Composite Endpoint Research Articles

Glucagon-like peptide-1 receptor agonists improve outcomes in individuals with type 2 diabetes with and without heart failure

BackgroundThe effectiveness of glucagon-like peptide-1 receptor agonists (GLP1Ras) for prevention of heart failure (HF) in patients with type 2 diabetes (T2DM) without HF and for risk of death in patients with T2DM with HF has not been fully elucidated in routine clinical practice. MethodsUsing the real-world global electronic medical record TriNetX database, individuals with T2DM and with or without HF who initiated either GLP1Ras or sitagliptin from 2017 to 2020 were retrospectively analyzed. In individuals with T2DM without HF, the primary outcome was a composite of all-cause mortality and a new diagnosis of HF within three years. In individuals with T2DM with HF, the primary outcome was all-cause mortality within three years. Propensity-score (PS) matching was used to adjust for over 100 baseline characteristics. ResultsA total of 65,598 individuals with T2DM without HF starting a GLP1Ras were PS matched with 65,598 starting sitagliptin. GLP1Ras were associated with a lower incidence of the composite endpoint (10.5 % versus 11.8 %, hazard ratio [HR] 0.82, [0.80–0.85], p < 0.001), mortality (HR 0.66 [0.63–0.69]) and new diagnosis of HF (HR 0.92 [0.88–0.96]). There were 6002 individuals in each group matched for T2DM and HF. Mortality was lower in the GLP1Ras group (17.6 % versus 22.8 %, HR 0.70 [0.65–0.76], p < 0.001). Results were consistent across subgroups. ConclusionsIn this global real-world data analysis, GLP1Ra use was associated with a lower risk of death and HF in individuals with T2DM without HF, and lower risk of death in those with HF.

The Predictive Value of T-Lymphocyte Subset Distribution for the Occurrence and Prognosis of Atrial Fibrillation

Introduction: The effect of T lymphocytes on atrial fibrillation (AF) is still unclear. We aimed to assess the associations between the T-lymphocyte subgroup distribution and incident AF and AF prognosis. Methods: Consecutive patients were enrolled from June 2020 to October 2021. Their T-cell subgroups, including CD3, CD4, and CD8 T cells, and the CD4/CD8 ratio (CDR) were measured. We assessed the relationships between the CDR and composite endpoints, including hospitalization due to heart failure, stroke or systemic embolism, and cardiovascular mortality rates. Results: A total of 45,905 patients, among whom 818 had AF, were enrolled. The proportions of the T-lymphocyte subgroups CD3 (OR: 0.9995; 95% CI: 0.9993–0.9997, p < 0.001), CD4 (OR: 0.9995; 95% CI: 0.9991–0.9998, p = 0.004), and CD8 (OR: 0.9988; 95% CI: 0.9984–0.9992, p < 0.001) and the CDR (OR: 1.2714; 95% CI: 1.1355–1.4165, p < 0.001) were correlated with AF incidence. The CDR was associated with AF incidence (OR: 1.1998; 95% CI: 1.0746–1.3336, p < 0.001) after adjustment. High CDR was associated with a higher rate of hospitalization due to heart failure (HR: 3.45; 95% CI: 1.71–6.96, p < 0.001), stroke, or systemic embolism (HR: 2.54; 95% CI: 1.32–4.91, p = 0.005), and cardiovascular mortality (HR: 2.25; 95% CI: 1.05–4.84, p = 0.038). There was no significant difference in all-cause mortality between CDR strata (HR: 1.61; 95% CI: 0.90–2.87, p = 0.111). Conclusion: Elevated CDR was positively associated with the incidence and prognosis of AF. This finding may help improve the prevention and treatment of AF.

Transcatheter Aortic Valve Implantation by Valve Type in Women With Small Annuli

Historically, women with aortic stenosis have experienced worse outcomes and inadequate recognition compared to men, being both underdiagnosed and undertreated, while also facing underrepresentation in clinical trials. To determine whether women with small aortic annuli undergoing transcatheter aortic valve replacement have better clinical and hemodynamic outcomes with a self-expanding valve (SEV) or balloon-expandable valve (BEV). The Small Annuli Randomized to Evolut or SAPIEN Trial (SMART) was a large-scale randomized clinical trial focusing on patients with small aortic annuli undergoing transcatheter aortic valve replacement, randomized to receive SEVs or BEVs and included 716 patients treated at 83 centers in Canada, Europe, Israel, and the US from April 2021 to October 2022. This prespecified secondary analysis reports clinical and hemodynamic findings for all 621 women enrolled in SMART. Data for this report were analyzed from February to April 2024. Transcatheter aortic valve replacement with an SEV or a BEV. The composite coprimary clinical end point comprised death, disabling stroke, or heart failure-related rehospitalization. The coprimary valve function end point was the incidence of bioprosthetic valve dysfunction, both assessed through 12 months. Secondary end points included the incidence of moderate or severe prosthesis-patient mismatch. A total of 621 women (mean [SD] age, 80.2 [6.2] years; 312 randomized to the SEV group and 309 to the BEV group) were included in the present analysis. At 12 months, there were no significant differences in the coprimary clinical end point between the SEV and BEV groups (9.4% vs 11.8%, absolute risk difference -2.3%; 95% CI -7.2 to 2.5, P = .35). However, SEV implantation was associated with less bioprosthetic valve dysfunction (8.4% vs 41.8%; absolute risk difference, -33.4%; 95% CI, -40.4 to -26.4; P < .001). SEV implantation resulted in lower aortic valve gradients and larger effective orifice areas at 30 days and 12 months and less mild or greater aortic regurgitation at 12 months compared to BEV implantation. Prosthesis-patient mismatch was significantly lower with SEVs, regardless of the definition used and adjustment for body mass index. Use of SEVs was associated with better quality of life outcomes as assessed by the Valve Academic Research Consortium-3 ordinal quality of life measure. Among women with severe symptomatic aortic stenosis and small aortic annuli undergoing transcatheter aortic valve replacement, the use of SEVs, compared to BEVs, resulted in similar clinical outcomes and a markedly reduced incidence of bioprosthetic valve dysfunction through 12 months, including a lower risk of prosthesis-patient mismatch and better 12-month quality of life. ClinicalTrials.gov Identifier: NCT04722250.

Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Recombinant Neorudin, a New Anticoagulant Drug in Patients With Acute Coronary Syndrome.

This study evaluated the safety, tolerability, pharmacodynamics, and pharmacokinetics of recombinant neorudin (EPR-hirudin [EH]) in patients with acute coronary syndrome (ACS), providing a basis for further therapeutic research. This open-label, single-center, nonrandomized, nonblinded, and noncontrolled trial categorized 24 patients with nonprogressive ACS who met the screening criteria into 3 groups. They received an intravenous injection of neorudin (0.4mg/kg), followed by an intravenous drip at doses of 0.15, 0.30, and 0.45mg/kg/h for 3 days in the low-, medium-, and high-dose groups, respectively. The safety, tolerability, pharmacodynamics, and pharmacokinetics of EH were assessed after treatment, indicating that neorudin was safe and well tolerated in nonprogressive ACS. No serious adverse events or clinical composite end points were observed. The activated partial thromboplastin time and thrombin time increased significantly and dose dependently following EH administration across all groups compared to pretreatment values. Conversely, thrombin activity significantly decreased after drug administration but returned to baseline levels shortly after drug withdrawal. Within the administered dose range, neorudin exposure increased with the dose, and its half-life was approximately 2hours. Neorudin was found to be safe and tolerable for treating patients with nonprogressive ACS, demonstrating therapeutic efficacy at doses up to 0.45mg/kg/h over a 3-day period.

ProGlide-AngioSeal versus ProGlide-FemoSeal for vascular access hemostasis posttranscatheter aortic valve implantation.

The hybrid strategy combining plug-based and suture-based vascular closure devices (VCD) was introduced as a promising technique for vascular access hemostasis after transcatheter aortic valve implantation (TAVI) with satisfactory outcomes. However, data comparing two plug-based VCDs each in the combination with a suture-based VCD, namely ProGlide/AngioSeal (P/AS) with ProGlide/FemoSeal (P/FS) VCDs, is still lacking. To compare the 30-day outcome of the hybrid strategy using P/AS versus P/FS for vascular access site closure after TAVI. A retrospective single-center observational study included 608 patients recruited from a prospective TAVI registry between 2016 and 2022. The composite endpoint was defined as any VCD-related major vascular complications and/or bleeding more than type 1 according to Valve Academic Research Consortium criteria. The current study reported a significantly higher rate of composite endpoint in P/AS group, which was driven by a higher rate of major bleeding (5.4% vs. 1.4%, p = 0.036). We also found a higher rate of VCD-related minor bleeding in P/AS group (16.3% vs. 8.1%, p = 0.013). Successful access site hemostasis was achieved in 71.7% of P/AS group versus 83.1% in P/FS group (p = 0.006). The presence of anterior wall calcification at the access site was significantly associated with the composite endpoint (adj odds ratio 2.49; 95% confidence interval (1.08-5.75), p = 0.032). The hybrid strategy for large bore vascular access closure using P/FS showed a potentially better 30-day outcomes compared with P/AS. The presence of anterior calcification at the access site carries a significant risk of VCD-related complications.

Pulsed Field Ablation to Treat Paroxysmal Atrial Fibrillation: Safety and Effectiveness in the AdmIRE Pivotal Trial.

Evidence from clinical trials of early pulsed field ablation (PFA) systems in treating atrial fibrillation has demonstrated their promising potential to reduce complications associated with conventional thermal modalities while maintaining efficacy. However, the lack of a fully integrated mapping system, a staple technology of most modern electrophysiology procedures, poses limitations in lesion creation and workflow options. A novel variable-loop PFA catheter integrated with an electroanatomic mapping system has been developed that allows for real-time nonfluoroscopic procedural guidance and lesion indexing as well as feedback of tissue-to-catheter proximity. AdmIRE (Assessment of Safety and Effectiveness in Treatment Management of Atrial Fibrillation With the Bosense-Webster Irreversible Electroporation Ablation System), a multicenter, single-arm, Food and Drug Administration investigational device exemption study, evaluated the long-term safety and effectiveness of this integrated PFA system in a large United States-based drug-refractory symptomatic paroxysmal atrial fibrillation patient population. Using the PFA catheter with a compatible electroanatomic mapping system, patients with drug-refractory symptomatic paroxysmal atrial fibrillation underwent pulmonary vein isolation. The primary safety end point was primary adverse event within 7 days of ablation. The primary effectiveness end point was a composite end point that included 12-month freedom from documented atrial tachyarrhythmia (ie, atrial fibrillation, atrial tachycardia, atrial flutter) episodes, failure to achieve pulmonary vein isolation, use of a nonstudy catheter for pulmonary vein isolation, repeat procedure (except for one redo during blanking), taking a new or previously failed class I or III antiarrhythmic drug at higher dose after blanking, or direct current cardioversion after blanking. At 30 centers, 277 patients with paroxysmal atrial fibrillation (61.5±10.3 years of age; 64.3% male) in the pivotal cohort underwent PFA. More than 25% of the procedures were performed without fluoroscopy. Median (Q1, Q3) pulmonary vein isolation procedure, fluoroscopy, and transpired PFA application times were 81.0 (61.0, 112.0), 7.1 (0.00, 14.3), and 31.0 (24.8, 40.9) minutes, respectively. The primary adverse event rate was 2.9% (8 of 272), with the most common complication being pericardial tamponade. The 12-month primary effectiveness end point was 74.6%. The 1-year freedom from atrial fibrillation, atrial tachycardia, or atrial flutter recurrence rate after blanking was 75.4%. Substantial improvements in quality of life were observed as early as 3 months after the procedure, concurrent with a reduction in multiple health care use measures. AdmIRE confirmed the safety and effectiveness of the variable-loop PFA catheter, with short procedure and PFA application times and low fluoroscopy exposure. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05293639.

Interpreting modern randomized controlled trials of medical therapy in inflammatory bowel disease.

Treatment options for the medical management of inflammatory bowel disease (IBD) have expanded substantially over the past decade. Multiple classes of advanced therapies, including both monoclonal antibodies and novel oral small molecules, are now available for the treatment of moderately-to-severely active Crohn's disease and ulcerative colitis, highlighted by the approvals of the first IL23p19 antagonists, selective Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators. These advances have been accompanied by the identification of novel targets and the rapid growth in both the number and size of IBD clinical trials. Over a dozen landmark randomized controlled trials (RCTs) have been completed in the past 5 years, including the first head-to-head biologic trials, the first combination biologic studies, and multiple phase III registrational trials of novel compounds with new co-primary and composite end points that will change the treatment landscape for years to come. Importantly, the methodology of RCTs in IBD has evolved substantially, with new trial designs, evaluation of unique patient populations, and different types of efficacy and safety end points being key innovations. In this Review, we provide a comprehensive evaluation of how modern RCTs of IBD medical therapies have evolved and the implications for their appraisal that will help guide the application of these data to clinical practice.

The efficacy of different biomarkers and endpoints to refine referrals for suspected prostate cancer: the TARGET study (Tiered integrAted tests for eaRly diaGnosis of clinically significant ProstatE Tumours).

The majority of men referred with a raised PSA for suspected prostate cancer will receive unnecessary tertiary investigations including MRI and biopsy. Here, we compared different types of biomarkers to refine tertiary referrals and when different definitions of clinically significant cancer were used. Data and samples from 798 men referred for a raised PSA (≥ 3ng/mL) and investigated through an MRI-guided biopsy pathway were accessed for this study. Bloods were acquired pre-biopsy for liquid biomarkers and germline DNA. Variables explored included PSA + Age (base model), free/total PSA (FTPSA), Prostate Health Index (phi), PSA density (PSAd), polygenic risk score (PRS) and MRI (≥ LIKERT 3). Different diagnostic endpoints for significant cancer (≥ grade group 2 [GG2], ≥ GG3, ≥ Cambridge Prognostic Group 2 [CPG2], ≥ CPG3) were tested. The added value of each biomarker to the base model was evaluated using logisticregression models, AUC and decision curve analysis (DCA) plots. The median age and PSA was 65years and 7.13ng/mL respectively. Depending on definition of clinical significance, ≥ grade group 2 (GG2) was detected in 57.0% (455/798), ≥ GG3 in 27.5% (220/798), ≥ CPG2 in 61.6% (492/798) and ≥ CPG3 in 42.6% (340/798). In the pre-MRI context, the PSA + Age (base model) AUC for prediction of ≥ GG2, ≥ GG3, ≥ CPG2 and ≥ CPG3 was 0.66, 0.68, 0.70 and 0.75 respectively. Adding phi and PSAd to base model improved performance across all diagnostic endpoints but was notably better when the composite CPG prognostic score was used: AUC 0.82, 0.82, 0.83, 0.82 and AUC 0.74, 0.73, 0.79, 0.79 respectively. In contrast, neither FTPSA or PRS scores improved performance especially in detection of ≥ GG3 and ≥ CPG3 disease. Combining biomarkers did not alter results. Models using phi and PSAd post-MRI also improved performances but again benefit varied with diagnostic endpoint. In DCA analysis, models which incorporated PSAd and phi in particular were effective at reducing use of MRI and/or biopsies especially for ≥ CPG3 disease. Incorporating phi or PSAd can refine and tier who is referred for tertiary imaging and/or biopsy after a raisedPSA test. Incremental value however varied depending on the definition of clinical significance and was particularly useful when composite prognostic endpoints are used.

Clinical Outcomes of Concomitant Coronary Artery Bypass Grafting During Ventricular Septal Myectomy.

The clinical characteristics and survival outcomes of patients who underwent concomitant coronary artery bypass grafting during septal myectomy have not been well studied. We reviewed patients who underwent both septal myectomy and coronary artery bypass grafting from 2009 to 2020. Causes of concomitant grafting and their impact on survival were analyzed. The median follow-up period was 5.1 years. A total of 320 patients underwent both grafting and myectomy. Of these, 69.7% and 28.1% underwent grafting attributed to atherosclerotic coronary artery disease and myocardial bridging, respectively. Patients who underwent grafting for coronary artery disease tended to be older, had a longer bypass time, and required more grafts compared with patients undergoing procedures because of myocardial bridging (all P<0.05). Postoperatively, the left ventricular outflow gradient significantly decreased from 85.4 mm Hg to 12.8 mm Hg (P<0.001) without perioperative death. The cumulative survival rates were 96.2% and 97.6% at 5 years in the coronary artery disease and myocardial bridging groups, respectively, and they were comparable to that of general myectomy cohort (hazard ratio [HR], 1.06 [95% CI, 0.47-2.36], P=0.895 and HR 0.75 [95% CI, 0.23-2.46], P=0.636, respectively). Sudden death accounted for 45.5% (5 of 11) of postoperative mortality. Analysis of composite end point events showed decreased morbidity with at least one arterial graft in the overall cohort (HR, 0.47 [95% CI, 0.23-0.94], P=0.034). Concomitant grafting in septal myectomy was found to be a safe procedure. Patients who underwent such surgery experienced favorable postoperative outcomes comparable to those who underwent septal myectomy alone, with a 5-year survival rate of >95% and improved functional class of >90%.

Superiority trials in invasive aspergillosis: a harsh reality check with the IA-DUET (HOVON502) trial.

The IA-DUET study aimed to compare azole-echinocandin combination with azole monotherapy for invasive aspergillosis. Recruitment was hindered by patient ineligibility, competing studies, and guidelines favoring combination therapy when azole resistance was unknown. The low IA-attributable mortality suggests future trials may benefit from cluster randomization or composite endpoints to enhance efficiency.

A Prospective, Randomized Trial of Bioresorbable Polymer Drug-Eluting Stents Versus Fully Bioresorbable Scaffolds in Patients Undergoing Coronary Stenting

Background: The performance of an everolimus-eluting bioresorbable scaffold (BRS) was inferior to an everolimus-eluting metallic drug-eluting stent (DES) with permanent polymer, mainly due the mechanical features of BRS technology. The performance of BRS as compared to metallic DES with bioresorbable polymers remains unstudied. Methods: This prospective, randomized, multicenter, clinical trial enrolled patients who underwent coronary stenting for de novo coronary lesions. Patients were randomly assigned to bioresorbable polymer everolimus-eluting stents (BP-EES) or everolimus-eluting BRS. The primary endpoint was percentage diameter stenosis (in-device) at 6- to 8-month angiographic surveillance. The main secondary endpoint was the device-oriented composite endpoint (DOCE) of cardiac death/target vessel-myocardial infarction/target lesion revascularization assessed after 12 months and 5 years. Results: The trial was prematurely terminated after the enrollment of 117 of 230 patients (BP-EES, n = 60; BRS, n = 57) due to safety issues associated with BRS technology. The primary endpoint of in-device diameter stenosis at angiographic surveillance was 12.5 ± 7.7% with BP-EES versus 19.3 ± 16.5% with BRS (p = 0.01). The DOCE occurred in 5.0% in the BP-EES group versus 12.3% of patients in the BRS group (hazard ratio [HR] 2.48, 95% confidence interval [CI] 0.64–9.58, p = 0.19) after 12 months and in 11.7% in the BP-EES group versus 26.4% of patients in the BRS group (HR 2.38, 95% CI 0.97–5.84, p = 0.06) after 5 years. Conclusions: BP-EES showed superior mid-term angiographic performance compared with BRS. Clinical event rates did not differ significantly between the groups up to 5 years of follow-up. These results should be interpreted with caution in view of the premature discontinuation of the study.

Vitamin D deficiency may increase the risk of acute kidney injury in patients with diabetes and predict a poorer outcome in patients with acute kidney injury

BackgoundPeople with diabetes are much more likely to develop acute kidney injury (AKI) than people without diabetes. Low 25-hydroxy-vitamin D [25(OH)D] concentrations increased the risk of AKI in specific populations. Few studies have explored the relationship between the 25(OH)D level and AKI in patients with diabetes. We conducted this study to investigate the relationship between the plasma level of 25(OH)D and the risk of AKI in patients with diabetes, and to evaluate whether the 25(OH)D level could be a good prognostic marker for AKI progression.MethodsA total of 347 patients with diabetes were retrospectively reviewed. The primary endpoint was the first event of AKI. The secondary endpoint is need-of-dialysis. AKI patients were further followed up for 6 months with the composite endpoint of end-stage renal disease (ESRD) or all-cause death. Kaplan–Meier survival analysis and Cox proportional hazards models were used.ResultsDuring a median follow-up of 12 weeks (12.3 ± 6.7), 105 incident AKI were identified. The middle and high tertiles of baseline 25(OH)D levels were associated with a significantly decreased risk of AKI and dialysis compared to the low tertile group (HR = 0.25, 95% CI 0.14–0.46; HR = 0.24, 95% CI 0.13–0.44, respectively, for AKI; HR = 0.15; 95% CI 0.05–0.46; HR = 0.12; 95% CI 0.03–0.42, respectively, for dialysis). Sensitivity analysis revealed similar trends after excluding participants without history of CKD. Furthermore, AKI patients with 25(OH)D deficiency were associated with a higher risk for ESRD or all-cause death (HR, 4.24; 95% CI, 1.80 to 9.97, P < 0.001).ConclusionA low 25 (OH) vitamin D is associated with a higher risk of AKI and dialysis in patients with diabetes. AKI patients with 25(OH)D deficiency were associated with a higher risk for ESRD or all-cause death.

9175 Pretransplant Clinical Characteristics Related To Change In Bone Mineral Density In Adults 1 Year After Allogeneic Hematopoietic Stem Cell Transplantation At Bucaramanga, Colombia Reference Center

Abstract Disclosure: G.A. Parra-Serrano: None. C.L. Sossa: None. K.J. Moreno Medina: None. M. Ochoa: None. A. Reyes Gonzalez: None. A. Plata: None. P. Mantilla Mantilla: None. Introduction: Hematopoietic stem cell transplantation (HSCT) , refractory to pharmacological management, increases 10-year survival by 80%, Chronic complications include alterations in bone metabolism, that increase appearance of osteoporosis (13.8 - 17%), non traumatic fractures, and loss of Bone mineral density (BMD) at the hip -4.2%, L1L4 -2% and femoral neck-9%. Methods Calculate Change at (BMD) in adults undergoing allogenic (HSCT) after 1y and determine pretransplant factors related to this change. Composite endpoint osteoporosis/lowbonemass (osteoporosis Tscore&amp;lt;-2.5 and/or low bone mass Zscore-2.0) 1 year after transplant, Adult patients Retrospective cohort study, ethical comittee approval, anonymized database, undergoing allogeneic (HSCT) between 2009 and 2022, (BMD) measured at lumbar spine (L1L4) and femoral neck before and one year after transplant; Also paraclinical variables: TSH, vitaminD, kidney function, glucocorticoid, Graft vs host disease, disease relapse, diabetes. Descriptive analisis performed, simple linear regresion analisis for delta L1L4 and femoral neck BMD before and 1 year after transplant, and multivariate regresion analisis for variables p&amp;lt;0.2 on simple lineal regression analysis . Results 123 patients, (48 included, 73 excluded (22 died, 50 densitometry data not suitable)). BMD change At lumbar spine, -4.7% (NS) , and at femoral neck -9.8% (p&amp;lt;0.05), Simple regression analysis no correlation for preclinical variables at lumbar spine. negative correlation between prednisolone dose at femoral neck BMD (p 0.007, coefficient B -0.0086 [IC95% -0.014, 0.0025]). Mutivariate regression analysis performed for BMD diference at femoral neck, after adjusting for variables p&amp;lt;0.2 on simple regression analysis, model that include (prednisone dose, diabetes and relapse before transplant showed Rsquare 0.19 coefficient 0.0092 p 0.003. For every gram of glucocorticoid (prednisolone) bone loss decrease -0.9% of BMD at femoral neck at 1 year follow up. Proportion of patients with composite osteoporosis/lowbonemass at femoral neck pre-transplant (n2) 4.17%, postransplant (n14) 29.17%. * p 0.0005. no difference observed at lumbar spine. Fracture incidence n2 (4%) at lumbar spine and n1 (2%) at femoral neck. Conclusions At femoral neck, People with HSCT present significant decrease in (BMD) and higuer incidence of Osteoporosis or low bone mass, not observed at lumbar spine, after adjusting for multiple variables. for every 1gr of prednisolone equivalent dose, (BMD) decrease -0.9%, at femoral neck p0.003. The model only explain 19% of change of BMD at femoral neck, that suggest immune response caused by allogenic transplantation might be responsible, in part, of BMD change. Presentation: 6/3/2024

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.

Combined Use of GDF-15 and NT-Pro BNP for Outcome Prediction in Patients with Acute Heart Failure

Background: Acute heart failure (AHF) is characterized by a complex pathophysiology. Aims: This study aimed to evaluate the usefulness of combined serial measurements of N-terminal pro-B-type natriuretic peptide (NT-pro BNP) and growth differentiation factor 15 (GDF-15) for predicting long-term outcomes in patients with AHF. Methods: This study included 104 consecutive patients hospitalized due to AHF. The mean (SD) age was 65 (±15) years. Blood samples were collected on admission, at discharge, and at a 30-day follow-up visit. The primary composite endpoint was all-cause mortality or rehospitalization due to heart failure (HF) at 1-year follow-up. Results: During follow-up, the primary endpoint occurred in 31 persons. In the ROC analysis, the optimal cut-off values of GDF-15 for predicting the outcome were 5115.5 pg/mL on admission, 4145 pg/mL at discharge, and 4218.5 pg/mL at the 30-day visit. For NT-pro BNP, the optimal cut-off reached 6011 ng/L, 1250 ng/L, and 1456.5 ng/L, respectively. Patients with both GDF-15 and NT-pro BNP levels above the cut-off value had a higher risk of the primary composite endpoint than patients with only one or none of the biomarkers elevated at three time points. At the 30-day visit, the model combining NT-pro BNP and GDF-15 showed the highest predictive value for the primary composite endpoint (area under the curve, 0.75). Conclusions: Combined serial measurements of NT-pro BNP and GDF-15 outperform single measurements in outcome prediction at 1-year follow-up in patients with AHF. The repetitive combined model may serve as a useful risk assessment tool and facilitate decision-making during long-term observation.

SGLT-2 Inhibitors Versus GLP-1 Receptor Agonists Effects on Kidney and Clinical Outcomes in Veterans with Type 2 Diabetes.

The primary aim compared kidney endpoints between patients with type 2 diabetes (T2D) 36 months after initiation on a sodium-glucose cotransporter-2 inhibitor (SGLT2i) or a GLP-1 receptor agonist (GLP-1RA). Secondary aims compared estimated glomerular filtration rate (eGFR), hemoglobin A1c (HbA1c), weight, and urine albumin-to-creatinine ratio (UACR) changes. We conducted a retrospective cohort study of propensity score matched veterans with T2D, baseline eGFR>20mL/min/1.73m2, and initiated on a SGLT2i vs GLP-1RA between 4/1/2009-9/1/2020. Cox proportional hazard models were constructed to evaluate effectiveness between both groups on composite endpoint (decline of >=40% in eGFR from baseline, ESRD event, and all-cause mortality) and its components adjusting for baseline characteristics. Spline models were constructed to evaluate eGFR change and linear mixed effects models were constructed to evaluate changes in HbA1c, weight, and UACR. We used an intent-to-treat (ITT) approach as our main analysis followed by a per-protocol (PP) approach excluding veterans who discontinued or switched therapy during the study period. A total of 29,146 propensity score matched veterans were included in SGLT2i and GLP-1RA groups (14,573 per group). In the ITT and PP analyses, veterans initiated on SGLT2i had a 35% (HR=0.65; 95% CI: 0.62, 0.68) and 34% (HR=0.66; 95% CI: 0.62, 0.69) reduction in the hazard of experiencing the composite endpoint compared to veterans initiated on GLP-1RA adjusting for baseline characteristics, respectively. Between 6-36 months, we found an improved chronic eGFR slope with SGLT2i compared to GLP-1RA in both ITT and PP analyses; +1.19 mL/min/1.73 m2 (95% CI: 0.93, 1.45) and +1.29 mL/min/1.73m2 (95% CI: 1.01, 1.57), respectively. The annual difference in chronic eGFR slope in both ITT and PP analyses were +0.97 mL/min/1.73m2/year (95% CI: 0.82, 1.11) and +1.08 mL/min/1.73m2/year (95% CI: 0.92, 1.25). Improved HbA1c, weight loss and UACR were reported for both groups. In this real-world study, veterans with T2D initiated on SGLT2i were associated with reduced hazard of experiencing mortality, worsening eGFR, or developing ESRD and improved glycemic, metabolic, and renal endpoints compared to GLP-1RA use.

Leukocyte Indices as Markers of Inflammation and Predictors of Outcome in Heart Failure with Preserved Ejection Fraction.

Background: The pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF) is suggested to be influenced by inflammation. Leukocyte indices, including the neutrophil-lymphocyte ratio (NLR), the monocyte-lymphocyte ratio (MLR), and the pan-immune inflammation value (PIV), can be utilized as biomarkers of systemic inflammation. Their prognostic utility is yet to be fully understood. Methods: Between December 2010 and May 2023, patients presenting to a tertiary referral center for HFpEF were included into a prospective registry. The association of the NLR, MLR, and PIV with the composite endpoint of all-cause mortality and HF-related hospitalization was tested utilizing Cox regression analysis. Results: In total, 479 patients (median 74.3, interquartile range (IQR): 69.22-78.3 years, 27.8% male) were included. Patients were observed for 43 (IQR: 11-70) months, during which a total of 267 (55.7%) patients met the primary endpoint. In a univariate Cox regression analysis, an above-the-median NLR implied a hazard ratio (HR) of 1.76 (95%-confidence interval (CI): 1.38-2.24, p < 0.001), an MLR of 1.46 (95%-CI: 1.14-1.86, p = 0.003), and a PIV of 1.67, 95%-CI: 1.30-2.13, p < 0.001) for the composite endpoint. After adjustment in a step-wise model, the NLR (HR: 1.81, 95%-CI: 1.22-2.69, p = 0.003), the MLR (HR: 1.57, 95%-CI: 1.06-2.34, p = 0.026), and the PIV (HR: 1.64, 95%-CI: 1.10-2.46, p = 0.015) remained significantly associated with the combined endpoint. Conclusions: The NLR, the MLR, and the PIV are simple biomarkers independently associated with outcomes in patients with HFpEF.

A retrospective review of intramuscular olanzapine and parenteral benzodiazepine coadministration in the emergency department.

Acute agitation is a common presenting symptom in medical and mental health emergencies that may require pharmacologic intervention. There is a manufacturer recommendation against intramuscular coadministration of olanzapine with parenteral (intramuscular or intravenous) benzodiazepines despite a deficiency of high-quality evidence. The purpose of this study was to contribute to available literature regarding intramuscular olanzapine and parenteral benzodiazepine use in acutely agitated patients in the emergency department (ED). This was a single-center retrospective chart review of adult ED patients who received intramuscular olanzapine and a parenteral benzodiazepine within 2 hours. The composite primary endpoint evaluated the occurrence of cardiac or respiratory compromise within 2 hours of medication administration. Secondary endpoints mirrored the primary endpoint within 30 minutes and evaluated the occurrence of cardiac arrest or desaturation in the ED outside the 2-hour window. One hundred eleven patients were included in the analysis, 64 (57.7%) of whom had documented vitals or oxygen status within 2 hours of medication administration. The composite primary endpoint occurred in 8 patients (12.5%), with only 1 patient requiring intervention with intravenous fluids. The secondary composite endpoint occurred in 2 (9.5%) of 21 patients with documented vitals or oxygen status within 30 minutes of treatment, neither of which required intervention. There were no identified events of intubation or significant cardiac events. Until better evidence is available, this combination therapy should, at minimum, include appropriate patient monitoring. Future studies should investigate risk factors for serious adverse effects.

Lateral QRS amplitude is independently associated with outcome after cardiac resynchronization therapy: Advancing patient selection?

BackgroundCardiac resynchronization therapy (CRT) is a cornerstone in the treatment of selected heart failure patients. However, a relevant proportion of patients do not show beneficial response. Identification of simple, additive, and outcome-relevant selection criteria may improve selection of patients. ObjectiveWe sought to determine whether baseline QRS amplitude is associated with outcome in CRT. MethodsQuantification of intrinsic, pre–CRT implantation QRS amplitude was performed in an observational multinational 2-center retrospective cohort analysis (derivation cohort Zurich, n = 178, 2000–2015; validation cohort Leuven, n = 183, 1999–2016) with a composite end point of all-cause mortality, ventricular assist device implantation, or heart transplantation at 5 years. ResultsHigher baseline to peak amplitude in lateral leads (lead I and V6) was associated with a lower risk of reaching the composite end point (lead I: hazard ratio, 0.86 [95% confidence interval, 0.78–0.95] per millivolt, P = .002; lead V6: hazard ratio, 0.94 [95% confidence interval, 0.88–1.00] per millivolt, P = .043). Concordance index–based comparison of quartile, spline, and receiver operating characteristic curve analysis suggested cutoff values of 6 mV for lead I and 3 mV for V6 for optimal discrimination of outcome. External validation confirmed the cutoff of 3 mV in lead V6 as a highly significant discriminator of outcome (P < .001) associated with a risk reduction of 65%. ConclusionLow QRS amplitude in lateral electrocardiogram leads is associated with higher risk of poor outcome in CRT patients. A cutoff of 3 mV in lead V6 proved highly discriminative. Further studies need to confirm the additive value of QRS amplitude in selection of patients for CRT and to assess whether CRT may be made available to more patients.

Cancer as an Independent Mortality Risk in Chronic Thromboembolic Pulmonary Hypertension

BackgroundThe management of chronic thromboembolic pulmonary hypertension (CTEPH) has advanced significantly in recent years, thereby improving patient prognosis. However, the impact of cancer on the outcomes of patients with CTEPH under current treatment remains unclear. This study aimed to investigate the prevalence of cancer in patients with CTEPH and determine how comorbid cancer affects their prognosis and clinical course. MethodsData from an ongoing Japanese prospective cohort study were analyzed. Prevalence and primary cancer sites were evaluated. The association of a history of cancer with a composite endpoint, including all-cause death, lung transplantation, and worsening of CTEPH, as well as venous thromboembolism and bleeding events, was assessed. ResultsOf the 1,270 patients in the cohort, 134 (10.6%) had a history of cancer, with the most common primary sites being the breast in women and the prostate in men. The incidence of composite outcome and all-cause death was higher in those with a history of cancer (p<0.001, log-rank test). In the Cox proportional hazard model, age- and sex-adjusted hazard ratios for the composite outcome and all-cause death were 2.69 (95% confidence interval, 1.48–4.89, p=0.001) and 4.25 (95% confidence interval, 1.98–9.10, p<0.001), respectively, for patients with a history of cancer. No significant differences in venous thromboembolism and bleeding events were observed between patients with and those without a history of cancer. ConclusionsA history of cancer, with a prevalence of 10.6%, is an independent risk factor for mortality in patients with CTEPH undergoing the currently recommended treatment.