Novel Trial Design: CHIEF-HF.

BACKGROUND: The expense of clinical trials mandates new strategies to efficiently generate evidence and test novel therapies. In this context, we designed a decentralized, patient-centered randomized clinical trial leveraging mobile technologies, rather than in-person site visits, to test the efficacy of 12 weeks of canagliflozin for the treatment of heart failure, regardless of ejection fraction or diabetes status, on the reduction of heart failure symptoms. METHODS: One thousand nine hundred patients will be enrolled with a medical record-confirmed diagnosis of heart failure, stratified by reduced (≤40%) or preserved (>40%) ejection fraction and randomized 1:1 to 100 mg daily of canagliflozin or matching placebo. The primary outcome will be the 12-week change in the total symptom score of the Kansas City Cardiomyopathy Questionnaire. Secondary outcomes will be daily step count and other scales of the Kansas City Cardiomyopathy Questionnaire. RESULTS: The trial is currently enrolling, even in the era of the coronavirus disease 2019 (COVID-19) pandemic. CONCLUSIONS: CHIEF-HF (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) is deploying a novel model of conducting a decentralized, patient-centered, randomized clinical trial for a new indication for canagliflozin to improve the symptoms of patients with heart failure. It can model a new method for more cost-effectively testing the efficacy of treatments using mobile technologies with patient-reported outcomes as the primary clinical end point of the trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04252287.

Assessment of Risk Factors and Clinical Outcomes in Hospitalized COVID-19 Patients with Candida spp. Co-infections: Species Distribution and Antifungal Susceptibility Patterns of Isolates.

INTRODUCTION: Fungal co-infections are considered an important complication in hospitalized patients with SARS-CoV-2 that can be attributed to disease aggravation, increased mortality, and poor outcomes. This study was conducted to determine the species distribution and antifungal susceptibility patterns of Candida isolates from hospitalized COVID-19 patients in Shiraz, Iran, in addition to associated risk factors and outcomes of co-infections with Candida species. MATERIALS AND METHODS: In this single-center study, a total of 106 hospitalized COVID-19 patients were evaluated for clinical characteristics and outcomes. Species identification was performed by ITS1-5.8S-ITS2 gene sequencing. Antifungal susceptibility testing to fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, amphotericin B, and nystatin was determined according to the M27-A3/S4 CLSI protocol. RESULTS: Candida species were recovered from 48% (51/106) of hospitalized COVID-19 patients. Statistical analysis showed that patients who had heart failure, bacterial co-infection, and were receiving empirical antifungal therapy had a higher risk of developing Candida co-infection. In total, 71 Candida isolates were recovered, of which C. albicans (69%) was the most prevalent isolate. The majority of the Candida isolates were susceptible to all classes of tested antifungal drugs. DISCUSSION: Our results elucidate a high rate of Candida co-infections among hospitalized COVID-19 patients. Comorbidities such as heart failure, HTN, COPD, bacterial infections as well as therapeutic interventions including catheterization, mechanical ventilation, and ICU admission increased the risk of Candida spp. isolation from the bloodstream, respiratory tract and urine samples, which led to a higher in-hospital mortality rate. Additionally, obtained data clarified that empirical antifungal therapy was not as successful as anticipated.

Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis.

INTRODUCTION: AFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron deficiency (ID) utilizing prespecified COVID-19 analyses. MATERIAL AND METHODS: We meta-analyzed efficacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF. RESULTS: FCM/FDI reduced the primary endpoint (RR = 0.81, 95% CI 0.69-0.95, p = 0.01, I2 = 0%), with the number needed to treat (NNT) being 7. Power was 73% and findings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Effects of FCM/FDI were neutral concerning CVD (OR = 0.88, 95% CI 0.71-1.09, p = 0.24, I2 = 0%). Power was 21% while findings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n = 3258) confirmed positive effects of FCM/FDI on the primary endpoint (RR = 0.77, 95% CI 0.66-0.90, p = 0.0008, I2 = 0%), with NNT being 6. Power was 91% while findings were robust (FI of 147 and FQ of 0.045). Effect on CVD was neutral (RR = 0.87, 95% CI 0.71-1.07, p = 0.18, I2 = 0%). Power was 10% while findings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR = 0.85, 95% CI 0.71-1.02, p = 0.09, I2 = 0%), vascular disorder (OR = 0.84, 95% CI 0.57-1.25, p = 0.34, I2 = 0%) and general or injection-site related disorders (OR = 1.39, 95% CI 0.88-1.29, p = 0.16, I2 = 30%) were comparable between groups. There was no relevant heterogeneity (I2 > 50%) between the trials for any of the analyzed outcomes. CONCLUSIONS: Use of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD, while effects on CVD alone are based on available level of data indeterminate. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI.

Intravenous iron in patients with heart failure and iron deficiency: an updated meta-analysis.

AIMS: For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about the effects in subgroups and the impact on mortality. We conducted a meta-analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF. METHODS AND RESULTS: We identified randomized trials published between 1 January 2000 and 5 November 2022 investigating the effect of IV iron versus standard care/placebo in patients with HF and ID in any clinical setting, regardless of HF phenotype. Trials of oral iron or not in English were not included. The main outcomes of interest were a composite of HHF and cardiovascular death (CVD), on HHF alone and on cardiovascular and all-cause mortality. Ten trials were identified with 3373 participants, of whom 1759 were assigned to IV iron. IV iron reduced the composite of recurrent HHF and CVD (rate ratio 0.75, 95% confidence interval [CI] 0.61-0.93; p < 0.01) and first HHF or CVD (odds ratio [OR] 0.72, 95% CI 0.53-0.99; p = 0.04). Effects on cardiovascular (OR 0.86, 95% CI 0.70-1.05; p = 0.14) and all-cause mortality (OR 0.93, 95% CI 0.78-1.12; p = 0.47) were inconclusive. Results were similar in analyses confined to the first year of follow-up, which was less disrupted by the COVID-19 pandemic. Subgroup analyses found little evidence of heterogeneity for the effect on the primary endpoint, although patients with transferrin saturation <20% (OR 0.67, 95% CI 0.49-0.92) may have benefited more than those with values ≥20% (OR 0.99, 95% CI 0.74-1.30) (heterogeneity p = 0.07). CONCLUSION: In patients with HF and ID, this meta-analysis suggests that IV iron reduces the risk of HHF but whether this is associated with a reduction in cardiovascular or all-cause mortality remains inconclusive.

Experiences of Facilitators and Inhibitors to Treatment Adherence in Patients with Heart Failure.

Treatment adherence is a fundamental aspect of heart failure (HF) management. This study aimed to explore the experiences of facilitators and inhibitors of treatment adherence in patients with HF. This descriptive qualitative study was conducted from May 2020 to June 2021. Participants including people with HF, their family caregivers and physicians, and nurses were selected purposefully, with the aim of obtaining sufficient information power. Semi-structured interviews were used to collect data. Data were analyzed using thematic analysis. Two main themes "the driving forces behind treatment adherence" and "the deterrent forces behind treatment adherence" emerged from the analysis. The first theme contained the following subthemes: "supportive family," "positive personality characteristics," and "having health literacy." The second theme consisted of "negligence," "psychological problems," "cultural, social, and economic problems," "physical limitations," and "lack of self-care management knowledge." Nurses can consider facilitators and inhibitors of treatment adherence in designing educational and care programs for patients with HF.

Potassium reduction with sodium zirconium cyclosilicate in patients with heart failure.

AIMS: Several patients with heart failure and reduced ejection fraction (HFrEF) do not receive renin-angiotensin-aldosterone system (RAAS) inhibitors at the recommended dose or at all, frequently due to actual or feared hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is an orally administered non-absorbed intestinal potassium binder proven to lower serum potassium concentrations. METHODS AND RESULTS: PRIORITIZE-HF was an international, multicentre, parallel-group, randomized, double-blind, placebo-controlled study to evaluate the benefits and risks of using SZC to intensify RAAS inhibitor therapy. Patients with symptomatic HFrEF were eligible and randomly assigned to receive SZC 5 g or placebo once daily for 12 weeks. Doses of study medication and RAAS inhibitors were titrated during the treatment period. The primary endpoint was the proportion of patients at 12 weeks in the following categories: (i) any RAAS inhibitor at less than target dose, and no MRA; (ii) any RAAS inhibitor at target dose and no MRA; (ii) MRA at less than target dose; and (iv) MRA at target dose. Due to challenges in participant management related to the COVID-19 pandemic, the study was prematurely terminated with 182 randomized patients. There was no statistically significant difference in the distribution of patients by RAAS inhibitor treatment categories at 3 months (P = 0.43). The proportion of patients at target MRA dose was numerically higher in the SZC group (56.4%) compared with the placebo group (47.0%). Overall, SZC was well tolerated. CONCLUSIONS: PRIORITIZE-HF was terminated prematurely due to COVID-19 and did not demonstrate a statistically significant increase in the intensity of RAAS inhibitor therapies with the potassium-reducing agent SZC compared with placebo.

Benefit of natriuresis and cardiac resynchronisation therapy in acute decompensated heart failure with cardiorenal syndrome and hypernatraemia.

A man in his eighties with acute heart failure and cardiorenal syndrome developed severe hypernatraemia with diuresis. In this situation, palliation is often considered when renal replacement therapy is inappropriate. The literature to guide treatment of dysnatraemia in this setting is limited. Diuretics often worsen hypernatraemia and fluid replacement exacerbates heart failure. We describe a successful approach to this clinical Catch-22: sequential nephron blockade with intravenous 5% dextrose. Seemingly counterintuitive, the natriuretic effect of this combination had not previously been compared with diuretic monotherapy for heart failure. Yet this immediately effective strategy generated a high natriuresis-to-diuresis ratio and functioned as a bridge to cardiac resynchronisation therapy (CRT). In conjunction with a low salt diet, CRT facilitated the maintenance of sodium homeostasis and fluid balance. Thus, by improving the underlying pathophysiology (ie, inadequate cardiac output), CRT may enhance the outcomes of patients with cardiorenal syndrome and hypernatraemia.

Rationale and design of the Effects of intensive Systolic blood Pressure lowering treatment in reducing RIsk of vascular evenTs (ESPRIT): A multicenter open-label randomized controlled trial.

BACKGROUND: Lowering blood pressure (BP) effectively reduces the risk of cardiovascular (CV) events in high CV risk individuals. The optimal target of BP lowering among high CV risk individuals remains unclear. METHODS: The Effects of intensive Systolic blood Pressure lowering treatment in reducing RIsk of vascular evenTs (ESPRIT) trial is a multi-center, open-label, randomized controlled trial to compare the efficacy and safety of intensive BP lowering strategy (Systolic BP target <120 mm Hg) and standard BP lowering strategy (Systolic BP target <140 mm Hg). Participants aged at least 50 years old with baseline systolic BP within 130 to 180 mm Hg at high CV risk, defined by established CV diseases or 2 major CV risk factors, were enrolled. The primary outcome is a composite CV outcome of myocardial infarction, coronary or non-coronary revascularization, hospitalization or emergency department visit from new-onset heart failure or acute decompensated heart failure, stroke, or death from CV diseases. Secondary outcomes include components of the primary composite outcome, all-cause death, a composite of the primary outcome or all-cause death, kidney outcomes, as well as cognitive outcomes. RESULTS: Despite of the interruption of COVID-19 outbreak, the ESPRIT trial successfully enrolled and randomized 11,255 participants from 116 hospitals or primary health care institutions. The mean age of the participants was 64.6 (standard deviation [SD], 7.1) years, 4,650 (41.3%) were women. Among them 28.9%, 26.9% and 38.7% had coronary heart disease, prior stroke and diabetes mellitus, respectively. COVID-19 outbreak affected the BP lowering titration process of the trial, and delayed the reach of BP target. CONCLUSIONS: The ESPRIT trial will address the important question on the optimal BP lowering target for individuals with high CV risk, and generate high quality evidence for treating millions of patients from East Asian countries.

Managing Covid-19 in patients with heart failure: current status and future prospects.

INTRODUCTION: COVID-19 may contribute to decompensation of previously stable chronic HF or cause a de-novo heart failure, which may come from the hyperinflammatory response and subsequent increase in metabolic demand. AREAS COVERED: Two independent investigators searched MEDLINE (via PubMed), Europe PMC, and ScienceDirect databases with the following search terms: COVID-19, heart failure, COVID-19 drugs, heart failure drugs, and device therapy. All of the included full-text articles were rigorously evaluated by both authors in case there was disagreement about whether research should be included or not. In total, 157 studies were included and underwent extensive reading by the authors. EXPERT OPINION: The World Health Organization (WHO) and the National Institute of Health (NIH) have published COVID-19 drug recommendations, although recommendations for HF-specific drug choices in COVID-19 are still lacking. We hope that this review can answer the void of comprehensive research data regarding the management options of HF in the COVID-19 condition so that clinicians can at least choose a more beneficial therapy or avoid combination therapies that have a high burden of side effects on HF; thus, morbidity and mortality in COVID-19 patients with HF may be reduced.

Review of Hydroxychloroquine Cardiotoxicity: Lessons From the COVID-19 Pandemic.

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) pandemic has popularized the usage of hydroxychloroquine and chloroquine (HCQ/CQ) as treatments for COVID-19. Previously used as anti-malarial and now commonly used in rheumatologic conditions, preliminary in vitro studies have demonstrated these medications also have anti-viral properties. Retinopathy and neuromyopathy are well recognized complications of using these treatments; however, cardiotoxicity is under-recognized. This review will discuss the implications and cardiotoxicity of HCQ/CQ, their mechanisms of action, and their utility in COVID-19. RECENT FINDINGS: Early clinical trials demonstrated a modest benefit of HCQ in COVID-19, causing a push for the usage of it. However, further large multi-center randomized control centers, demonstrated no benefit, and even a trend towards worse outcomes. The predominant cardiac complication observed with HCQ in COVID-19 was cardiac arrhythmias and prolonging of the QT interval. However, with chronic usage of HCQ/CQ, the development of heart failure (HF) and cardiomyopathy (CM) can occur. Although, most adverse cardiac events related to HCQ/CQ usage in COVID-19 were secondary to conduction disorders given the short duration of treatment, HCQ/CQ can cause CM and HF, with chronic usage. Given the insufficient evidence, HCQ/CQ usage in COVID-19 is not routinely recommended, especially with novel therapies now being developed and used. Additionally, usage of HCQ/CQ should prompt initial cardiac evaluation with ECG, and yearly monitoring, with consideration for advanced imaging if clinically warranted. The diagnosis of HCQ/CQ cardiomyopathy is important, as prompt cessation can allow for recovery when these changes are still reversible.

Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain. METHODS: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis. RESULTS: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).

A multicenter program for electronic health record screening for patients with heart failure with preserved ejection fraction: Lessons from the DELIVER-EHR initiative.

Efficiency in clinical trial recruitment and enrollment remains a major challenge in many areas of clinical medicine. In particular, despite the prevalence of heart failure with preserved ejection fraction (HFpEF), identifying patients with HFpEF for clinical trials has proven to be especially challenging. In this manuscript, we review strategies for contemporary clinical trial recruitment and present insights from the results of the DELIVER Electronic Health Record (EHR) Screening Initiative. The DELIVER trial was designed to evaluate the effects of dapagliflozin on clinical outcomes in patients with HFpEF. Within this trial, the multicenter DELIVER EHR Screening Initiative utilized EHR-based techniques in order to improve recruitment at selected sites in the United States. For this initiative, we developed and deployed a computable phenotype from the trial's eligibility criteria along with additional EHR tools at interested sites. Sites were then surveyed at the end of the program regarding lessons learned. Six sites were recruited, trained, and supported to utilize the EHR methodology and computable phenotype. Sites found the initiative to be helpful in identifying eligible patients and cited the individualized expert technical support as a critical factor in utilizing the program effectively. We found that the major challenge of implementation was the process of converting traditional inclusion/exclusion criteria into a computable phenotype within an established and ongoing trial. Other significant challenges noted by sites were the following: impact of the COVID-19 pandemic, engagement/support by local institutions, and limited availability of internal EHR experts/resources to execute programming. The study represents a proof-of-concept in the ability to utilize EHR-based tools in clinical trial recruitment for patients with HFpEF and provides important lessons for future initiatives. ClinicalTrials.gov Identifier: NCT03619213.

Empagliflozin reduces markers of acute kidney injury in patients with acute decompensated heart failure.

AIMS: In this prospective, placebo-controlled, double-blind, exploratory study, we examined early and more delayed effects of empagliflozin treatment on haemodynamic parameters (primary endpoint: cardiac output) and kidney function including parameters of acute kidney injury (AKI) in patients with acute decompensated heart failure (HF). METHODS AND RESULTS: Patients with acute decompensated HF with or without diabetes were randomized to empagliflozin 10 mg or placebo for 30 days. Haemodynamic, laboratory, and urinary parameters were assessed after 6 h, 1 day, 3 days, 7 days, and 30 days of treatment. Median time between hospital admission and randomization was 72 h. Baseline characteristics were not different in the empagliflozin (n = 10) and placebo (n = 9) groups. Empagliflozin led to a significant increase in urinary glucose excretion throughout the study (baseline: 37 ± 15 mg/24 h; Day 1: 14 565 ± 8663 mg/24 h; P = 0.001). Empagliflozin did not affect the primary endpoint of cardiac index or on systemic vascular resistance index at any time point. However, empagliflozin significantly reduced parameters of AKI (urinary TIMP-2 and IGFBP7 by NephroCheck® as indicators of tubular kidney damage), which became significant after 3 days of treatment [placebo: 1.1 ± 1.1 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.02] and remained significant at the 7 day time point [placebo: 2.5 ± 3.8 (ng/mL)2 /1000; empagliflozin: 0.3 ± 0.2 (ng/mL)2 /1000; P = 0.003]. CONCLUSIONS: In this study, empagliflozin treatment did not affect haemodynamic parameters but significantly reduced markers of tubular injury in patients with acute decompensated HF.

Targeting and Modulation of the Natriuretic Peptide System in Covid-19: A Single or Double-Edged Effect?

Natriuretic peptide system (NPS) is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and natriuretic peptide precursor C (NPC), that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase (NEP), also known as neprilysin. Coronavirus disease 2019 (Covid-19) pandemic may lead to acute lung injury (ALI) and/or respiratory distress syndrome (ARDS). The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs and may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in managing Covid-19.