Review of the National Institute for Health and Care Excellence guidelines on chronic heart failure.

Guidelines are more accessible than ever and represent an important tool in clinical practice. The National Institute for Health and Care Excellence (NICE) has developed recommendations for heart failure diagnosis and management based not only on morbidity and mortality trial outcome data but also in-depth economic analysis, with a focus on generalisability to UK National Health Service clinical practice. There is broad consistency in structure and content between NICE guidelines and those produced by major cardiovascular organisations such as the American College of Cardiology/American Heart Association and the European Society of Cardiology. However, important differences do exist-largely attributable to publication timing-a factor that is enhanced by the rapid pace of heart failure research. This article reviews the most recent iteration of NICE chronic heart failure guidelines and compares them with major guidelines on an international scale. Variations in recommendations will be explored including implications for NICE guideline updates in the future.

Where Are We With Treatment and Prevention of Heart Failure in Patients Post-Myocardial Infarction?

As a result of the widespread use of reperfusion therapies and secondary prevention over the last 30 years, there has been a dramatic reduction in the risk of mortality and development of heart failure (HF) following acute myocardial infarction (MI). Despite this, the development of chronic HF remains a common occurrence in the days, months, and years following MI. Neurohormonal inhibition remains the mainstay of pharmacologic prevention of HF following MI, with recent trials showing an additive benefit of a neprilysin inhibitor or a sodium glucose co-transporter 2 inhibitor in reducing the risk of development of HF but no significant effect on mortality. Novel imaging tools may help refine risk stratification in high-risk patients and allow greater targeting of preventative therapies in patients most likely to benefit. Research is ongoing into novel therapies aiming to minimize the degree of myocardial damage and prevention of progressive adverse remodeling following MI.

Effect of PCI on Health Status in Ischemic Left Ventricular Dysfunction: Insights From REVIVED-BCIS2.

BACKGROUND: In the REVIVED-BCIS2 (Revascularization for Ischemic Ventricular Dysfunction) trial, percutaneous coronary intervention (PCI) did not reduce the incidence of death or hospitalization for heart failure (HHF). OBJECTIVES: This prespecified secondary analysis investigated the effect of PCI on health status measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) combined with the primary outcome in a win ratio. METHODS: Participants with severe ischemic left ventricular dysfunction were randomized to either PCI in addition to optimal medical therapy (OMT) (PCI) or OMT alone (OMT). The primary outcome was a hierarchical composite of all-cause death, HHF, and KCCQ-Overall Summary Score (OSS) at 24 months analyzed using the unmatched win ratio. The key secondary endpoint was a KCCQ-OSS responder analysis. RESULTS: A total of 347 participants were randomized to PCI and 353 to OMT. Median age was 70.0 years (Q1-Q3: 63.3-76.1 years). Mean left ventricular ejection fraction was 27.0 ± 6.7%. PCI did not improve the primary endpoint (win ratio for PCI vs OMT: 1.05; 95% CI: 0.88-1.26; P = 0.58). PCI resulted in more KCCQ-OSS responders than OMT at 6 months (54.1% vs 40.7%; OR: 1.96; 95% CI: 1.41-2.71; P < 0.001) and fewer deteriorators (25.2% vs 31.4%; OR: 0.69; 95% CI: 0.47-1.00; P = 0.048). PCI did not impact KCCQ-OSS responders or deteriorators at 12 or 24 months. CONCLUSIONS: PCI did not improve the hierarchical composite of death, HHF, and health status at 2 years. PCI improved KCCQ-OSS at 6 months, but this benefit was not sustained to 1- or 2-year follow-up. (Revacularization for Ischemic Ventricular Dysfunction [REVIVED-BCIS2]; NCT01920048).

Intravenous iron and SGLT2 inhibitors in iron-deficient patients with heart failure and reduced ejection fraction.

AIMS: To explore the potential interaction between use of SGLT2 inhibitors and the increase in haemoglobin in patients randomized to intravenous iron or the control group in the IRONMAN (Effectiveness of Intravenous Iron Treatment versus Standard Care in Patients with Heart Failure and Iron Deficiency) trial. METHODS AND RESULTS: This was a post hoc exploratory analysis of the IRONMAN trial which randomized patients with heart failure, a left ventricular ejection fraction (LVEF) ≤ 45% and iron deficiency (transferrin saturation <20% or ferritin <100 µg/L) to open label intravenous ferric derisomaltose or usual care. Of the 1137 randomized patients, 29 (2.6%) were taking an SGLT2 inhibitor at baseline. The mean (SD) change in haemoglobin from baseline at 4 weeks in those taking an SGLT2 inhibitor at baseline was 1.3 (1.2) g/dL in patients randomized to ferric derisomaltose and 0.1 (0.7) g/dL in the usual care group; between-group difference = 1.0 g/dL (95% CI 0.1, 1.8). The equivalent numbers in the no SGLT2 inhibitor group were 0.6 (0.9) g/dL in those randomized to ferric derisomaltose and 0.1 (0.8) g/dL in the usual care group; between-group difference = 0.4 g/dL (95% CI 0.3, 1.6); interaction P value = 0.10. No patient receiving an SGLT2 inhibitor at baseline developed polycythaemia during follow-up (defined as haemoglobin >16.5 g/dL [men] or >16 g/dL [women]). CONCLUSIONS: In the IRONMAN trial, there was a trend to a greater increase in haemoglobin with ferric derisomaltose in iron-deficient patients taking an SGLT2 inhibitor at baseline, as compared with those not taking one.

Predictors of heart failure readmission and all-cause mortality in patients with acute heart failure.

BACKGROUND: Predischarge risk stratification of patients with acute heart failure (AHF) could facilitate tailored treatment and follow-up, however, simple scores to predict short-term risk for HF readmission or death are lacking. METHODS: We sought to develop a congestion-focused risk score using data from a prospective, two-center observational study in adults hospitalized for AHF. Laboratory data were collected on admission. Patients underwent physical examination, 4-zone, and in a subset 8-zone, lung ultrasound (LUS), and echocardiography at baseline. A second LUS was performed before discharge in a subset of patients. The primary endpoint was the composite of HF hospitalization or all-cause death. RESULTS: Among 350 patients (median age 75 years, 43% women), 88 participants (25%) were hospitalized or died within 90 days after discharge. A stepwise Cox regression model selected four significant independent predictors of the composite outcome, and each was assigned points proportional to its regression coefficient: NT-proBNP ≥2000 pg/mL (admission) (3 points), systolic blood pressure < 120 mmHg (baseline) (2 points), left atrial volume index ≥60 mL/m2 (baseline) (1 point) and ≥ 9 B-lines on predischarge 4-zone LUS (3 points). This risk score provided adequate risk discrimination for the composite outcome (HR 1.48 per 1 point increase, 95% confidence interval: 1.32-1.67, p < 0.001, C-statistic: 0.70). In a subset of patients with 8-zone LUS data (n = 176), results were similar (C-statistic: 0.72). CONCLUSIONS: A four-variable risk score integrating clinical, laboratory and ultrasound data may provide a simple approach for risk discrimination for 90-day adverse outcomes in patients with AHF if validated in future investigations.

Dapagliflozin and Days of Full Health Lost in the DAPA-HF Trial.

BACKGROUND: Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. OBJECTIVES: To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. METHODS: The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. RESULTS: Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (-3.8 days [95% CI: -6.6 to -1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire-overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization -0.9 days [-0.7%] at 120 days, -2.3 days [-1.0%] at 240 days, and -4.8 days [-1.3%] at 360 days). CONCLUSIONS: Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124).

Interleukin-6 and Cardiovascular Events in Healthy Adults: MESA.

Background: Elevated interleukin (IL)-6 levels have been linked to adverse outcomes in patients with and without baseline cardiovascular disease (CVD). Objectives: The purpose of this study was to examine the association between circulating IL-6 levels and CVD events without baseline CVD across racial and ethnic groups. Methods: We conducted an observational analysis utilizing the MESA (Multi-Ethnic Study of Atherosclerosis), a multicenter, prospective community-based study of CVD at baseline from four racial and ethnic groups. IL-6 levels were measured at the time of enrollment (visit 1) and were divided into 3 terciles. Patient baseline characteristics and outcomes, including all-cause mortality, CV mortality, heart failure, and non-CV mortality, were included. Cox proportional hazard regression models were used to assess associations between IL-6 levels and study outcomes with IL-6 tercile 1 as reference. Results: Of 6,622 individuals, over half were women (53%) with a median age of 62 (IQR: 53-70) years. Racial and ethnic composition was non-Hispanic White (39%) followed by African American (27%), Hispanic (22%), and Chinese American (12%). Compared to tercile 1, participants with IL-6 tercile 3 had a higher adjusted risk of and all-cause mortality (HR: 1.98 [95% CI: 1.67-2.36]), CV mortality (HR: 1.55 [95% CI: 1.05-2.30]), non-CV mortality (HR: 2.05 [95% CI: 1.65-2.56]), and heart failure (HR: 1.48 [95% CI: 0.99-2.19]). When tested as a continuous variable, higher levels of IL-6 were associated with an increased risk of all individual outcomes. Compared to non-Hispanic White participants, the unadjusted and adjusted risk of all outcomes across all races and ethnicities was similar across all IL-6 terciles. Conclusions: High levels of circulating IL-6 are associated with worse CV outcomes and increased all-cause mortality consistently across all racial and ethnic groups.

Dapagliflozin and Timing of Prior Heart Failure Hospitalization: A Patient-Level Meta-Analysis of DAPA-HF and DELIVER.

BACKGROUND: Patients recently hospitalized for heart failure (HF) are at a higher risk of adverse clinical outcomes, but they may experience a greater absolute and relative benefit from effective therapies than individuals who are considered more "stable." OBJECTIVES: The authors examined the effects of dapagliflozin according to the timing of prior HF hospitalization in a patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure). METHODS: A total of 11,007 patients were randomized in DAPA-HF and DELIVER. The primary outcome was the composite of worsening HF or cardiovascular death. RESULTS: In total, 12.4% were hospitalized for HF within 3 months of randomization, 14.2% between 3 and 12 months, and 16.8% more than 1 year before randomization, whereas 56.5% had not been hospitalized. The risk of the primary endpoint was inversely associated with time from prior HF hospitalization, and patients with a recent HF hospitalization had the highest risk. Compared with placebo, dapagliflozin reduced the risk of the primary outcome across HF hospitalization category (0-3 months, HR: 0.66 [95% CI: 0.55-0.81]; 3-12 months, HR: 0.73 [95% CI: 0.59-0.90]; >1 year, HR: 0.91 [95% CI: 0.74-1.12]; and no prior hospitalization, HR: 0.83 [95% CI: 0.73-0.94]; Pinteraction = 0.09). The number of patients needed to treat with dapagliflozin to prevent 1 event over the median follow-up of 22 months was 13, 20, 23, and 28, respectively. The beneficial effect was consistent across the range of LVEF regardless of HF hospitalization category. CONCLUSIONS: The relative benefits of dapagliflozin were consistent across the range of LVEF regardless of the timing of the most recent HF hospitalization with a greater absolute benefit in patients with recent hospitalization.

Dapagliflozin and quality of life measured using the EuroQol 5-dimension questionnaire in patients with heart failure with reduced and mildly reduced/preserved ejection fraction.

AIMS: Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. METHODS AND RESULTS: We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72-0.91) in Q2, 0.74 (0.65-0.84) in Q3, and 0.62 (0.54-0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. CONCLUSIONS: Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction.

Effect of dapagliflozin in patients with diabetes and heart failure with mildly reduced or preserved ejection fraction according to background glucose-lowering therapy: A pre-specified analysis of the DELIVER trial.

AIMS: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain. METHODS AND RESULTS: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; pinteraction = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs. CONCLUSIONS: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT.

Empagliflozin to prevent progressive adverse remodelling after myocardial infarction (EMPRESS-MI): rationale and design.

AIMS: Patients with a reduced left ventricular ejection fraction (LVEF) following an acute myocardial infarction (MI) are at risk of progressive adverse cardiac remodelling that can lead to the development of heart failure and death. The early addition of a sodium-glucose cotransporter 2 (SGLT2) inhibitor to standard treatment may delay or prevent progressive adverse remodelling in these patients. METHODS AND RESULTS: EMpagliflozin to PREvent worSening of left ventricular volumes and Systolic function after Myocardial Infarction (EMPRESS-MI) is a randomized, double-blind, placebo-controlled, multi-centre trial designed to assess the effect of empagliflozin on cardiac remodelling evaluated using cardiovascular magnetic resonance (CMR) in 100 patients with left ventricular systolic dysfunction following MI. Eligible patients were those ≥12 h and ≤14 days following acute MI, with an LVEF <45% by CMR. Patients were randomized to empagliflozin 10 mg once a day or matching placebo. The primary outcome will be change in left ventricular end-systolic volume indexed to body surface area over 24 weeks from randomization. Secondary endpoints include measures of left ventricular and atrial volumes, left ventricular mass, LVEF, and circulating cardiac biomarkers. CONCLUSIONS: EMPRESS-MI will assess the effect of the SGLT2 inhibitor empagliflozin on cardiac remodelling in patients with left ventricular systolic dysfunction after an acute MI.

Prognostic Models for Mortality and Morbidity in Heart Failure With Preserved Ejection Fraction.

Importance: Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. Objective: To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Design, Setting, and Participants: Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Exposures: Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Results: Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. Conclusions and Relevance: In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

Effect of Neprilysin Inhibition on Alzheimer Disease Plasma Biomarkers: A Secondary Analysis of a Randomized Clinical Trial.

This exploratory analysis of a randomized clinical trial evaluates the effect of neprilysin inhibition on Alzheimer disease blood biomarkers in patients with heart disease.