Declining risk of sudden death in heart failure

No abstract available

Non-ischaemic cardiomyopathy, sudden death and implantable defibrillators: a review and meta-analysis

Objective: The recent Danish Study to Assess the Efficacy of ICDs in Patients with Non-ischemic Systolic Heart Failure on Mortality (DANISH) trial suggested that implantable cardioverter defibrillators (ICDs) do not reduce overall mortality in patients with non-ischaemic cardiomyopathy (NICM), despite reducing sudden cardiac death. We performed an updated meta-analysis to examine the impact of ICD therapy on mortality in NICM patients. Methods: A systematic search for studies that examined the effect of ICDs on outcomes in NICM was performed. Our analysis compared patients randomised to an ICD with those randomised to no ICD, and examined the endpoint of overall mortality. Results: Six primary prevention trials and two secondary prevention trials were identified that met the pre-specified search criteria. Using a fixed-effects model, analysis of primary prevention trials revealed a reduction in overall mortality with ICD therapy (RR 0.76, 95% CI 0.65 to 0.91). Conclusions: Although our updated meta-analysis demonstrates a survival benefit of ICD therapy, the effect is substantively weakened by the inclusion of the DANISH trial—which is both the largest and most recent of the analysed trials—indicating that the residual pooled benefit of ICDs may reflect the risk of sudden death in older trials which included patients treated sub-optimally by contemporary standards. As such, these data must be interpreted cautiously. The results of the DANISH trial emphasise that there is no ‘one size fits all’ indication for primary prevention ICDs in NICM patients, and clinicians must consider age and comorbidity on an individual basis when determining whether a defibrillator is appropriate

Association is not causation: treatment effects cannot be estimated from observational data in heart failure

Aims: Treatment ‘effects’ are often inferred from non-randomized and observational studies. These studies have inherent biases and limitations, which may make therapeutic inferences based on their results unreliable. We compared the conflicting findings of these studies to those of prospective randomized controlled trials (RCTs) in relation to pharmacological treatments for heart failure (HF). Methods and results: We searched Medline and Embase to identify studies of the association between non-randomized drug therapy and all-cause mortality in patients with HF until 31 December 2017. The treatments of interest were: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists (MRAs), statins, and digoxin. We compared the findings of these observational studies with those of relevant RCTs. We identified 92 publications, reporting 94 non-randomized studies, describing 158 estimates of the ‘effect’ of the six treatments of interest on all-cause mortality, i.e. some studies examined more than one treatment and/or HF phenotype. These six treatments had been tested in 25 RCTs. For example, two pivotal RCTs showed that MRAs reduced mortality in patients with HF with reduced ejection fraction. However, only one of 12 non-randomized studies found that MRAs were of benefit, with 10 finding a neutral effect, and one a harmful effect. Conclusion: This comprehensive comparison of studies of non-randomized data with the findings of RCTs in HF shows that it is not possible to make reliable therapeutic inferences from observational associations. While trials undoubtedly leave gaps in evidence and enrol selected participants, they clearly remain the best guide to the treatment of patients

Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction.

Aims: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-β peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. Methods and results: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18–96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33–1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75–1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. Conclusion: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted

Catheter ablation for atrial fibrillation with heart failure

No abstract available

Who benefits from a defibrillator—balancing the risk of sudden versus non-sudden death

Purpose of Review: Treatment with a defibrillator can reduce the risk of sudden death by terminating ventricular arrhythmias. The identification of patient groups in whom this function reduces overall mortality is challenging. In this review, we summarise the evidence for who benefits from a defibrillator. Recent Findings: Recent evidence suggests that contemporary pharmacologic and non-defibrillator device therapies are altering the potential risks and benefits of a defibrillator. Summary: Who benefits from a defibrillator is determined by both the risk of sudden death and the competing risk of other, non-sudden causes of death. The balance of these risks is changing, which calls into question whether historic evidence for the use of defibrillators remains robust in the modern era

A re-examination of the BEST Trial using composite outcomes, including emergency department visits

Objectives: The influence of choice of endpoint on trial size, duration, and interpretation of results was examined in patients with heart failure who were enrolled in BEST (Beta-blocker Evaluation of Survival Trial). Background: The choice of endpoints in heart failure trials has evolved over the past 3 decades. Methods: In the BEST trial, we used Cox regression analysis to examine the effect of bucindolol on the current standard composite of cardiovascular death or heart failure hospitalization (CVD/HFH) compared with the original primary mortality endpoint and the expanded composite that included emergency department (ED) visits. We also undertook an analysis of recurrent events primarily using the Lin, Wei, Ying, and Yang model. Results: Overall, 448 (33%) patients on placebo and 411 (30%) patients on bucindolol died (hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78 to 1.02; p = 0.11). A total of 730 (54%) patients experienced CVD/HFH on placebo and 624 (46%) on bucindolol (HR: 0.80; 95% CI: 0.72 to 0.89; p < 0.001). Adding ED visits increased these numbers to 768 (57%) and 668 (49%), respectively (HR: 0.81; 95% CI: 0.73 to 0.90; p < 0.001). A total of 568 (42%) patients on placebo experienced HFH compared with 476 (35%) patients on bucindolol (HR: 0.78; 95% CI: 0.69 to 0.89; p < 0.001), with a total of 1,333 and 1,124 admissions, respectively. With the same statistical assumptions, using the composite endpoint instead of all-cause mortality would have reduced the trial size by 40% and follow-up duration by 69%. The rate ratio for recurrent events (CVD/HFH) was 0.83 (95% CI: 0.73 to 0.94; p = 0.003). Conclusions: Choice of endpoint has major implications for trial size and duration, as well as interpretation of results. The value of broader composite endpoints and inclusion of recurrent events needs further investigation. (Beta Blocker Evaluation in Survival Trial [BEST]; NCT00000560

Anticoagulation therapy in heart failure and sinus rhythm: a systematic review and meta-analysis

Objective: Heart failure is a prothrombotic state, and it has been hypothesised that thrombosis and embolism cause non-fatal and fatal events in heart failure and reduced ejection fraction (HFrEF). We sought to determine the effect of anticoagulant therapy on clinical outcomes in patients with HFrEF who are in sinus rhythm. Methods: We conducted an updated systematic review and meta-analysis to examine the effect of anticoagulation therapy in patients with HFrEF in sinus rhythm. Our analysis compared patients randomised to anticoagulant therapy with those randomised to antiplatelet therapy, placebo or control, and examined the endpoints of all-cause mortality, (re)hospitalisation for worsening heart failure, non-fatal myocardial infarction, non-fatal stroke of any aetiology and major haemorrhage. Results: Five trials were identified that met the prespecified search criteria. Compared with control therapy, anticoagulant treatment did not reduce all-cause mortality (risk ratio [RR] 0.99, 95% CI 0.90 to 1.08), (re)hospitalisation for heart failure (RR 0.97, 95% CI 0.82 to 1.13) or non-fatal myocardial infarction (RR 0.92, 95% CI 0.75 to 1.13). Anticoagulation did reduce the rate of non-fatal stroke (RR 0.63, 95% CI 0.49 to 0.81, p=0.001), but this was offset by an increase in the incidence of major haemorrhage (RR 1.88, 95% CI 1.49 to 2.38, p=0.001). Conclusions: Our meta-analysis provides evidence to oppose the hypothesis that thrombosis or embolism plays an important role in the morbidity and mortality associated with HFrEF, with the exception of stroke-related morbidity

Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction. A report from the Irbesartan in Heart Failure with Preserved Ejection Fraction Trial (I-Preserve)

Background—In patients with HF and preserved ejection fraction (HFpEF), little is known about the characteristics of and outcomes in those with and without diabetes. Methods—We examined clinical and echocardiographic characteristics and outcomes in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), according to history of diabetes. Cox regression models were used to estimate hazard ratios (HR) for cardiovascular outcomes adjusted for known predictors, including age, sex, natriuretic peptides, and comorbidity. Echocardiographic data were available in 745 patients and were additionally adjusted for in supplementary analyses. Results—Overall, 1134 of 4128 patients (27%) had diabetes. Compared to those without diabetes, they were more likely to have a history of myocardial infarction (28% vs. 22%), higher BMI (31kg/m2 vs. 29kg/m2), worse Minnesota living with HF score (48 vs. 40), higher median NT-proBNP concentration (403 vs 320 pg/ml; all p<0.01), more signs of congestion but no significant difference in LVEF. Patients with diabetes had a greater left ventricular (LV) mass and left atrial area than patients without diabetes. Doppler E wave velocity (86 vs 76 cm/sec, p<0.0001) and the ratio of E/e' (11.7 vs 10.4, p=0.010) were higher in patients with diabetes. Over a median follow-up of 4.1 years, cardiovascular death or HF hospitalization occurred in 34% of patients with diabetes vs. 22% of those without diabetes; adjusted HR 1.75 (95% CI 1.49-2.05) and 28% vs. 19% of patients with and without diabetes died; adjusted HR 1.59 (1.33-1.91). Conclusions—In HFpEF, patients with diabetes have more signs of congestion, worse quality of life, higher NT-proBNP levels, and a poorer prognosis. They also display greater structural and functional echocardiographic abnormalities. Further investigation is needed to determine the mediators of the adverse impact of diabetes on outcomes in HFPEF, and whether they are modifiable

Influence of Sacubitril/Valsartan (LCZ696) on 30-day readmission after heart failure hospitalization

Background: Patients with heart failure (HF) are at high risk for hospital readmission in the first 30 days following HF hospitalization. Objectives: This study sought to determine if treatment with sacubitril/valsartan (LCZ696) reduces rates of hospital readmission at 30-days following HF hospitalization compared with enalapril. Methods: We assessed the risk of 30-day readmission for any cause following investigator-reported hospitalizations for HF in the PARADIGM-HF trial, which randomized 8,399 participants with HF and reduced ejection fraction to treatment with LCZ696 or enalapril. Results: Accounting for multiple hospitalizations per patient, there were 2,383 investigator-reported HF hospitalizations, of which 1,076 (45.2%) occurred in subjects assigned to LCZ696 and 1,307 (54.8%) occurred in subjects assigned to enalapril. Rates of readmission for any cause at 30 days were 17.8% in LCZ696-assigned subjects and 21.0% in enalapril-assigned subjects (odds ratio: 0.74; 95% confidence interval: 0.56 to 0.97; p = 0.031). Rates of readmission for HF at 30-days were also lower in subjects assigned to LCZ696 (9.7% vs. 13.4%; odds ratio: 0.62; 95% confidence interval: 0.45 to 0.87; p = 0.006). The reduction in both all-cause and HF readmissions with LCZ696 was maintained when the time window from discharge was extended to 60 days and in sensitivity analyses restricted to adjudicated HF hospitalizations. Conclusions: Compared with enalapril, treatment with LCZ696 reduces 30-day readmissions for any cause following discharge from HF hospitalization