Total Heart Failure Hospitalizations Research Articles

Randomized investigation of the MitraClip device in heart failure: Design and rationale of the RESHAPE-HF2 trial design.

The safety and effectiveness of the MitraClip device to treat functional mitral regurgitation (FMR) has been tested in previous clinical trials yielding somewhat heterogeneous results in heart failure (HF) patients. Over time, the MitraClip device system has been modified and clinical practice evolved to consider also less severely diseased HF patients with FMR for this therapeutic option. The RESHAPE-HF2 trial aims to assess the safety and effectiveness of the MitraClip device system on top of medical therapy considered optimal in the treatment of clinically significant FMR in symptomatic patients with chronic HF. The RESHAPE-HF2 is an investigator-initiated, prospective, randomized, parallel-controlled, multicentre trial designed to evaluate the use of the MitraClip device (used in the most up-to-date version as available at sites) plus optimal standard of care therapy (device group) compared to optimal standard of care therapy alone (control group). Eligible subjects have signs and symptoms of HF (New York Heart Association [NYHA] class II-IV despite optimal therapy), and have moderate-to-severe or severe FMR, as confirmed by a central echocardiography core laboratory; have an ejection fraction between ≥20% and ≤50% (initially 15-35% for NYHA class II patients, and 15-45% for NYHA class III/IV patients); have been adequately treated per applicable standards, and have received appropriate revascularization and cardiac resynchronization therapy, if eligible; had a HF hospitalization or elevated natriuretic peptides (B-type natriuretic peptide [BNP] ≥300 pg/ml or N-terminal proBNP ≥1000 pg/ml) in the last 90 days; and in whom isolated mitral valve surgery is not a recommended treatment option. The trial has three primary endpoints, which are these: (i) the composite rate of total (first and recurrent) HF hospitalizations and cardiovascular death during 24 months of follow-up, (ii) the rate of total (i.e. first and recurrent) HF hospitalizations within 24 months, and (iii) the change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire overall score. The three primary endpoints will be analysed using the Hochberg procedure to control the familywise type I error rate across the three hypotheses. The RESHAPE-HF2 trial will provide sound evidence on the MitraClip device and its effects in HF patients with FMR. The recruitment was recently completed with 506 randomized patients.

Sacubitril/Valsartan-Related Hypotension in Patients With Heart Failure and Preserved or Mildly Reduced Ejection Fraction

BackgroundHypotension is a potential adverse effect of sacubitril/valsartan, but there are limited data regarding the predictors and implications of treatment-related hypotension in heart failure (HF) with mildly reduced and preserved ejection fraction. ObjectivesWe investigated predictors of treatment-associated hypotension, clinical outcomes after hypotension, and the relationship between left ventricular ejection fraction (LVEF) and incidence of hypotension in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial. MethodsPARAGON-HF randomized patients with chronic HF (≥45%) to sacubitril/valsartan or valsartan. Following randomization, hypotension was defined as investigator-reported hypotension with a systolic blood pressure <100 mm Hg. Predictors of hypotension were assessed using multivariable Cox models. Associations between hypotension and clinical outcomes were evaluated in time-updated Cox models. The relationship among treatment, LVEF, and incident rates of hypotension and clinical outcomes was estimated using Poisson regression models. ResultsOf 4,796 patients in PARAGON-HF, 637 (13%) experienced hypotension, more frequently in the sacubitril/valsartan arm (P < 0.001). Following documented hypotension, patients had higher risk of cardiovascular death and total HF hospitalizations (adjusted RR: 1.63; 95% CI: 1.27-2.09; P < 0.001) and all-cause death (adjusted HR: 1.62; 95% CI: 1.28-2.05; P < 0.001). LVEF modified the association between sacubitril/valsartan and risk of hypotension (Pinteraction = 0.019) such that patients with LVEF ≥60% experienced substantially higher treatment-related risks of hypotension. ConclusionsIn PARAGON-HF, a higher LVEF was associated with an increased risk of hypotension in patients treated with sacubitril/valsartan compared with valsartan. Because these subjects are also less likely to derive clinical benefit from sacubitril/valsartan, our data reinforce that the benefit/risk ratio favors the use of sacubitril/valsartan in patients with LVEF below normal, but not at higher LVEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)

Dapagliflozin versus sacubitril-valsartan for heart failure with mildly reduced or preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is associated with an increased risk of heart failure (HF) hospitalizations and cardiovascular death (CVD). Both dapagliflozin and sacubitril-valsartan have recently shown convincing reductions in the combined risk of CVD and HF hospitalizations in patients with HF and mildly reduced ejection fraction (HFmrEF) or HFpEF. We aimed to investigate the cost-per-outcome implications of dapagliflozin vs sacubitril-valsartan in the treatment of HFmrEF or HFpEF patients. We compared the annualized cost needed to treat (CNT) to prevent the composite outcome of total HF hospitalizations and CVD with dapagliflozin or sacubitril-valsartan. The CNT was estimated by multiplying the annualized number needed to treat (aNNT) by the annual cost of therapy. The aNNT was calculated based on data collected from the DELIVER trial for dapagliflozin and a pooled analysis of the PARAGLIDE-HF and PARAGON-HF trials for sacubitril-valsartan. Costs were based on 2022 US prices. Scenario analyses were performed to attenuate the differences in the studies' populations. The aNNT with dapagliflozin in DELIVER was 30 (95% confidence interval [CI]: 21-62) versus 44 (95% CI: 25-311) with sacubitril-valsartan in a pooled analysis of PARAGLIDE-HF and PARAGON-HF, with an annual cost of $4,951 and $5,576, respectively. The corresponding CNTs were $148,547.13 (95% CI: $103,982.99-$306,997.39) for dapagliflozin and $245,346.77 (95% CI: $139,401.58-1,734,155.60) for sacubitril-valsartan for preventing the composite outcome of CVD and HF hospitalizations. The CNT for preventing all-cause mortality was lower for dapagliflozin than sacubitril-valsartan $1,128,958.15 [CI: $401,077.24-∞] vs $2,185,816.71 [CI: $607,790.87-∞]. Dapagliflozin provides a better monetary value than sacubitril-valsartan in preventing the composite outcome of total HF hospitalizations and CVD among patients with HFmrEF or HFpEF.

Benefits of intravenous iron supplementation in heart failure.

Introduction: Iron deficiency (ID) is one of the most frequent comorbidities in patients with heart failure (HF) and is estimated to be present in up to 80% of acute patients regardless of their ejection fraction. Randomized controlled trials have shown that supplementary intravenous iron results in improved clinical outcomes; however, the current understanding of the effects of intravenous iron on morbidity and mortality remains limited. Study and results: The meta-analysis pooled individual participant data from three randomized placebo-controlled trials of ferric carboxymaltose (FCM) in adult patients (n = 4,501) with heart failure and iron deficiency (CONFIRM-HF, AFFIRM-AHF, and HEART-FID). FCM therapy significantly reduced the co-primary composite endpoint of total cardiovascular hospitalizations and cardiovascular death, with a rate ratio (RR 0.86; 95% CI 0.75 to 0.98; p = 0.029). FCM therapy was associated with a 17% relative rate reduction in total cardiovascular hospitalizations (RR 0.83; 95% CI 0.73 to 0.96; p = 0.009) and a 16% relative rate reduction in total heart failure hospitalizations (RR 0.84; 95% CI 0.71 to 0.98; p = 0.025). Lessons learned: The meta-analysis shows that in iron-deficient patients with heart failure and reduced or mildly reduced left ventricular ejection fraction, intravenous ferric carboxymaltose (FCM) is associated with a reduced risk of total cardiovascular hospitalization and cardiovascular mortality. These findings indicate that intravenous FCM should be considered in iron-deficient patients with heart failure and reduced or mildly reduced ejection fractions.

Daprodustat and Heart Failure in CKD.

Patients with chronic kidney disease (CKD) are at higher risk for heart failure. The hypoxia inducible factor prolyl hydroxylase inhibitor daprodustat is an orally acting alternative to conventional injectable erythropoietin-stimulating agents (ESA) for the treatment of anemia in patients with CKD. Whether daprodustat affects the risk of heart failure hospitalization is unknown. The ASCEND-D (n=2,964) and ASCEND-ND (n=3,872) trials compared daprodustat to conventional ESA in patients with anemia of CKD who did or did not require dialysis, respectively. We identified risk factors for heart failure hospitalization and assessed the effect of daprodustat compared to conventional ESA on heart failure hospitalizations. History of heart failure, diabetes, and higher systolic blood pressure were independently associated with heart failure hospitalization in both trials, irrespective of treatment assignment. The number of first heart failure hospitalizations was greater in the daprodustat arm in patients not receiving dialysis (hazard ratio [HR] 1.22 [0.95-1.56], p=0.12] and in patients receiving dialysis (HR 1.10 [0.84-1.45], p=0.47), though these differences were not statistically significant. HRs in patients with and without history of heart failure were 1.37 (0.89-2.11) vs 1.08 (0.79-1.46) (p-interaction=0.36) in ASCEND-ND, and 1.52 (0.97-2.38) vs 0.93 (0.66-1.30) (p-interaction=0.09) in ASCEND-D, respectively. In post hoc analyses, daprodustat increased total (first and recurrent) heart failure hospitalizations in participants not receiving dialysis (rate ratio 1.46 [1.11-1.92], p=0.007) ) but not in participants receiving dialysis (rate ratio 1.01 [0.74-1.39], p=0.93). Daprodustat did not significantly affect the risk of a composite outcome of first heart failure hospitalization or death. A greater number of first heart failure hospitalization events occurred in patients treated with daprodustat compared with conventional ESA, but this difference did not reach statistical significance. Differences in the number of heart failure hospitalization events were most apparent in patients not receiving dialysis and in patients with history of heart failure.

Clinical implications of subclinical left ventricular dysfunction in heart failure with preserved ejection fraction: The PARAGON-HF study.

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. 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). 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.

Recurrent Hospitalizations and Response to Vericiguat in Heart Failure and Reduced Ejection Fraction

BackgroundIn VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction. ObjectivesThis study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization. MethodsThe treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro–B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported. ResultsThere were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro–B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo. ConclusionsAdditional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)

The effects of Dapagliflozin in type 2 diabetes mellitus patients with complications of cardiovascular disease

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder in which concomitant insulin resistance and beta-cell impairment lead to hyperglycemia. Cardiovascular problems are more common in T2DM but after the discovery of the dapagliflozin class of SGLT2 (Sodium-glucose co-transporter 2) inhibitor, the rate of cardiovascular disease (CVD) reduced slightly including heart failure (HF). Numerous recent clinical studies emphasized that dapagliflozin as monotherapy and combined therapy with another hypoglycemic agent help to improve glycaemic control and decrease blood pressure and body weight. In the present review, the safety and efficacy of dapagliflozin have been highlighted in patients with HFrEF(Heart failure with reduced ejection fraction), after comparison with placebo and dapagliflozin. It decreased the risk of total HF hospitalizations and cardiovascular death with a low-hypoglycaemic effect. Recurrent hospitalizations are a common problem in patients with HFrEF and it is also preventable. This review article also emphasized the comparative effects of drugs and placebo to prove the effectiveness of drugs and a further reduction in the rate of heart failure. The mild adverse effect is observed in clinical trials where urinary tract infection is most common.

The beneficial effects of adherence to outpatient telecare intervention on clinical outcomes after an episode of acute heart failure: insights from the prospective randomised controlled AMULET trial

Abstract Background The prevention of hospitalisations and deaths is a major therapeutic aim in patients with heart failure (HF). In our previously published prospective randomised controlled trial, we demonstrated that an outpatient intervention comprising nurse-led non-invasive assessments, telemedicine support and remote cardiologist decision-making (AMULET telecare) reduced the risk of HF hospitalisation or cardiovascular death by 31% during the 12-month follow-up in HF patients after an episode of acute HF. Purpose To present the results of the prespecified per-protocol analysis of the AMULET trial that reveal the impact of AMULET telecare adherence on the prognosis of patients. Methods Patients with HF and left ventricular ejection fraction (LVEF) ≤49% and who experienced an episode of acute HF in the past 6 months were randomly assigned to receive either AMULET telecare (n=298) or standard care (n=305). Those who completed the predefined schedule of AMULET telecare (n=190) and all standard care patients were included in the per-protocol population. Results In this per-protocol analysis, when compared to standard care, the implementation of AMULET telecare reduced the risk of the primary outcome, a composite of unplanned HF hospitalisation or cardiovascular death (by 51%), and the following secondary outcomes: first unplanned HF hospitalisation, first unplanned cardiovascular hospitalisation, first all-cause unplanned hospitalisation, total unplanned HF hospitalisations and the number of days lost due to HF hospitalisations or death. There was no statistically significant difference in cardiovascular mortality, mortality due to HF and overall mortality between the study groups (Table). Conclusions Adherence to AMULET telecare enhances the positive effects of this intervention on the prognosis of HF patients with an LVEF≤49% after an episode of acute HF.

Intravenous Iron for Heart Failure: Updated Systematic Review and Meta-Analysis.

While the administration of intravenous (IV) iron to those with heart failure has been implicated to be associated with a possible reduction in hospitalizations and improvement in symptoms, a recent large multicenter trial only showed modest benefits in reducing hospitalization, necessitating the updated systematic review. We conducted a systematic review and meta-analysis, searching the MEDLINE and EMBASE database until January 9, 2023. Outcomes included total heart failure hospitalizations, first heart failure hospitalization, six-minute walk test (6MWT) distance, and incidence of infection. There were 13 studies with 3410 participants (1,790 with IV iron). Pooled analysis that reported the incidence of cardiovascular death showed that patients with IV iron did not have significantly lower odds of cardiovascular death or first heart failure hospitalization. In contrast, those who received IV iron had significantly lower total heart failure hospitalization (pooled odds ratio (OR) 0.63, 95% confidence interval (CI) 0.44-0.90, I2 59.0%, P = .017) and a composite of cardiovascular death and first heart failure hospitalization (pooled OR 0.55, 95% CI 0.47-0.64, I2 0%, P = .656). While the efficacy is modest, IV iron therapy could be associated with reduced hospitalization for heart failure without significant adverse events.

Current Role of SLGT2 Inhibitors in the Management of the Whole Spectrum of Heart Failure: Focus on Dapagliflozin.

Heart failure (HF) is associated with a high morbidity and mortality burden. In light of more recent evidence, SGLT2 inhibitors are currently recommended as first-line therapy in managing patients with HF, regardless of ejection fraction, to reduce HF burden. The DAPA-HF and DELIVER trials, and particularly, the pooled analysis of both studies, have shown that dapagliflozin significantly reduces the risk of cardiovascular death, all-cause death, total HF hospitalizations, and MACE in the whole spectrum of HF, with sustained benefits over time. Recent data have shown that the full implementation of dapagliflozin in clinical practice would translate into a robust reduction in hospitalizations for HF and death in real-life populations. Many pathophysiological mechanisms have been involved in these benefits, particularly the positive effects of dapagliflozin on reversing cardiac (atrial and ventricular) remodeling, reducing cardiac fibrosis and inflammation, and improving endothelial dysfunction. In this manuscript, we reviewed from a practical point of view the role of dapagliflozin in the management of the whole spectrum of patients with HF.

Use of Win Statistics to Analyze Outcomes in the DAPA-HF and DELIVER Trials

BackgroundThe primary end point in most heart failure (HF) trials is a composite of time to a first worsening HF event or cardiovascular death. Prevention of recurrent events and improvements in symptoms/quality of life are also important for patients but are usually analyzed separately. Win statistics can integrate all these outcomes into a single composite end point, which is analyzed in hierarchical order, reflecting the clinical importance of each component.MethodsThe Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF, n=4744) and Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER, n=6263) trials enrolled patients with New York Heart Association class II, III, or IV HF, elevated natriuretic peptides, and either an ejection fraction of 40% or less (DAPA-HF) or greater than 40% and left atrial enlargement/left ventricular hypertrophy (DELIVER). We examined the effects of dapagliflozin compared with placebo on a hierarchical composite outcome, including cardiovascular death, total (first and recurrent) HF hospitalizations, total urgent HF visits, and improvement/deterioration in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS; range from 0 to 100, with a higher score indicating fewer symptoms and physical limitations) at 8 months.ResultsFor this composite outcome, the win ratio was 1.30 (95% confidence interval [CI], 1.23 to 1.36) in the pooled cohort, 1.33 (95% CI, 1.23 to 1.43) in the DAPA-HF trial, and 1.27 (95% CI, 1.18 to 1.36) in the DELIVER trial. Win odds and net benefit in overall patients were 1.19 (95% CI, 1.14 to 1.24) and 8.7% (95% CI, 6.6 to 10.9%), respectively. In the overall pooled cohort, the majority of wins and losses were accounted for by KCCQ-TSS; 52.4% were settled by the KCCQ-TSS tier in the pooled cohort.ConclusionsIn both the DAPA-HF and DELIVER trials, dapagliflozin led to a significant improvement in composite outcomes that incorporated patient-reported outcomes along with total HF events, as well as cardiovascular deaths. These analyses provided a comprehensive presentation of win statistics and illustrated the utility and flexibility of win statistics in describing the effects of dapagliflozin in two recent clinical trials in patients with HF. (Funded by British Heart Foundation Centre of Research Excellence and others; clinical trial registration numbers, NCT03036124 and NCT03619213.)

Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis

BackgroundMedical treatment for heart failure with preserved ejection (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) has weaker evidence compared with reduced ejection fraction, despite recent trials with an angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose co-transporter 2 inhibitors (SGLT2is). ObjectivesThe authors aimed to estimate the aggregate therapeutic benefit of drugs for HFmrEF and HFpEF. MethodsThe authors performed a systematic review of MEDLINE, CENTRAL, and Web of Science for randomized trials including patients with heart failure (HF) and left ventricular ejection fraction (LVEF) >40%, treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (analyzed together as renin-angiotensin system inhibitors [RASi]), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), digoxin, ARNI, and SGLT2i. An additive component network meta-analysis was performed. The primary outcome was a composite of cardiovascular (CV) death and first hospitalization for heart failure (HHF); secondary outcomes were CV death, total HHF, and all-cause mortality. ResultsThe authors identified 13 studies with a total of 29,875 patients and a mean LVEF of 56.3% ± 8.7%. ARNI, MRA, and SGLT2i separately, but not RASi, BB, or digoxin, reduced the primary composite outcome compared with placebo. The combination of ARNI, BB, MRA, and SGLT2i was the most effective (HR: 0.47 [95% CI: 0.31-0.70]); this was largely explained by the triple combination of ARNI, MRA, and SGLT2i (HR: 0.56 [95% CI 0.43-0.71]). Results were similar for CV death (HR: 0.63 [95% CI 0.43-0.91] for ARNI, MRA, and SGLT2i) or total HHF (HR: 0.49 [95% CI 0.33-0.71] for ARNI, MRA, and SGLT2i) alone. In a subgroup analysis, only SGLT2i had a consistent benefit among all LVEF subgroups, whereas the triple combination had the greatest benefit in HFmrEF, robust benefit in patients with LVEF 50% to 59%, and a statistically marginal benefit in patients with LVEF ≥60%. ConclusionsIn patients with HF and LVEF>40%, the quadruple combination of ARNI, BB, MRA, and SGLT2i provides the largest reduction in the risk of CV death and HHF; driven by the robust effect of the triple combination of ARNI, MRA, and SGLT2i. The benefit was more pronounced in HFmrEF patients.

Efficacy of ferric carboxymaltose in heart failure with iron deficiency: an individual patient data meta-analysis.

Whereas a beneficial effect of intravenous ferric carboxymaltose (FCM) on symptoms and exercise capacity among patients with iron deficiency and heart failure (HF) has been consistently demonstrated, the effects of treatment on clinical events remain the subject of research. This meta-analysis aimed to characterize the effects of FCM therapy on hospitalizations and mortality. Patient-level data from randomized, placebo-controlled FCM trials including adults with HF and iron deficiency with ≥52 weeks follow-up were analysed. The co-primary efficacy endpoints were (i) composite of total/recurrent cardiovascular hospitalizations and cardiovascular death and (ii) composite of total HF hospitalizations and cardiovascular death, through 52 weeks. Key secondary endpoints included individual composite endpoint components. Event rates were analysed using a negative binomial model. Treatment-emergent adverse events were also examined. Three FCM trials with a total of 4501 patients were included. Ferric carboxymaltose was associated with a significantly reduced risk of co-primary endpoint 1 (rate ratio 0.86; 95% confidence interval 0.75-0.98; P = .029; Cochran Q: 0.008), with a trend towards a reduction of co-primary endpoint 2 (rate ratio 0.87; 95% confidence interval 0.75-1.01; P = .076; Cochran Q: 0.024). Treatment effects appeared to result from reduced hospitalization rates, not improved survival. Treatment appeared to have a good safety profile and was well tolerated. In iron-deficient patients with HF with reduced left ventricular ejection fraction, intravenous FCM was associated with significantly reduced risk of hospital admissions for HF and cardiovascular causes, with no apparent effect on mortality.

Intravenous ferric carboxymaltose for iron repletion following acute heart failure in patients with and without diabetes: a subgroup analysis of the randomized AFFIRM-AHF trial.

In AFFIRM-AHF, treatment of iron deficiency with intravenous ferric carboxymaltose (FCM) reduced the risk of heart failure (HF) hospitalization and improved quality of life (QoL) vs placebo in patients stabilized following an acute HF (AHF) episode, with no effect on cardiovascular (CV) death. Diabetes and iron deficiency frequently accompany AHF. This post hoc analysis explored the effects of diabetes on outcomes in AFFIRM-AHF patients. Patients were stratified by diabetes yes/no at baseline. The effects of FCM vs placebo on primary (total HF hospitalizations and CV death) and secondary (total CV hospitalizations and CV death; CV death; total HF hospitalizations; time to first HF hospitalization or CV death; and days lost due to HF hospitalizations or CV death) endpoints at Week 52 and change vs baseline in disease-specific QoL (12-item Kansas City Cardiomyopathy Questionnaire [KCCQ-12]) at Week 24 were assessed by subgroup. For each endpoint, the interaction between diabetes status and treatment outcome was explored. Of 1108 AFFIRM-AHF patients, 475 (FCM: 231; placebo: 244) had diabetes and 633 (FCM:327; placebo: 306) did not have diabetes. Patients with diabetes were more commonly male (61.5% vs 50.9%), with a higher frequency of ischemic HF etiology (57.9% vs 39.0%), prior HF history (77.7% vs 66.5%), and comorbidities (including previous myocardial infarction [49.3% vs 32.9%] and chronic kidney disease [51.4% vs 32.4%]) than those without diabetes. The annualized event rate/100patient-years with FCM vs placebo for the primary endpoint was 66.9 vs 80.9 in patients with diabetes (rate ratio [RR]: 0.83, 95% CI 0.58-1.81) and 51.3 vs 66.9 in patients without diabetes (RR:0.77, 95% CI 0.55-1.07), with no significant interaction between diabetes status and treatment effect (pinteraction = 0.76). Similar findings were observed for secondary outcomes. Change from baseline in KCCQ-12 overall summary score was numerically greater with FCM vs placebo at almost all time points in both subgroups, with no interaction between diabetes and treatment effect at Week 24. The clinical and QoL benefits observed with intravenous FCM in patients with iron deficiency following stabilization from an AHF episode are independent of diabetes status. Trial registration Clinicaltrials.gov, NCT02937454 (registered 10.18.2016).

Knowledge about self-efficacy and outcomes in patients with heart failure and reduced ejection fraction.

Although education in self-management is thought to be an important aspect of the care of patients with heart failure, little is known about whether self-rated knowledge of self-management is associated with outcomes. The aim of this study was to assess the relationship between patient-reported knowledge of self-management and clinical outcomes in patients with heart failure and reduced ejection fraction (HFrEF). Using individual patient data from three recent clinical trials enrolling participants with HFrEF, we examined patient characteristics and clinical outcomes according to responses to the 'self-efficacy' questions of the Kansas City Cardiomyopathy Questionnaire. One question quantifies patients' understanding of how to prevent heart failure exacerbations ('prevention' question) and the other how to manage complications when they arise ('response' question). Self-reported answers from patients were pragmatically divided into: poor (do not understand at all, do not understand very well, somewhat understand), fair (mostly understand), and good (completely understand). Cox-proportional hazard models were used to evaluate time-to-first occurrence of each endpoint, and negative binomial regression analysis was performed to compare the composite of total (first and repeat) heart failure hospitalizations and cardiovascular death across the above-defined groups. Of patients (n = 17 629) completing the 'prevention' question, 4197 (23.8%), 6897 (39.1%), and 6535 (37.1%) patients had poor, fair, and good self-rated knowledge, respectively. Of those completing the 'response' question (n = 17 637), 4033 (22.9%), 5463 (31.0%), and 8141 (46.2%) patients had poor, fair, and good self-rated knowledge, respectively. For both questions, patients with 'poor' knowledge were older, more often female, and had a worse heart failure profile but similar treatment. The rates (95% confidence interval) per 100 person-years for the primary composite outcome for 'poor', 'moderate' and 'good' self-rated knowledge in answer to the 'prevention' question were 12.83 (12.11-13.60), 12.08 (11.53-12.65) and 11.55 (11.00-12.12), respectively, and for the 'response' question were 12.88 (12.13-13.67), 12.22 (11.60-12.86) and 11.56 (11.07-12.07), respectively. The lower event rates in patients with 'good' self-rate knowledge were accounted for by lower rates of cardiovascular (and all-cause) death and not hospitalization for worsening heart failure. Poor patient-reported 'self-efficacy' may be associated with higher rates of mortality. Evaluation of knowledge of 'self-efficacy' may provide prognostic information and a guide to which patients may benefit from further education about self-management.

Clinical Features, Socioeconomic Status, Management, and Outcomes of Acute Heart Failure: PEACE MENA Registry Phase I Results.

PEACE MENA (Program for the Evaluation and Management of Cardiac Events in the Middle East and North Africa) is a prospective registry in Arab countries for in-patients with acute myocardial infarction (AMI) or acute heart failure (AHF). Here, we report the baseline characteristics and outcomes of in-patients with AHF who were enrolled during the first 14 months of the recruitment phase. A prospective, multi-centre, multi-country study including patients hospitalized with AHF was conducted. Clinical characteristics, echocardiogram, BNP (B-type natriuretic peptide), socioeconomic status, management, 1-month, and 1-year outcomes are reported. Between April 2019 and June 2020, a total of 1258 adults with AHF from 16 Arab countries were recruited. Their mean age was 63.3 (±15) years, 56.8% were men, 65% had monthly income ≤US$ 500, and 56% had limited education. Furthermore, 55% had diabetes mellitus, 67% had hypertension; 55% had HFrEF (heart failure with reduced ejection fraction), and 19% had HFpEF (heart failure with preserved ejection fraction). At 1 year, 3.6% had a heart failure-related device (0-22%) and 7.3% used an angiotensin receptor neprilysin inhibitor (0-43%). Mortality was 4.4% per 1 month and 11.77% per 1-year post-discharge. Compared with higher-income patients, lower-income patients had a higher 1-year total heart failure hospitalization rate (45.6 vs 29.9%, p=0.001), and the 1-year mortality difference was not statistically significant (13.2 vs 8.8%, p=0.059). Most of the patients with AHF in Arab countries had a high burden of cardiac risk factors, low income, and low education status with great heterogeneity in key performance indicators of AHF management among Arab countries.

POINT: Should New Drug Development in Heart Failure Focus on Patients Discharged From an Acute Heart Failure Admission? Lessons From Recent Studies

POINT: Should New Drug Development in Heart Failure Focus on Patients Discharged From an Acute Heart Failure Admission? Lessons From Recent Studies

Improved prognosis after cardiac resynchronization therapy over a decade.

The past decade has seen an increased delivery of cardiac resynchronization therapy (CRT) for patients with heart failure (HF). We explored whether clinical outcomes after CRT have changed from the perspective of an entire public healthcare system. A national database covering the population of England (56.3 million in 2019) was used to explore clinical outcomes after CRT from 2010 to 2019. A total of 64 698 consecutive patients (age 71.4 ± 11.7 years; 74.8% male) underwent CRT-defibrillation [n = 32 313 (49.7%)] or CRT-pacing [n = 32 655 (50.3%)] implantation. From 2010-2011 to 2018-2019, there was a 76% increase in CRT implantations. During the same period, the proportion of patients with hypertension (59.6-73.4%), diabetes (26.5-30.8%), and chronic kidney disease (8.62-22.5%) increased, as did the Charlson comorbidity index (CCI ≥ 3 from 20.0% to 25.1%) (all P < 0.001). Total mortality decreased at 30 days (1.43-1.09%) and 1 year (9.51-8.13%) after implantation (both P < 0.001). At 2 years, total mortality [hazard ratio (HR): 0.72; 95% confidence interval (CI) 0.69-0.76] and total mortality or HF hospitalization (HR: 0.59; 95% CI 0.57-0.62) decreased from 2010-2011 to 2018-2019, after correction for age, race, sex, device type (CRT-defibrillation or pacing), comorbidities (hypertension, diabetes, chronic kidney disease, and myocardial infarction), or the CCI (HR: 0.81; 95% CI 0.77-0.85). From the perspective of an entire public health system, survival has improved and HF hospitalizations have decreased after CRT implantation over the past decade. This prognostic improvement has occurred despite an increasing comorbidity burden.

Safety and Efficacy of Empagliflozin and Diuretic Use in Patients with Heart Failure and Preserved Ejection Fraction

The diuretic effect of sodium-glucose cotransporter 2 inhibitors may result in interaction with background diuretic therapy in patients with heart failure and preserved ejection fraction (HFpEF). To assess the safety and efficacy of empagliflozin in combination with background diuretic therapy and the association of empagliflozin with the need for conventional diuretics. This was a post hoc analysis of the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved). EMPEROR-Preserved was a phase 3, randomized, placebo-controlled, double-blind clinical trial conducted from March 2017 to April 2021. Patients with class II to IV heart failure and left ventricular ejection fraction greater than 40% were included. Of 5988 patients enrolled, 5815 (97.1%) had baseline data on diuretic use and were included in this analysis, which was conducted from November 2021 to August 2022. Participants in EMPEROR-Preserved were randomized to empagliflozin or placebo. In this analysis, participants were divided into 4 subgroups: no diuretics and furosemide-equivalent diuretic dose of less than 40 mg, 40 mg, and greater than 40 mg at baseline. The main outcomes of interest were first hospitalization for heart failure (HHF) or cardiovascular death (CV death) and its components. Association of empagliflozin vs placebo with outcomes by baseline diuretic status (no diuretic vs any dose) and dose (no diuretic, <40 mg, 40 mg, and > 40mg) was assessed. Association of empagliflozin use with changes in diuretic therapy was also studied. Among 5815 patients (mean [SD] age, 71.9 [9.4] years; 2594 [44.6%] female) with known baseline diuretic use, 1179 (20.3%) were not taking diuretics, 1725 (29.7%) were taking less than 40 mg, 1772 (30.5%) were taking 40 mg, and 1139 (19.6%) were taking greater than 40 mg. In the placebo arm, patients with higher diuretic doses had worse outcomes. Empagliflozin decreased the risk of HHF or CV death, regardless of background diuretic status (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93] for the diuretic group vs HR, 0.72; 95% CI, 0.48-1.06 for the nondiuretic group; P for interaction = .58). Similarly, diuretic status was not associated with changes in improvements in first HHF, total HHF, rate of decline in estimated glomerular filtration rate, and Kansas City Cardiomyopathy Questionnaire 23 clinical summary score with empagliflozin. Findings were consistent when patients were categorized by diuretic dose. Empagliflozin was associated with a decreased likelihood of diuretic dose escalation (HR, 0.74; 95% CI, 0.65-0.84) and an increased likelihood of de-escalation (HR, 1.15; 95% CI, 1.02-1.30). Empagliflozin was associated with an increased risk of volume depletion in patients taking diuretics (HR, 1.34; 95% CI, 1.13-1.59). In this study, treatment with empagliflozin was similar regardless of diuretic use or dose. Empagliflozin use was associated with decreased conventional diuretic dosing. ClinicalTrials.gov Identifier: NCT03057951.