Showing papers by "Bertram Pitt published in 2023"

Effect of Torsemide vs Furosemide After Discharge on All-Cause Mortality in Patients Hospitalized With Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

Abstract: Importance Although furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide. Objective To determine whether torsemide results in decreased mortality compared with furosemide among patients hospitalized for heart failure. Design, Setting, and Participants TRANSFORM-HF was an open-label, pragmatic randomized trial that recruited 2859 participants hospitalized with heart failure (regardless of ejection fraction) at 60 hospitals in the United States. Recruitment occurred from June 2018 through March 2022, with follow-up through 30 months for death and 12 months for hospitalizations. The final date for follow-up data collection was July 2022. Interventions Loop diuretic strategy of torsemide (n = 1431) or furosemide (n = 1428) with investigator-selected dosage. Main Outcomes and Measures The primary outcome was all-cause mortality in a time-to-event analysis. There were 5 secondary outcomes with all-cause mortality or all-cause hospitalization and total hospitalizations assessed over 12 months being highest in the hierarchy. The prespecified primary hypothesis was that torsemide would reduce all-cause mortality by 20% compared with furosemide. Results TRANSFORM-HF randomized 2859 participants with a median age of 65 years (IQR, 56-75), 36.9% were women, and 33.9% were Black. Over a median follow-up of 17.4 months, a total of 113 patients (53 [3.7%] in the torsemide group and 60 [4.2%] in the furosemide group) withdrew consent from the trial prior to completion. Death occurred in 373 of 1431 patients (26.1%) in the torsemide group and 374 of 1428 patients (26.2%) in the furosemide group (hazard ratio, 1.02 [95% CI, 0.89-1.18]). Over 12 months following randomization, all-cause mortality or all-cause hospitalization occurred in 677 patients (47.3%) in the torsemide group and 704 patients (49.3%) in the furosemide group (hazard ratio, 0.92 [95% CI, 0.83-1.02]). There were 940 total hospitalizations among 536 participants in the torsemide group and 987 total hospitalizations among 577 participants in the furosemide group (rate ratio, 0.94 [95% CI, 0.84-1.07]). Results were similar across prespecified subgroups, including among patients with reduced, mildly reduced, or preserved ejection fraction. Conclusions and Relevance Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months. However, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence. Trial Registration ClinicalTrials.gov Identifier: NCT03296813.

Outcomes with Finerenone in Participants with Stage 4 CKD and Type 2 Diabetes

Abstract: Visual Abstract Background Patients with stage 4 CKD and type 2 diabetes have limited treatment options to reduce their persistent cardiovascular and kidney risk. In Finerenone in Chronic Kidney Disease and Type 2 Diabetes (FIDELITY), a prespecified pooled analysis of Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD), finerenone improved heart-kidney outcomes in participants with CKD and type 2 diabetes. Methods This FIDELITY subgroup analysis investigated the effects of finerenone in participants with stage 4 CKD (eGFR <30 ml/min per 1.73 m2). Efficacy outcomes included a cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite (kidney failure, sustained ≥57% decrease in eGFR from baseline, or kidney disease death). Results Of 13,023 participants, 890 (7%) had stage 4 CKD. The hazard ratio for risk of cardiovascular composite outcome with finerenone versus placebo was 0.78 (95% confidence interval, 0.57 to 1.07). The kidney composite outcome proportional hazards assumption was not met for the overall study period, with a protective effect only shown up to 2 years, after which the direction of association was inconsistent, and an observed loss of precision over time incurred on finerenone versus placebo risk differences. Nonetheless, albuminuria and rate of eGFR decline were consistently reduced with finerenone versus placebo. Adverse events were balanced between treatment arms. Hyperkalemia was the most common adverse event reported (stage 4 CKD: 26% and 13% for finerenone versus placebo, respectively); however, the incidence of hyperkalemia leading to permanent discontinuation was low (stage 4 CKD: 3% and 2% for finerenone versus placebo, respectively). Conclusions The cardiovascular benefits and safety profile of finerenone in participants with stage 4 CKD were consistent with the overall FIDELITY population; this was also the case for albuminuria and the rate of eGFR decline. The effects on the composite kidney outcome were not consistent over time.

Finerenone and effects on mortality in chronic kidney disease and type 2 diabetes: a FIDELITY analysis

Abstract: Abstract Aims Finerenone reduces the risk of cardiovascular events in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). We investigated the causes of mortality in the FIDELITY population. Methods and results The FIDELITY prespecified pooled data analysis from FIDELIO-DKD and FIGARO-DKD excluded patients with heart failure and reduced ejection fraction. Outcomes included intention-to-treat and prespecified on-treatment analyses of the risk of all-cause and cardiovascular mortality. Of 13 026 patients [mean age, 64.8 years; mean estimated glomerular filtration rate (eGFR), 57.6 mL/min/1.73 m2], 99.8% were on renin–angiotensin system inhibitors. Finerenone reduced the incidence of all-cause and cardiovascular mortality vs. placebo (8.5% vs. 9.4% and 4.9% vs. 5.6%, respectively) and demonstrated significant on-treatment reductions [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.70–0.96; P = 0.014 and HR, 0.82; 95% CI, 0.67–0.99; P = 0.040, respectively]. Cardiovascular-related mortality was most common, and finerenone lowered the incidence of sudden cardiac death vs. placebo [1.3% (incidence rate 0.44/100 patient-years) vs. 1.8% (0.58/100 patient-years), respectively; HR, 0.75; 95% CI, 0.57–0.996; P = 0.046]. The effects of finerenone on mortality were similar across all Kidney Disease: Improving Global Outcomes risk groups. Event probability with finerenone at 4 years was consistent irrespective of baseline urine albumin-to-creatinine ratio, but seemingly more pronounced in patients with higher baseline eGFR. Conclusion In FIDELITY, finerenone significantly reduced the risk of all-cause and cardiovascular mortality vs. placebo in patients with T2D across a broad spectrum of CKD stages while on treatment, as well as sudden cardiac death in the intention-to-treat population. Clinical trials registration FIDELIO-DKD and FIGARO-DKD are registered with ClinicalTrials.gov, numbers NCT02540993 and NCT02545049, respectively (funded by Bayer AG).

Effects of finerenone in people with chronic kidney disease and type 2 diabetes are independent of HbA1c at baseline, HbA1c variability, diabetes duration and insulin use at baseline

Abstract: To evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, diabetes duration and baseline insulin use on cardiorenal outcomes and diabetes progression.

Eligibility for sotagliflozin in a real-world heart failure population based on the SOLOIST-WHF trial enrolment criteria: Data from the swedish heart failure registry.

Abstract: AIMS The SOLOIST-WHF trial demonstrated efficacy of sotagliflozin in patients with type 2 diabetes mellitus (T2DM) and recent worsening heart failure (HF) regardless of ejection fraction (EF). Selection criteria in trials may limit their generalizability. Therefore, we aimed to investigate eligibility for sotagliflozin based on the SOLOIST-WHF criteria in a real-world HF population. METHODS AND RESULTS SOLOIST-WHF criteria were applied to patients stabilized after HF hospitalization in the Swedish HF Registry according to 1) literal scenario (all inclusion/exclusion criteria) or 2) pragmatic scenario (only criteria likely to influence treatment decisions). Of 5453 inpatients with T2DM and recent worsening HF, 51.4% had reduced EF (HFrEF), 19.1% mildly reduced (HFmrEF), and 29.5% preserved EF (HFpEF). Eligibility (literal) was: 27.2% (32.4% in HFrEF, 24.7% in HFmrEF, 19.7% in HFpEF) and eligibility (pragmatic) was 62.8% (69.1%, 60.3%, 53.4%, respectively). In the literal scenario, criteria limiting eligibility were HF duration < 3 months, eGFR <30 ml/min/1.73m2, age > 85 years, acute coronary syndrome < 3 months, and insufficiently high N-terminal pro-B-type natriuretic peptide levels. Eligible vs. non-eligible patients had more severe HF, higher cardiovascular (CV) comorbidity burden, higher use of HF treatments, and higher event rates (all-cause death 30.8 vs. 27.2 per 100 patient-years, CV death 19.1 vs. 16.6, and HF hospitalization 36.7 vs. 24.0). CONCLUSION In this large, real-world HF cohort with T2DM, ∼1/3 of patients were eligible for sotagliflozin in the literal and ∼2/3 of patients in the pragmatic scenario. Eligible patients had more severe HF and higher event rates, in particular CV and HF events.

Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function

Abstract: Preservation quality of donor hearts is a key determinant of transplant success. Preservation duration beyond 4 hours is associated with primary graft dysfunction (PGD). Given transport time constraints, geographical limitations exist for donor-recipient matching, leading to donor heart underutilization. Here, we showed that metabolic reprogramming through up-regulation of the enzyme immune response gene 1 (IRG1) and its product itaconate improved heart function after prolonged preservation. Irg1 transcript induction was achieved by adding the histone deacetylase (HDAC) inhibitor valproic acid (VPA) to a histidine-tryptophan-ketoglutarate solution used for donor heart preservation. VPA increased acetylated H3K27 occupancy at the IRG1 enhancer and IRG1 transcript expression in human donor hearts. IRG1 converts aconitate to itaconate, which has both anti-inflammatory and antioxidant properties. Accordingly, our studies showed that Irg1 transcript up-regulation by VPA treatment increased nuclear translocation of nuclear factor erythroid 2–related factor 2 (Nrf2) in mice, which was accompanied by increased antioxidant protein expression [hemeoxygenase 1 (HO1) and superoxide dismutase 1 (SOD1)]. Deletion of Irg1 in mice (Irg1−/−) negated the antioxidant and cardioprotective effects of VPA. Consistent with itaconate’s ability to inhibit succinate dehydrogenase, VPA treatment of human hearts increased itaconate availability and reduced succinate accumulation during preservation. VPA similarly increased IRG1 expression in pig donor hearts and improved its function in an ex vivo cardiac perfusion system both at the clinical 4-hour preservation threshold and at 10 hours. These results suggest that augmentation of cardioprotective immune-metabolomic pathways may be a promising therapeutic strategy for improving donor heart function in transplantation. Description Valproic acid improves donor heart function after reperfusion by up-regulating IRG1 expression and itaconate to activate antioxidant pathways. Extending the shelf life of donor hearts Organ transplantation is a life-saving procedure for many diseases but is hindered by strict time limits on ischemia to preserve donor tissue integrity. Here Lei et al. demonstrated that perfusion of human, mouse or pig hearts with the histone deacetylase inhibitor valproic acid could substantially extend cold storage time without compromising cardiac function. Metabolic and gene expression analysis indicated that valproic acid administration increased immune response gene 1 (IRG1) and its product itaconate, which led to reduced inflammation and oxidative stress. These results suggest that regulation of cellular metabolism through pharmacological treatment may be a potential way to improve donor organ preservation for transplantation. —AW

Modifiability of Composite Cardiovascular Risk Associated With Chronic Kidney Disease in Type 2 Diabetes With Finerenone.

Abstract: Importance It is currently unclear whether chronic kidney disease (CKD)-associated cardiovascular risk in type 2 diabetes (T2D) is modifiable. Objective To examine whether cardiovascular risk can be modified with finerenone in patients with T2D and CKD. Design, Setting, and Participants Incidence rates from Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial Programme Analysis (FIDELITY), a pooled analysis of 2 phase 3 trials (including patients with CKD and T2D randomly assigned to receive finerenone or placebo) were combined with National Health and Nutrition Examination Survey data to simulate the number of composite cardiovascular events that may be prevented per year with finerenone at a population level. Data were analyzed over 4 years of consecutive National Health and Nutrition Examination Survey data cycles (2015-2016 and 2017-2018). Main Outcomes and Measures Incidence rates of cardiovascular events (composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, or hospitalization for heart failure) were estimated over a median of 3.0 years by estimated glomerular filtration rate (eGFR) and albuminuria categories. The outcome was analyzed using Cox proportional hazards models stratified by study, region, eGFR and albuminuria categories at screening, and cardiovascular disease history. Results This subanalysis included a total of 13 026 participants (mean [SD] age, 64.8 [9.5] years; 9088 male [69.8%]). Lower eGFR and higher albuminuria were associated with higher incidences of cardiovascular events. For recipients in the placebo group with an eGFR of 90 or greater, incidence rates per 100 patient-years were 2.38 (95% CI, 1.03-4.29) in those with a urine albumin to creatinine ratio (UACR) less than 300 mg/g and 3.78 (95% CI, 2.91-4.75) in those with UACR of 300 mg/g or greater. In those with eGFR less than 30, incidence rates increased to 6.54 (95% CI, 4.19-9.40) vs 8.74 (95% CI, 6.78-10.93), respectively. In both continuous and categorical models, finerenone was associated with a reduction in composite cardiovascular risk (hazard ratio, 0.86; 95% CI, 0.78-0.95; P = .002) irrespective of eGFR and UACR (P value for interaction = .66). In 6.4 million treatment-eligible individuals (95% CI, 5.4-7.4 million), 1 year of finerenone treatment was simulated to prevent 38 359 cardiovascular events (95% CI, 31 741-44 852), including approximately 14 000 hospitalizations for heart failure, with 66% (25 357 of 38 360) prevented in patients with eGFR of 60 or greater. Conclusions and Relevance Results of this subanalysis of the FIDELITY analysis suggest that CKD-associated composite cardiovascular risk may be modifiable with finerenone treatment in patients with T2D, those with eGFR of 25 or higher, and those with UACR of 30 mg/g or greater. UACR screening to identify patients with T2D and albuminuria with eGFR of 60 or greater may provide significant opportunities for population benefits.

The impact of obesity on cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes treated with finerenone: Post hoc analysis of the FIDELITY study.

Abstract: AIM To assess the effect of finerenone on the risk of cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes, with and without obesity. MATERIALS AND METHODS A post hoc analysis of the prespecified pooled FIDELITY dataset assessed the association between waist circumference (WC), composite cardiovascular and kidney outcomes, and the effects of finerenone. Participants were stratified by WC risk groups (representing visceral obesity) as low-risk or high-very high-risk (H-/VH-risk). RESULTS Of 12 986 patients analysed, 90.8% occupied the H-/VH-risk WC group. Incidence of the composite cardiovascular outcome was similar between finerenone and placebo in the low-risk WC group (hazard ratio [HR] 1.03; 95% confidence interval [CI], 0.72-1.47); finerenone reduced the risk in the H-/VH-risk WC group (HR 0.85; 95% CI, 0.77-0.93). For the kidney outcome, the risk was similar in the low-risk WC group (HR 0.98; 95% CI, 0.66-1.46) and reduced within the H-/VH-risk WC group (HR 0.75; 95% CI, 0.65-0.87) with finerenone versus placebo. There was no significant heterogeneity between the low-risk and H-/VH-risk WC groups for cardiovascular and kidney composite outcomes (P interaction = .26 and .34, respectively). The apparent greater benefit of finerenone on cardiorenal outcomes but lack of significant heterogeneity observed in H-/VH-risk WC patients may be because of the small size of the low-risk group. Adverse events were consistent across WC groups. CONCLUSION In FIDELITY, benefits of finerenone in lowering the risk of cardiovascular and kidney outcomes were not significantly modified by patient obesity.

Sodium polystyrene is unsafe and should not be prescribed for the treatment of hyperkalemia: primum non nocere!

Abstract: ‘Old generation’ potassium binders (i.e. sodium (SPS) and calcium (CPS) polystyrene sulfonate) are used widely, but with substantial heterogeneity across countries to treat hyperkalaemia (HK). However there is no randomized data to support their chronic use to manage HK, nor have they been shown to have a renin angiotensin aldosterone system inhibitor (RAASi) enabling effect. These compounds have poor tolerability, unpredictable onset of action and magnitude of potassium lowering. Furthermore, SPS may induce fluid overload owing to the fact that it exchanges potassium for sodium. Its use has also been associated with colonic necrosis, as emphasized by a black box warning from the US FDA. In contrast, two new K-binders patiromer and sodium zirconium cyclosilicate (SZC) have been shown to be safe and well tolerated for the chronic management of HK, thereby enabling RAASi optimization, as acknowledged by the latest international cardiorenal guidelines. In view of the lack of reliable evidence in regard to the efficacy and safety of the’ old generation ‘ K-binders compared to the placebo-controlled randomized and real-word evidence demonstrating the safety, efficacy and RAASi enabling effect of the new K-binders clinicians should now use the new potassium binders to treat HK (primum non nocere !).

Resistant hypertension: cardiorenal protection with mineralocorticoid receptor blockade.

Abstract: Journal Article Resistant hypertension: cardiorenal protection with mineralocorticoid receptor blockade Get access Bertram Pitt, Bertram Pitt Department of Medicine, University of Michigan Medicine, Ann Arbor, MI, USA https://orcid.org/0000-0001-5880-275X Search for other works by this author on: Oxford Academic PubMed Google Scholar George L Bakris George L Bakris Department of Medicine, University of Chicago Medicine, 5841 S. Maryland Ave. MC 1027, Chicago, IL 60637, USA Corresponding author. Tel: 1-773-702-7936, Fax: 1-773-834-2735, E-mail: gbakris@uchicago.edu https://orcid.org/0000-0003-1183-1267 Search for other works by this author on: Oxford Academic PubMed Google Scholar European Heart Journal, ehad299, https://doi.org/10.1093/eurheartj/ehad299 Published: 24 May 2023

Dapagliflozin Improves Heart Failure Symptoms and Physical Limitations Across the Full Range of Ejection Fraction: Pooled Patient-Level Analysis From DEFINE-HF and PRESERVED-HF Trials

Abstract: BACKGROUND: Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. METHODS: Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. RESULTS: Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6–7.5]; P<0.001). This was consistent in participants with EF≤40 (4.6 points [95% CI, 1.0–8.1]; P=0.01), >40 to ≤60 (4.9 points [95% CI, 0.8–9.0]; P=0.02) and >60% (6.8 points [95% CI, 1.5–12.1]; P=0.01; Pinteraction=0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously (Pinteraction=0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all Pinteractionvalues nonsignificant). CONCLUSIONS: In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02653482 and NCT03030235.

272-OR: The Efficacy of Sotagliflozin on Heart-Failure Related Outcomes Is Independent of Baseline A1C

Abstract: Background: SGLT inhibitors reduce the risk of cardiovascular (CV) events in patients with heart failure (HF) and chronic kidney disease regardless of diabetes status. Although the SOLOIST-WHF and SCORED trials enrolled high CV risk patients with T2DM, participants had a wide range of baseline A1C values. Thus, the present analysis evaluated the effects of sotagliflozin relative to placebo on cardiovascular (CV) death and total HF-related outcomes by baseline A1C range. Methods: SOLOIST-WHF had no baseline A1C entry criteria (baseline median = 7.1%, range = 4.5, 15.0%), while SCORED randomized patients with T2DM and an A1C ≥7% at screening (8.3%, 6.5, 17.3%). Natural cubic splines from Poisson regression models estimated the relationships between continuous A1C and the primary endpoint for both studies: total number of CV deaths, hospitalizations for HF, and urgent visits for HF. Results: Within each trial, patients with higher baseline A1C experienced higher event rates (spline effect p=0.0349 and 0.0014 for SOLOIST-WHF and SCORED, respectively). Sotagliflozin reduced the primary outcome in each trial (p for treatment <0.0001 for both SOLOIST-WHF and SCORED) and this did not differ across A1C (p for interaction >0.10; Figure). Conclusion: Sotagliflozin was effective in reducing the risk of CV death and HF-related events independent of baseline A1C. R.Aggarwal: None. D.L.Bhatt: Board Member; Bristol-Myers Squibb Company, Research Support; Lexicon Pharmaceuticals, Inc., Sanofi, Lilly, Boehringer Ingelheim Inc., AstraZeneca, Novo Nordisk. M.Szarek: Consultant; Amarin Corporation, ESPERION Therapeutics, Inc., Other Relationship; Janssen Pharmaceuticals, Inc., Research Support; Lexicon Pharmaceuticals, Inc., Regeneron, Sanofi, Bayer Inc. M.J.Davies: Employee; Lexicon Pharmaceuticals, Inc. P.L.Banks: Employee; Lexicon Pharmaceuticals, Inc. B.Pitt: Consultant; Bayer Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Vifor Pharma Management Ltd., Lexicon Pharmaceuticals, Inc., PhaseBio Pharmaceuticals, Inc., KBP Bioscience, Merck & Co., Inc. P.G.Steg: Advisory Panel; Merck & Co., Inc., Consultant; Sanofi, Amarin Corporation, Amgen Inc., BMS, PhaseBio Pharmaceuticals, Inc., Idorsia Pharmaceuticals Ltd., Novartis AG, Janssen Pharmaceuticals, Inc., AstraZeneca, Research Support; Lexicon Pharmaceuticals, Inc.

Mineralocorticoid receptor antagonist use in renal dialysis: will evidence from prospective randomized trials confirm the results from ‘real‐world’ evidence?

Abstract: In patients with end-stage renal disease (ESRD) on chronic renal dialysis the cardiovascular (CV) mortality rate is 10 to 20 times higher than in the general population and among adults younger than 45 years of age the mortality rate is approximately 100 times higher than that in the general population. Hence, treatments to improve survival, more specifically CV outcomes, in this population are urgently needed.1,2 Activation of mineralocorticoid receptors (MR) in patients with chronic kidney disease (CKD) leads to adverse outcomes, especially hospitalization for heart failure (HF), ventricular arrhythmias, sudden cardiac death as well as progression of CKD to ESRD2,3 through several mechanisms, including inflammation, oxidative stress, endothelial dysfunction, vascular fibrosis, stiffening and calcification,3–5 all of which are relevant in patients undergoing renal dialysis.2 MR antagonists (MRAs) are currently approved and/or are recommended in European and international guidelines in patients with resistant hypertension, diabetic nephropathy and in HF with a reduced ejection fraction (HFrEF), where they are one of the ‘four pillars’ along with angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), sacubitril/valsartan, beta-blockers, and sodium–glucose cotransporter 2 inhibitors. MRAs are therefore prime candidates to be assessed in prospective randomized clinical trials in patients undergoing renal dialysis. However, in view of the risk of

Effect of Torsemide Versus Furosemide on Symptoms and Quality of Life Among Patients Hospitalized for Heart Failure: The TRANSFORM-HF Randomized Clinical Trial

Abstract: Background: Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. Methods: TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomly assigned in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on prespecified secondary end points, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; assessed as adjusted mean difference in change from baseline; range, 0–100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (range, 0–6; score ≥3 supporting evaluation for depression) over 12 months. Results: Baseline data were available for 2787 (97.5%) patients for KCCQ-CSS and 2624 (91.8%) patients for Patient Health Questionnaire-2. Median (interquartile range) baseline KCCQ-CSS was 42 (27–60) in the torsemide group and 40 (24–59) in the furosemide group. At 12 months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference, 0.06 [95% CI, –2.26 to 2.37]; P=0.96) or the proportion of patients with Patient Health Questionnaire-2 score ≥3 (15.1% versus 13.2%: P=0.34). Results for KCCQ-CSS were similar at 1 month (adjusted mean difference, 1.36 [95% CI, –0.64 to 3.36]; P=0.18) and 6-month follow-up (adjusted mean difference, –0.37 [95% CI, –2.52 to 1.78]; P=0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent before hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. Conclusions: Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, previous loop diuretic use, and baseline health status. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03296813.

407-P: Efficacy of Finerenone in Patients with Abnormal Markers of Liver Steatosis and Fibrosis—A FIDELITY Subgroup Analysis

Abstract: Introduction: Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, showed cardiorenal benefits vs placebo in patients with chronic kidney disease and type 2 diabetes. Here, we analyzed patients with liver function abnormalities in FIDELITY, a prespecified pooled dataset from the FIDELIO-DKD and FIGARO-DKD trials. Methods: Patients with urine albumin-to-creatinine ratio ≥30-≤5000 mg/g and estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2 and type 2 diabetes were analyzed according to elevated transaminases, high risk of steatosis (hepatic steatosis index [HSI] >36), and risk of intermediate to advanced fibrosis (Fibrosis-4 Index [FIB-4] scores >1.30, >2.67, and >3.25). Changes in liver function and in kidney (kidney failure, sustained 57% eGFR decline, or renal death) and cardiovascular (CV; CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite outcomes were assessed. Results: Across 13,026 patients, finerenone reduced the risk of kidney and CV outcomes compared with placebo in patients with elevated transaminases (HR=0.75; 95% CI 0.50-1.13 and HR=0.81; 95% CI 0.62-1.07, respectively), at high risk of steatosis (HR=0.75; 95% CI 0.64-0.88 and HR=0.85; 95% CI 0.77-0.95, respectively), and at high risk of intermediate fibrosis (HR=0.75; 95% CI 0.60-0.93 and HR=0.76; 95% CI 0.67-0.87, respectively), with stronger reductions in the risk of the CV composite outcome at higher FIB-4 scores (HR=0.61; 95% CI 0.41-0.92; p-value for interaction=0.13 and HR=0.48; 95% CI 0.25-0.90; p-value for interaction=0.03 for FIB-4 >2.67 and >3.25, respectively). Liver transaminase levels remained consistent between treatment groups throughout the study. Conclusions: Finerenone demonstrated robust and consistent cardiorenal benefits in patients with abnormal liver function and even more profound CV benefits in patients with higher FIB-4 scores. N.Perakakis: Advisory Panel; Bayer Inc., Other Relationship; Novo Nordisk, Novo Nordisk. P.Kolkhof: Employee; BAYER AG. R.Lawatscheck: Employee; Bayer Inc. C.Scott: None. G.Bakris: Advisory Panel; Janssen Pharmaceuticals, Inc., Consultant; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Other Relationship; Bayer Inc. S.R.Bornstein: None. A.L.Birkenfeld: None. A.Linkermann: None. S.Anker: Advisory Panel; AstraZeneca, Novartis AG, Consultant; Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Vifor Pharma Management Ltd., Research Support; Abbott, Vifor Pharma Management Ltd. G.Filippatos: Other Relationship; Boehringer-Ingelheim, Bayer Inc., Amgen Inc., Medtronic, Vifor Pharma Management Ltd., Novartis, Servier Laboratories. B.Pitt: Consultant; Bayer Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Vifor Pharma Management Ltd., Lexicon Pharmaceuticals, Inc., PhaseBio Pharmaceuticals, Inc., KBP Bioscience, Merck & Co., Inc. P.Rossing: Other Relationship; Abbott Diagnostics, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Novo Nordisk, Merck KGaA, Gilead Sciences, Inc., Sanofi. L.M.Ruilope: Advisory Panel; Bayer Inc.

Time to clinical benefit of eplerenone among patients with heart failure and reduced ejection fraction: a subgroups analysis from EMPHASIS-HF trial.

Abstract: AIM Eplerenone reduces the risk of cardiovascular death or first hospitalization for heart failure (HF) in patients with HF and a reduced ejection fraction (HFrEF), but it is still frequently underused in routine practice. We evaluated the time course of benefits of eplerenone after its initiation in HFrEF patients from EMPHASIS-HF trial. METHODS AND RESULTS The EMPHASIS-HF trial was a double-blind randomized clinical trial assessing the effect of eplerenone in patients (N=2737, age 68.6±7.6 years, 22.3% women) with HFrEF and mild symptoms. The time trajectories for the effect of eplerenone vs. placebo on the primary composite end point (cardiovascular death or first hospitalization for HF) were investigated using Cox proportional hazards models with truncated data at each day post-randomization. Significant statistical reduction in the primary composite endpoint was observed 26 days after randomization (HR, 0.58; 95% CI, 0.34-1.00). Eplerenone was first associated with a significant reduction in the primary endpoint in 35 days or less in most subgroups, including patients with HF history ≥ 18 months (day 24), glomerular filtration rate < 60 ml/min (day 12), ischemic HF aetiology (day 28), age ≥ 65 (day 28), narrow QRS (day 30), higher MAGGIC score (day 35), lower potassium (day 30), left ventricular ejection fraction ≥ 30% (day 28) or already treated with betablockers (day 25). CONCLUSIONS Eplerenone provides statistically significant and clinically meaningful benefits shortly after treatment initiation in most patients, irrespective of clinical profile. This result reinforces the need for an early initiation of eplerenone in HFrEF, as part of rapidly instituting guideline directed medical therapy. This article is protected by copyright. All rights reserved.

#4486 validation of a ckd progression risk prediction model in the fidelity trial population

Abstract: Chronic kidney disease (CKD) is often underrecognised until later stages when most of the kidney function is lost and the therapeutic window for disease-modifying therapy is narrow [1]. We previously developed a lab-based risk prediction model to accurately predict CKD progression in adults at all stages of CKD [2]. Here, we describe a validation of our model in the clinical trial population of FIDELITY, a prespecified pooled analysis of the phase III FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049) trials for the nonsteroidal mineralocorticoid receptor antagonist finerenone [3]. We performed a post hoc analysis of all participants from the FIDELITY database, irrespective of estimated glomerular filtration rate (eGFR) or albuminuria stage. Baseline values for the underlying laboratory tests required for the model, Klinrisk, were extracted from the complete blood count, comprehensive metabolic panel and urine albumin-to-creatinine ratio (UACR). The predicted outcome was a ≥40% decline in eGFR or kidney failure. We calculated discrimination ability of the model and calibration using area under the curve (AUC), Brier scores and calibration plots in the overall population, and stratified by treatment assignment. Sensitivity analyses examined the accuracy of the models in predicting ≥57% decline in eGFR, as well as the change in risk score over time. Kidney Disease: Improving Global Outcomes (KDIGO) heat map categories were used as the reference standard. We included 13,026 participants with a mean age of 64.8 ± 9.5 years, mean eGFR of 57.6 ± 21.7 ml/min/1.73 m2, and median UACR of 58.2 mg/mmol (interquartile range 22.4–129.6). At time horizons of 2 and 4 years, 984 and 1795 patients experienced a primary outcome event, respectively. The Klinrisk model predicted progression accurately, with an AUC of 0.81 (95% confidence interval [CI] 0.79–0.82) at 2 years and 0.86 (95% CI 0.84–0.87) at 4 years, compared with the KDIGO heatmap categories (AUC of 0.59 [95% CI 0.58–0.60] at 2 years and 0.66 [95% CI 0.65–0.68] at 4 years). Calibration was appropriate (Brier score of 0.067 [95% CI 0.064–0.070] at 2 years and 0.115 [95% CI 0.109–0.120] at 4 years). Similar discrimination accuracy was seen for the ≥57% decline outcome (C-statistic 0.88, 95% CI 0.87–0.90) at 3 years. Based on routinely collected lab data, our machine learning model (Klinrisk) accurately predicts CKD progression events in a well characterized global clinical trial population. Prospective implementation of the model in clinical trial enrolment as well as clinical care pathways is needed.