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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.

SGLT2 inhibitors are strongly recommended in guidelines to treat patients with heart failure with reduced ejection fraction, but their clinical benefits at higher ejection fractions are less well established. Two large-scale trials, DELIVER and EMPEROR-Preserved, in heart failure with mildly reduced or preserved ejection fraction have been done, providing power to examine therapeutic effects on cardiovascular mortality and in patient subgroups when combined with the earlier trials in reduced ejection fraction. We did a prespecified meta-analysis of DELIVER and EMPEROR-Preserved, and subsequently included trials that enrolled patients with reduced ejection fraction (DAPA-HF and EMPEROR-Reduced) and those admitted to hospital with worsening heart failure, irrespective of ejection fraction (SOLOIST-WHF). Using trial-level data with harmonised endpoint definitions, we did a fixed-effects meta-analysis to estimate the effect of SGLT2 inhibitors on various clinical endpoints in heart failure The primary endpoint for this meta-analysis was time from randomisation to the occurrence of the composite of cardiovascular death or hospitalisation for heart failure. We assessed heterogeneity in treatment effects for the primary endpoint across subgroups of interest. This study is registered with PROSPERO, CRD42022327527. Among 12 251 participants from DELIVER and EMPEROR-Preserved, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalisation for heart failure (hazard ratio 0·80 [95% CI 0·73-0·87]) with consistent reductions in both components: cardiovascular death (0·88 [0·77-1·00]) and first hospitalisation for heart failure (0·74 [0·67-0·83]). In the broader context of the five trials of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalisation for heart failure (0·77 [0·72-0·82]), cardiovascular death (0·87 [0·79-0·95]), first hospitalisation for heart failure (0·72 [0·67-0·78]), and all-cause mortality (0·92 [0·86-0·99]). These treatment effects for each of the studied endpoints were consistently observed in both the trials of heart failure with mildly reduced or preserved ejection fraction and across all five trials. Treatment effects on the primary endpoint were generally consistent across the 14 subgroups examined, including ejection fraction. SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalisations for heart failure in a broad range of patients with heart failure, supporting their role as a foundational therapy for heart failure, irrespective of ejection fraction or care setting. None.

Abstract Aims This meta-analysis provides summary odds ratio (OR) estimates for associations between treatment with (vs. without) renin–angiotensin system blockers and risk of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and coronavirus disease 2019 (CoViD-19) severity (including case-fatality) in patients with hypertension, and in all patients (irrespective of hypertension). Methods and results PubMed, EMBASE, Web of Science, Google Scholar, medRxiv, and SSRN were searched (2 May 2020 to 12 August 2020) for non-randomized observational CoViD-19 studies. Event/patient numbers were extracted, comparing angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB) treatment (and each separately), to treatment with neither drug, for the outcomes: (i) likelihood of SARS-CoV-2 infection; (ii) CoViD-19 severity [including hospitalization, intensive therapy unit (ITU), ventilation]; (iii) case-fatality. The risk of bias was assessed (ROBINS-I). Random-effects meta-analysis estimates were pooled. Eighty-six studies including 459 755 patients (103 317 with hypertension), were analysed. In patients with hypertension, ACE inhibitor or ARB treatment was not associated with a greater likelihood of SARS-CoV-2 infection in 60 141 patients (OR 1.06, 95% CI 0.99–1.14), hospitalization in 5925 patients (OR 0.90, 0.62–1.31), ITU in 7218 patients (OR 1.06, 0.73–1.56), ventilation (or ITU/ventilation/death) in 13 163 patients (OR 0.91, 0.72–1.15) or case-fatality in 18 735 patients with 2893 deaths (OR 0.75, 0.61–0.92). Conclusion Angiotensin-converting enzyme inhibitors and ARBs appear safe in the context of SARS-CoV-2 infection and should not be discontinued. PROSPERO registration number CRD42020186996.

Whether the sodium–glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction (≤40% and >40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)). A total of 11,007 participants with a mean ejection fraction of 44% (s.d. 14%) were included. Dapagliflozin reduced the risk of death from cardiovascular causes (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76–0.97; P  = 0.01), death from any cause (HR 0.90, 95% CI 0.82–0.99; P  = 0.03), total hospital admissions for heart failure (rate ratio 0.71, 95% CI 0.65–0.78; P  < 0.001) and MACEs (HR 0.90, 95% CI 0.81–1.00; P  = 0.045). There was no evidence that the effect of dapagliflozin differed by ejection fraction. In a patient-level pooled meta-analysis covering the full range of ejection fractions in patients with heart failure, dapagliflozin reduced the risk of death from cardiovascular causes and hospital admissions for heart failure (PROSPERO: CRD42022346524). A pre-specified meta-analysis of pooled, individual patient-level data from the DELIVER and DAPA-HF trials, testing dapagliflozin in patients with heart failure, demonstrates reductions in risk of cardiovascular-associated deaths and hospital admissions for heart failure, regardless of ejection fraction.

ObjectiveHeart failure (HF) is common with high associated morbidity and mortality. UK National Institute for Health and Clinical Excellence (NICE) Guidelines suggest prioritising assessment by natriuretic peptide (NP) level, with patients with high NP levels assessed within 2 weeks. We evaluated adherence to NICE guidelines in the post-COVID-19 era.MethodsWe conducted a retrospective audit of consecutive referrals to a HF diagnostic pathway across seven hospitals in the West of Scotland (between 5 January and 2 June 2022). Patients were categorised by NP level according to NICE Guidelines: NT-proBNP 400–2000 ng/L (echocardiogram within 6 weeks) or >2000 ng/L (echocardiogram within 2 weeks). Time-to-echocardiogram was recorded, and 1-year outcomes (HF hospitalisation, death) were obtained from electronic records.ResultsOf the 899 patients (median age 79 years, 56% female) referred for echocardiography on the HF diagnostic pathway, 264 (29%) and 635 (71%) had an NT-proBNP >2000 ng/L and 400–2000 ng/L, respectively. Only 20 (8%) patients with NT-proBNP >2000 ng/L and 51 (8%) patients with NT-proBNP 400–2000 ng/L received an echocardiogram within the recommended timeframe. 252 (28%) patients were diagnosed with HF, 110 (42%) and 142 (22%) in the NT-proBNP >2000 ng/L and 400–2000 ng/L groups, respectively, p<0.001. One-year mortality was 12% and was higher in the >2000 ng/L NT-proBNP group at 21% compared with 9% in the 400–2000 ng/L group.ConclusionHigh NP levels identified a high-risk group who are more likely to have HF and a higher risk of mortality. Few patients received echocardiography within the NICE Guideline-recommended timeframe. Patients with high NP levels should be investigated with the same urgency as suspected cancer.

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.

Remarkable recent advances have revolutionized the field of heart failure. Survival has improved among individuals with heart failure and a reduced ejection fraction and for the first time, new therapies have been shown to improve outcomes across the entire ejection fraction spectrum of heart failure. Great strides have been taken in the treatment of specific cardiomyopathies such as cardiac amyloidosis and hypertrophic cardiomyopathy, whereby conditions once considered incurable can now be effectively managed with novel genetic and molecular approaches. Yet there remain substantial residual unmet needs in heart failure. The translation of successful clinical trials to improved patient outcomes is limited by large gaps in implementation of care, widespread lack of disease awareness and poor understanding of the socioeconomic determinants of outcomes and how to address disparities. Ongoing clinical trials, advances in phenotype segmentation for precision medicine and the rise in technology solutions all offer hope for the future. Recent years have seen major advances in heart failure treatment, but gaps in implementation and disparities in care remain; this Review outlines the current state of the field.

Aims Data on long‐term treatment effects are scarce, despite the intent to use new therapies for many years and the need of patients, physicians and payers to have a better understanding of the lifetime benefits of treatments. The restricted mean or median survival time (RMST) calculated using age instead of time, hypothetically enables estimation of long‐term gain in event‐free or overall survival from the short‐term (within‐trial) effects of an intervention, compared with its control. Tha aim of the study is to use trials with long‐term follow‐up available through extension studies to compare the long‐term projections estimated using RMST from within‐trial follow‐up data with the actual long‐term outcomes in the extension studies. Methods and results We estimated the median long‐term survival time using age instead of follow‐up time and compared these model‐based projections with the actual long‐term estimates in the (i) SCD‐HeFT trial vs. SCD‐HeFT long‐term outcomes; (ii) SOLVD trial vs. SOLVD 12 year follow‐up; (iii) STICH trial vs. STICHES; and (iv) ACCORD study vs. ACCORDION. In the long‐term follow‐up of SCD‐HeFT, gain in survival with ICD vs. placebo over a median of 11.0 years was +1.4 years of life. The RMST model‐derived survival projection from the within‐trial data (median follow‐up of 3.4 years) gave an estimated survival gain of +1.2 years. In STICHES, over a median follow‐up of 9.8 years, coronary artery bypass grafting (CABG) vs. medical care led to a survival extension of +1.4 years in favour of CABG. RMST projections using within‐trial data from STICH (median follow‐up of 4.9 years), gave an extended survival of +2.4 years in favour of CABG in younger patients. In the long‐term follow‐up of SOLVD, enalapril vs. placebo led to a survival gain of +0.8 years over a median follow‐up of 12.1 years. The RMST projections from the within‐trial data (median follow‐up of 2.8 years) gave a survival extension of +0.3 years in favour of enalapril. In the long‐term follow‐up ACCORDION study, with a median follow‐up of 8.8 years, intensive vs. a standard anti‐hyperglycaemic treatment did not influence long‐term survival, which was concordant with the RMST projections from the short‐term ACCORD study with median follow‐up of 4.9 years. Conclusions Age‐based survival projections using within‐trial data generally provided concordant results with the actual survival measured in long‐term follow‐up extension studies. Our findings suggest that age‐based lifetime projections may be used as means to assess the long‐term treatment effects.

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.