Dapagliflozin and Apparent Treatment-Resistant Hypertension in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The DELIVER Trial.

BACKGROUND: Apparent treatment-resistant hypertension (aTRH) is prevalent and associated with adverse outcomes in heart failure with mildly reduced or preserved ejection fraction. Less is known about the potential role of sodium-glucose co-transporter 2 inhibition in this high-risk population. In this post hoc analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), we evaluated clinical profiles and treatment effects of dapagliflozin among participants with aTRH. METHODS: DELIVER participants were categorized on the basis of baseline blood pressure (BP), with aTRH defined as BP ≥140/90 mm Hg (≥130/80 mm Hg if diabetes) despite treatment with 3 antihypertensive drugs including a diuretic. Nonresistant hypertension was defined as BP above threshold but not meeting aTRH criteria. Controlled BP was defined as BP under threshold. Incidence of the primary outcome (cardiovascular death or worsening heart failure event), key secondary outcomes, and safety events was assessed by baseline BP category. RESULTS: Among 6263 DELIVER participants, 3766 (60.1%) had controlled BP, 1779 (28.4%) had nonresistant hypertension, and 718 (11.5%) had aTRH at baseline. Participants with aTRH had more cardiometabolic comorbidities and tended to have higher left ventricular ejection fraction and worse kidney function. Rates of the primary outcome were 8.7 per 100 patient-years in those with controlled BP, 8.5 per 100 patient-years in the nonresistant hypertension group, and 9.5 per 100 patient-years in the aTRH group. Relative treatment benefits of dapagliflozin versus placebo on the primary outcome were consistent across BP categories (Pinteraction=0.114). Participants with aTRH exhibited the greatest absolute reduction in the rate of primary events with dapagliflozin (4.1 per 100 patient-years) compared with nonresistant hypertension (2.7 per 100 patient-years) and controlled BP (0.8 per 100 patient-years). Irrespective of assigned treatment, participants with aTRH experienced a higher rate of reported vascular events, including myocardial infarction and stroke, over study follow-up. Dapagliflozin modestly reduced systolic BP (by ≈1 to 3 mm Hg) without increasing risk of hypotension, hypovolemia, or other serious adverse events, irrespective of BP category, but did not improve the proportion of participants with aTRH attaining goal BP over time. CONCLUSIONS: aTRH was identified in >1 in 10 patients with heart failure and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin consistently improved clinical outcomes and was well-tolerated, including among those with aTRH. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.

Risk Stratification and Treatment of Obesity for Primary and Secondary Prevention of Cardiovascular Disease.

PURPOSE OF REVIEW: In this review, we discuss contemporary and emerging approaches for risk stratification and management of excess adiposity for the primary and secondary prevention of cardiovascular disease. RECENT FINDINGS: Obesity is simultaneously a pandemic-scale disease and major risk factor for the incidence and progression of a wide range of cardiometabolic conditions, but risk stratification and treatment remain clinically challenging. However, sex-, race-, and ethnicity-sensitive anthropometric measures, body composition-focused imaging, and health burden-centric staging systems have emerged as important facilitators of holistic risk prediction. Further, expanding therapeutic approaches, including comprehensive lifestyle programs, anti-obesity pharmacotherapies, device/endoscopy-based interventions, metabolic surgery, and novel healthcare delivery resources offer new empowerment for cardiovascular risk reduction in individuals with obesity. Personalized risk stratification and weight management are central to reducing the lifetime prevalence and impact of cardiovascular disease. Further evidence informing long-term safety, efficacy, and cost-effectiveness of novel approaches targeting obesity are critically needed.

Duration of Heart Failure With Preserved Ejection Fraction and Outcomes With Sacubitril/Valsartan: Insights From the PARAGON-HF Trial.

OBJECTIVE: In this post hoc analysis of the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial, we evaluated clinical outcomes and responses to sacubitril/valsartan by duration of heart failure (HF) with left ventricular ejection fraction ≥ 45% at initial diagnosis. METHODS AND RESULTS: The primary outcome was a composite of total hospitalizations due to HF and cardiovascular deaths, analyzed by using a semiparametric proportional rates method, stratified by geographic region. Among 4784 (99.7%) randomized participants in the PARAGON-HF trial for whom baseline HF duration was captured, 1359 (28%) had durations of HF of < 6 months, 1295 (27%) of 6 months-2 years, and 2130 (45%) of > 2 years. Longer HF duration was associated with higher comorbidity burdens, worse health status and lower rates of prior hospitalization due to HF. Over a median follow-up of 35 months, longer HF duration was associated with a higher risk of first and recurrent primary events (per 100 patient-years): < 6 months, 12.0 (95% CI, 10.4-14.0); 6 months-2 years, 12.2 (10.6-14.2); > 2 years, 15.8 (14.2-17.5). Relative treatment effects of sacubitril/valsartan vs valsartan were consistent, irrespective of baseline HF duration on the primary endpoint (Pinteraction = 0.112). Clinically meaningful (≥ 5 point) improvements in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores were also similarly observed, irrespective of HF duration; (Pinteraction = 0.112). Adverse events were similar between treatment arms across HF duration categories. CONCLUSIONS: In PARAGON-HF, longer HF duration was independently predictive of adverse HF outcomes. Treatment effects of sacubitril/valsartan were consistent, irrespective of baseline HF duration, suggesting that even ambulatory patients with longstanding HFpEF and predominantly mild symptoms stand to benefit from treatment optimization.

Prevalence of Cardiovascular-Kidney-Metabolic Syndrome Stages in US Adults, 2011-2020.

This cross-sectional study assesses the prevalence and temporal evolution of cardiovascular-kidney-metabolic syndrome stages.

Chapter 2: Clinical and Mechanistic Potential of Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors in Heart Failure with Preserved Ejection Fraction.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as an important approach for the treatment of heart failure in patients with or without diabetes. Although the precise mechanisms underpinning their clinical impact remain incompletely resolved, mechanistic studies and insights from major clinical trials have demonstrated the impact of SGLT2 inhibitors on numerous cardio-renal-metabolic pathways of relevance to heart failure with preserved ejection fraction (HFpEF), which, in the contemporary era, constitutes approximately half of all patients with heart failure. Despite rates of morbidity and mortality that are commensurate with those of heart failure with reduced ejection fraction, disease-modifying therapies have comparatively been severely lacking. As such, HFpEF remains among the greatest unmet needs in cardiovascular medicine. Within the past decade, HFpEF has been established as a highly integrated disorder, involving not only the cardiovascular system, but also the lungs, kidneys, skeletal muscle, and adipose tissue. Given their multisystem impact, SGLT2i offer unique promise in addressing the complex pathophysiology of HFpEF, and in recent randomized controlled trials, were shown to significantly reduce heart failure events and cardiovascular death in patients with HFpEF. Herein, we discuss several proposed mechanisms of clinical benefit of SGLT2i in HFpEF.

Qualitative evaluation of artificial intelligence-generated weight management diet plans.

Importance: The transformative potential of artificial intelligence (AI), particularly via large language models, is increasingly being manifested in healthcare. Dietary interventions are foundational to weight management efforts, but whether AI techniques are presently capable of generating clinically applicable diet plans has not been evaluated. Objective: Our study sought to evaluate the potential of personalized AI-generated weight-loss diet plans for clinical applications by employing a survey-based assessment conducted by experts in the fields of obesity medicine and clinical nutrition. Design setting and participants: We utilized ChatGPT (4.0) to create weight-loss diet plans and selected two control diet plans from tertiary medical centers for comparison. Dietitians, physicians, and nurse practitioners specializing in obesity medicine or nutrition were invited to provide feedback on the AI-generated plans. Each plan was assessed blindly based on its effectiveness, balanced-ness, comprehensiveness, flexibility, and applicability. Personalized plans for hypothetical patients with specific health conditions were also evaluated. Main outcomes and measures: The primary outcomes measured included the indistinguishability of the AI diet plan from human-created plans, and the potential of personalized AI-generated diet plans for real-world clinical applications. Results: Of 95 participants, 67 completed the survey and were included in the final analysis. No significant differences were found among the three weight-loss diet plans in any evaluation category. Among the 14 experts who believed that they could identify the AI plan, only five did so correctly. In an evaluation involving 57 experts, the AI-generated personalized weight-loss diet plan was assessed, with scores above neutral for all evaluation variables. Several limitations, of the AI-generated plans were highlighted, including conflicting dietary considerations, lack of affordability, and insufficient specificity in recommendations, such as exact portion sizes. These limitations suggest that refining inputs could enhance the quality and applicability of AI-generated diet plans. Conclusion: Despite certain limitations, our study highlights the potential of AI-generated diet plans for clinical applications. AI-generated dietary plans were frequently indistinguishable from diet plans widely used at major tertiary medical centers. Although further refinement and prospective studies are needed, these findings illustrate the potential of AI in advancing personalized weight-centric care.

Contemporary American and European Guidelines for Heart Failure Management: JACC: Heart Failure Guideline Comparison.

This review serves to compare contemporary clinical practice recommendations for the management of heart failure (HF), as codified in the 2021 European Society of Cardiology (ESC) guideline, the 2022 American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Failure Society of America (HFSA) guideline, and the 2023 focused update of the 2021 ESC document. Overall, these guidelines aim to solidify significant advances throughout the HF continuum since the publication of previous full guideline iterations (2013 and 2016 for the ACC/AHA and ESC, respectively). All guidelines provide new recommendations for an increasingly complex landscape of HF care, with focus on primary HF prevention, HF stages, rapid initiation and optimization of evidence-based pharmacotherapies, overlapping cardiac and noncardiac comorbidities, device-based therapies, and management pathways for special groups of patients, including those with cardiac amyloidosis. Importantly, the ACC/AHA/HFSA document features special emphasis on HF risk prediction and screening, cost/value, social determinants of health, and health care disparities. The review discusses major similarities and differences between these recent guidelines and guideline updates, as well as their potential downstream implications for clinical care.

Cardiovascular-kidney-metabolic overlap in heart failure with preserved ejection fraction: Cardiac structure and function, clinical outcomes, and response to sacubitril/valsartan in PARAGON-HF.

AIMS: Cardiovascular-kidney-metabolic (CKM) multimorbidity is prevalent among individuals with heart failure (HF), but whether cardiac structure and function, clinical outcomes, and treatment response to sacubitril/valsartan vary in relation to CKM status is unknown. METHODS AND RESULTS: In this PARAGON-HF post-hoc analysis, we evaluated the impact of CKM multimorbidity (atherosclerotic cardiovascular [CV] disease, chronic kidney disease, and type 2 diabetes) on cardiac structure and function, clinical outcomes, and treatment effects of sacubitril/valsartan versus valsartan. The primary outcome was a composite of total HF hospitalizations and CV death. Secondary outcomes included the individual components of the primary outcome and a composite kidney outcome (sustained estimated glomerular filtration rate reduction of ≥50%, end-stage kidney disease, or kidney-related death). At baseline, 35.2% had one CKM condition, 33.3% had two, 15.9% had three, and only 15.6% had HF alone. CKM multimorbidity was associated with higher septal and posterior wall thickness, lower global longitudinal strain, higher E/e', and worse right ventricular function. Total HF hospitalizations or CV death increased with greater CKM multimorbidity, with the highest relative risk observed with three CKM conditions (rate ratio 3.06, 95% confidence interval 2.33-4.03), compared with HF alone. Treatment effects of sacubitril/valsartan were consistent irrespective of the number of CKM conditions for the primary endpoint (pinteraction = 0.75), CV death (pinteraction = 0.82), total HF hospitalizations (pinteraction = 0.67), and the composite kidney endpoint (pinteraction = 0.99). CONCLUSIONS: Cardiovascular-kidney-metabolic multimorbidity was common in PARAGON-HF and associated with adverse changes in cardiac structure and function and with a stepwise increase in risk of clinical outcomes. Treatment effects of sacubitril/valsartan were consistent irrespective of CKM burden. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01920711.

Kidney Outcomes Among Medicare Beneficiaries After Hospitalization for Heart Failure.

Importance: Kidney health has received increasing focus as part of comprehensive heart failure (HF) treatment efforts. However, the occurrence of clinically relevant kidney outcomes in contemporary populations with HF has not been well studied. Objective: To examine rates of incident dialysis and acute kidney injury (AKI) among Medicare beneficiaries after HF hospitalization. Design, Setting, and Participants: This retrospective cohort study evaluated adults aged 65 years or older who were hospitalized for HF across 372 sites in the Get With The Guidelines-Heart Failure registry in the US between January 1, 2014, and December 31, 2018. Patients younger than 65 years or requiring dialysis either during or prior to hospitalization were excluded. Data were analyzed from May 4, 2021, to March 8, 2024. Main Outcomes and Measures: The primary outcome was inpatient dialysis initiation in the year after HF hospitalization and was ascertained via linkage with Medicare claims data. Other all-cause and cause-specific hospitalizations were also evaluated. The covariate-adjusted association between discharge estimated glomerular filtration rate (eGFR) and 1-year postdischarge outcomes was examined using Cox proportional hazards regression models. Results: Overall, among 85 298 patients included in the analysis (mean [SD] age, 80 [9] years; 53% women) mean (SD) left ventricular ejection fraction was 47% (16%) and mean (SD) eGFR was 53 (29) mL/min per 1.73 m2; 54 010 (63%) had an eGFR less than 60 mL/min per 1.73 m2. By 1 year after HF hospitalization, 6% had progressed to dialysis, 7% had progressed to dialysis or end-stage kidney disease, and 7% had been readmitted for AKI. Incident dialysis increased steeply with lower discharge eGFR category: compared with patients with an eGFR of 60 mL/min per 1.73 m2 or more, individuals with an eGFR of 45 to less than 60 and of less than 30 mL/min per 1.73 m2 had higher rates of dialysis readmission (45 to <60: adjusted hazard ratio [AHR], 2.16 [95% CI, 1.86-2.51]; <30: AHR, 28.46 [95% CI, 25.25-32.08]). Lower discharge eGFR (per 10 mL/min per 1.73 m2 decrease) was independently associated with a higher rate of readmission for dialysis (AHR, 2.23; 95% CI, 2.14-2.32), dialysis or end-stage kidney disease (AHR, 2.34; 95% CI, 2.24-2.44), and AKI (AHR, 1.25; 95% CI, 1.23-1.27), with similar findings for all-cause mortality, all-cause readmission, and HF readmission. Baseline left ventricular ejection fraction did not modify the covariate-adjusted association between lower discharge eGFR and kidney outcomes. Conclusions and Relevance: In this study, older adults with HF had substantial risk of kidney complications, with an estimated 6% progressing to dialysis in the year after HF hospitalization. These findings emphasize the need for health care approaches prioritizing kidney health in this high-risk population.

Effect of dapagliflozin in patients with diabetes and heart failure with mildly reduced or preserved ejection fraction according to background glucose-lowering therapy: A pre-specified analysis of the DELIVER trial.

AIMS: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain. METHODS AND RESULTS: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; pinteraction = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs. CONCLUSIONS: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

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 m2, 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.

Cardiac Myosin Inhibitors for Managing Obstructive Hypertrophic Cardiomyopathy: JACC: Heart Failure State-of-the-Art Review.

Hypertrophic cardiomyopathy (HCM) is frequently caused by pathogenic variants in genes encoding sarcomere proteins and is characterized by left ventricular (LV) hypertrophy, hypercontractility, and-in many cases-left ventricular outflow tract (LVOT) obstruction. Despite standard management, obstructive HCM (oHCM) can still cause substantial morbidity, highlighting the critical need for more effective disease-specific therapeutic approaches. Over the past decade, improved understanding of the molecular pathobiology of HCM has culminated in development of cardiac myosin inhibitors (CMIs), a novel drug class that in recent randomized clinical trials has been shown to decrease LVOT obstruction, improve exercise capacity, and ameliorate symptom burden in patients with oHCM. Although promising, areas of uncertainty remain, including the long-term safety and efficacy of CMIs and whether they have the potential to modify progression of disease. Herein, we review key milestones in the clinical development of CMIs, contextualize CMIs with established oHCM therapies, and discuss future challenges and opportunities for the use of CMIs across the HCM spectrum.