Inhibition of neurohumoural pathways such as the renin angiotensin aldosterone and sympathetic nervous systems is central to the understanding and treatment of heart failure (HF). Conversely, until ...recently, potentially beneficial augmentation of neurohumoural systems such as the natriuretic peptides has had limited therapeutic success. Administration of synthetic natriuretic peptides has not improved outcomes in acute HF but modulation of the natriuretic system through inhibition of the enzyme that degrades natriuretic (and other vasoactive) peptides, neprilysin, has proven to be successful. After initial failures with neprilysin inhibition alone or dual neprilysin-angiotensin converting enzyme (ACE) inhibition, the Prospective comparison of angiotensin receptor neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF) trial demonstrated that morbidity and mortality can be improved with the angiotensin receptor blocker neprilysin inhibitor sacubitril/valsartan (formerly LCZ696). In comparison to the ACE inhibitor enalapril, sacubitril/valsartan reduced the occurrence of the primary end point (cardiovascular death or hospitalisation for HF) by 20% with a 16% reduction in all-cause mortality. These findings suggest that sacubitril/valsartan should replace an ACE inhibitor or angiotensin receptor blocker as the foundation of treatment of symptomatic patients (NYHA II-IV) with HF and a reduced ejection fraction. This review will explore the background to neprilysin inhibition in HF, the results of the PARADIGM-HF trial and offer guidance on how to use sacubitril/valsartan in clinical practice.
Sodium‐glucose cotransporter 2 inhibitors (SGLT‐2is) were originally developed for the treatment of hyperglycaemia in type 2 diabetes. Because of regulatory requirements to show the safety of this ...new class of drugs, a large randomized cardiovascular (CV) outcomes trial was completed but this showed that instead of having a neutral effect on heart failure (HF) outcomes, that these drugs could reduce HF outcomes in this population. Subsequent trials with SGLT‐2is have shown that HF hospitalizations are reduced by 30% and CV death or HF hospitalization by 21% in patients with type 2 diabetes. These findings have extended to patients with HF with reduced and mildly reduced or preserved ejection fraction in whom further HF hospitalizations are reduced by 28% and CV death or HF hospitalizations reduced by 23%, and that it is becoming a central therapy for the treatment of HF. Moreover, the benefit in patients with HF is observed regardless of the presence or absence of type 2 diabetes. Similarly, in patients with chronic kidney disease and albuminuria, with and without type 2 diabetes, the benefit of SGLT‐2is is clearly seen with a 44% reduction in HF hospitalization and 25% reduction in CV death or HF hospitalization. These trials support the use of SGLT‐2is in improving HF outcomes in a broad range of patients, from those with type 2 diabetes, chronic kidney disease and those with pre‐existing HF regardless of ejection fraction.
Aims
Pulmonary congestion is an important finding in patients with heart failure (HF) that can be quantified by lung ultrasound (LUS). We conducted a systematic review to describe dynamic changes in ...LUS findings of pulmonary congestion (B‐lines) in HF and to examine the prognostic utility of B‐lines in HF.
Methods and results
We searched online databases for studies conducted in patients with chronic or acute HF that used LUS to assess dynamic changes or the prognostic value of pulmonary congestion. We included studies in adult populations, published in English, and conducted in ≥25 patients. Of 1327 identified studies, 13 (25–290 patients) met the inclusion criteria: six reported on dynamic changes in LUS findings (438 patients) and seven on the prognostic value of B‐lines in HF (953 patients). In acute HF, B‐line number changed within as few as 3 h of HF treatment. In acute HF, ≥15 B‐lines on 28‐zone LUS at discharge identified patients at a more than five‐fold risk for HF readmission or death. Similarly, in ambulatory patients with chronic HF, ≥3 B‐lines on five‐ or eight‐zone LUS marked those at a nearly four‐fold risk for 6‐month HF hospitalization or death.
Conclusions
Lung ultrasound findings change rapidly in response to HF therapy. This technique may represent a useful and non‐invasive method to track dynamic changes in pulmonary congestion. Furthermore, residual congestion at the time of discharge in acute HF or in ambulatory patients with chronic HF may identify those at high risk for adverse events.
Three drug classes (mineralocorticoid receptor antagonists MRAs, angiotensin receptor–neprilysin inhibitors ARNIs, and sodium/glucose cotransporter 2 SGLT2 inhibitors) reduce mortality in patients ...with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF.
In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker).
The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30–0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 95% CI 0·37–0·67), hospital admission for heart failure alone (0·32 0·24–0·43), and all-cause mortality (0·53 0·40–0·70). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy.
Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.
None.
The risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including ...angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail.
We analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter-defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization.
Sudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P=0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer-standing diagnosis.
Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence-based medications on this cause of death. (Funded by the China Scholarship Council and the University of Glasgow.).
Chronic kidney disease is common in the general population and associated with excess cardiovascular disease (CVD), but kidney function does not feature in current CVD risk-prediction models. We ...tested three formulae for estimated glomerular filtration rate (eGFR) to determine which was the most clinically informative for predicting CVD and mortality. Using data from 440,526 participants from UK Biobank, eGFR was calculated using serum creatinine, cystatin C (eGFRcys) and creatinine-cystatin C. Associations of each eGFR with CVD outcome and mortality were compared using Cox models and adjusting for atherosclerotic risk factors (per relevant risk scores), and the predictive utility was determined by the C-statistic and categorical net reclassification index. We show that eGFRcys is most strongly associated with CVD and mortality, and, along with albuminuria, adds predictive discrimination to current CVD risk scores, whilst traditional creatinine-based measures are weakly associated with risk. Clinicians should consider measuring eGFRcys as part of cardiovascular risk assessment.
Abstract
Aims
The aim of this study was to examine the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection ...fraction (HFrEF).
Methods and results
In a post hoc analysis of DAPA-HF, we examined serious adverse event reports related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF (ventricular fibrillation in 15 patients, ventricular tachycardia in 86, ‘other’ ventricular arrhythmia/tachyarrhythmia in 12, and torsade de pointes in 2 patients). A total of 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Eight patients survived resuscitation from cardiac arrest. Independent predictors of the composite outcome (first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest or sudden death), ranked by chi-square value, were log-transformed N-terminal pro-B-type natriuretic peptide, history of ventricular arrhythmia, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 140/2373 patients (5.9%) experienced the composite outcome compared with 175/2371 patients (7.4%) in the placebo group hazard ratio 0.79 (95% confidence interval 0.63–0.99), P = 0.037, and the effect was consistent across each of the components of the composite outcome.
Conclusions
Dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF.
Clinical trial registration
ClinicalTrials.gov unique identifier: NCT03036124 (DAPA-HF).
Graphical Abstract
DAPA-HF: trial design and main findings. BMI, body mass index; BP, blood pressure; CI, confidence interval; HF, heart failure; HFrEF, heart failure and reduced ejection fraction; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NT-proBNP, N-terminal pro-B-type natriuretic peptide.
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