Optimization of Evidence-Based Heart Failure Medications After an Acute Heart Failure Admission: A Secondary Analysis of the STRONG-HF Randomized Clinical Trial.

Importance: The Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro-Brain Natriuretic Peptide Testing of Heart Failure Therapies (STRONG-HF) trial strived for rapid uptitration aiming to reach 100% optimal doses of guideline-directed medical therapy (GDMT) within 2 weeks after discharge from an acute heart failure (AHF) admission. Objective: To assess the association between degree of GDMT doses achieved in high-intensity care and outcomes. Design, Setting, and Participants: This was a post hoc secondary analysis of the STRONG-HF randomized clinical trial, conducted from May 2018 to September 2022. Included in the study were patients with AHF who were not treated with optimal doses of GDMT before and after discharge from an AHF admission. Data were analyzed from January to October 2023. Interventions: The mean percentage of the doses of 3 classes of HF medications (renin-angiotensin system inhibitors, ß-blockers, and mineralocorticoid receptor antagonists) relative to their optimal doses was computed. Patients were classified into 3 dose categories: low (<50%), medium (≥50% to <90%), and high (≥90%). Dose and dose group were included as a time-dependent covariate in Cox regression models, which were used to test whether outcomes differed by dose. Main Outcome Measures: Post hoc secondary analyses of postdischarge 180-day HF readmission or death and 90-day change in quality of life. Results: A total of 515 patients (mean [SD] age, 62.7 [13.4] years; 311 male [60.4%]) assigned high-intensity care were included in this analysis. At 2 weeks, 39 patients (7.6%) achieved low doses, 254 patients (49.3%) achieved medium doses, and 222 patients (43.1%) achieved high doses. Patients with lower blood pressure and more congestion were less likely to be uptitrated to optimal GDMT doses at week 2. As a continuous time-dependent covariate, an increase of 10% in the average percentage optimal dose was associated with a reduction in 180-day HF readmission or all-cause death (primary end point: adjusted hazard ratio [aHR], 0.89; 95% CI, 0.81-0.98; P = .01) and a decrease in 180-day all-cause mortality (aHR, 0.84; 95% CI, 0.73-0.95; P = .007). Quality of life at 90 days, measured by the EQ-5D visual analog scale, improved more in patients treated with higher doses of GDMT (mean difference, 0.10; 95% CI, -4.88 to 5.07 and 3.13; 95% CI, -1.98 to 8.24 points in the medium- and high-dose groups relative to the low-dose group, respectively; P = .07). Adverse events to day 90 occurred less frequently in participants with HIC who were prescribed higher GDMT doses at week 2. Conclusions and Relevance: Results of this post hoc analysis of the STRONG-HF randomized clinical trial show that, among patients randomly assigned to high-intensity care, achieving higher doses of HF GDMT 2 weeks after discharge was feasible and safe in most patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03412201.

Patiromer for the management of hyperkalemia in heart failure with reduced ejection fraction: the DIAMOND trial.

AIMS: To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13-43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: -0.10 mmol/l (95% confidence interval, CI -0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. CONCLUSION: Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

Iron deficiency in pulmonary arterial hypertension: perspectives.

In left heart failure, iron supplementation (IS) is a first-line treatment option, regardless of anemia. Pulmonary arterial hypertension (PAH), a rare disease leading to right heart failure, is also associated with iron deficiency. While it is a much debated topic, recent evidence demonstrate that restoration of iron stores results in improved right ventricular function and exercise tolerance. Hence, IS may also be considered as an option in the treatment of PAH.

Diagnosis and Treatment of Iron Deficiency in Heart Failure: OFICSel study by the French Heart Failure Working Group.

AIMS: Iron deficiency (ID) occurs in about 50% of patients with heart failure (HF). The European Society of Cardiology (ESC) recommends ID diagnostic testing in newly diagnosed patients with HF and during follow-up, with intravenous iron supplementation (IS) only recommended in patients with HF with reduced ejection fraction (HFrEF). This study aimed to assess prevalence, clinical characteristics, and application of ESC guidelines for ID and IS in patients with HF in the real-life clinical setting. METHODS AND RESULTS: The French transversal multicentre OFICSel registry (300 cardiologists) conducted in 2017 included patients hospitalized for HF at least once in the previous 5 years. Diverse adult patients were eligible including inpatients and outpatients and those with acute and chronic HF. Data were collected from cardiologists and patients using study-specific surveys. Data included demographic and clinical data, as well as HF and ID management data. Overall, 2822 patients, mainly male (69.3%) with a median age of 69 years (interquartile range 58-78), were included. A total of 1075 patients (38.1%) were tested for ID, with 364 (33.9%) diagnosed. Of these, 168 (46.2%) received IS: 128 (76.2%) intravenous IS and 40 (23.8%) oral. Among the 201 patients with HFrEF diagnosed with ID, 99 (49.3%) received IS: 79 (79.8%) intravenous IS and 20 (20.2%) oral. CONCLUSIONS: In clinical practice, only one-third of patients with HF had a diagnostic test for ID. In patients with ID with HFrEF, only 39.3% received intravenous IS as recommended. Thus, in general, cardiologists should be encouraged to follow the ESC guidelines to ensure optimal treatment for patients with HF.

Towards Holistic Heart Failure Management-How to Tackle the Iron Deficiency Epidemic?

PURPOSE OF REVIEW: Heart failure (HF) is a common, costly, disabling, and deadly clinical syndrome and often associated with one or several co-morbidities complicating its treatment or worsening its symptoms. During the last decade, iron deficiency (ID) got recognized as a frequent, debilitating yet easily treatable co-morbidity in HF. In this review, we focus on new evidence that emerged during the last 5 years and discuss the epidemiology, the causes, and the clinical consequences of ID in HF. RECENT FINDINGS: Apart from replenishing iron stores, intravenous iron improves patients' symptoms, perceived quality of life (QoL), exercise capacity, and hospitalization rates. These beneficial effects cannot be attributed to oral iron, as increased hepcidin levels, typical in inflammatory states such as HF, preclude resorption of iron from the gut. Intravenous iron is the only valid treatment option for ID in HF. However, there are several burning research questions and gaps in evidence remaining in this research field.

HypnosIS to faciLitate trans-Esophageal echocardiograPhy Tolerance: The I-SLEPT study.

BACKGROUND: Trans-oesophageal echocardiography (TOE) is one of the major diagnostic tests in cardiovascular medicine, but the procedure is associated with some discomfort for the patient. AIM: To determine the additive value of hypnosis as a means of improving patient comfort during TOE. METHODS: We randomly assigned 98 patients with non-emergency indications for TOE to a 30-minute hypnosis session combined with topical oropharyngeal anaesthesia (HYP group) or topical oropharyngeal anaesthesia only (CTRL group) before the procedure. The primary efficacy endpoint was the level of patient discomfort assessed using a visual analogue scale (VAS). RESULTS: The VAS score was significantly reduced in the HYP group compared with the CTRL group (6 [5; 8] vs. 7 [5; 9]; P=0.046). No statistically significant differences were observed in terms of procedure failure (HYP group 2.2% vs. CTRL group 3.9%; P=1.00) and procedure length (HYP group 7 [5; 11] minutes vs. CTRL group 8 [7; 11] minutes; P=0.29). However, the patients' subjective estimations of the length of the procedure were significantly shorter in the HYP group than in the CTRL group (8 [5; 10] vs. 10 [10; 20] minutes; P<0.0001). There were no major adverse events in either group. The reported minor events rate was lower in the HYP group (36% vs. 57%; P=0.04). CONCLUSION: Hypnosis is an efficient alternative or complementary method for improving patient comfort during TOE.

High prevalence of iron deficiency in patients with acute decompensated heart failure.

AIMS: Limited data are available on iron parameters in patients hospitalized for decompensation of chronic heart failure. METHODS AND RESULTS: Iron parameters of patients hospitalized for decompensation of chronic heart failure were prospectively assessed during the 72 h after hospital admission. Iron deficiency was defined according to the 2012 European Society of Cardiology Guidelines. Overall, 411 men (75 ± 12 years; 75% NYHA functional classes III/IV) and 421 women (81 ± 11 years; 71% NYHA classes III/IV) were evaluated. The prevalence of iron deficiency was 69% in men and 75% in women (including 41% and 49% with absolute iron deficiency, respectively). The prevalence of anaemia in men (<13 g/dL) was 68% and in women (<12 g/dL) it was 52%. Among non-anaemic patients, the prevalence of iron deficiency was 57% in men and 79% in women. Only 9% of patients received iron supplementation at the time of admission (oral, 9%; intravenous, 0.2%). Multivariate analysis showed that anaemia and antiplatelet treatment in men, and diabetes and low C-reactive protein in women, were independently associated with iron deficiency. CONCLUSIONS: Iron deficiency is very common in patients admitted for acute decompensated heart failure, even among non-anaemic patients. Given the benefit of iron therapy in chronic heart failure, our results emphasize the need to assess iron status not only in chronic heart failure patients, but even more so in those admitted for worsening heart failure, regardless of gender, heart failure severity, or haemoglobin level. Initiating iron therapy in hospitalized heart failure patients needs to be investigated.

Iron deficiency: an emerging therapeutic target in heart failure.

In patients with heart failure, iron deficiency is frequent but overlooked, with a prevalence of 30%-50%. Since it contributes to cardiac and peripheral muscle dysfunction, iron deficiency is associated with poorer clinical outcomes and a greater risk of death, independent of haemoglobin level. Therefore, iron deficiency emerges as a new comorbidity and a therapeutic target of chronic heart failure in addition to chronic renal insufficiency, anaemia and diabetes. In a series of placebo-controlled, randomised studies in patients with heart failure and iron deficiency, intravenous iron had a favourable effect on exercise capacity, functional class, LVEF, renal function and quality of life. These clinical studies were performed in the context of a renewed interest in iron metabolism. During the past 10 years, knowledge about the transport, storage and homeostasis of iron has improved dramatically, and new molecules involved in iron metabolism have been described (eg, hepcidin, ferroportin, divalent metal transporter 1). Recent European guidelines recommend the monitoring of iron parameters (ie, serum ferritin, transferrin saturation) for all patients with heart failure. Ongoing clinical trials will explore the benefits of iron deficiency correction on various heart failure parameters.

Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice.

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.

Mortality and morbidity reduction with Candesartan in patients with chronic heart failure and left ventricular systolic dysfunction: results of the CHARM low-left ventricular ejection fraction trials.

BACKGROUND: Patients with symptomatic chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) have a high risk of death and hospitalization for CHF deterioration despite therapies with angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and even an aldosterone antagonist. To determine whether the angiotensin-receptor blocker (ARB) candesartan decreases cardiovascular mortality, morbidity, and all-cause mortality in patients with CHF and depressed LVEF, a prespecified analysis of the combined Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) low LVEF trials was performed. CHARM is a randomized, double-blind, placebo-controlled, multicenter, international trial program. METHODS AND RESULTS: New York Heart Association (NYHA) class II through IV CHF patients with an LVEF of < or =40% were randomized to candesartan or placebo in 2 complementary parallel trials (CHARM-Alternative, for patients who cannot tolerate ACE inhibitors, and CHARM-Added, for patients who were receiving ACE inhibitors). Mortality and morbidity were determined in 4576 low LVEF patients (2289 candesartan and 2287 placebo), titrated as tolerated to a target dose of 32 mg once daily, and observed for 2 to 4 years (median, 40 months). The primary outcome (time to first event by intention to treat) was cardiovascular death or CHF hospitalization for each trial, with all-cause mortality a secondary end point in the pooled analysis of the low LVEF trials. Of the patients in the candesartan group, 817 (35.7%) experienced cardiovascular death or a CHF hospitalization as compared with 944 (41.3%) in the placebo group (HR 0.82; 95% CI 0.74 to 0.90; P<0.001) with reduced risk for both cardiovascular deaths (521 [22.8%] versus 599 [26.2%]; HR 0.84 [95% CI 0.75 to 0.95]; P=0.005) and CHF hospitalizations (516 [22.5%] versus 642 [28.1%]; HR 0.76 [95% CI 0.68 to 0.85]; P<0.001). It is important to note that all-cause mortality also was significantly reduced by candesartan (642 [28.0%] versus 708 [31.0%]; HR 0.88 [95% CI 0.79 to 0.98]; P=0.018). No significant heterogeneity for the beneficial effects of candesartan was found across prespecified and subsequently identified subgroups including treatment with ACE inhibitors, beta-blockers, an aldosterone antagonist, or their combinations. The study drug was discontinued because of adverse effects by 23.1% of patients in the candesartan group and 18.8% in the placebo group; the reasons included increased creatinine (7.1% versus 3.5%), hypotension (4.2% versus 2.1%), and hyperkalemia (2.8% versus 0.5%), respectively (all P<0.001). CONCLUSIONS: Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF < or =40% when added to standard therapies including ACE inhibitors, beta-blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted.