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Aims Heart failure with reduced ejection fraction (HFrEF) and chronic obstructive pulmonary disease (COPD) individually cause significant morbidity and mortality. Their coexistence is associated with even worse outcomes, partly due to suboptimal heart failure therapy, especially underutilisation of beta-blockers. Our aim was to investigate outcomes in HFrEF patients with and without COPD, and the effects of mineralocorticoid receptor antagonists (MRAs) on outcomes. Methods and results We studied the effect of MRA therapy in a post-hoc pooled analysis of 4397 HFrEF patients in the RALES and EMPHASIS-HF trials. The primary endpoint was the composite of heart failure hospitalisation or cardiovascular death. A total of 625 (14.2%) of the 4397 patients had COPD. Patients with COPD were older, more often male, and smokers, but less frequently treated with a beta-blocker. In patients with COPD, event rates (per 100 person-years) for the primary endpoint and for all-cause mortality were 25.2 (95% confidence interval 22.1-28.7) and 17.2 (14.9-19.9), respectively, compared with 19.9 (18.8-21.1) and 12.8 (12.0-13.7) in participants without COPD. The risks of all-cause hospitalisation and sudden death were also higher in patients with COPD. The benefit of MRA, compared with placebo, was consistent in patients with or without COPD for all outcomes, e.g. hazard ratio for the primary outcome 0.66 (0.50-0.85) for COPD and 0.65 (0.58-0.73) for no COPD (interaction p = 0.93). MRA-induced hyperkalaemia was less frequent in patients with COPD. Conclusions In RALES and EMPHASIS-HF, one-in-seven patients with HFrEF had coexisting COPD. HFrEF patients with COPD had worse outcomes than those without. The benefits of MRAs were consistent, regardless of COPD status. [ABSTRACT FROM AUTHOR]

Aims Outpatient treatment for the worsening of signs and symptoms of heart failure (HF) is usually not incorporated in the main outcomes of HF trials. Patients with HF and a preserved ejection fraction (HFpEF) may experience frequent episodes of outpatient worsening HF. The aim of this study was to evaluate the frequency, prognostic impact, and the effect of spironolactone on outpatient diuretic intensification (ODI), among 1767 patients enrolled in TOPCAT-Americas. Methods and results Time-updated Cox models and win ratio analysis. ODI was defined by a post-randomization loop diuretic dose increase or new initiation. The median follow-up was 2.9 years. At baseline, 1362 (77%) patients were taking loop diuretics. During the follow-up, 685 (38.8%) patients experienced ODI, which was associated with a higher risk of subsequent cardiovascular events and death [adjusted hazard ratio (HR) for HF hospitalization or cardiovascular death 1.67, 95% confidence interval (CI) 1.36-2.04; HR for cardiovascular death 2.17, 95% CI 1.64-2.87); and HR for all-cause mortality 1.75, 95% CI 1.41-2.16] (p <0.001 for all outcomes). Adding ODI to the composite of HF hospitalization or cardiovascular death increased the event rate by three-fold in the placebo group (from 10.4 to 29.9 events per 100 person-years). Spironolactone treatment led to a 26% relative reduction of the extended composite of ODI or HF hospitalization or cardiovascular death (HR 0.74, 95% CI 0.65-0.85; p <0.001) compared with a 16% relative reduction of HF hospitalization or cardiovascular death (HR 0.84, 95% CI 0.70-0.99; p =0.044). Using win ratio provided similar estimates. Conclusion In HFpEF, ODI was frequent and independently associated with subsequent cardiovascular events. Spironolactone significantly reduced an extended composite outcome incorporating ODI. [ABSTRACT FROM AUTHOR]

Aims In patients with current or a history of hyperkalaemia, treatment with renin-angiotensin-aldosterone system inhibitors (RAASi) is often compromised. Patiromer, a novel potassium (K+) binder, may improve serum K+ levels and adherence to RAASi. Methods The DIAMOND trial will enroll ~820 patients with heart failure with reduced ejection fraction (HFrEF; ejection fraction =40%). Patients meeting the screening criteria will enter a single-blinded run-in phase where they will be started or continued on a mineralocorticoid receptor antagonist (MRA) titrated to 50mg/day and other RAASi therapy to =50% target dose, and patiromer. Patiromer will be titrated up to a maximum three packs/day (8.4 g/pack) to achieve optimal doses of RAASi without hyperkalaemia. The run-in phase will last up to 12weeks, following which patients will undergo double-blind randomization in a 1:1 ratio to receive either continued patiromer or placebo (patiromer withdrawal). The primary endpoint is the mean difference in serum K+ from randomization between patiromer and placebo arms. Secondary endpoints will include hyperkalaemia events with K+ value >5.5 mEq/L, durable enablement of MRA at target dose, investigator-reported adverse events of hyperkalaemia, hyperkalaemia-related clinical endpoints and an overall RAASi use score (using a 0-8-point scale) comprising all-cause death, occurrence of cardiovascular hospitalization or usage of comprehensive heart failure medication. Conclusion The DIAMOND trial is designed to determine if patiromer can favourably impact K+ control in patients with HFrEF with hyperkalaemia or a history of hyperkalaemia leading to RAASi therapy compromise, and in turn improve RAASi use. [ABSTRACT FROM AUTHOR]

Aims To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. Methods and results Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction =35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n=748; enalapril, n=696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n=486; enalapril, n=528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). Conclusion In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses. [ABSTRACT FROM AUTHOR]

Background Observational data have described the association of blood pressure (BP) with mortality as 'J-shaped', meaning that mortality rates increase below a certain BP threshold. We aimed to analyse the associations between BP and prognosis in a population of acute myocardial infarction (MI) patients with heart failure (HF) and/or systolic dysfunction. Methods and results The datasets included in this pooling initiative are derived from four trials: CAPRICORN, EPHESUS, OPTIMAAL, and VALIANT. A total of 28 771 patients were included in this analysis. Arithmetic means of all office BP values measured throughout follow-up were used. The primary outcome was cardiovascular death. The mean age was 65±11.5 years and 30% were female. Patients in the lower systolic BP (SBP) quintiles had higher rates of cardiovascular death (reference: SBP 121-128 mmHg) [adjusted hazard ratio (HR) 2.49, 95% confidence interval (CI) 2.26-2.74 for SBP =112 mmHg, and HR 1.29, 95% CI 1.16-1.43 for SBP 113-120 mmHg]. The findings for HF hospitalization and MI were similar. However, stroke rates were higher in patients within the highest SBP quintile (reference: SBP 121-128 mmHg) (HR 1.38, 95% CI 1.11-1.72). Patients who died had a much shorter follow-up (0.7 vs. 2.1 years), less BP measurements (4.6 vs. 9.8) and lower mean BP (-8mmHg in the last SBP measurement compared with patients who remained alive during the follow-up), suggesting that the associations of low BP and increased cardiovascular death represent a reverse causality phenomenon. Conclusion Systolic BP values <125mmHg were associated with increased cardiovascular death, but these findings likely represent a reverse causality phenomenon. [ABSTRACT FROM AUTHOR]

Aims An excessive production of aldosterone influences outcome in patients with heart failure (HF) and in obese patients. Findings from laboratory studies suggest that chronic aldosterone blockade maybe more beneficial in abdominally obese HF-prone rats. In the current study, we investigated if the clinical response to a mineralocorticoid receptor antagonist in mildly symptomatic HF patients varied by abdominal obesity. Methods and results A total of 2587 NYHA class II, reduced ejection fraction HF (HFrEF) patients enrolled in the EMPHASIS-HF trial were randomly assigned to eplerenone and placebo. In this post hoc analysis, patients were categorized according to waist circumference (WC) (normal if WC < 102 cm in men and<88 cm in women; abdominal obesity if WC = 102 cm in men and=88 cm women). The potential statistical interaction between the treatment and WC was assessed on the primary endpoint of death from cardiovascular causes or hospitalization for HF and other secondary endpoints. Over a median follow-up of 21 months, a significant benefit of eplerenone for the primary outcome was noted in both normal [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.61-0.98, P = 0.03] and increased (HR 0.48, 95% CI 0.37-0.63, P < 0.0001) WC subgroups, but the latter patients appeared to receive greater benefit than patients with normal WC (P for interaction = 0.01). This suggests a significant quantitative (treatment effect varies in magnitude by subgroup, but is always in same direction) rather than a qualitative interaction (direction of the treatment effect varies by subgroup) between eplerenone and WC in the adjusted analysis. Mean doses of eplerenone, blood pressure and serum potassium changes and adverse events were similar between WC subgroups. Conclusion In EMPHASIS-HF, eplerenone improved outcomes in HFrEF patients with and without abdominal obesity, although the benefit appeared to be more pronounced among those with abdominal obesity. The findings are potentially hypothesis generating and need to be replicated in other HFrEF populations. [ABSTRACT FROM AUTHOR]

The aim of personalized medicine is to offer a tailored approach to each patient in order to provide the most effective therapy, while reducing risks and side effects. The use of mineralocorticoid receptor antagonists (MRAs) has demonstrated major benefits in heart failure with reduced ejection fraction (HFrEF), results with challenging inconsistencies in heart failure with preserved ejection fraction (HFpEF), and 'neutral' preliminary results in acute heart failure. Data derived from landmark trials are generally applied in a 'one size fits all' manner and the development and implementation of more personalized MRA management would offer the potential to improve outcomes and reduce side effects. However, the personalization of pharmacotherapy regimens remains poorly defined in the cardiovascular field (in light of current knowledge) and until further trials targeting specific subpopulations have been conducted, MRAs should be provided to the great majority of HFrEF patients in the absence of contraindication. Spironolactone should be considered for symptomatic HFpEF patients with elevated natriuretic peptides. In the near future, trials should target HFrEF patients using exclusion criteria sourced from landmark trials (e.g. severe renal impairment), select more homogeneous HFpEF populations (e.g. with elevated BNP and structural abnormalities on echocardiography), and determine which patients are likely to benefit from MRAs (e.g. according to prespecified biomarkers). [ABSTRACT FROM AUTHOR]

Aims: Left ventricular mechanical dyssynchrony has been described in heart failure with preserved ejection fraction (HFpEF), but its prognostic significance is not known.Methods and Results: Of 3445 patients with HFpEF enrolled in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, dyssynchrony analysis was performed on 424 patients (12%) by multiple speckle tracking echocardiography strain-based criteria. The primary dyssynchrony analysis was the standard deviation of the time to peak longitudinal strain (SD T2P LS). Cox proportional hazards models assessed the association of dyssynchrony with the composite outcome of cardiovascular death or heart failure hospitalization. Mean age was 70 ± 10 years, LVEF was 60 ± 8%, and QRS duration was 101 ± 27 ms. Worse dyssynchrony, reflected in SD T2P LS, was associated with wider QRS, prior myocardial infarction, larger LV volume and mass, and worse systolic (lower LVEF and global longitudinal strain) and diastolic (lower e' and higher E/e') function. During a median follow-up of 2.6 (interquartile range 1.5-3.8) years, 107 patients experienced the composite outcome. Worse dyssynchrony was associated with the composite outcome in unadjusted analysis [hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.01-1.07; P = 0.021, per 10 ms increase], but not after adjusting for clinical characteristics, or after further adjustment for LVEF, AF, NYHA class, stroke, heart rate, creatinine, haematocrit, and QRS duration (HR 1.03, 95% CI 0.99-1.06; P = 0.16, per 10 ms increase).Conclusion: Worse LV mechanical dyssynchrony, assessed by speckle tracking echocardiography, is not an independent predictor of adverse outcomes in HFpEF, suggesting that mechanical dyssynchrony is unlikely to be an important mechanism underlying this syndrome. These findings warrant validation in an independent study specifically designed to assess the prognostic utility of mechanical dyssynchrony in HFpEF.Trial Registration: NCT00094302. [ABSTRACT FROM AUTHOR]

Aims Although hypokalaemia is common among patients with heart failure (HF), the prognostic significance of baseline hypokalaemia and hypokalaemia during follow-up in HF patients receiving a mineralocorticoid receptor antagonist (MRA) remains uncertain. Methods and results Results of the EMPHASIS-HF trial in patients (n = 2737) with HF and reduced EF with mild symptoms, randomized to eplerenone or placebo, were analysed with regard to the presence or occurrence of hypokalaemia (serum K+ <4.0 mmol/L) and the risk of cardiovascular death or hospitalization for HF (primary endpoint). Median follow-up was 21 months. Baseline hypokalaemia and hypokalaemia during follow-up were common occurrences (19.6% and 40.6%, respectively). Hypokalaemia during follow-up was associated with worse outcomes in multivariable analyses [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.05-1.52, P = 0.01] without evidence of interaction with eplerenone. In contrast, baseline hypokalaemia was associated with outcomes in the placebo group (HR 1.37, 95% CI 1.05-1.79, P = 0.02) but not in the eplerenone group (HR 0.87, 95% CI 0.62-1.23, P = 0.44; P for interaction=0.04). Concurrently, eplerenone was found to be more protective in patients with baseline hypokalaemia vs. patients without baseline hypokalaemia compared with placebo (HR 0.44, 95% 0.30-0.64, P < 0.0001 vs. 0.69, 95% CI 0.57-0.83, P = 0.0001; P for interaction=0.04). In patients without baseline hypokalaemia, eplerenone use decreased the rate of hypokalaemia during follow-up (HR 0.69, 95% CI 0.59-0.80, P < 0.001). A potassium level >4.0 mmol/L at 1 month after randomization mediated 26.0% (0.6-51.4%) of the eplerenone treatment effect (P = 0.04). Conclusion In HF patients receiving optimal therapy but not treated with eplerenone, baseline hypokalaemia was associated with worse outcomes. Conversely, hypokalaemia amplified the treatment effect of eplerenone. [ABSTRACT FROM AUTHOR]

Aims: To determine the influence of baseline beta-blocker use on long-term prognosis of myocardial infarction (MI) survivors complicated with heart failure (HF) or with left ventricular dysfunction and with history of chronic obstructive pulmonary disease (COPD). Methods and results:Among the 28 771 patients from the High-Risk MI Database Initiative we identified 1573 patients with a baseline history of COPD. We evaluated the association between beta-blocker use at baseline (822 with beta-blocker and 751 without) on the rates of all-cause and cardiovascular mortality. On univariable Cox analysis, beta-blocker use was found to be associated with lower rates of both all-cause [hazard ratio (HR)=0.61, 95% confidence interval (CI) 0.51-0.75, P <0.0001] and cardiovascular mortality (HR=0.63, 95% CI 0.51-0.78, P <0.0001). After extensive adjustment for confounding, including 24 baseline covariates, COPD patients still benefited from beta-blocker usage (HR=0.73, 95% CI 0.60-0.90, P =0.002 for all-cause mortality; HR=0.77, 95% CI 0.61-0.97, P =0.025 for cardiovascular mortality). Adjusting for propensity scores (PS) constructed from the 24 aforementioned baseline characteristics provided similar results. In a cohort of 561 pairs of patients taking or not taking beta-blocker matched on PS using a 1:1 nearest-neighbour matching method, patients treated with beta-blocker experienced fewer all-cause deaths (HR=0.71, 95% CI 0.56-0.89, P =0.003) and cardiovascular deaths (HR=0.76, 95% CI 0.59-0.97, P =0.032). Conclusions In the specific setting of a well-treated cohort of high-risk MI survivors, beta-blockers were associated with better outcomes in patients with COPD. [ABSTRACT FROM AUTHOR]