Total Heart Failure Hospitalizations Research Articles

Real-World Experience of Angiotensin Receptor–Neprilysin Inhibition in Reduced Ejection Fraction Heart Failure Patients With Advanced Kidney Disease

ObjectiveTo investigate the effectiveness and safety of angiotensin receptor-neprilysin inhibitors (ARNIs) in real-world patients with heart failure with reduced ejection fraction (HFrEF) and advanced chronic kidney disease (estimated glomerular filtration rate [eGFR] < 30 mL/min per 1.73 m2), which have been excluded from the landmark trials. Patients and MethodsThis study examined 3281 patients pooled from two multicenter HFrEF cohorts, and 661 patients with baseline eGFR less than 30 mL/min per 1.73 m2 were further analyzed (the Taiwan Society of Cardiology – Heart Failure with reduced Ejection Fraction (TSOC-HFrEF) registry: May 1, 2013 to October 31, 2014, and the Treatment with Angiotensin Receptor neprilysin inhibitor fOr Taiwan Heart Failure patients (TAROT-HF) study: March 1, 2017, to December 31, 2018). Propensity score matching was performed to adjust for confounders. At 1-year follow-up, all-cause mortality, total heart failure hospitalizations, renal function, and left ventricular ejection fraction (LVEF) were used as the endpoints. ResultsAfter propensity score matching, 510 patients (age, 69.8±13.9 years; male, 61.0%; mean LVEF, 29.8±7.3%; mean eGFR, 19.8±9.0 mL/min per 1.73 m2) were included in the final analysis, including 278 patients receiving ARNI treatment (ARNI group) and 232 patients not on ARNI treatment (non-ARNI group). Baseline characteristics were comparable between the two groups. At 1 year, eGFR and LVEF measurements were significantly higher in the ARNI group than in the non-ARNI group (25.0±17.1 mL/min per 1.73 m2 vs 21.4±17.5 mL/min per 1.73 m2; P=.04; and 40.1±12.9% vs. 33.1±10.8%, P<.001, respectively). The ARNI group had significantly lower risks of 1-year all-cause mortality (19.4 vs 30.9 per 100-person year; P=.02), and total HF rehospitalizations (70.0 vs 110.4 per 100-person year; P=.01) than non-ARNI users. ConclusionOur results show the effectiveness of ARNIs in HFrEF patients with advanced chronic kidney disease in a real-world setting.

Effects of Empagliflozin in Women and Men With Heart Failure and Preserved Ejection Fraction.

Background:Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction).Methods:The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%–49%, 50%–59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed.Results:Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; Pinteraction=0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; Pinteraction=0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score.Conclusions:Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.

Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction

BackgroundFrailty is an increasingly common problem, and frail patients are less likely to receive new pharmacologic therapies because the risk–benefit profile is perceived to be less favorable than in nonfrail patients. ObjectivesThis study investigated the efficacy of sacubitril/valsartan according to frailty status in 4,796 patients with heart failure with preserved ejection fraction randomized in the PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. MethodsFrailty was measured by using the Rockwood cumulative deficit approach. The primary endpoint was total heart failure hospitalizations or cardiovascular death. ResultsA frailty index (FI) was calculable in 4,795 patients. In total, 45.2% had class 1 frailty (FI ≤0.210, not frail), 43.5% had class 2 frailty (FI 0.211-0.310, more frail), and 11.4% had class 3 frailty (FI ≥0.311, most frail). There was a graded relationship between FI class and the primary endpoint, with a significantly higher risk associated with greater frailty (class 1: reference; class 2 rate ratio: 2.19 [95% CI: 1.85-2.60]; class 3 rate ratio: 3.29 [95% CI: 2.65-4.09]). The effect of sacubitril/valsartan vs valsartan on the primary endpoint from lowest to highest FI class (as a rate ratio) was: 0.98 [95% CI: 0.76-1.27], 0.92 [95% CI: 0.76-1.12], and 0.69 [95% CI: 0.51-0.95]), respectively (Pinteraction = 0.23). When FI was examined as a continuous variable, the interaction with treatment was significant for the primary outcome (Pinteraction = 0.002) and total heart failure hospitalizations (Pinteraction < 0.001), with those most frail deriving greater benefit. ConclusionsFrailty was common in heart failure with preserved ejection fraction and associated with worse outcomes. Compared with valsartan, sacubitril/valsartan seemed to show a greater reduction in the primary endpoint with increasing frailty, although this was not significant when FI was examined as a categorical variable. (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Relaxin-2, pathophysiological insights and outcomes in heart failure with preserved ejection fraction: Findings from the NETDiamond cohort

AimsThe role of relaxin-2 as a circulating marker in heart failure (HF) with preserved ejection fraction (HFpEF) is poorly understood. We aimed to characterize relaxin-2 circulating levels in a population of chronic HFpEF patients and their association with long-term prognosis. MethodsRelaxin-2 serum levels were measured in 85 chronic HFpEF patients from a prospective cohort study (NETDiamond). Clinical, imaging, and analytical data were compared across relaxin-2 tertiles. The primary outcome was a composite of cardiovascular death, HF hospitalisation, acute HF episode or diuretic intensification and the secondary outcome a composite of cardiovascular death and total HF hospitalisations. Cox regression and negative binomial models were used to assess the relation between relaxin-2 and the outcomes. ResultsRelaxin-2 levels were positively associated with left atrial volume, left ventricular mass and peripheral oedema, and negatively associated with ischemic heart disease and statin use. Higher relaxin-2 levels were associated with an increased risk of primary outcome, even after adjustment for age, B-type natriuretic peptide (BNP) and glomerular filtration rate (eGFR) (adjusted HR = 2.80, 95%CI 1.4–7.3, p = 0.034 for tertile 3). They were also associated with the occurrence of the secondary outcome (Incidence Rate Ratio = 5.28, 95%CI 1.2–23.2, p = 0.027), but this significance was lost when simultaneously adjusted for BNP and eGFR. ConclusionIn chronic HFpEF patients, higher relaxin-2 circulating levels were associated with left chambers remodelling, congestion, and adverse prognosis. These findings support a potential role for relaxin-2 as a pathophysiological agent and as a circulating biomarker in HFpEF.

The non-steroidal mineralocorticoid receptor antagonist finerenone is a novel therapeutic option for patients with Type 2 diabetes and chronic kidney disease.

Despite strong preclinical data supporting the use of mineralocorticoid receptor antagonists (MRAs) to provide cardiorenal protection in rodent models of diabetes, the clinical evidence of their utility in treating chronic kidney disease (CKD) has been limited. Two major clinical trials (FIDELIO-DKD and FIGARO-DKD) including more than 13,000 patients with albuminuric CKD and Type 2 diabetes randomized to placebo or finerenone (MRA) have recently provided exciting results showing a significant risk reduction for kidney and cardiovascular outcomes. In this review, we will summarize the major findings of these trials, together with post-hoc and pooled analyses that have allowed evaluation of the efficacy and safety of finerenone across the spectrum of CKD, revealing significant protective effects of finerenone against kidney failure, new-onset atrial fibrillation or flutter, new-onset heart failure, cardiovascular death, and first and total heart-failure hospitalizations. Moreover, we will discuss the current evidence that supports the combined use of MRAs with sodium-glucose co-transporter-2 inhibitors, either by providing an additive cardiorenal benefit or by decreasing the risk of hyperkalemia. Although the mechanisms of protection by finerenone have only been partially explored in patients, rodent studies have shed light on its anti-inflammatory and anti-fibrotic effects in models of kidney disease, which is one of the main drivers for testing the efficacy of finerenone in non-diabetic CKD patients in the ongoing FIND-CKD trial.

Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes.

Background:Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated.Methods:Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes.Results:Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; Pinteraction=0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m2 in patients without diabetes; Pinteraction=0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome (Pinteraction=0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo.Conclusions:In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.

Empagliflozin Improves Outcomes in Patients With Heart Failure and Preserved Ejection Fraction Irrespective of Age

BackgroundEmpagliflozin reduces cardiovascular death (CVD) or heart failure (HF) hospitalization (HFH) in patients with HF and preserved ejection fraction. Treatment effects and safety in relation to age have not been studied. ObjectivesThe purpose of this study was to evaluate the interplay of age and empagliflozin effects in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). MethodsWe grouped patients (n = 5,988) according to their baseline age (<65 years [n = 1,199], 65-74 years [n = 2,214], 75-79 years [n = 1,276], ≥80 years [n = 1,299]). We explored the influence of age on empagliflozin effects on CVD or HFH (primary outcome), total HFH, rate of decline in estimated glomerular filtration rate, health-related quality of life with the Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score, and frequency of adverse events. ResultsConsidering only patients on placebo, the incidence of primary outcomes (P trend = 0.02) and CVD (P trend = 0.003) increased with age. Empagliflozin reduced primary outcomes (P trend = 0.33), first HFH (P trend = 0.22), and first and recurrent HFH (P trend = 0.11) across all age groups with an effect being similar at ≥75 years (P interaction = 0.22) or >80 years (P interaction = 0.51). Empagliflozin improved Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score at week 52 and attenuated the decline of estimated glomerular filtration rate without age interaction (P = 0.48 and P = 0.32, respectively). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the age groups. ConclusionsEmpagliflozin reduced primary outcomes and first and recurrent HFH and improved symptoms across a broad age spectrum. High age was not associated with reduced efficacy or meaningful intolerability. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT0305951)

Prognostic Implications of N-Terminal Pro–B-Type Natriuretic Peptide and High-Sensitivity Cardiac Troponin T in EMPEROR-Preserved

BackgroundN-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) are associated with disease severity and outcomes among patients with heart failure (HF) with preserved ejection fraction. ObjectivesThe authors evaluated associations between both biomarkers and clinical outcomes in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction) trial. MethodsOf 5,988 study participants, 5,986 (99.9%) and 5,825 (97.3%) had available baseline NT-proBNP and hs-cTnT; postbaseline NT-proBNP was also available. Baseline characteristics were expressed by biomarker quartiles. The effect of empagliflozin on cardiovascular death/ HF hospitalization, the individual components, total HF hospitalizations, slope of decline of estimated glomerular filtration rate (eGFR), and a composite renal endpoint were examined across biomarker quartiles. Change in NT-proBNP across study visits as a function of treatment assignment was also assessed. ResultsHigher baseline NT-proBNP and hs-cTnT concentrations were associated with more comorbidities and worse HF severity. Incidence rates for cardiac and renal outcomes were 2- to 5-fold higher among those in the highest vs lowest NT-proBNP or hs-cTnT quartiles. Empagliflozin consistently reduced the risk for cardiovascular events and reduced slope of eGFR decline across NT-proBNP or hs-cTnT quartiles. Empagliflozin treatment modestly lowered NT-proBNP; by 100 weeks, the adjusted mean difference in NT-proBNP from placebo was 7%. Increase in NT-proBNP from baseline to 12 weeks was strongly associated with risk of cardiovascular death/HF hospitalization. ConclusionsThe benefit of empagliflozin on cardiac outcomes and decline of eGFR is preserved across the wide range of baseline NT-proBNP and hs-cTnT evaluated. Empagliflozin modestly reduces NT-proBNP in HF with preserved ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT03057951)

Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial

ObjectivesIn this study, the authors sought to assess the relationship between AFF and outcomes, the treatment response to sacubitril/valsartan and first-detected AFF in patients with HFpEF enrolled in the PARAGON-HF trial. BackgroundAtrial fibrillation and flutter (AFF) are common in heart failure with preserved ejection fraction (HFpEF) and increase the risk of adverse outcomes. MethodsA total of 4,776 patients formed 3 groups: those with AFF according to electrocardiography (ECG) at enrollment (n = 1,552; 33%), those with history of AFF but without AFF on ECG at enrollment (n = 1,005; 21%), and those without history of AFF or AFF on ECG at enrollment (n = 2,219, 46%). We assessed outcomes, treatment response to sacubitril/valsartan in each group, and the risk associated with first-detected AFF in patients without any known AFF. The primary outcome was a composite of total heart failure hospitalizations and cardiovascular death. ResultsHistory of AFF and AFF at enrollment were associated with higher risk of the primary outcome (risk ratio [RR]: 1.36 [95% CI: 1.12-1.65] and RR: 1.31 [1.11-1.54], respectively), than no AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan. Post randomization AFF occurred in 12% of patients without previous AFF and was associated with 2.8-fold higher risk of the primary outcome, but it was not influenced by sacubitril/valsartan. ConclusionsHistory of AFF and AFF on ECG at enrollment were associated with a higher risk of the primary outcome. First-detected AFF was not influenced by sacubitril/valsartan, yet it was associated with increased risk of all subsequent outcomes and may represent a potential target for future HFpEF trials. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)

Sodium-glucose cotransporter-2 inhibitors in heart failure: an updated meta-analysis.

AimsWe aimed to examine efficacy and safety outcomes of sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) for the treatment of heart failure (HF), especially in patients with heart failure with preserved ejection fraction (HFpEF).Methods and resultsPubMed, Web of Science, and Cochrane Library were searched to identify randomized controlled trials comparing SGLT2i vs. placebo in HF patients. A total of 10 studies with 23 852 HF patients were eventually included. Compared with placebo, SGLT2i is associated with a lower incidence of composite of first hospitalization for heart failure (HHF) or cardiovascular death (CV death) [hazard ratio (HR) = 0.76 95% confidence interval (CI) = 0.71–0.81], which is consistent regardless of the diabetes status, type of gliflozines used, and follow‐up duration. SGLT2i can reduce the risk of total HHF or CV death (HR = 0.74, 95%CI = 0.68–0.81), first HHF (HR = 0.69, 95%CI = 0.64–0.75), CV death (HR = 0.88, 95%CI = 0.80–0.96), any death (HR = 0.90, 95%CI = 0.83–0.97), and any serious events (HR = 0.90, 95%CI = 0.87–0.93) in HF patients, at the cost of increased risk of urinary tract infections (risk ratio = 1.17, 95%CI = 1.03–1.33). In HFpEF patients, SGLT2i is associated with a significant reduction of composite of first HHF or CV death (HR = 0.81, 95%CI = 0.73–0.91), first HHF (HR = 0.71, 95%CI = 0.62–0.82), and total HHF or CV death (HR = 0.61, 95%CI = 0.43–0.86).ConclusionsSodium‐glucose cotransporter‐2 inhibitor contributed to better efficacy outcomes in overall HF patients and showed an inspiring breakthrough in the treatment of HFpEF.

Repetitive milrinone therapy in ambulatory advanced heart failure patients.

BackgroundAdvanced heart failure (HF) patients usually poorly tolerate guideline‐directed HF medical therapy (GDMT) and suffer high rates of morbidity and mortality. The use of continuous inotropes in the outpatient settings is hampered by previous data showing excess morbidity. We aimed to assess the safety and efficacy of repetitive, intermittent, short‐term intravenous milrinone therapy in advanced HF patients with an intention to introduce and up‐titrate GDMT and improve functional class.HypothesisRepetitive, intermittent milrinone therapy may assist with the stabilization of advanced HF patients.MethodsAdvanced HF patients treated with beta‐blockers and implanted with defibrillators were initiated with repetitive, intermittent short‐term intravenous milrinone therapy at our HF outpatient unit. Patients were prospectively followed with defibrillator interrogation, functional class assessment, B‐natriuretic peptide (BNP) levels, and echocardiography parameters.ResultsThe cohort included 24 patients with a mean 330 ± 240 days of milrinone therapy exposure. Mean age was 73 ± 6 years with male predominance (96%). Following milrinone therapy, median BNP levels decreased significantly (882 [286−3768] to 631 [278−1378] pg/ml, p = .017) with a significant reduction in the number of patients with New York Heart Association (NYHA) Class III and IV (p = .012, 0.013) and an increase in number of patients on GDMT. Importantly, the number of total sustained ventricular tachycardia events and HF hospitalizations did not change.ConclusionsIn this small cohort of advanced HF, repetitive, intermittent, short‐term milrinone therapy was found to be safe and potentially efficacious.

Natriuretic peptide-based inclusion criteria in heart failure with preserved ejection fraction clinical trials: insights from PARAGON-HF.

Natriuretic peptides (NPs) are now routinely incorporated as key inclusion criteria in clinical trials of heart failure with preserved ejection fraction (HFpEF) as objective measures of risk. An early amendment in PARAGON-HF required all participants to have elevated NP concentrations, but some were enrolled pre-amendment, providing a unique opportunity to understand the influence of enrolment pathway in HFpEF clinical trials. Among 4796 participants in PARAGON-HF, 193 (4.0%) did not meet the final NP-based enrolment criteria (N-terminal pro-B-type natriuretic peptide >300 pg/ml for patients in sinus rhythm or >900 pg/ml for patients in atrial fibrillation/flutter). These patients had lower rates of the primary endpoint of total heart failure hospitalizations and cardiovascular death as compared with patients meeting final enrolment criteria (8.6 [6.7-11.2] events per 100 patient-years vs. 14.0 [13.4-14.7] events per 100 patient-years; p=0.01). The rate ratio for the treatment effect comparing sacubitril/valsartan with valsartan was 0.85 (95% confidence interval 0.74-0.99; p=0.04) in those who met final criteria. Natriuretic peptides are an important tool in HFpEF clinical trials to objectively affirm diagnoses and enrich clinical event rates.

Sodium-glucose cotransporter 2 inhibitors in heart failure with reduced or preserved ejection fraction: a meta-analysis.

AimsSodium‐glucose cotransporter 2 (SGLT2) inhibitors have been shown to be an effective therapy in improving heart failure outcomes. We conducted a meta‐analysis of randomized controlled trials to evaluate the efficacy of SGLT2 inhibitors in heart failure patients with either a reduced or preserved ejection fraction.Methods and resultsWe searched MEDLINE and EMBASE for large (≥1000 patients) randomized controlled trials evaluating the effects of SGLT2 inhibitors compared with placebo in the setting of heart failure until September 2021. Our primary outcome was the composite of heart failure hospitalization and cardiovascular death, and secondary outcomes included all‐cause mortality and total heart failure hospitalizations. We pooled hazard ratios and risk ratios and evaluated risk of bias with the Cochrane Collaboration tool. Four randomized controlled trials (DAPA HF, EMPEROR‐Preserved, EMPEROR‐Reduced, and SOLOIST‐WHF) were included (n = 15 684); two of which evaluated patients with a reduced LVEF, one of which evaluated patients with a preserved LVEF, and one of which included both. Treatment with SGLT2 inhibitors resulted in a significant reduction in the composite of CV death and heart failure hospitalization (HR: 0.76, 95% CI: 0.70, 0.82, I 2: 0%, P < 0.00001). This was consistent in sub‐groups of patients with LVEF ≤40% (n = 9199, HR: 0.74, 95% CI: 0.68, 0.81, I 2: 0%) and LVEF >40% (n = 6482, HR: 0.78, 95% CI: 0.68, 0.89, I 2: 0%, P‐for‐interaction: 0.57), as well as in sub‐groups of patients with and without diabetes mellitus at baseline (P‐for‐interaction: 0.81). SGLT2 inhibitors were associated with a significant reduction in cardiovascular death (HR: 0.87, 95% CI: 0.79, 0.97, I 2: 0%, P < 0.00001) and total heart failure hospitalization (RR: 0.71, 95% CI: 0.67, 0.76, I 2: 0%, P < 0.00001); although a potential trend towards reduced all‐cause mortality was noted with SGLT2 inhibitors, no statistically significant difference was observed (HR: 0.91, 95% CI: 0.83, 1.00, I 2: 14%, P = 0.05).ConclusionsSodium‐glucose cotransporter 2 inhibitors reduce cardiovascular death and heart failure hospitalization among patients with heart failure, regardless of LVEF status.

Impact of anaemia and the effect of empagliflozin in heart failure with reduced ejection fraction: findings from EMPEROR-Reduced.

AimsAnaemia is frequent among patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with poor outcomes. Sodium–glucose co‐transporter 2 inhibitors (SGLT2i) increase haematocrit and may correct anaemia. This study aims to investigate the impact of empagliflozin on haematocrit and anaemia, and whether anaemia influenced the effect of empagliflozin in EMPEROR‐Reduced.Methods and resultsMixed‐effects models and survival analysis. A total of 3726 patients (out of 3730) had baseline haematocrit values, 3013 (81%) had no anaemia and 713 (19%) had anaemia. Patients with anaemia were older (70.4 vs. 66.0 years), had lower body mass index (26.6 vs. 28.2 kg/m2), lower estimated glomerular filtration rate (54.2 vs. 63.9 ml/min/1.73 m2), and higher N‐terminal pro‐B‐type natriuretic peptide (2362 vs. 1800 pg/ml). Compared to patients without anaemia, those with anaemia had 1.5 to 2.5‐fold higher rates of cardiovascular and all‐cause mortality, total HF hospitalizations, and kidney composite outcomes. The effect of empagliflozin to reduce the primary composite outcome of cardiovascular death or HF hospitalizations, total HF hospitalizations, and kidney composite outcome was not modified by baseline anaemia status (interaction p > 0.1 for all). Compared to placebo, empagliflozin rapidly (as early as week 4) increased haematocrit and haemoglobin and reduced the rates of new‐onset anaemia throughout the follow‐up (22.6% in placebo vs. 12.3% in empagliflozin; hazard ratio 0.49, 95% confidence interval 0.41–0.59; p < 0.001).ConclusionsAnaemia was associated with poor outcomes. Empagliflozin reduced new‐onset anaemia throughout the follow‐up and improved HF and kidney outcomes irrespective of anaemia status at baseline.

Transthyretin V142I Genetic Variant and Cardiac Remodeling, Injury, and Heart Failure Risk in Black Adults

ObjectivesThis study evaluated the association of transthyretin (TTR) gene variant, in which isoleucine substitutes for valine at position 122 (V142I), with cardiac structure, function, and heart failure (HF) risk among middle-aged Black adults. BackgroundThe valine-to-isoleucine substitution in the TTR protein is prevalent in Black individuals and causes cardiac amyloidosis. MethodsJackson Heart Study participants without HF at baseline who had available data on the TTR V142I variant were included. The association of the TTR V142I variant with baseline echocardiographic parameters and repeated measures of high-sensitivity cardiac troponin-I (hs-cTnI) was assessed using adjusted linear regression models and linear mixed models, respectively. Adjusted Cox models, restricted mean survival time analysis, and Anderson-Gill models were constructed to determine the association of TTR V142I variant with the risk of incident HF, survival free of HF, and total HF hospitalizations. ResultsA total of 119 of 2,960 participants (4%) were heterozygous carriers of the TTR V142I variant. The TTR V142I variant was not associated with measures of cardiac parameters at baseline but was associated with a greater increase in high-sensitivity troponin I (hs-TnI) levels over time. In adjusted Cox models, TTR V142I variant carriers had significantly higher risk of incident HF (HR: 1.80; 95% CI: 1.07-3.05; P = 0.03), lower survival free of HF (mean difference: 4.0 year; 95% CI: 0.6-6.2 years); P = 0.02), and higher risk of overall HF hospitalizations (HR: 2.12; 95% CI: 1.23-3.63; P = 0.007). ConclusionsThe TTR V142I variant in middle-aged Black adults is not associated with adverse cardiac remodeling but was associated with a significantly higher burden of chronic myocardial injury, and greater risk of incident HF and overall HF hospitalizations.

Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction.

AimsNo therapy has shown to reduce the risk of hospitalization for heart failure across the entire range of ejection fractions seen in clinical practice. We assessed the influence of ejection fraction on the effect of the sodium–glucose cotransporter 2 inhibitor empagliflozin on heart failure outcomes.Methods and resultsA pooled analysis was performed on both the EMPEROR-Reduced and EMPEROR-Preserved trials (9718 patients; 4860 empagliflozin and 4858 placebo), and patients were grouped based on ejection fraction: <25% (n = 999), 25–34% (n = 2230), 35–44% (n = 1272), 45–54% (n = 2260), 55–64% (n = 2092), and ≥65% (n = 865). Outcomes assessed included (i) time to first hospitalization for heart failure or cardiovascular mortality, (ii) time to first heart failure hospitalization, (iii) total (first and recurrent) hospitalizations for heart failure, and (iv) health status assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). The risk of cardiovascular death and hospitalization for heart failure declined progressively as ejection fraction increased from <25% to ≥65%. Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalization, mainly by reducing heart failure hospitalizations. Empagliflozin reduced the risk of heart failure hospitalization by ≈30% in all ejection fraction subgroups, with an attenuated effect in patients with an ejection fraction ≥65%. Hazard ratios and 95% confidence intervals were: ejection fraction <25%: 0.73 (0.55–0.96); ejection fraction 25–34%: 0.63 (0.50–0.78); ejection fraction 35–44%: 0.72 (0.52–0.98); ejection fraction 45–54%: 0.66 (0.50–0.86); ejection fraction 55–64%: 0.70 (0.53–0.92); and ejection fraction ≥65%: 1.05 (0.70–1.58). Other heart failure outcomes and measures, including KCCQ, showed a similar response pattern. Sex did not influence the responses to empagliflozin.ConclusionThe magnitude of the effect of empagliflozin on heart failure outcomes was clinically meaningful and similar in patients with ejection fractions <25% to <65%, but was attenuated in patients with an ejection fraction ≥65%.Key QuestionHow does ejection fraction influence the effects of empagliflozin in patients with heart failure and either a reduced or a preserved ejection fraction?Key FindingThe magnitude of the effect of empagliflozin on heart failure outcomes and health status was similar in patients with ejection fractions <25% to <65%, but it was attenuated in patients with an ejection fraction ≥65%.Take Home MessageThe consistency of the response in patients with ejection fractions of <25% to <65% distinguishes the effects of empagliflozin from other drugs that have been evaluated across the full spectrum of ejection fractions in patients with heart failure.

A year in heart failure: an update of recent findings.

Major changes have occurred in these last years in heart failure (HF) management. Landmark trials and the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of HF have established four classes of drugs for treatment of HF with reduced ejection fraction: angiotensin‐converting enzyme inhibitors or an angiotensin receptor‐neprilysin inhibitor, beta‐blockers, mineralocorticoid receptor antagonists, and sodium‐glucose co‐transporter 2 inhibitors, namely, dapagliflozin or empagliflozin. These drugs consistently showed benefits on mortality, HF hospitalizations, and quality of life. Correction of iron deficiency is indicated to improve symptoms and reduce HF hospitalizations. AFFIRM‐AHF showed 26% reduction in total HF hospitalizations with ferric carboxymaltose vs. placebo in patients hospitalized for acute HF (P = 0.013). The guanylate cyclase activator vericiguat and the myosin activator omecamtiv mecarbil improved outcomes in randomized placebo‐controlled trials, and vericiguat is now approved for clinical practice. Treatment of HF with preserved ejection fraction (HFpEF) was a major unmet clinical need until this year when the results of EMPEROR‐Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic HFpEF) were issued. Compared with placebo, empagliflozin reduced by 21% (hazard ratio, 0.79; 95% confidence interval, 0.69 to 0.90; P < 0.001), the primary outcome of cardiovascular death or HF hospitalization. Advances in the treatment of specific phenotypes of HF, including atrial fibrillation, valvular heart disease, cardiomyopathies, cardiac amyloidosis, and cancer‐related HF, also occurred. Coronavirus disease 2019 (COVID‐19) pandemic still plays a major role in HF epidemiology and management. All these aspects are highlighted in this review.

Impact of Chronic Obstructive Pulmonary Disease in Patients With Heart Failure With Preserved Ejection Fraction: Insights From PARAGON-HF.

BackgroundLittle is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF).Methods and ResultsWe examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P<0.001) and had worse New York Heart Association functional class (class III/IV 24% versus 19%), worse Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (69 versus 76; P<0.001) and more frequent history of heart failure hospitalization (54% versus 47%; P<0.001). The decrement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores with COPD was greater than for other common comorbidities. Patients with COPD had echocardiographic right ventricular enlargement, higher serum creatinine (100 μmol/L versus 96 μmol/L) and neutrophil‐to‐lymphocyte ratio (2.7 versus 2.5), than those without COPD. After multivariable adjustment, COPD was associated with worse outcomes: adjusted rate ratio for the primary outcome 1.51 (95% CI, 1.25–1.83), total heart failure hospitalization 1.54 (95% CI, 1.24–1.90), cardiovascular death (adjusted hazard ratio [HR], 1.42; 95% CI, 1.10–1.82), and all‐cause death (adjusted HR, 1.52; 95% CI, 1.25–1.84). COPD was associated with worse outcomes than other comorbidities and Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores declined more in patients with COPD than in those without.ConclusionsApproximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Efficacy of Dapagliflozin in Black Versus White Patients With Heart Failure and Reduced Ejection Fraction

ObjectivesThis study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure). BackgroundBlack patients may respond differently to certain treatments for HFrEF than White patients. MethodsPatients with New York Heart Association functional class II to IV with an ejection fraction of ≤40% and elevated N-terminal pro–B-type natriuretic peptide were eligible for DAPA-HF. Because >99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. ResultsOf the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients. ConclusionsDapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)

Readmissions, Death and Its Associated Predictors in Heart Failure With Preserved Versus Reduced Ejection Fraction.

BackgroundData on rehospitalizations for heart failure (HF) in Asia are scarce. We sought to determine the burden and predictors of HF (first and recurrent) rehospitalizations and all‐cause mortality in patients with HF and preserved versus reduced ejection fraction (preserved EF, ≥50%; reduced EF, <40%), in the multinational ASIAN‐HF (Asian Sudden Cardiac Death in Heart Failure) registry.Methods and ResultsPatients with symptomatic (stage C) chronic HF were followed up for death and recurrent HF hospitalizations for 1 year. Predictors of HF hospitalizations or all‐cause mortality were examined with Cox regression for time to first event and other methods for recurrent events analyses. Among 1666 patients with HF with preserved EF (mean age, 68±12 years; 50% women), and 4479 with HF with reduced EF (mean age, 61±13 years; 22% women), there were 642 and 2302 readmissions, with 28% and 45% attributed to HF, respectively. The 1‐year composite event rate for first HF hospitalization or all‐cause death was 11% and 21%, and for total HF hospitalization and all‐cause death was 17.7 and 38.7 per 100 patient‐years in HF with preserved EF and HF with reduced EF, respectively. In HF with preserved EF, consistent independent predictors of these clinical end points included enrollment as an inpatient, Southeast Asian location, and comorbid chronic kidney disease or atrial fibrillation. The same variables were predictive of outcomes in HF with reduced EF except atrial fibrillation, and also included Northeast Asian location, older age, elevated heart rate, decreased systolic blood pressure, diabetes, smoking, and non‐usage of beta blockers.ConclusionsOne‐year HF rehospitalization and mortality rates were high among Asian patients with HF. Predictors of outcomes identified in this study could aid in risk stratification and timely interventions.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01633398.