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The angiotensin receptor–neprilysin inhibitor LCZ696 was compared with the ACE inhibitor enalapril in patients with advanced heart failure. LCZ696 was superior to enalapril in all outcomes. Neprilysin inhibition may replace ACE inhibition for the treatment of heart failure. Angiotensin-converting–enzyme (ACE) inhibitors have been the cornerstone of the treatment for heart failure and a reduced ejection fraction for nearly 25 years, since enalapril was shown to reduce the risk of death in two trials. 1 , 2 Long-term treatment with enalapril decreased the relative risk of death by 16% among patients with mild-to-moderate symptoms. 2 The effect of angiotensin-receptor blockers (ARBs) on mortality has been inconsistent, 3 , 4 and thus, these drugs are recommended primarily for patients who have unacceptable side effects (primarily cough) while receiving ACE inhibitors. Subsequent studies showed that the use of beta-blockers and mineralocorticoid-receptor antagonists, when added to ACE . . .

Key Points Seasonal variations across a broad range of populations and climates (but predominantly derived from the temperate climates of Europe) have been documented in all types of cardiovascular disease (CVD) Most studies report 'winter peaks' in CVD-related hospitalizations and mortality; event rates in winter are typically 10–20% greater than during 'summer troughs' CVD seasonality is probably caused by a complex interaction between the susceptibility of individuals and a range of environmental factors (including ambient temperature) CVD seasonality is most pronounced in individuals living in milder climates, who are least prepared for extreme weather variations A lag effect, potentially modulated by air pollution levels and concurrent influenza, has been documented after 'cold snaps' Potential exists to attenuate seasonality in CVD via multifaceted interventions that modulate exposure to various provocations to the cardiovascular system in high-risk individuals (those with established CVD) Cardiovascular disease (CVD) follows a seasonal pattern in many populations, often peaking after 'cold snaps'. In this Review, Stewart and colleagues identify the physiological and environmental factors that contribute to seasonality in nearly all forms of CVD, and describe the potential strategies that might attenuate peaks in cardiovascular events during cold and hot periods of the year. Cardiovascular disease (CVD) follows a seasonal pattern in many populations. Broadly defined winter peaks and clusters of all subtypes of CVD after 'cold snaps' are consistently described, with corollary peaks linked to heat waves. Individuals living in milder climates might be more vulnerable to seasonality. Although seasonal variation in CVD is largely driven by predictable changes in weather conditions, a complex interaction between ambient environmental conditions and the individual is evident. Behavioural and physiological responses to seasonal change modulate susceptibility to cardiovascular seasonality. The heterogeneity in environmental conditions and population dynamics across the globe means that a definitive study of this complex phenomenon is unlikely. However, given the size of the problem and a range of possible targets to reduce seasonal provocation of CVD in vulnerable individuals, scope exists for both greater recognition of the problem and application of multifaceted interventions to attenuate its effects. In this Review, we identify the physiological and environmental factors that contribute to seasonality in nearly all forms of CVD, highlight findings from large-scale population studies of this phenomenon across the globe, and describe the potential strategies that might attenuate peaks in cardiovascular events during cold and hot periods of the year.

In this trial, 2737 patients with heart failure and LV systolic dysfunction were given eplerenone or placebo in addition to recommended therapy. Eplerenone significantly reduced the risk of the primary outcome, a composite of death or hospitalization. The activation of mineralocorticoid receptors by aldosterone and cortisol has deleterious effects in patients with cardiovascular disease. 1 In the placebo-controlled Randomized Aldactone Evaluation Study (RALES), 2 adding the mineralocorticoid-receptor antagonist spironolactone to recommended therapy in patients with systolic heart failure and moderate-to-severe symptoms (i.e., New York Heart Association [NYHA] functional class III or IV symptoms) decreased the rate of death from any cause and the risk of hospitalization for cardiovascular reasons. In the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), 3 the selective mineralocorticoid-receptor antagonist eplerenone, added to recommended medical therapy, reduced the rates of death from any . . .

Sodium–glucose cotransporter (SGLT)2 inhibitors have been demonstrated to reduce cardiovascular events, particularly heart failure, in cardiovascular outcome trials. Here, we review the proposed mechanistic underpinnings of this benefit. Specifically, we focus on the role of SGLT2 inhibitors in optimising ventricular loading conditions through their effect on diuresis and natriuresis, in addition to reducing afterload and improving vascular structure and function. Further insights into the role of SGLT2 inhibition in myocardial metabolism and substrate utilisation are outlined. Finally, we discuss two emerging themes: how SGLT2 inhibitors may regulate Na+/H+ exchange at the level of the heart and kidney and how they may modulate adipokine production. The mechanistic discussion is placed in the context of completed and ongoing trials of SGLT2 inhibitors in the prevention and treatment of heart failure in individuals with and without diabetes.

Rosiglitazone is an insulin sensitiser used in combination with metformin, a sulfonylurea, or both, for lowering blood glucose in people with type 2 diabetes. We assessed cardiovascular outcomes after addition of rosiglitazone to either metformin or sulfonylurea compared with the combination of the two over 5–7 years of follow-up. We also assessed comparative safety. In a multicentre, open-label trial, 4447 patients with type 2 diabetes on metformin or sulfonylurea monotherapy with mean haemoglobin A1c (HbA1c) of 7·9% were randomly assigned to addition of rosiglitazone (n=2220) or to a combination of metformin and sulfonylurea (active control group, n=2227). The primary endpoint was cardiovascular hospitalisation or cardiovascular death, with a hazard ratio (HR) non-inferiority margin of 1·20. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00379769. 321 people in the rosiglitazone group and 323 in the active control group experienced the primary outcome during a mean 5·5-year follow-up, meeting the criterion of non-inferiority (HR 0·99, 95% CI 0·85–1·16). HR was 0·84 (0·59–1·18) for cardiovascular death, 1·14 (0·80–1·63) for myocardial infarction, and 0·72 (0·49–1·06) for stroke. Heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the active control group (HR 2·10, 1·35–3·27, risk difference per 1000 person-years 2·6, 1·1–4·1). Upper and distal lower limb fracture rates were increased mainly in women randomly assigned to rosiglitazone. Mean HbA1c was lower in the rosiglitazone group than in the control group at 5 years. Addition of rosiglitazone to glucose-lowering therapy in people with type 2 diabetes is confirmed to increase the risk of heart failure and of some fractures, mainly in women. Although the data are inconclusive about any possible effect on myocardial infarction, rosiglitazone does not increase the risk of overall cardiovascular morbidity or mortality compared with standard glucose-lowering drugs. GlaxoSmithKline plc, UK.

Dalcetrapib, an inhibitor of cholesteryl ester transfer protein, raises HDL cholesterol levels. In this clinical trial involving patients with an acute coronary syndrome, dalcetrapib had no beneficial effect on clinical outcomes, despite raising HDL cholesterol levels. High-density lipoproteins (HDLs) participate in the process of cellular cholesterol efflux and may have additional protective effects against atherothrombosis. 1 An inverse association between levels of HDL cholesterol and incident events of coronary heart disease has been shown in observational studies 2 , 3 and persists in most post hoc analyses and meta-analyses of trials of statin therapy for patients with cardiovascular risk factors, chronic cardiovascular disease, or recent acute coronary syndrome. 4 – 10 However, it remains uncertain whether pharmacologic intervention that raises HDL cholesterol levels results in decreased cardiovascular risk. 11 – 16 Moreover, changes in HDL cholesterol levels may not reflect changes in the . . .

Comorbidities are common in patients with heart failure (HF) and complicate treatment and outcomes. We identified patterns of multimorbidity in Asian patients with HF and their association with patients' quality of life (QoL) and health outcomes. We used data on 6,480 patients with chronic HF (1,204 with preserved ejection fraction) enrolled between 1 October 2012 and 6 October 2016 in the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry. The ASIAN-HF registry is a prospective cohort study, with patients prospectively enrolled from in- and outpatient clinics from 11 Asian regions (Hong Kong, Taiwan, China, Japan, Korea, India, Malaysia, Thailand, Singapore, Indonesia, and Philippines). Latent class analysis was used to identify patterns of multimorbidity. The primary outcome was defined as a composite of all-cause mortality or HF hospitalization within 1 year. To assess differences in QoL, we used the Kansas City Cardiomyopathy Questionnaire. We identified 5 distinct multimorbidity groups: elderly/atrial fibrillation (AF) (N = 1,048; oldest, more AF), metabolic (N = 1,129; obesity, diabetes, hypertension), young (N = 1,759; youngest, low comorbidity rates, non-ischemic etiology), ischemic (N = 1,261; ischemic etiology), and lean diabetic (N = 1,283; diabetic, hypertensive, low prevalence of obesity, high prevalence of chronic kidney disease). Patients in the lean diabetic group had the worst QoL, more severe signs and symptoms of HF, and the highest rate of the primary combined outcome within 1 year (29% versus 11% in the young group) (p for all <0.001). Adjusting for confounders (demographics, New York Heart Association class, and medication) the lean diabetic (hazard ratio [HR] 1.79, 95% CI 1.46-2.22), elderly/AF (HR 1.57, 95% CI 1.26-1.96), ischemic (HR 1.51, 95% CI 1.22-1.88), and metabolic (HR 1.28, 95% CI 1.02-1.60) groups had higher rates of the primary combined outcome compared to the young group. Potential limitations include site selection and participation bias. Among Asian patients with HF, comorbidities naturally clustered in 5 distinct patterns, each differentially impacting patients' QoL and health outcomes. These data underscore the importance of studying multimorbidity in HF and the need for more comprehensive approaches in phenotyping patients with HF and multimorbidity. ClinicalTrials.gov NCT01633398.

In this trial, patients with systolic heart failure and anemia were assigned to receive either darbepoetin alfa or placebo. At 28 months, there was no significant difference in the rate of death from any cause or hospitalization for worsening heart failure. Anemia is common in patients with heart failure, and patients with both heart failure and anemia have a lower functional capacity, worse quality of life, and higher rates of hospitalization and death 1 – 3 than those without anemia. 4 , 5 The cause of anemia in patients with heart failure is often unknown but may be related to an absolute or relative deficiency of, or resistance to, erythropoietin. Anemia in such patients is associated with impaired renal function, inflammation, and use of renin–angiotensin system blockers. 6 , 7 Small studies have suggested that increasing the hemoglobin level with the use of an erythropoiesis-stimulating agent (ESA) . . .

The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.

Effective management of heart failure is complex, and ensuring evidence-based practice presents a major challenge to health services worldwide. Over the past decade, the United Kingdom introduced a series of national initiatives to improve evidence-based heart failure management, including a landmark pay-for-performance scheme in primary care and a national audit in secondary care started in 2004 and 2007, respectively. Quality improvement efforts have been evaluated within individual clinical settings, but patterns of care across its continuum, although a critical component of chronic disease management, have not been studied. We have designed this study to investigate patients' trajectories of care around the time of diagnosis and their variation over time by age, sex, and socioeconomic status. For this retrospective population-based study, we used linked primary and secondary health records from a representative sample of the UK population provided by the Clinical Practice Research Datalink (CPRD). We identified 93,074 individuals newly diagnosed with heart failure between 2002 and 2014, with a mean age of 76.7 years and of which 49% were women. We examined five indicators of care: (i) diagnosis care setting (inpatient or outpatient), (ii) posthospitalisation follow-up in primary care, (iii) diagnostic investigations, (iv) prescription of essential drugs, and (v) drug treatment dose. We used Poisson and linear regression models to calculate category-specific risk ratios (RRs) or adjusted differences and 95% confidence intervals (CIs), adjusting for year of diagnosis, age, sex, region, and socioeconomic status. From 2002 to 2014, indicators of care presented diverging trends. Outpatient diagnoses and follow-up after hospital discharge in primary care declined substantially (ranging from 56% in 2002 to 36% in 2014, RR 0.64 [0.62, 0.67] and 20% to 14%, RR 0.73 [0.65, 0.82], respectively). Primary care referral for diagnostic investigations and appropriate initiation of beta blockers and angiotensin-converting-enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) both increased significantly (37% versus 82%, RR 2.24 [2.15, 2.34] and 18% versus 63%, RR 3.48 [2.72, 4.43], respectively). Yet, the average daily dose prescribed remained below guideline recommendations (42% for ACE-Is or ARBs, 29% for beta blockers in 2014) and was largely unchanged beyond the first 30 days after diagnosis. Despite increasing rates of treatment initiation, the overall dose prescribed to patients in the 12 months following diagnosis improved little over the period of study (adjusted difference for the combined dose of beta blocker and ACE-I or ARB: +6% [+2%, +10%]). Women and patients aged over 75 years presented significant gaps across all five indicators of care. Our study was limited by the available clinical information, which did not include exact left ventricular ejection fraction values, investigations performed during hospital admissions, or information about follow-up in community heart failure clinics. Management of heart failure patients in the UK presents important shortcomings that affect screening, continuity of care, and medication titration and disproportionally impact women and older people. National reporting and incentive schemes confined to individual clinical settings have been insufficient to identify these gaps and address patients' long-term care needs.