Total Heart Failure Hospitalizations Research Articles

Rationale and design of the FAIR-HF2-DZHK05 trial: Ferric carboxymaltose assessment of morbidity and mortality in patients with iron deficiency and chronic heart failure.

While it is widely accepted that intravenous (IV) iron improves functional capacity, symptoms, and cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) diagnosed with iron deficiency (ID), three recently published cardiovascular outcome trials (AFFIRM-AHF, IRONMAN and HEART-FID) of IV iron supplementation in HF failed to demonstrate a significant benefit on their respective primary endpoints. Dosing of IV iron after the initial correction of baseline ID-by design or as a result of trial circumstances-was relatively low (i.e. <500 mg/year). The primary objective of the FAIR-HF2 trial is to evaluate the treatment effect of ferric carboxymaltose (FCM) compared with placebo in ambulatory patients with HFrEF using a higher dose of IV iron during follow-up (i.e. >1000 mg/year). The second objective of the study is to create prospective evidence for patients fulfilling the new definition of ID for patients with HF, i.e. for those with a transferrin saturation <20%. FAIR-HF2 is an investigator-initiated, multicentre, randomized, double-blind, placebo-controlled trial that has recruited 1105 patients with chronic HF with a left ventricular ejection fraction of ≤45% and concomitant ID, defined as serum ferritin <100 ng/ml or serum ferritin 100-299 ng/ml with a transferrin saturation <20%. Patients were consented and randomized to receive either IV FCM (treatment) or saline (placebo). During an estimated median follow-up of over 2 years, patients underwent a placebo-controlled repletion and maintenance phase, with an initial iron supplementation of up to 2000 mg, followed by 500 mg every 4 months unless stop criteria of haemoglobin >16 mg/dl or serum ferritin >800 ng/ml are met on repeat visits. The trial will evaluate three primary hypotheses: (i) time to first event of cardiovascular death or hospitalization for HF, (ii) the rate of total (first and recurrent) HF hospitalizations (both analysed in the full study population), and (iii) the time to first event of cardiovascular death or hospitalization for HF in patients with a transferrin saturation <20% at baseline. The familywise type I error rate across the three primary endpoint hypotheses will be controlled using the Hochberg procedure (alpha 0.05). The FAIR-HF2 will evaluate the efficacy of FCM in patients with HFrEF in improving cardiovascular outcomes by utilizing a more aggressive approach towards iron supplementation ensuring prevention of transitional ID after initial repletion targets have been met.

Near-universal prevalence of central adiposity in heart failure with preserved ejection fraction: the PARAGON-HF trial.

An expansion of fat mass is an integral feature of patients with heart failure and preserved ejection fraction (HFpEF). While body mass index (BMI) is the most common anthropometric measure, a measure of central adiposity-the waist-to-height ratio (WHtR)-focuses on body fat content and distribution; is not distorted by bone or muscle mass, sex, or ethnicity; and may be particularly relevant in HFpEF. The PARAGON-HF trial randomized 4796 patients with heart failure and ejection fraction ≥45% to valsartan or sacubitril/valsartan. The current work characterizes the association of BMI and WHtR with clinical features, outcomes, and the response to neprilysin inhibition. About half (49%) of the participants were considered obese by BMI (≥30 kg/m2), but nearly every patient (96%) had central adiposity (WHtR ≥0.5). Among patients who were not obese (BMI <30 kg/m2), 860 (37%) had marked central adiposity (WHtR ≥0.6). Higher BMI and WHtR were both associated with higher risk of total heart failure hospitalizations, but as compared with BMI, WHtR was linearly associated with heart failure outcomes and identified a higher proportion of patients who had a particularly elevated risk (i.e., 30% or greater). An obesity-survival paradox (i.e., improved outcomes in those with greater adiposity) was apparent with BMI in unadjusted analyses, but it was not observed with WHtR. Although neprilysin inhibition appeared to have greater effects on heart failure outcomes in patients with higher BMI and WHtR, analyses of interaction with obesity metrics did not show significant heterogeneity across the range of values for adiposity. In PARAGON-HF, in contrast with BMI, nearly every patient with HFpEF had central adiposity (as assessed by WHtR), and the risks of adverse heart failure events were more robustly related to WHtR. These data challenge the current reliance on BMI as an appropriate metric of adiposity, and they suggest that-rather than obesity-related HFpEF being regarded as a select HFpEF subgroup-central adiposity is a ubiquitous feature of HFpEF.

Efficacy and safety of intravenous iron therapy in heart failure patients with iron deficiency: a systematic review and meta-analysis of randomized controlled trials

Introduction. Heart failure is a diverse life-threatening condition with complex biology and demanding therapeutic goals. Even when anemic patients are excluded, up to 59% of heart failure patients have low ferritin levels, making them especially vulnerable to iron deficiency. We aim to explore the benefits and safety of intravenous iron therapy among patients with heart failure and iron deficiency. Material and methods. We have searched the literature on PubMed (MEDLINE), Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (WoS), and EMBASE until 31st August, 2023. We used RevMan V. 5.4 to pool dichotomous data using a risk ratio (RR) with a 95% confidence interval (CI). This review has been registered and published in PROSPERO (CRD42023471419) Results. Fourteen randomized controlled trials with 6,626 patients were included. The intravenous iron group was favored over the control group in reducing hospital admissions for heart failure (first event) (RR= 0.83, 95% CI 0.71 to 0.97; p = 0.02) and (total events) (RR= 0.81, 95% CI 0.74 to 0.89; p &lt; 0.0001). Also, the iron group had a 21% lower risk in terms of cardiovascular death and hospital admission for heart failure (number of events, rate per 100 patients in a year) (RR= 0.79, 95% CI 0.74 to 0.85; p &lt; 0.00001). Concerning the adverse events, both ferric carboxymaltose and ferric derisomaltose showed a beneficial effect in reducing the cardiac disorder (RR= 0.81, 95% CI 0.76 to 0.87; p &lt;0.0001), and (RR= 0.82, 95% CI 0.71 to 0.95; p = 0.009), respectively. Conclusions. Intravenous iron infusion in patients with heart failure has a favorable safety profile. It reduces total hospitalizations for heart failure and cardiovascular mortality, with no effect on all-cause mortality, cardiovascular mortality alone, or first-time hospitalization for heart failure.

Heart failure outcomes captured by adverse event reporting in participants with type 2 diabetes and atherosclerotic cardiovascular disease: Observations from the VERTIS CV trial.

In VERTIS CV, ertugliflozin was associated with a 30% risk reduction for adjudication-confirmed, first and total hospitalizations for heart failure (HHF) in participants with type 2 diabetes and atherosclerotic cardiovascular disease. We evaluated the impact of ertugliflozin on the broader spectrum of all reported heart failure (HF) events independent of adjudication confirmation. Data from participants who received ertugliflozin (5 or 15 mg) were pooled and compared versus placebo. HF events included all investigator-reported HF adverse events (AEs) and serious AEs (SAEs) based on the narrow standardized Medical Dictionary for Regulatory Activities (MedDRA) query 'cardiac failure'. Terms for orthopnoea, dyspnoea, and peripheral oedema were evaluated separately. The effect of ertugliflozin on the first HF event was assessed by Cox proportional hazard models. Total HF events were assessed by Andersen-Gill models to account for first and recurrent events. A total of 8238 participants received ≥1 dose of ertugliflozin or placebo (mean follow-up 3.5 years). Investigator-reported HF events and AE capture yielded 420 first and 627 total HF events (vs. 238 and 345 adjudication-confirmed HHF events, respectively, in the primary analyses). Ertugliflozin reduced the risk for first (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.57-0.84; p < 0.001) and total HF AEs (HR 0.66; 95% CI 0.57-0.78; p < 0.001), with similar results for first and total HF SAEs. Additionally, ertugliflozin reduced oedema risk, but not orthopnoea/dyspnoea. The effect of ertugliflozin was consistent across the spectrum of total investigator-reported HF AEs and was similar in magnitude to adjudicated HHF events.

Empagliflozin in acute myocardial infarction in patients with and without type 2 diabetes: A pre-specified analysis of the EMPACT-MI trial.

In the EMPACT-MI trial, empagliflozin reduced heart failure (HF) hospitalizations but not mortality in acute myocardial infarction (MI). Contemporary reports of clinical event rates with and without type 2 diabetes mellitus (T2DM) in acute MI trials are sparse. The treatment effect of empagliflozin in those with and without T2DM in acute MI is unknown. A total of 6522 patients with acute MI with newly reduced left ventricular ejection fraction (LVEF) to <45%, congestion, or both, were randomized to empagliflozin 10 mg or placebo. The primary endpoint was time to first HF hospitalization or all-cause death. Rates of endpoints with and without T2DM and the efficacy and safety of empagliflozin according to T2DM status were assessed. Overall, 32% had T2DM; 14% had pre-diabetes; 16% were normoglycaemic; 38% had unknown glycaemic status. Patients with T2DM, compared to those without T2DM, were at higher risk of time to first HF hospitalization or all-cause death (hazard ratio [HR] 1.44; 95% confidence interval[CI] 1.06-1.95) and all-cause death (HR 1.70; 95% CI 1.13-2.56). T2DM did not confer a higher risk of first HF hospitalization (HR 1.22, 95% CI 0.82-1.83). Empagliflozin reduced first and total HF hospitalizations, but not all-cause mortality, regardless of presence or absence of T2DM. The safety profile of empagliflozin was the same with and without T2DM. Patients with acute MI, LVEF <45% and/or congestion who had T2DM were at a higher risk of mortality than those without T2DM. Empagliflozin reduced first and total HF hospitalizations regardless of the presence or absence of T2DM.

Multiparametric Assessment of Right Ventricular Dysfunction in Heart Failure: An Analysis From PARAGON-HF.

This study aims to characterize right ventricular dysfunction (RVD) in heart failure (HF) with preserved ejection fraction and understand the cumulative prognostic value of abnormal RV echocardiographic parameters in HF with preserved ejection fraction. Data from 809 patients in the PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blocker Global Outcomes in HF With Preserved Ejection Fraction) echocardiographic substudy (55% women, mean age 74±8 years) were analyzed. Correlates of RVD (defined as tricuspid annular plane systolic excursion <1.7 cm, fractional area change <35% or absolute RV free wall longitudinal strain <20%) were identified using multivariable logistic regression models. We further assessed the prognostic value of the number of abnormal RV parameters (0, 1, ≥2) on total HF hospitalizations (HFH) and cardiovascular death, total HFH, first HFH or cardiovascular death, all-cause death, and cardiovascular death. RVD was identified in 461 (57%) patients. Correlates of RVD included older age, higher heart rate, atrial fibrillation/flutter, greater left ventricle wall thickness, higher N-terminal pro-B-type natriuretic peptide levels, lower systolic blood pressure, and lower left ventricle absolute global longitudinal strain. These results were consistent across sexes, except atrial fibrillation/flutter and LV wall thickness, which were associated with a higher risk of RVD in men but not in women. Participants with ≥2 abnormal RV parameters had a significantly higher adjusted risk of total HFH and cardiovascular death (rate ratio, 2.13 [95% CI, 1.13-4.01]), first HFH or cardiovascular death, all-cause death, and cardiovascular death. Conversely, an isolated abnormal RV parameter was not associated with a worse outcome. RV measures may underestimate the burden of RVD in HF with preserved ejection fraction when considered in isolation. Clinicians should consider multiple dimensions to comprehensively assess RV function in patients with HF with preserved ejection fraction.

The Efficacy and Safety of Ferric Carboxymaltose in Heart Failure with Reduced Ejection Fraction and Iron Deficiency: An Updated Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Iron deficiency (ID) often coexists with heart failure (HF), and its prevalence increases with the severity of HF. Intravenous ferric carboxymaltose (FCM) has been associated with improvements in clinical outcomes, functional capacity, and quality of life (QoL) in patients with HF and ID. However, while earlier studies showed favorable results, more recent studies have failed to demonstrate significant improvements in outcomes for patients with heart failure with reduced ejection fraction (HFrEF) and ID. This meta-analysis seeks to provide updated insights into the effectiveness and safety of FCM compared to placebo/standard of care (SoC) among patients with HFrEF and ID/iron deficiency anemia (IDA). Methods: We performed a systematic review and meta-analysis of the literature from inception to December 2023, utilizing databases such as MEDLINE (via PubMed), Google Scholar, the Cochrane Library, ClinicalTrials.gov, and the ScienceDirect portal. A statistical analysis was carried out using RevMan 5.4 with a random-effects model. Dichotomous outcomes were reported as odds ratios (OR), while continuous outcomes were presented as the weighted mean difference (WMD) with corresponding 95% confidence intervals (CI), and heterogeneity was assessed using the I2 test. Results: The final analysis included data from six randomized controlled trials (RCTs), comprising 5132 patients. Our findings indicate a significant reduction in total HF hospitalizations among patients with HFrEF and ID/IDA treated with FCM compared to those receiving the placebo or SoC, with an OR of 0.59 (95% CI: 0.40 to 0.88, p < 0.010). However, no statistically significant difference was observed in the total number of deaths between the FCM and placebo/SoC groups (OR: 0.85; 95% CI: 0.70 to 1.03, p = 0.09), non-HF hospitalizations (OR: 0.71; 95% CI: 0.41 to 1.25, p = 0.24), or the composite outcome of cardiovascular hospitalizations and cardiovascular deaths (OR: 0.65; 95% CI: 0.40 to 1.04, p = 0.07). Regarding functional capacity, as assessed by the change in 6-min walk test (6MWT) distance, no significant improvement was found, with a weighted mean difference (WMD) of 14.03 (95% CI: -10.94 to 38.99, p = 0.27). QoL, measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) score, also did not show significant enhancement, with a WMD of 3.85 (95% CI: -0.55 to 8.24, p = 0.09). Furthermore, the safety analysis revealed no significant difference in the incidence of serious adverse events between the FCM and placebo/SoC groups, with an OR of 0.73 (95% CI: 0.49 to 1.10, p = 0.13). Conclusions: In patients with HFrEF and IDA, treatment with intravenous FCM significantly lowers the risk of total HF hospitalizations but does not appear to affect functional capacity, QoL, or mortality.

Effect of sacubitril/valsartan in heart failure with preserved ejection fraction across the age spectrum in PARAGON-HF.

To evaluate clinical outcomes, echocardiographic features, and the efficacy and safety of sacubitril/valsartan compared to valsartan across age groups in the PARAGON-HF trial. A total of 4796 participants ≥50 years of age with chronic heart failure (HF) and left ventricular ejection fraction (LVEF) ≥45% were divided into three age groups: <65 years (n = 825), 65-74 years (n = 1772), and ≥75 years (n = 2199). Echocardiograms of 1097 patients were analysed in a standardized fashion at a core imaging laboratory. The primary composite outcome was total HF hospitalizations and cardiovascular (CV) death. Older patients were more likely to experience primary composite outcomes (compared to patients <65 years, adjusted rate ratio [aRR] for ≥75 years: 1.39, 95% confidence interval [CI] 1.21-1.61), total HF hospitalization (aRR 1.27, 95% CI 1.09-1.49), and CV death (adjusted hazard ratio [aHR] 2.04, 95% CI 1.44-2.87). Age did not modify the effect of sacubitril/valsartan compared to valsartan on primary composite endpoint (pinteraction = 0.79) in the overall population or in those with LVEF ≤57%. Older adults randomized to sacubitril/valsartan were more likely to develop hypotension compared to those receiving valsartan (pinteraction = 0.026). Older patients had smaller left ventricular chamber sizes, higher LVEF, and were more likely to have abnormal measures of diastolic function. Older patients with HF with preserved ejection fraction had higher event rates than younger patients, more adverse events overall, and more hypotension when treated with sacubitril/valsartan; however, the treatment benefits of sacubitril/valsartan were retained in older patients.

Relationship Between Left Ventricular Ejection Fraction and ICD-10 Codes Among Patients Hospitalized With Heart Failure.

While left ventricular ejection fraction (LVEF) represents an important means by which to classify patients with heart failure (HF), relatively little is known about the distribution of LVEFs among patients hospitalized for HF based on their International Classification of Disease (ICD)-10 code. We performed a retrospective cross-sectional analysis of patients admitted to a large integrated health system within the western US between January 1, 2018 and October 1, 2022 with a principal diagnosis of HF (defined by ICD-10 codes: I50.2, systolic HF; I50.3, diastolic HF; I50.4, combined systolic and diastolic HF; I11.0, hypertensive heart disease with HF; and I13.0 and I13.2, hypertensive heart disease with HF and chronic kidney disease). Over nearly 5 years, 61,238 HF hospitalizations occurred, of which 49,772 (81%) had a LVEF available by echocardiography within the preceding 3 months. Whereas most patients hospitalized with systolic HF (n = 2220) as well as systolic and diastolic heart failure (n = 1582) had an LVEF ≤ 40% (86.2% and 74.8%, respectively), most patients hospitalized with diastolic HF (n = 1542) had an LVEF ≥ 50% (94.0%) (Figure). A much greater range of LVEFs were noted for those with hypertensive heart disease with HF (n = 18,092) and hypertensive heart disease with HF and CKD (n = 26,336) (Figure). While there was relatively good concordance between LVEF and the ICD-10 code-defined HF type for systolic HF, diastolic HF, and systolic and diastolic HF, these codes represent a small subset (~10%) of total HF hospitalizations.

Abstract 4122650: 1-year comparison of quadruple therapy sequencing strategies for heart failure with reduced ejection fraction using an individual-based state-transition microsimulation model

Introduction: Guidelines recommend quadruple therapy (angiotensin receptor blocker-neprilysin inhibitor [ARNI]), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose co-transporter 2 inhibitor [SGLT2I]) as the cornerstone of heart failure (HF) with reduced ejection fraction (HFrEF) management. Yet, guidelines do not propose a specific order of initiation and titration (or “sequencing strategy”) of these agents, due to the absence of trial evidence. Aims: To model the 1-year efficacy and harms of proposed HFrEF quadruple therapy sequencing strategies using a microsimulation model. Methods: We conducted an individual-based state-transition microsimulation modeling study to compare the 1-year cumulative incidence of death, total HF hospitalization, and adverse events with 6 different HFrEF medication sequencing strategies (emulating 2 different traditional strategies, 2 two-drug combinations, a "cluster" strategy, and four-drug "simultaneous" strategy), each with two versions (weekly or biweekly medication adjustments), applied to treatment-naïve outpatients with HFrEF. We modeled death as an incidence at 1 year, and total HF hospitalization (first and recurrent events) and adverse events (bradycardia, hyperkalemia, hypotension, and renal impairment) as incidence rates per 100 patient-years. Results: At 1 year, an estimated 15.5% died without treatment compared to 6.9% with the traditional sequence adjusted biweekly, and 5.2-6.3% with other sequencing strategies. Similarly, the HF hospitalization rate decreased from 32.8 per 100 patient-years with no treatment to 11.1 per 100 patient-years traditional sequencing adjusted biweekly, and 6.9-9 per 100 patient-years with other strategies. The incidence rates of medication-related adverse events per 100 patient-years were: hypotension (5.8-6.9), renal impairment (4.6-6.0), bradycardia (2.9-3.2), and hyperkalemia (approximately 0.5). Conclusions: For treatment-naïve outpatients with HFrEF, pharmacotherapy sequencing strategies that started 2 to 4 medications on the first visit reduced the risk of death and hospitalization at 1 year compared to a traditional sequencing strategy. Weekly medication adjustments did not outperform biweekly adjustments when &gt;=2 medications were started on the initial visit. These findings can inform clinicians and policymakers in developing HFrEF medication optimization programs with sequencing strategy protocols that fit the local practical context.

Angiotensin Receptor Neprilysin Inhibition and Cardiovascular Outcomes Across the Kidney Function Spectrum: The PARAGON-HF Trial.

Lower estimated glomerular filtration rate (eGFR) may be one of the major reasons for hesitation or failure to initiate potentially beneficial therapies in patients with heart failure (HF). This study sought to assess if the effects of sacubitril/valsartan (vs valsartan) on cardiovascular outcomes differ according to baseline kidney function in patients with HF with preserved ejection fraction. The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial was global clinical trial of 4,796 patients with chronic HF and left ventricular ejection fraction (LVEF)≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the effect of treatment on cardiovascular outcomes using Cox regression models, stratified by region, and assessed for differential treatment effects according to the baseline eGFR and ejection fraction. At randomization, mean eGFR was 67 ± 19mL/min/1.73m2; 1,955 (41%) participants had an eGFR<60mL/min/1.73m2. Compared with valsartan, sacubitril/valsartan reduced the primary cardiovascular outcome (cardiovascular death and total HF hospitalizations) to a greater extent among those with lower baseline eGFR (Pinteraction=0.07 for continuous eGFR), and was most pronounced for those with eGFR≤45mL/min/1.73m2 (RR:0.69; 95%CI: 0.51-0.94). The influence of eGFR on the treatment effect for cardiovascular death was nonlinear, with the most pronounced treatment effect for those with baseline eGFR<45mL/min/1.73m2 (HR: 0.65; 95%CI: 0.43-0.97). In further subgroup analyses according to LVEF and eGFR, the treatment effect for the primary outcome was most pronounced among those with LVEF≤57% and eGFR≤45mL/min/1.73m2 (HR: 0.66; 95%CI: 0.45-0.97). In the PARAGON-HF trial, the benefits of sacubitril/valsartan to reduce the frequency of HF hospitalizations and cardiovascular death were most apparent in patients with lower baseline eGFR and lower ejection fraction. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in HeartFailure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Vericiguat Global Study in Participants with Chronic Heart Failure: Design of the VICTOR trial.

In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy. The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo. VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF.

Efficacy and safety of intravenous iron therapy in heart failure patients with iron deficiency: a systematic review and meta-analysis of randomized controlled trials

Abstract Background Heart failure is a diverse life-threatening condition with complex biology and demanding therapeutic goals. Even when anemic patients are excluded, up to 59% of heart failure patients have low ferritin levels, making them especially vulnerable to iron deficiency. Purpose To assess the complete data derived from Randomized controlled trials concerning the benefits and safety of IV ferric carboxymaltose therapy among patients with heart failure with iron deficiency. Methods A systematic review and meta-analysis of randomized controlled trials obtained from PubMed, WOS, SCOPUS, EMBASE, and Cochrane up to August 31, 2023. We used RevMan V. 5.4 to pool dichotomous data using a risk ratio (RR) with a 95% confidence interval (CI). Results We included 14 randomized controlled trials with a total of 6,626 patients. The IV iron group was favored over the control group in reducing hospital admissions for heart failure (first event) (RR= 0.83, 95% CI 0.71 to 0.97; p = 0.02) and (total events) (RR= 0.81, 95% CI 0.74 to 0.89; p &amp;lt; 0.0001). Also, the iron group had a 21% lower risk in terms of cardiovascular death and hospital admission for HF (number of events, rate per 100 patients in a year) (RR= 0.79, 95% CI 0.74 to 0.85; p &amp;lt; 0.00001). Concerning the adverse events, both ferric carboxymaltose and ferric derisomaltose showed a beneficial effect in reducing the cardiac disorder (RR= 0.81, 95% CI 0.76 to 0.87; p &amp;lt;0.0001), and (RR= 0.82, 95% CI 0.71 to 0.95; p = 0.009), respectively. Conclusion IV iron infusion in patients with heart failure has a favorable safety profile. It reduces total hospitalizations for heart failure and cardiovascular mortality, with no effect on all-cause mortality, cardiovascular mortality alone, or first-time hospitalization for heart failure.

Prevalent and incident anemia in PARAGON-HF

Abstract Background Anemia is a common comorbidity in patients with heart failure (HF) and is associated with adverse prognosis. Renin-angiotensin system inhibitors (RASi) have been shown to lower hemoglobin levels, potentially related to direct reductions in erythropoetin levels and hematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anemia in patients with HF with mildly reduced or preserved ejection fraction. Methods PARAGON-HF was a global, multicenter randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction≥45%. Anemia was defined as hemoglobin &amp;lt;120 g/L in women and &amp;lt;130 g/L in men. We evaluated changes in hemoglobin, risks of incident anemia and new oral iron initiation during follow-up. We also assessed treatment effects on the primary composite endpoint of total HF hospitalizations (HFH) and cardiovascular (CV) death according to anemia status. Results Among 4,795 participants with a hemoglobin measurement available, 1,111 (23.2%) had anemia at randomization of which 3.5%, 77.7%, and 18.8% were characterized as micro-, normo-, and macrocytic anemia. 5.6% were treated with oral iron at baseline. Over a 2.7-year median follow-up period, patients with anemia were at nearly twice the risk of the primary outcome (21.6 vs. 11.5 per 100py; rate ratio 1.90; 95% CI: 1.62-2.21; P&amp;lt;0.001). Compared with valsartan, sacubitril/valsartan significantly slowed the decline in hemoglobin levels by 1.4 g/L (95% CI: 0.4-2.4 g/L; P = 0.005; Figure 1 Panel A). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anemia (30.3% vs. 37.6%; HR 0.76; 95% CI: 0.68-0.85; P&amp;lt;0.001; Figure 1 Panel B) and starting oral iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI: 0.67-0.97; P = 0.026; Figure 2). Treatment effects of sacubitril/valsartan vs. valsartan on the primary endpoint were consistent among patients with and without anemia (Pinteraction=1.00). Conclusions Among patients with HF with mildly reduced or preserved ejection fraction, treatment with sacubitril/valsartan resulted in slower declines in hemoglobin, lower rates of incident anemia, and fewer new initiations of iron therapy compared with RASi.

Clinical Correlates and Prognostic Impact of Cognitive Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemic attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first heart failure hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

Analysis of the PARAGON-HF Study Results Using Win Ratio.

The PARAGON-HF study (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) investigated the effect of sacubitril-valsartan in heart failure (HF) with preserved ejection fraction. The results, which were analyzed using conventional statistical methods, did not find a significant reduction in the primary composite end point of cardiovascular death and total hospitalization for HF. Recent clinical trials used win ratio statistics that enable the incorporation of multiple outcome aspects into the primary end point and can detect positive outcomes with fewer patients. In this study, we assessed the effect of sacubitril-valsartan on outcomes using the win ratio to analyze results from patients included in the PARAGON-HF study. In the PARAGON-HF study, 4822 patients with HF with preserved ejection fraction were randomized either to sacubitril-valsartan or valsartan groups. In the present study, the primary outcome was a hierarchical composite of time to cardiovascular death, total number of hospitalization for HF, time to first hospitalization for HF, time to renal composite outcome, and change in the Kansas City Cardiomyopathy Questionnaire total symptom score at 8 months analyzed using a win ratio statistical model. Using this approach, we found that a greater number of patients who received sacubitril-valsartan experienced clinical benefits compared with those who received valsartan (win ratio, 1.13 [95% CI, 1.04-1.23]; P=0.005). This clinical advantage was evident in patients regardless of whether the left ventricular ejection fraction was above or below the median, that is, the left ventricular ejection fraction of 57%, and regardless of sex (Pinteraction=0.76 for the left ventricular ejection fraction and 0.73 for sex). Employing the innovative win ratio approach, sacubitril-valsartan demonstrated significant clinical benefits among patients with HF with preserved ejection fraction. Notably, this benefit was observed irrespective of left ventricular ejection fraction and sex. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Sacubitril/valsartan reduces incident anaemia and iron therapy utilization in heart failure: The PARAGON-HF trial.

Renin-angiotensin system inhibitors (RASi) have been shown to lower haemoglobin levels, potentially related to reductions in erythropoietin levels and haematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anaemia in patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). PARAGON-HF was a global, multicentre randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction ≥45%. We evaluated haemoglobin trajectory and risks of incident anaemia and new iron therapy initiation during follow-up. Among 4795 participants, 1111 (23.2%) had anaemia at randomization and 5.6% were treated with iron at baseline. Over a median follow-up of 2.9 years, patients with anaemia were at significantly higher risk for total HF hospitalizations and cardiovascular death, compared with those without anaemia (21.6 vs. 11.5 per 100 patient-years; adjusted rate ratio 1.31; 95% confidence interval [CI] 1.12-1.54; p = 0.001). Sacubitril/valsartan slightly slowed the decline in haemoglobin levels by 0.1 g/dl (95% CI 0.0-0.2 g/dl; p = 0.005). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anaemia (30.3% vs. 37.6%; hazard ratio [HR] 0.76; 95% CI 0.68-0.85; p < 0.001) and starting iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI 0.67-0.97; p = 0.026). Treatment effects of sacubitril/valsartan versus valsartan on total HF hospitalizations and cardiovascular death were consistent among patients across the haemoglobin spectrum (pinteraction = 0.60). Among patients with HFmrEF/HFpEF, treatment with sacubitril/valsartan resulted in modestly smaller declines in haemoglobin, lower rates of incident anaemia, and fewer new initiations of iron therapy compared with RASi. ClinicalTrials.gov ID NCT01920711.

Mineralocorticoid receptor antagonists in heart failure: an individual patient level meta-analysis

Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisations and death in patients with heart failure and reduced ejection fraction (HFrEF), but the benefit in patients with heart failure and mildly reduced ejection fraction (HFmrEF) or heart failure and preserved ejection fraction (HFpEF) is unclear. We evaluated the effect of MRAs in four trials that enrolled patients with heart failure across the range of ejection fraction. This is a prespecified, individual patient level meta-analysis of the RALES (spironolactone) and EMPHASIS-HF (eplerenone) trials, which enrolled patients with HFrEF, and of the TOPCAT (spironolactone) and FINEARTS-HF (finerenone) trials, which enrolled patients with HFmrEF or HFpEF. The primary outcome of this meta-analysis was a composite of time to first hospitalisation for heart failure or cardiovascular death. We also estimated the effect of MRAs on components of this composite, total (first or repeat) heart failure hospitalisations (with and without cardiovascular deaths), and all-cause death. Safety outcomes were also assessed, including serum creatinine, estimated glomerular filtration rate, serum potassium, and systolic blood pressure. An interaction between trials and treatment was tested to examine the heterogeneity of effect in these populations. This study is registered with PROSPERO, CRD42024541487. 13 846 patients were included in the four trials. MRAs reduced the risk of cardiovascular death or heart failure hospitalisation (hazard ratio 0·77 [95% CI 0·72-0·83]). There was a statistically significant interaction by trials and treatment (p for interaction=0·0012) due to the greater efficacy in HFrEF (0·66 [0·59-0·73]) compared with HFmrEF or HFpEF (0·87 [0·79-0·95]). We observed significant reductions in heart failure hospitalisation in the HFrEF trials (0·63 [0·55-0·72]) and the HFmrEF or HFpEF trials (0·82 [0·74-0·91]). The same pattern was observed for total heart failure hospitalisations with or without cardiovascular death. Cardiovascular death was reduced in the HFrEF trials (0·72 [0·63-0·82]) but not in the HFmrEF or HFpEF trials (0·92 [0·80-1·05]). All-cause death was also reduced in the HFrEF trials (0·73 [0·65-0·83]) but not in the HFmrEF or HFpEF trials (0·94 [0·85-1·03]). With an MRA, the risk of hyperkalaemia was doubled compared with placebo (odds ratio 2·27 [95% CI 2·02-2·56]), but the incidence of serious hyperkalaemia (serum potassium >6·0 mmol/L) was low (2·9% vs 1·4%); the risk of hypokalaemia (potassium <3·5 mmol/L) was halved (0·51 [0·45-0·57]; 7% vs 14%). Steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF or HFpEF. None.

Efficacy and safety of low-dose digoxin in patients with heart failure. Rationale and design of the DECISION trial.

Digoxin is the oldest drug in cardiovascular (CV) medicine, and one trial conducted >25 years ago showed a reduction in heart failure (HF) hospitalizations but no effect on mortality. However, later studies suggested that the dose of digoxin used in that trial (and other studies) may have been too high. The DECISION (Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands) trial will examine the efficacy and safety of low-dose digoxin in HF patients with reduced or mildly reduced left ventricular ejection fraction (LVEF) with a background of contemporary HF treatment. The DECISION trial is a randomized, double-blind, parallel-group, placebo-controlled event-driven outcome trial which will investigate the efficacy and safety of low-dose digoxin in patients with chronic HF and LVEF <50%. Both patients with sinus rhythm and atrial fibrillation will be enrolled and will be randomized (1:1) to low-dose digoxin or matching placebo. To maintain a target serum digoxin concentration of 0.5-0.9 ng/ml, dose adjustments are made throughout follow-up based on serum digoxin measurements with dummy values for the placebo group. The primary endpoint is a composite of CV mortality and total HF hospitalizations or total urgent hospital visits for worsening HF, and all endpoints are adjudicated blindly by a Clinical Event Committee. The estimated sample size was 982 patients who will be followed for a median of 3 years, and in December 2023 enrolment was completed after 1002 patients. The DECISION trial will provide important evidence regarding the effect of (low-dose) digoxin on CV mortality and total HF hospitalizations and urgent hospital visits when added to contemporary HF treatment of patients with reduced or mildly reduced LVEF. ClinicalTrials.gov identifier: NCT03783429.

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.

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. 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). 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. ClinicalTrials.gov NCT01920711.