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Larry A Weinrauch,1–4 Brian Claggett,1,4 Jiankang Liu,1 Peter V Finn,1 Matthew R Weir,5 Daniel E Weiner,6 John A D’Elia2–4 1Cardiovascular Division, Brigham and Women’s Hospital, 2Kidney and Hypertension Section, Joslin Diabetes Center, 3Department of Medicine, Beth Israel Deaconess Hospital, 4Harvard Medical School, Boston, MA, 5Division of Nephrology, Department of Medicine, University of Maryland, College Park, MD, 6Division of Nephrology, Tufts University School of Medicine, Boston, MA, USA Background: Tobacco use remains an international health problem with between 10% and 40% of adults currently using tobacco. Given the rising number of patients either awaiting or having received a kidney transplant and the absence of smoking cessation as the criterion for transplantation in guidelines, we explored the association between smoking status and clinical outcomes in kidney transplant recipients. Patients and methods: In this post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplant trial, the associations between smoking status, defined as never having smoked, formerly or currently smoking, and both all-cause mortality and graft survival were assessed using Cox proportional hazards models. Fatal events were centrally adjudicated into prespecified categories: all-cause, cardiovascular and non-cardiovascular causes. Graft loss was defined as return to dialysis or retransplantation. Clinical Trials URL: http://www.clinicaltrials.gov/show/NCT00064753. Results: Among 4110 transplant recipients, there were 451 current smokers and 1611 former smokers. The mortality rate per 100 patient-years was 4.0 (71 deaths) for smokers, 3.5 (226 deaths) for former smokers and 2.4 (116 deaths) for never smokers. Hazard ratio for mortality for current smokers was 1.70 (CI=1.26–2.29, p=0.001) and for former smokers was 1.21 (0.98–1.50, p=0.08) with 1.0 representing never smokers. As the number of cardiovascular deaths was similar in each group (all p>0.3), the differences between groups was driven by non-cardiovascular death rates. Current smokers (2.39; 1.62–3.61, p100% increased risk of non-cardiovascular death, 70% greater risk of all-cause mortality and a 50% greater risk of graft loss, a risk not seen in former smokers. These findings confirm previous non-adjudicated observations that smoking is associated with adverse clinical outcomes and suggest that more emphasis should be placed on smoking cessation prior to kidney transplantation. Keywords: tobacco, infection, infectious death, transplant loss, graft loss, non-cardiovascular mortality, diabetes

Larry A Weinrauch,1–4 Jiankang Liu,1 Brian Claggett,1 Peter V Finn,1 Matthew R Weir,5 John A D’Elia2–4 1Cardiovascular Division, Brigham and Women’s Hospital, 2Kidney and Hypertension Section, Joslin Diabetes Center, 3Department of Medicine, Beth Israel Deaconess Hospital, 4Harvard Medical School, Boston, MA, 5Division of Nephrology, Department of Medicine, University of Maryland, Baltimore, MD, USA Introduction: Single-center and observational studies have suggested that calcium channel blocking agents may decrease the expression of sepsis in individual populations. In the renal transplant population, a role for calcium channel blockers in allograft protection and in prevention of sepsis has been postulated. We hypothesized that any important survival benefit or risk related to chronic use of calcium channel blocking agents should be discernable through an analysis of a large database of stable recipients of renal allografts who had enrolled in a large international trial.Methods: A retrospective analysis of 4,110 renal transplant recipients who enrolled in the international Folic Acid for Vascular Outcome Reduction in Transplantation trial between 2002 and 2007 and were followed until 2010 was undertaken comparing cohorts (FAVORIT) of patients either taking (n=1,436) or not taking (n=2,674) calcium channel blocking medications. The endpoint was all-cause mortality (cardiovascular, noncardiovascular mortality, or unknown). Results were adjusted for country, age, race, sex, smoker, systolic blood pressure, diabetes mellitus, low-density lipoprotein, and chronic kidney disease status.Results: There were no statistically significant differences in incidence rates of cardiovascular, noncardiovascular, and all-cause mortality between patients taking or not taking calcium channel blocking medications.Conclusion: Although physiologic reasoning and small series results suggest a benefit for calcium channel blocking agents for allograft protection and sepsis prevention in immunosuppressed patients, we find no clear survival benefit in a large international renal transplant trial. Keywords: sepsis, immunosuppression, allograft survival, kidney transplant, calcium channel blockade, mortality

Larry A Weinrauch,1–4 John A D’Elia,2–4 Matthew R Weir,5 Suphamai Bunnapradist,6 Peter Finn,1 Jiankang Liu,1 Brian Claggett,1 Anthony P Monaco3,4 1Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, 2Kidney and Hypertension Section,Joslin Diabetes Center, Boston, MA, 3Medicine and Surgery, Beth Israel Deaconess Medical Center, Boston MA, 4Harvard Medical School, Boston MA, 5University of Maryland School of Medicine, Baltimore, MD, 6Division of Nephrology, Department of Medicine University of California at Los Angeles, Los Angeles, CA, USA Abstract: Although survival has improved for kidney transplant recipients over the past ­several decades, long-term survival in diabetic cohorts still is significantly less than that of non-diabetic cohorts. We hypothesized that among stable kidney transplant recipients, there might be differences between subgroups with and without diabetes with respect to prevalence of prior cardiovascular events and post-transplant antihypertensive and immunosuppressive therapy. We performed a post hoc analysis of participants in the Folic Acid for Vascular Outcome Reduction in Transplant (FAVORIT) trial, a multicenter international trial of 4110 prevalent kidney transplant recipients enrolled from 2002 to 2007 evaluating the effect of homocysteine-lowering vitamin therapy on cardiovascular outcomes. There were 2447 participants without diabetes, 166 with type 1 diabetes, and 1447 with type 2 diabetes at study entry, which occurred on average 4 years post-transplant. Recipients with diabetes had a greater prevalence of prior cardiovascular events, were more likely to have required multiple medications to control hypertension, and were more likely to have received tacrolimus as opposed to cyclosporine than the non-diabetic transplant recipients (all p

BACKGROUND In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. METHODS We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. RESULTS A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. CONCLUSIONS Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicaITrials.gov number, NCT02924727.). [ABSTRACT FROM AUTHOR]

BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitaliza-tion for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. METHODS We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovas. cular death, as assessed in a time-to-event analysis. RESULTS Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. CONCLUSIONS Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.) [ABSTRACT FROM AUTHOR]

BACKGROUND One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.) [ABSTRACT FROM AUTHOR]

BACKGROUND The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [Cl], 0.75 to 1.01; P=0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% Cl, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% Cl, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% Cl, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% Cl, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% Cl, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. [ABSTRACT FROM AUTHOR]

Objectives: Whether vaginal estradiol use is associated with an increased risk of recurrent venous thromboembolism (VTE) in women with prior VTE is unknown. We sought to evaluate the association between vaginal estradiol use and recurrent VTE in women with prior VTE., Methods: We performed a nationwide nested case-control study among 44 024 women aged ≥45 years who developed a first VTE without a history of vaginal estrogen use prior to VTE diagnosis. Cases with recurrent VTE were matched 1:2 on birth year with controls using incidence density sampling. Exposure to vaginal estradiol tablets was categorized into current use (0-2 months before index), prior use (2-24 months before index) and past use (more than 24 months prior to index)., Results: We identified 5066 cases and 10 127 age-matched controls. In fully adjusted analysis vaginal estrogen was not associated with recurrent VTE with a hazard ratio of 0.75, p = .07 for current use, 0.83, p = .13 for prior use, and 1.24, p = .06 for past use., Conclusion: Use of vaginal estradiol tablets in women with prior VTE was not associated with an increased rate of recurrent VTE. Our study indicates that vaginal estradiol therapy is unlikely to increase risk of recurrent VTE in women with prior VTE., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM)., Methods and Results: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation., Conclusions: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Background: The health-related quality of life (HRQOL) and cardiopulmonary exercise testing (CPET) performance of individuals with subclinical and early stage hypertrophic cardiomyopathy (HCM) have not been systematically studied. Improved understanding will inform the natural history of HCM and factors influencing well-being., Methods: VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM) participants with early stage sarcomeric HCM (primary analysis cohort) and subclinical HCM (sarcomere variant without left ventricular hypertrophy comprising the exploratory cohort) who completed baseline and year 2 HRQOL assessment via the pediatric quality of life inventory and CPET were studied. Metrics correlating with baseline HRQOL and CPET performance were identified. The impact of valsartan treatment on these measures was analyzed in the early stage cohort., Results: Two hundred participants were included: 166 with early stage HCM (mean age, 23±10 years; 40% female; 97% White; and 92% New York Heart Association class I) and 34 subclinical sarcomere variant carriers (mean age, 16±5 years; 50% female; and 100% White). Baseline HRQOL was good in both cohorts, although slightly better in subclinical HCM (composite pediatric quality of life score 84.6±10.6 versus 90.2±9.8; P =0.005). Both cohorts demonstrated mildly reduced functional status (mean percent predicted peak oxygen uptake 73±16 versus 78±12 mL/kg per minute; P =0.18). Percent predicted peak oxygen uptake and peak oxygen pulse correlated with HRQOL. Valsartan improved physical HRQOL in early stage HCM (adjusted mean change in pediatric quality of life score +4.1 versus placebo; P =0.01) but did not significantly impact CPET performance., Conclusions: Functional capacity can be impaired in young, healthy people with early stage HCM, despite New York Heart Association class I status and good HRQOL. Peak oxygen uptake was similarly decreased in subclinical HCM despite normal left ventricular wall thickness and excellent HRQOL. Valsartan improved physical pediatric quality of life scores but did not significantly impact CPET performance. Further studies are needed for validation and to understand how to improve patient experience., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534., Competing Interests: Dr Day is involved in consulting for Lexicon Pharmaceuticals; is on the Data Monitoring Committee of Cytokinetics; and receives funding from Lexicon Pharmaceuticals and Bristol Myers Squibb. Dr Canter is a consultant for Bristol Myers Squibb and receives research support from Tenaya, Merck, and Novartis (none relevant). Dr Bach receives research support (institutional only) from MyoKardia, Bristol Myers Squibb, and Cytokinetics, outside of the submitted work. Dr Wheeler receives research support and in-kind support from MyoKardia Inc, a wholly owned subsidiary of Bristol Myers Squibb, and research support from Cytokinetics Inc and Novartis Inc, all outside of the submitted work. Dr Rossano is a consultant for AskBio, American Regent, Bayer, BioMarin, Bristol Myers Squibb, Enzyvant, and Merck. Dr Owens has been consulting for Bristol Myers Squibb, Cytokinetics, Pfizer, Tenaya, BioMarin, Lexicon, Lexeo, Edgewise, and Stealth Therapeutics and receives research support from Bristol Myers Squibb. Dr Mestroni receives research funding from Bristol Myers Squibb, Tenaya Therapeutics, Pfizer, BioMarin, Greenstone Bioscience, and Spark Therapeutics. Dr Taylor receives research funding from Bristol Myers Squibb, Tenaya Therapeutics, Rocket Pharmaceuticals, BioMarin, and Spark Therapeutics. Dr Patel receives a research grant from GE Healthcare. Dr Soslow is involved in unrelated consulting for Sarepta, Pfizer, Immunoforge, and WCG Imaging. Dr Claggett is involved in statistical consulting for Alnylam, Cardurion, Corvia, CVRx, Cytokinetics, Intellia, and Rocket. Dr Ho is a consultant for and receives research funding from Bristol Myers Squib, Pfizer, Cytokinetics, Tenaya, BioMarin, viz.AI, and Lexicon (none relevant). The other authors report no conflicts.

Clinical trials are vital for assessing therapeutic interventions. The associated data monitoring committees (DMCs) safeguard patient interests and enhance trial integrity, thus promoting timely, reliable evaluations of those interventions. We face an urgent need to recruit and train new DMC members. The HFC (Heart Failure Collaboratory), a multidisciplinary public-private consortium of academics, trialists, patients, industry representatives, and government agencies, is working to improve the clinical trial ecosystem. The HFC aims to improve clinical trial efficiency and quality by standardizing concepts, and to help meet the demand for experienced individuals on DMCs by creating a standardized approach to training new members. This paper discusses the HFC's training workshop, and an apprenticeship model for new DMC members. It describes opportunities and challenges DMCs face, along with common myths and best practices learned through previous experiences, with an emphasis on data confidentiality and need for quality independent statistical reporting groups., Competing Interests: Funding Support and Author Disclosures Dr Fleming has received consulting fees from the National Institutes of Health, the World Health Organization, the Food and Drug Administration, and the pharmaceutical and biotech industry in the design, monitoring, and analysis of clinical trials; and he has received fees for serving on several industry-sponsored Data Monitoring Committees (DMCs). Dr Wittes has received compensation for her membership on several DMCs sponsored by industry, government, and not-for-profit organizations; and has received consulting fees from a variety of pharmaceutical and medical device companies. Dr Bristow is the President/CEO/Director at ARCA biopharma. Dr Rockhold has received consulting fees from Intercept, Clover, and Inventprise; has received compensation for serving on several industry-sponsored DMCs; and holds stock in Clover, GSK, Athira, Spence, Adaptic, and Doctor Evidence. Dr Claggett has received consulting fees from Alnylam, Axon, Cardior, Cardurion, CVRx, Cytokinetics, Intellia, and Rocket. Dr Abraham has received consulting fees from Boehringer Ingelheim, Cardionomic, Zoll Respicardia, scPharmaceuticals, Sensible Medical, and Vectorious; has received salary support from V-Wave Medical; and has served as a speaker for Edwards Lifesciences. Dr Lindenfeld has received consulting fees from Abbott, ADI, Alleviant, Amgen, AstraZeneca, Axon, Boston Scientific, Cordio, CVRx, Cytokinetics, Edwards Lifesciences, Medtronic, Merck, VWave, Vascular Dynamics, Vectorious, and Whiteswell; and has received grants from Analog Devices Inc, AstraZeneca, and Volumetrix. Dr DeMets has received consulting fees from the National Institutes of Health, the U.S. Food and Drug Administration, and the pharmaceutical and medical device industry on the design, monitoring, and analysis of clinical trials; and he has received compensation for serving on several recent industry-sponsored data and safety monitoring committees or steering committees including AstraZeneca, Bristol Meyers Squib, GSK, Merck, Boston Scientific, Medtronic, USONA, LivaNova, AnthosTherapy, ARCA biopharma, Duke Clinical Research Institute, and the Population Health Research Institute of Hamilton Ontario. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction)., Methods: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events., Results: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P =0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype., Conclusions: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711., Competing Interests: Dr Jhund reports receiving grant support from Boehringer Ingelheim and fees for serving on an advisory board from Cytokinetics. Dr Anand reports receiving fees for serving on a steering committee from AstraZeneca, ARCA biopharma, Amgen, and LivaNova; fees for serving as chair of a data and safety monitoring board from Boston Scientific; fees for serving on an end-point committee from Boehringer Ingelheim; and fees for serving on an advisory board from Zensun. Dr Claggett received consulting fees from AOBiome, Biogen, Boehringer Ingelheim, Corvia Medical, Gilead Sciences, and MyoKardia. Dr Desai received consulting fees from Abbott, Boehringer Ingelheim, DalCor Pharmaceuticals, and Regeneron; grant support, paid to Brigham and Women’s Hospital, consulting fees, and fees for serving on an advisory board from Alnylam Pharmaceuticals and AstraZeneca; consulting fees and fees for serving on a steering committee from Biofourmis; consulting fees and fees for serving on a data and safety monitoring committee from Boston Scientific; fees for serving on an advisory board from Corvidia; and fees for serving on an advisory board and consulting fees from Relypsa. Drs Chiang, Gong, and Lefkowitz are employed by Novartis Pharmaceuticals. Dr Lam received grant support and fees for serving on an advisory board from Boston Scientific and Roche Diagnostics; grant support, fees for serving on an advisory board, and fees for serving on steering committees from Bayer; grant support from Medtronics; grant support and fees for serving on a steering committee from Vifor Pharma; fees for serving on an advisory board and fees for serving on steering committees from AstraZeneca and Novartis; fees for serving on an advisory board from Amgen, Boehringer Ingelheim, and Abbott Diagnostics; consulting fees from Merck and Stealth BioTherapeutics; fees for serving on a steering committee from Janssen Research and Development; lecture fees and consulting fees from Menarini; and fees for serving on a scientific committee from Corvia Medical and holding a pending patent (PCT/SG2016/050217) on a method regarding diagnosis and prognosis of chronic heart failure. Dr Maggioni received fees for serving on a study committee from Bayer and Fresenius. Dr Packer received consulting fees from AbbVie, Akcea Therapeutics, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead Sciences, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance Biopharma. Dr Rouleau received consulting fees from AstraZeneca. Dr van Veldhuisen received fees for serving on a steering committee and travel support from ARCA Biopharma and Corvia Medical. Dr Zannad received fees for serving on a steering committee from Janssen, Bayer, Boston Scientific, CVRx, and Boehringer Ingelheim; consulting fees from Amgen, Vifor Pharma–Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, and Merck; and consulting fees and fees for serving on a steering committee from AstraZeneca and serving as founder of cardiorenal and CVCT. Dr Zile received fees for serving on a steering committee from Abbott and Ironwood Pharma; consulting fees from Boston Scientific and MyoKardia; grant support and fees for serving on a steering committee from CVRx and Medtronic; fees for serving on an eligibility committee from EBR Systems and V-Wave; fees for serving on a clinical-events committee from Endotronics; and fees for serving on a data and safety monitoring board from Merck. Dr Solomon received grant support, paid to Brigham and Women’s Hospital, and consulting fees from Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, MyoKardia, Novartis, Theracos, Bayer, and Cytokinetics; grant support, paid to Brigham and Women’s Hospital, from Bellerophon Therapeutics, Celladon, Ionis Pharmaceuticals, Lonestar Heart, Mesoblast, Sanofi Pasteur, and Eidos Therapeutics; consulting fees from Akros Pharma, Corvia Medical, Ironwood Pharma, Merck, Roche, Takeda Pharmaceutical, Quantum Genomics, AOBiome, Cardiac Dimensions, Tenaya Therapeutics, and Daiichi Sankyo; and fees for serving on a data and safety monitoring board from Janssen. Dr McMurray reports that his employer, Glasgow University, has been paid by Novartis for serving as an executive committee member and coprincipal investigator of ATMOSPHERE, PARADIGM-HF, and PARAGON-HF trials and executive/steering committee member of the PARADISE-MI and PERSPECTIVE trials (with sacubitril/valsartan) and for meetings/presentations related to these trials, aliskiren, and sacubitril-valsartan. Novartis has also paid for his travel and accommodation for some of these meetings. Glasgow University has also been paid by Novartis for advisory board; by Bayer for serving as a steering committee member of the PANACHE trial using neladenoson bialanate (BAY 1067197); by Cardiorentis for serving as a steering committee member and end-point committee chair for the TRUE-AHF trial and attending meetings related to this trial; by Cardiorentis for travel and accommodation to attend some of these meetings; by Amgen for serving as steering committee member for the ATOMIC-HF and COSMIC-HF trials and attending meetings related to this trial; by Amgen for travel and accommodation for some of these meetings; by Oxford University (which received a grant from Bayer, which manufactures acarbose) for serving as a steering committee member for the ACE trial (using acarbose) and attending meetings related to this trial; by Theracos for serving as principal investigator for the BEST trial and attending meetings related to this trial; by Theracos for travel and accommodation to attend some of these meetings; by Abbvie (which manufactures atrasentan) for serving as steering committee member for the SONAR trial (using atrasentan) and to attend meetings related to this trial; by Abbvie for his travel and accommodation to attend some of these meetings; by DalCor Pharmaceuticals for serving as steering committee member for the Dal-GenE trial and to attend meetings related to this trial; by Pfizer for serving on the data safety monitoring committee for the SPIRE trial and to attend meetings related to this trial; by Merck for serving on the data safety monitoring committee for the MK-3102 program, for the VICTORIA trial, and to attend meetings related to these trials; by AstraZeneca (which markets dapagliflozin) for serving as principal investigator of DAPA-HF and coprincipal investigator of DELIVER (trials using dapagliflozin on heart failure) and to attend meetings related trial; by AstraZeneca for his travel and accommodation to attend meetings; by GSK for serving as coprincipal investigator and steering committee member for the Harmony-Outcomes trial (albiglutide) and the trials ASCEND-D and ASCEND-ND, using daprodustat, respectively, and to attend meetings related to these trials; by GSK for his travel and accommodation to attend some of the meetings; by BMS for serving as a steering committee member for the STAND-UP clinical trial (using an HNO donor) on heart failure and to attend meetings related to this trial; and by Kings College Hospital (which has received a grant from KRUK and Vifor-Fresenius, which manufactures intravenous iron) for serving as steering committee member for the PIVOTAL trial (using intravenous iron) and for running the end-point adjudication committee for this trial, to attend meetings related to PIVOTAL, and for his travel and accommodation for to attend some of the meetings. All payments were made through consultancies with Glasgow University, and Dr McMurray has not received any personal payments in relation to the trials or drugs. The other authors report no conflicts. The study supporters had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Objectives: To summarize current evidence of high-dose influenza vaccine (HD-IV) vs standard-dose (SD-IV) regarding severe clinical outcomes., Methods: A prespecified meta-analysis was conducted to assess relative vaccine effectiveness (rVE) of HD-IV vs SD-IV in reducing the rates of (1) pneumonia and influenza (P&I) hospitalization, (2) all hospitalizations, and (3) all-cause death in adults ≥ 65 years in randomized controlled trials. Pooled effect sizes were estimated using fixed-effects models with the inverse variance method., Results: Five randomized trials were included encompassing 105,685 individuals. HD-IV vs SD-IV reduced P&I hospitalizations (rVE: 23.5 %, [95 %CI: 12.3 to 33.2]). HD-IV vs SD-IV also reduced rate of all-cause hospitalizations (rVE: 7.3 %, [95 %CI: 4.5 to 10.0]). No significant differences were observed in death rates (rVE = 1.6 % ([95 %CI: -2.0 to 5.0]) in HD-IV vs SD-IV. Sensitivity analyses omitting trials with participants sharing the same comorbidity, trials with ≥ 100 events, and random-effects models provided comparable estimates for all outcomes., Conclusions: HD-IV reduced the incidence of P&I and all-cause hospitalization vs SD-IV in adults ≥ 65 years in randomized trials, through no significant difference was observed in all-cause death rates. These findings, supported by evidence from several randomized studies, can benefit from replication in a fully powered, individually randomized trial., Competing Interests: Declaration of Competing Interest KGS has served on advisory boards for Sanofi. MML, RH, and MD are full-time employees of Sanofi and may hold stocks and/or shares in the company. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi, Theracos, US2. AI and consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. TBS is chief investigator of the Boston Scientific financed ”DANLOGIC-HF” trial, the Sanofi financed “NUDGE-FLU” trial, the Sanofi financed “DANFLU-1″ trial, the Sanofi financed “DANFLU-2″ trial and steering committee member of the Boston Scientific sponsored “LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System” trial, the Amgen sponsored GALACTIC-HF trial, the Boehringer Ingelheim financed EASi-KIDNEY trial and served on advisory boards for Sanofi, Amgen, CSL Seqirus and GSK and received speaker honorariums from Bayer, Novartis, Sanofi, GE Healthcare and GSK and received research grants from Boston Scientific, GE Healthcare, AstraZeneca, Novo Nordisk, and Sanofi and consulted for Novo Nordisk, IQVIA and Parexel. The remaining authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Whether, and how, cardioprotective effects of antiretroviral treatment (ART) in adolescents with perinatal HIV infection (APHIV) vary with age at treatment initiation is unknown. We used magnetic resonance imaging to compare cardiac status between APHIV initiated on ART at < 5 years of age (early ART, n = 37) and ≥ 5 years of age (delayed ART, n = 34) versus HIV-uninfected peers (n = 21), reporting z-score mean differences adjusted for confounders. Relative to HIV-uninfected adolescents, APHIV with early ART had higher left ventricular (LV) global circumferential strain (GCS) [adjusted mean (95%CI) z-score: 0.53 (0.13, 0.92)] and maximum indexed left atrium volume (LAVi) [adjusted z-score: 0.55 (0.08, 1.02)]. In contrast, APHIV with delayed ART had greater indexed LV end-diastolic volume (LVEDVi) [adjusted z-score: 0.47 (0.09, 0.86)] and extracellular volume fraction [adjusted z-score: 0.79 (0.20, 1.37)], but lower GCS [adjusted z-score: -0.51 (-0.91, -0.10)] than HIV-uninfected peers. APHIV had distinct albeit subclinical cardiac phenotypes depending on ART initiation age. Changes in early ART suggested comparatively worse diastology with preserved systolic function while delayed ART was associated with comparatively increased diffuse fibrosis and LV dilatation with reduced systolic function. The long-term clinical significance of these changes remains to be determined., (© 2024. The Author(s).)

Importance: Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments., Objectives: To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population., Design, Setting, and Participants: A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024., Exposure: V142I carrier status (n = 754, 3.2%)., Main Outcomes and Measures: Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data., Results: Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant., Conclusions and Relevance: Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

Aims: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF., Methods and Results: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m 2 , elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials., Conclusions: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329)., Methods: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil., Results: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2)., Conclusions: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI., Competing Interests: DISCLOSURES GMF has received research grants from NHLBI, American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, Astra-Zeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. SDS reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study; grants (via Brigham and Women's Hospital) from Actelion, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bellerophon Therapeutics, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos Therapeutics, Eli Lilly, Gilead Sciences,GlaxoSmithKline, Ionis Pharmaceuticals, Mesoblast,Myocardium, the National Heart, Lung, and Blood Institute, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos; and consulting fees from Abbott Laboratories, Action Pharma, Akros Pharma, Alnylam Pharmaceuticals, American Regent, Amgen, Arena Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior Pharmaceuticals, Cardurion Pharmaceuticals, CellProthera, Corvia Medical, Cytokinetics, Daiichi Sankyo, Dinaqor, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Merck & Co, Moderna, Myokardia, Novartis, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta Therapeutics, Tenaya Therapeutics, Theracos, and Tremeau Pharmaceuticals. MM reports receiving personal fees from Amgen and Servier Laboratories during the conduct of the study and personal fees from Abbott Laboratories, Actelion, AstraZeneca, Edwards Lifesciences, LivaNova, Vifor Pharma, and Windtree Therapeutics. JJVM reports receiving travel fees and nonfinancial support (via the University of Glasgow) from Amgen during the conduct of the study; travel fees and nonfinancial support (via the University of Glasgow) from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Cyclerion Therapeutics, Cytokinetics, DalCor Pharmaceuticals, GlaxoSmithKline, Novartis, Pfizer, Servier Laboratories, and Theracos; and personal fees from Abbott Laboratories, Hikma Pharmaceuticals, Servier Laboratories, and Sun Pharmaceutical Industries. RD reports receiving grants from Amgen during the conduct of the study. BC reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study and consulting fees from Amgen, Boehringer Ingelheim, Corvia Medical, Myokardia, and Novartis. DEL is supported in part by grants from the National Institutes of Health (P50MD017351, R01HL132154), has received research funding or support from Amgen, Astra Zeneca, Janssen, Eli Lilly, and Somalogic, and has acted as consultant to ACI Clinical (Abbott Laboratories), AstraZeneca, Cytokinetics, Duke Clinical Research Institute (CONNECT-HF), Illumina, Janssen, Martin Pharmaceuticals, Ortho Clinical Diagnostics, and Otsuka. HV reports being a national leader of GALACTIC-HF and has received lecture fees and consultation fees from Amgen. RDL reports research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis and funding for educational activities or lectures from Pfizer and Daiichi Sankyo and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novo Nordisk. S-IM reports being a national leader of GALACTIC-HF and has received lecture and consultation fees from Amgen. TB-S reports being a steering committee member of the Amgen-financed GALACTIC-HF trial, chief investigator and steering committee chair of the Sanofi Pasteur-financed NUDGE-FLU trial; chief investigator and steering committee chair of the Sanofi Pasteur-financed DANFLU-1 trial; steering committee member of LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System trial; is on the advisory boards of Sanofi Pasteur, Amgen and GSK; receives speaker honoraria from Bayer, Novartis, Sanofi Pasteur, and GSK and research grants from GE Healthcare and Sanofi Pasteur. SBH, PHD, SK, and FIM are employees of Cytokinetics. JRT reports receiving grants from Amgen and Cytokinetics, personal fees from Amgen, Cytokinetics and Servier Laboratories, and nonfinancial support from Amgen and Cytokinetics during the conduct of the study; grants from Abbott Laboratories, Bayer, Boerhinger Ingelheim, Bristol Myers Squibb, EBR Systems, LivaNova, Medtronic, Novartis, and Windtree Therapeutics; and personal fees from Amgen, AstraZeneca, Cytokinetics, Merck & Co, and Servier Laboratories. All other authors report no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions., Objective: To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach., Design, Setting, and Participants: Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023., Exposures: Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death., Results: Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk., Conclusions and Relevance: In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

Aims: Left ventricular (LV) subclinical impairment has been described in heart failure with preserved ejection fraction (HFpEF). We assessed the relationship between LV myocardial deformation by strain imaging and recurrent hospitalization for heart failure (HF) or cardiovascular death in a large international HFpEF population., Methods and Results: We assessed two-dimensional speckle-tracking based global longitudinal strain (GLS) in 790 patients (mean age 74 ± 8 years, 54% female) with adequate image quality enrolled in the PARAGON-HF echocardiography study. We examined the relationship of GLS with total HF hospitalizations and cardiovascular death (the primary composite outcome) after accounting for clinical confounders. Approximately 47% of the population had evidence of LV subclinical dysfunction, defined as absolute GLS <16%. Impaired GLS was significantly associated with higher values of circulating baseline N-terminal pro-B-type-natriuretic peptide. After a median follow-up of 3.0 years, there were 407 total HF hospitalizations and cardiovascular deaths. After multivariable adjustment, worse GLS was associated with a greater risk for the primary composite outcome (adjusted hazard ratio per 1% decrease: 1.06; 95% confidence interval 1.02-1.11; p = 0.008). GLS did not modify the treatment effect of sacubitril/valsartan compared with valsartan for the composite outcome (p for interaction >0.1)., Conclusions: In a large HFpEF population, impaired LV function was observed even among patients with preserved ejection fraction, and was associated with an increased risk of total HF hospitalizations or cardiovascular death, accounting for clinical confounders. These findings highlight the key role of subtle LV systolic impairment in the pathophysiology of HFpEF., (© 2024 European Society of Cardiology.)