after reviewing the literature. These included objectifiable laboratory or clinical parameters as well as subjective symptoms of the patient. In addition, nine fetal parameters were taken into account. The clinicians were asked to rate presented parameters as an indication for delivery on a Likert scale from 0 to 4 (no indication to absolute indication without delay). For each item, the predefined cut-off for group consensus was ≥70% agreement. A total of 126 experts were approached. Sixty-nine experts (54.8%) took part in the first round; of those 50 completed the entire Delphi procedure. A consensus was reached on 14 parameters to be considered rapid preparation for delivery without delay (4 points on the Likert scale). These were among others hepatic hematoma or liver capsule rupture, acute liver failure with fulminant coagulation disorder or disseminated intravascular coagulation, eclampsia, pathologic findings in imaging (e.g. cMRI) or electrocardiogram arranged for new onset of headache or retrosternal pain, respectively. Twenty-six parameters were rated as factors that should be considered in the decision without being absolute (1 to 3 points), and 13 parameters should have no influence on the decision to deliver (0 points). No consensus on severe hypertension as an indication for delivery could be reached for blood pressure values below 220/140mmHg. A consensus was reached on whether to deliver in preeclampsia typic clinical findings and symptoms. The results can serve as guidance for current clinical practice and for the definition of clinical endpoints in intervention studies. Nevertheless, the isolated criteria are a theoretical construction since the combined deterioration or summation of several factors rather than a single factor most likely influences the decision to deliver and reflect the severity of preeclampsia. Moreover, the degree of hypertension as an indication for delivery remains controversial, unless the patient suffers additionally from complaints. Future research should be enforced to incorporate long-term risks for the mother into a decision aid.

Meaningful changes in motor function in Duchenne muscular dystrophy (DMD): A multi-center study.

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to <18 years and receiving steroids. Minimal clinically important differences (MCIDs) for worsening were also estimated. Estimated MDC thresholds for >80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.

Incidence and predictors of 2-year mortality following percutaneous left atrial appendage occlusion in the EWOLUTION trial.

Sufficient survival time following left atrial appendage occlusion (LAAO) is essential for ensuring the efficacy and cost-effectiveness of this strategy for stroke prevention. Understanding prognostic factors for early mortality after LAAO could optimize patient selection. In the current study, we perform an in-depth analysis of 2-year mortality after LAAO, focusing particularly on potential predictors. The EWOLUTION registry is a real-world cohort comprising 1020 patients that underwent LAAO. Endpoint definitions were pre-specified, and death was categorized as cardiovascular, non-cardiovascular, or unknown origin. Mortality rates were calculated from Kaplan-Meier estimates. Baseline characteristics significantly associated with death in univariate Cox regression analysis were incorporated into the multivariate analysis. All multivariate predictors were included in a risk model. Two-year mortality rate was 16.4% [confidence interval (CI): 14.0-18.7%], with 50% of patients dying from a non-cardiovascular cause. Multivariate baseline predictors of 2-year mortality included age [hazard ratio (HR) 1.05, CI: 1.03-1.08, per year increase], heart failure (HR 1.73, CI: 1.24-2.41), vascular disease (HR 1.47, CI: 1.05-2.05), valvular disease (HR 1.63, CI: 1.15-2.33), abnormal liver function (HR 1.80, CI: 1.02-3.17), and abnormal renal function (HR 1.58, CI: 1.10-2.27). Mortality rate exhibited a gradual rise as the number of risk factors increased, reaching 46.1% in patients presenting with five or six risk factors. One in six patients died within 2 years after LAAO. We identified six independent predictors of mortality. When combined, this model showed a gradual increase in mortality rate with a growing number of risk factors, which may guide appropriate patient selection for LAAO. The original EWOLUTION registry was registered at clinicaltrials.gov under identifier NCT01972282.

TOWARDS Study: Patient-Derived Xenograft Engraftment Predicts Poor Survival in Patients With Newly Diagnosed Triple-Negative Breast Cancer.

Assessing risk of recurrence for nonmetastatic triple-negative breast cancer (TNBC) is a key determinant of therapeutic strategy. The best predictor of recurrence risk is failure to achieve a pathologic complete response after preoperative chemotherapy, but it imperfectly correlates with the definitive end points of relapse-free and overall survival (OS). The inability to accurately predict recurrence has led to increasingly toxic treatment regimens for patients with early-stage TNBC. Better assays for recurrence risk are needed to tailor aggressive therapy for patients who need it and avoid overtreatment and unnecessary toxicity for those at low risk. The purpose of this study was to determine if patient-derived xenograft (PDX) engraftment of newly diagnosed breast tumors can serve as an accurate predictor of recurrence and death from breast cancer. This study was a blinded noninterventional trial comprising 80 patients with newly diagnosed, nonmetastatic, estrogen receptor (ER)-negative or ER-low breast cancer. PDX engraftment was strongly associated with relapse in 1 year: 8 of 18 (44.4%) patients whose tumors engrafted relapsed versus 1 of 62 (1.6%) patients whose tumors did not engraft (P < .0001). Patients whose tumors engrafted had a hazard ratio (HR) for relapse of 17.5. HRs for OS and breast cancer-specific survival in PDX+ patients were 21.1 and 39.5, respectively. We report that the ability of a tumor to engraft as a PDX predicts early recurrence by serving as a functional readout of aggressiveness and prospectively identifies the most devastating tumors. This provides new opportunity to develop surrogate assays, such as biomarkers of engraftment, which will extend the clinical feasibility of this finding.

Blood metabolomic and postpartum depression: a mendelian randomization study

BackgroundPostpartum depression is a complex mental health condition that often occurs after childbirth and is characterized by persistent sadness, anxiety, and fatigue. Recent research suggests a metabolic component to the disorder. This study aims to investigate the causal relationship between blood metabolites and postpartum depression using mendelian randomization (MR).MethodsThis study used a bi-directional MR framework to investigate the causal relationship between 1,400 metabolic biomarkers and postpartum depression. We used two specific genome-wide association studies datasets: one with single nucleotide polymorphisms data from mothers diagnosed with postpartum depression and another with blood metabolite data, both of which focused on people of European ancestry. Genetic variants were chosen as instrumental variables from both datasets using strict criteria to improve the robustness of the MR analysis. The combination of these datasets enabled a thorough examination of genetic influences on metabolic profiles associated with postpartum depression. Statistical analyses were conducted using techniques such as inverse variance weighting, weighted median, and model-based estimation, which enabled rigorous causal inference from the observed associations. postpartum depression was defined using endpoint definitions approved by the FinnGen study’s clinical expert groups, which included leading experts in their respective medical fields.ResultsThe MR analysis identified seven metabolites that could be linked to postpartum depression. Out of these, one metabolite was found to be protective, while six were associated with an increased risk of developing the condition. The results were consistent across multiple MR methods, indicating a significant correlation.ConclusionsThis study emphasizes the potential of metabolomics for understanding postpartum depression. The discovery of specific metabolites associated with the condition sheds new insights on its pathophysiology and opens up possibilities for future research into targeted treatment strategies.

#1906 Lung ultrasound as a valid tool for fluid assessment in dialysis patients: a systematic review

Abstract Background and Aims The evaluation of hydration status in dialysis patients is a crucial aspect of their care. Focused lung ultrasound has garnered attention as a cost-effective and accessible tool for assessing hydration status, particularly through the detection of B-lines. Despite its potential, there is a lack of comprehensive systematic reviews addressing the clinical utility of lung ultrasound in fluid assessment for dialysis patients. Method A systematic search was conducted on PubMed, MEDLINE, EMBASE, Cochrane, and Web of Science. Two independent reviewers screened titles, abstracts, and full texts, with a third reviewer consulted in cases of discrepancy. Inclusion criteria encompassed papers utilizing lung ultrasound to evaluate fluid status in dialysis patients. Exclusion criteria were: abstracts or posters and papers not investigating at least one of the following endpoints: B-type natriuretic peptide, cardiovascular events, inferior vena cava, preload, NYHA classification, ultrafiltration/weight reduction, blood pressure, total body water/bioimpedance, hospitalization, mortality, and clinical evaluations. A modified QUADAS2-score was employed for assessment of risk of bias and applicability by two independent investigators. The protocol was registered at Prospero (CRD42022334147). Results A total of 2543 papers were identified of which 156 underwent full-text screening. Of these, 49 papers were included in the review, comprising seven randomised controlled trials and 41 observational studies. The most common study aim was impact assessment of ultrafiltration on the quantity of B-lines. However, numerous studies investigated the correlation between lung ultrasound and various endpoints such as bioimpedance, chest x-ray, and clinical examination. Overall, the included papers were characterized by noteworthy heterogeneity in terms of ultrasound protocol, encompassing differences in number of scanning zone (8-28), B-lines cut-off points, and definitions of endpoint. The QUADAS assessment revealed risk of bias in the included studies, most commonly related to a lack of blinding and, consequently, an impact on the interpretation of index test results. Only n=24 studies (49%) scored “low” risk of bias. Regarding patient selection, the numbers were even lower with only n=17 studies (34%) scoring “low” on risk of bias. Conclusion The collective evidence on clinical utility of lung ultrasound for fluid assessment of dialysis patients is characterised by notable heterogeneity and risk of bias, precluding meta-analysis. Well-designed large scale studies are still warranted to determine the optimal ultrasound protocol. Future studies should establish guidelines for scanned zones and consensus cut-offs to enhance homogeneity.