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The article discusses issues related to undertaking cardiovascular outcome trials in patients with advanced stages of chronic kidney diseases and those who are on dialysis. Topics discussed include ways to define cardiovascular events such as acute coronary syndrome and heart failure in patients with later stages of chronic kidney diseases, baseline troponin concentrations in patients with chronic kidney disease and rates of cardiovascular morbidity and mortality in patients.

Abstract: Background: Transatlantic differences in outcomes in heart failure after acute myocardial infarction (AMI) have not been examined in propensity-matched studies. Methods: In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), there were significant imbalances in baseline characteristics between patients from North America (n =858) and Europe (n =4646). Propensity scores for North America, calculated for each patient using 64 baseline characteristics, were used to assemble 298 pairs of patients who were well balanced on all measured baseline characteristics. Matched Cox regression models were used to estimate transatlantic differences in outcomes. Results: There was no transatlantic difference in all-cause mortality during 16 months of mean follow-up of (matched hazard ratio {HR}, 1.00; 95% confidence interval {CI}, 0.64–1.57; P =1.000). All-cause hospitalization occurred in 175 (rate, 8974/10,000 person-years) and 137 (rate, 5249/10,000 person-years) patients respectively from North America and Europe (matched HR when North America was compared with Europe, 1.89; 95% CI, 1.41–2.52; P <0.0001). Matched HRs (95% CIs) for cardiovascular and non-cardiovascular hospitalization for North America were respectively 1.35 (0.92–1.97; P =0.125) and 1.89 (1.31–2.72; P <0.0001). Among 5504 pre-match patients, unadjusted, multivariable-adjusted, and propensity-adjusted HRs for all-cause hospitalization for North America were 1.52 (95% CI, 1.38–1.68; P <0.0001), 1.16 (95% CI, 1.02–1.31; P =0.020), 1.41 (95% CI, 1.17–1.70; P <0.0001). Conclusion: Despite major transatlantic differences in baseline characteristics, there was no difference in post-AMI mortality. The increased non-cardiovascular hospitalization in North America may in part be due to transatlantic differences in patient preferences and access to care. [Copyright &y& Elsevier]

Abstract: Background: Low serum magnesium levels may cause fatal ventricular arrhythmias. However, their long-term effects on mortality and morbidity in chronic heart failure patients are relatively unknown. Methods: We studied 1569 chronic systolic and diastolic heart failure patients with normal sinus rhythm who participated in the Digitalis Investigation Group trial and had serum magnesium data available at one month. Of these, 741 patients had normal (>2 mEq/L) and 828 had low (≤2 mEq/L) serum magnesium levels. Propensity scores for having low serum magnesium levels were calculated for each patient using a non-parsimonious multivariable logistic regression model, and were used to match 560 (76%) low-magnesium patients with 560 normal-magnesium patients. Effects of low-magnesium on mortality and hospitalization during a mean follow-up of 36 months were assessed using matched Cox regression analyses. Results: All-cause mortality occurred in 156 (rate, 915/10,000 person-years) normal- magnesium and 171 (rate, 1034/10,000 person-years) low-magnesium patients, respectively, during 1704 and 1653 years of follow-up (hazard ratio, 1.23; 95% confidence interval, 0.97–1.57; p =0.089). Cardiovascular mortality occurred in 110 (rate, 646/10,000 person-years) normal-magnesium and 133 (rate, 805/10,000 person-years) low-magnesium patients (hazard ratio, 1.38, 95% confidence interval, 1.04–1.83, p =0.024). Hazard ratios and 95% confidence intervals for all-cause and cardiovascular hospitalizations were respectively 1.18 (0.99–1.42; p =0.068) and 1.14 (0.94–1.39; p =0.182). Conclusions: In a propensity-matched population of ambulatory chronic heart failure patients who were balanced in all measured baseline covariates, serum magnesium level 2 mEq/L or less was associated with increased cardiovascular mortality, but had no association with cardiovascular hospitalization. [Copyright &y& Elsevier]

Abstract: Background: In heart failure (HF), digoxin at low serum digoxin concentrations (SDC) reduces all-cause mortality and HF hospitalizations. However, the effects of digoxin on other cause-specific outcomes have not been studied in a propensity-matched cohort. Methods: The Digitalis Investigation Group trial, conducted during 1991–1993, enrolled 7788 ambulatory chronic HF patients. This analysis focuses on 4843 patients: 982 receiving digoxin with low (0.5–0.9 ng/ml) SDC at one month, and 3861 receiving placebo and alive at one month. Propensity scores for low SDC, calculated using a non-parsimonious multivariable logistic regression model, were used to match 982 low-SDC patients with 982 placebo patients. Matched Cox regression analyses were used to determine the effect of digoxin at low SDC on outcomes. Results: All-cause mortality occurred in 315 placebo (rate, 1071/10,000 person-years) and 288 low-SDC digoxin (rate, 871/10,000 person-years) patients, respectively, during 2940 and 3305 years of follow up (hazard ratio {HR}, 0.81, 95% confidence interval {CI}, 0.68–0.98; p =0.028). Cardiovascular hospitalizations occurred in 493 placebo (2359/10,000 person-year) and 471 low-SDC digoxin (1963/10,000 person-year) patients, respectively during 2090 and 2399 years of follow up (HR, 0.82, 95% CI, 0.70–0.95; P =0.010). Low-SDC digoxin to placebo HR (95%CI) for HF mortality and HF hospitalizations were respectively, 0.65 (0.45–0.92; P =0.015) and 0.63 (0.52–0.77; P <0.0001). Low-dose digoxin (≤0.125 mg/day) was the strongest independent predictor of low SDC (adjusted odd ratio, 2.07, 95% CI 1.54–2.80). Conclusions: Digoxin at low SDC significantly reduced mortality and hospitalizations in ambulatory chronic systolic and diastolic HF patients. [Copyright &y& Elsevier]

Abstract: Aims: Because of the prognostic importance of LV dysfunction following an AMI and the increasing use of electrical and/or mechanical interventions in patients with LV systolic dysfunction, this retrospective analysis of EPHESUS patients with LVEF ≤30% at baseline was conducted to determine the value of eplerenone in this setting. Methods and results: In EPHESUS, 6632 patients with LVEF ≤40% and clinical heart failure (HF) post-AMI who were receiving standard therapy were randomized to eplerenone 25 mg/day titrated to 50 mg/day or placebo for a mean follow-up of 16 months. Treatment with eplerenone in the subgroup of patients with LVEF ≤30% (N =2106) resulted in relative risk reductions of 21% versus placebo in both all-cause mortality (P =0.012) and cardiovascular (CV) mortality/CV hospitalization (P =0.001), and 23% for CV mortality (P =0.008). The relative risk of sudden cardiac death (SCD) was reduced 33% (P =0.01) and HF mortality/HF hospitalization was reduced 25% (P =0.005) with eplerenone compared with placebo. Within 30 days of randomization, eplerenone resulted in relative risk reductions of 43% for all-cause mortality (P =0.002), 29% for CV mortality/CV hospitalization (P =0.006), and 58% for SCD (P =0.008). Conclusions: Treatment with eplerenone plus standard therapy in patients with post-AMI HF and LVEF ≤30% provided significant incremental benefits in reducing both early and late mortality and morbidity. [Copyright &y& Elsevier]

Objectives: This study sought to assess the impact of the selective aldosterone blocker eplerenone on mortality 30 days after randomization in patients after acute myocardial infarction (AMI) with a left ventricular ejection fraction (LVEF) ≤40% and clinical signs of heart failure. Background: In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), eplerenone reduced all-cause mortality by 15% (p = 0.008) over a mean follow-up of 16 months when used with standard therapy in patients after AMI with an LVEF ≤40% and clinical signs of heart failure. Methods: We analyzed the effect of eplerenone 25 mg/day initiated 3 to 14 days after AMI (mean, 7.3 days) on the co-primary end points of time to death from any cause and the composite end point of time to death from cardiovascular (CV) causes or hospitalization for CV events, and the secondary end points of CV mortality, sudden cardiac death, and fatal/nonfatal hospitalization for heart failure, after 30 days of therapy in the EPHESUS trial. Results: At 30 days after randomization, eplerenone reduced the risk of all-cause mortality by 31% (3.2% vs. 4.6% in eplerenone and placebo-treated patients, respectively; p = 0.004) and reduced the risk of CV mortality/CV hospitalization by 13% (8.6% vs. 9.9% in eplerenone and placebo-treated patients, respectively; p = 0.074). Eplerenone also reduced the risk of CV mortality by 32% (p = 0.003) and the risk of sudden cardiac death by 37% (p = 0.051). Conclusions: Eplerenone 25 mg/day significantly reduced all-cause mortality 30 days after randomization (when initiated at a mean of 7.3 days after AMI) in addition to conventional therapy in patients with an LVEF ≤40% and signs of heart failure. Based on its early survival benefit, eplerenone should be administered in the hospital after AMI. [Copyright &y& Elsevier]

Background: The ELITE study showed an association between the angiotensin II antagonist losartan and an unexpected survival benefit in elderly heart-failure patients, compared with captopril, an angiotensin-converting-enzyme (ACE) inhibitor. We did the ELITE II Losartan Heart Failure Survival Study to confirm whether losartan is superior to captopril in improving survival and is better tolerated.Methods: We undertook a double-blind, randomised, controlled trial of 3,152 patients aged 60 years or older with New York Heart Association class II-IV heart failure and ejection fraction of 40% or less. Patients, stratified for beta-blocker use, were randomly assigned losartan (n=1,578) titrated to 50 mg once daily or captopril (n=1,574) titrated to 50 mg three times daily. The primary and secondary endpoints were all-cause mortality, and sudden death or resuscitated arrest. We assessed safety and tolerability. Analysis was by intention to treat.Findings: Median follow-up was 555 days. There were no significant differences in all-cause mortality (11.7 vs 10.4% average annual mortality rate) or sudden death or resuscitated arrests (9.0 vs 7.3%) between the two treatment groups (hazard ratios 1.13 [95.7% CI 0.95-1.35], p=0.16 and 1.25 [95% CI 0.98-1.60], p=0.08). Significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9.7 vs 14.7%, p<0.001), including cough (0.3 vs 2.7%). [ABSTRACT FROM AUTHOR]

Renin-angiotensin system inhibitors improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, less is known about their effectiveness in patients with HFrEF and advanced kidney disease. In the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF), 1582 patients with HFrEF (ejection fraction ≤40%) had advanced kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m2). Of these, 829 were not receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) prior to admission, of whom 214 were initiated on these drugs prior to discharge. We calculated propensity scores for receipt of these drugs for each of the 829 patients and assembled a matched cohort of 388 patients, balanced on 47 baseline characteristics (mean age 78 years; 52% women; 10% African American; 73% receiving beta-blockers). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated comparing 2-year outcomes in 194 patients initiated on ACE inhibitors or ARBs to 194 patients not initiated on those drugs. The combined endpoint of heart failure readmission or all-cause mortality occurred in 79% and 84% of patients initiated and not initiated on ACE inhibitors or ARBs, respectively (HR associated with initiation, 0.79; 95% CI, 0.63-0.98). Respective HRs (95% CI) for the individual endpoints of - Respective HRs (95% CI) for the individual endpoints of all-cause mortality and heart failure readmission were 0.81 (0.63–1.03) and 0.63 (0.47–0.85). The findings from our study add new information to the body of cumulative evidence that suggest that renin-angiotensin system inhibitors may improve clinical outcomes in patients with HFrEF and advanced kidney disease. These hypothesis-generating findings need to be replicated in contemporary patients. [ABSTRACT FROM AUTHOR]

The article informs that the cause of mortality was reduced more with candesartan than with placebo, mainly because of fewer cardiovascular deaths. Fewer patients who received candesartan had the composite outcome of cardiovascular death or hospital admission for chronic heart failure (CHF) than did patients who received placebo in the CHARM-Added and CHARM-Alternative component trials. In patients with CHF, the angiotensin receptor blocker candesartan reduced mortality and hospital admissions for worsening CHF. Patients with reduced left ventricular ejection fraction with or without baseline angiotensin converting enzyme inhibitor treatment showed the most benefit.

Key Points: Question: Does torsemide reduce all-cause mortality compared with furosemide in patients with heart failure following hospitalization? Findings: In this randomized clinical trial of 2859 patients, 26.1% of patients randomized to torsemide and 26.2% randomized to furosemide died over a median follow-up of 17.4 months without a significant difference between groups. Meaning: Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months; however, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence. Importance: Although furosemide is the most commonly used loop diuretic in patients with heart failure, some studies suggest a potential benefit for torsemide. Objective: To determine whether torsemide results in decreased mortality compared with furosemide among patients hospitalized for heart failure. Design, Setting, and Participants: TRANSFORM-HF was an open-label, pragmatic randomized trial that recruited 2859 participants hospitalized with heart failure (regardless of ejection fraction) at 60 hospitals in the United States. Recruitment occurred from June 2018 through March 2022, with follow-up through 30 months for death and 12 months for hospitalizations. The final date for follow-up data collection was July 2022. Interventions: Loop diuretic strategy of torsemide (n = 1431) or furosemide (n = 1428) with investigator-selected dosage. Main Outcomes and Measures: The primary outcome was all-cause mortality in a time-to-event analysis. There were 5 secondary outcomes with all-cause mortality or all-cause hospitalization and total hospitalizations assessed over 12 months being highest in the hierarchy. The prespecified primary hypothesis was that torsemide would reduce all-cause mortality by 20% compared with furosemide. Results: TRANSFORM-HF randomized 2859 participants with a median age of 65 years (IQR, 56-75), 36.9% were women, and 33.9% were Black. Over a median follow-up of 17.4 months, a total of 113 patients (53 [3.7%] in the torsemide group and 60 [4.2%] in the furosemide group) withdrew consent from the trial prior to completion. Death occurred in 373 of 1431 patients (26.1%) in the torsemide group and 374 of 1428 patients (26.2%) in the furosemide group (hazard ratio, 1.02 [95% CI, 0.89-1.18]). Over 12 months following randomization, all-cause mortality or all-cause hospitalization occurred in 677 patients (47.3%) in the torsemide group and 704 patients (49.3%) in the furosemide group (hazard ratio, 0.92 [95% CI, 0.83-1.02]). There were 940 total hospitalizations among 536 participants in the torsemide group and 987 total hospitalizations among 577 participants in the furosemide group (rate ratio, 0.94 [95% CI, 0.84-1.07]). Results were similar across prespecified subgroups, including among patients with reduced, mildly reduced, or preserved ejection fraction. Conclusions and Relevance: Among patients discharged after hospitalization for heart failure, torsemide compared with furosemide did not result in a significant difference in all-cause mortality over 12 months. However, interpretation of these findings is limited by loss to follow-up and participant crossover and nonadherence. Trial Registration: ClinicalTrials.gov Identifier: NCT03296813 This clinical trial compares the efficacy of torsemide vs furosemide in decreasing the risk of death from any cause among patients hospitalized for heart failure (regardless of ejection fraction). [ABSTRACT FROM AUTHOR]

The article presents the author's views on a research which finds that N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided management reduces rehospitalization of heart failure (HF) patients. The author observes that adding NT-proBNP-guided management in HF results in significant reduction in mortality, however, it is still unclear whether measurement of NT-proBNP should become a routine part of HF management.

The article presents information on the review of effectiveness of the remote patient monitoring (RPM) for management of patients with heart failures. The studies assessed the effects of RPM in patients with chronic heart failure. Many databases were searched for full-text articles of randomized controlled trials. The study highlighted that RPM reduces mortality and hospitalization for heart failure in comparison to usual care. Also discussion on the result is presented.

The article comments on a study by W. Marz, et. al. on the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and risk of cardiovascular (CV) and all-cause mortality in patients with coronary artery disease (CAD). According to the author, the study results extend the prognostic use of NT-proBNP and may improve risk stratification in patients with CAD.

Presents a study that investigated the association of serum digoxin levels with mortality and hospitalization in patients with congestive heart failure and systolic left ventricular dysfunction. Design; Intervention; Outcome measures; Results; Commentary.

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]

Clinical trials have demonstrated morbidity and mortality benefits of mineralocorticoid receptor antagonists ( MRAs) in patients with heart failure. These studies have used either spironolactone or eplerenone as the MRA. It is generally believed that these two agents have the same effects, and the data from studies using one drug could be extrapolated for the other. National and international guidelines do not generally discriminate between spironolactone and eplerenone, but strongly recommend using an MRA for patients with heart failure due to LV systolic dysfunction and post-infarct LV systolic dysfunction. There are no major clinical trials directly comparing the efficacy of these two drugs. This article aims to compare the pharmacokinetics and pharmacodynamics of spironolactone and eplerenone, and to analyse the available data for their cardiovascular indications and adverse effects. We have also addressed the role of special circumstances including co-morbidities, concomitant drug therapy, cost, and licensing restrictions in choosing an appropriate MRA for a particular patient, thus combining an evidence-based approach with personalized medicine. [ABSTRACT FROM AUTHOR]

Background: The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented.Objectives: The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists.Methods: Of the 11,900 hospitalized patients with HFrEF (EF ≤45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled.Results: Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778).Conclusions: Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Aim To evaluate canrenone effects compared to other therapies on cardiovascular mortality in patients with chronic heart failure (CHF) and preserved systolic function after 10 years of evaluation. Methods We enrolled 532 patients with CHF and preserved systolic function. Patients were followed with a mean follow-up of 10 years: 166 patients were in therapy with canrenone, while 336 patients were in conventional therapy. We re-evaluated these data after 10 years, together with the rate of death and survival. Results Systolic and diastolic blood pressure were lower with canrenone compared to the group not treated with canrenone, both in supine and orthostatism. In the group treated with canrenone we recorded a lower value of fasting plasma glucose and glycated hemoglobin. Uric acid was lower in the group treated with canrenone, no differences were observed regarding creatinine, sodium, potassium, brain natriuretic peptide (BNP), pro-BNP or plasma renin activity (PRA), while aldosterone levels were reduced in canrenone group compared to control. After 10 years, left ventricular mass was lower in canrenone group. We recorded a more pronounced progression of NYHA class in controls compared to patients treated with canrenone, with also a higher number of deaths. A higher number of deaths was recorded in control group in the 68–83 years range compared to canrenone. A higher incidence of death was reported among patients without hypercholesterolemia in control group; this was not significant in patients treated with canrenone. A longer survival was observed in patients treated with canrenone. Conclusion Administered to patients with CHF and preserved systolic fraction, reduced mortality and extended the life. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) is inversely associated with adverse cardiovascular outcomes in healthy populations, but the impact of physical activity in patients with heart failure (HF) with preserved ejection fraction is less well characterized.Methods: The baseline self-reported PA of 1751 subjects enrolled in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) was categorized as poor, intermediate, or ideal PA with American Heart Association criteria. PA was related to the primary composite outcome (HF hospitalization, cardiovascular mortality, or aborted cardiac arrest), its components, and all-cause mortality with the use of multivariable Cox models.Results: The mean age at enrollment was 68.6±9.6 years. Few patients met American Heart Association criteria for ideal activity (11% ideal, 14% intermediate, 75% poor). Over a median follow-up of 2.4 years, the primary composite outcome occurred in 519 patients (397 HF hospitalizations, 222 cardiovascular deaths, and 6 aborted cardiac arrests). Compared with those with ideal baseline PA, poor and intermediate baseline PA was associated with a greater risk of the primary outcome (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.28-3.28; HR, 1.95; 95% CI, 1.15-3.33, respectively), HF hospitalization (HR, 1.93; 95% CI, 1.16-3.22; HR, 1.84; 95% CI, 1.02-3.31), cardiovascular mortality (HR, 4.36; 95% CI, 1.37-13.83; HR, 4.05; 95% CI, 1.17-14.04), and all-cause mortality (HR, 2.95; 95% CI, 1.44-6.02; HR, 2.05; 95% CI, 0.90-4.67) after multivariable adjustment for potential confounders.Conclusions: In patients with HF with preserved ejection fraction, both poor and intermediate self-reported PA were associated with higher risk of HF hospitalization and mortality.Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302. [ABSTRACT FROM AUTHOR]

Background: 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.Methods: 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.Results: 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.Conclusions: 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.). [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]

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]

Aims: Serum uric acid (SUA) levels are associated with poorer outcomes in healthy cohorts and patients with stable and unstable coronary heart disease. We investigated the relationship between SUA and clinical outcomes in subjects with acute myocardial infarction (MI) complicated by reduced left ventricular (LV) function, heart failure (HF), or both.Methods and Results: Univariable and multivariable Cox proportional hazards modelling was performed to study the association of baseline SUA and all-cause mortality, cardiovascular (CV) mortality, and HF hospitalization in an individual patient meta-analysis of four merged large randomized trials (CAPRICORN, EPHESUS, OPTIMAAL, and VALIANT). Three trials (excluding VALIANT) reported SUA, which was available in a total of 12 677 subjects. The ranges of SUA for quartiles I-IV were 45-280, 281-344, 345-420, and 420-1640 mmol/L, respectively. While almost 90% of patients in the lowest SUA quartile were alive after a mean follow-up of 23 ± 11 months, <70% were alive in the highest SUA quartile. Compared with the lowest SUA quartile as reference, hazard ratios (HRs) and 95% confidence intervals (CIs) of SUA quartiles III and IV showed an increase in all-cause mortality [HR 1.18, 95% CI 0.95-1.46, and HR 1.36, 95% CI 1.11-1.67) and CV mortality (HR 1.27, 95% 1.01-1.61, and HR 1.47, 95% CI 1.17-1.83). SUA quartiles III and IV also exhibited increased HF hospitalization (HR 1.22, 95% CI 1.09-1.36, and HR 1.28, 95% CI 1.14-1.43; P < 0.001 for all comparisons) in multivariable analyses. The addition of SUA was associated with a significant improvement in reclassification to predict CV mortality (net reclassification improvement 17.6%, 95% CI 14.9-20.5%, P < 0.001).Conclusions: Elevated SUA is associated with poor outcomes in patients after MI complicated by reduced LV function, HF, or both. The quantification of SUA, a low-cost routinely available biomarker, could improve risk stratification of patients with complicated MI. [ABSTRACT FROM AUTHOR]

Aims We examined the relationship between different degrees of QRS prolongation and different QRS morphologies and clinical outcomes in patients with heart failure, reduced ejection fraction (HF-REF), and mild symptoms in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). We also evaluated the effect of eplerenone in these patients according to QRS duration/morphology. Methods and results Patients were categorized as: QRS duration (ms) (i) <120 (n = 1375); (ii) 120-149 (n = 517); and (iii) ≥150 (n = 383), and QRS morphology (i) normal (n = 1252); (ii) left bundle branch block (BBB) (n = 608); and (iii) right BBB/intraventricular conduction defect (IVCD) (n = 415). The outcomes examined were the composite of cardiovascular death or heart failure hospitalization and all-cause mortality. Both abnormal QRS duration and QRS morphology were associated with higher risk, e.g. the rates of the composite outcome were: 10.2, 17.6, and 15.5 per 100 patient-years in the <120, 120-149, and ≥150 ms groups, respectively. Eplerenone reduced the risk of the primary outcome and mortality, compared with placebo, consistently across the QRS duration/morphology subgroups. Conclusion We found that even moderate prolongation of QRS duration and right BBB/IVCD were associated with a high risk of adverse outcomes in HF-REF. Eplerenone was similarly effective, irrespective of QRS duration/morphology. [ABSTRACT FROM AUTHOR]

Aims EPHESUS was a multicentre, double-blind clinical trial in which 6632 patients with acute myocardial infarction ( AMI) complicated by LV systolic dysfunction ( LVSD) were randomized to receive eplerenone ( n = 3319) or placebo ( n = 3313). A total of 1580 EPHESUS patients were treated with PCI, which is now the standard treatment for AMI. This EPHESUS substudy examined the effects of eplerenone upon cardiovascular outcomes in PCI-treated patients. Methods and results EPHESUS patients were divided into PCI-treated and non- PCI-treated cohorts, and the effect of eplerenone upon mortality and other major adverse cardiovascular outcomes was assessed in each cohort. The PCI-treated patients ( n = 1580) were younger, and had better renal function and fewer co-morbidities than non- PCI-treated patients ( n = 5052). Cardiovascular mortality was significantly lower in PCI-treated patients as compared with non- PCI-treated patients (7% vs. 16%, P < 0.0001). However, the incidence of non-fatal events was similar in PCI-treated and non- PCI-treated cohorts. There was no statistical difference between the PCI-treated and non- PCI-treated cohorts in the primary or secondary outcomes of the trial. Eplerenone administration, compared with placebo, in the PCI-treated cohort did not affect PCI-related clinical outcomes, including recurrence of angina, the occurrence of acute coronary syndromes, or the need for further revascularization. Conclusions The beneficial effects of eplerenone in the EPHESUS trial exist for both PCI- and non- PCI-treated AMI patients with LVSD. Eplerenone has minimal, if any, effect upon reducing PCI-related adverse events in the PCI-treated cohort. [ABSTRACT FROM AUTHOR]

The article presents information on the effects of the acadesine, an adenosine-regulating agent on the morbidity and mortality associated with the coronary artery bypass grafting (CABG), which could be high in the patients with poor left ventricular function. It informs that the several drugs with purported cardioprotective effects including sodium-proton exchange inhibitor, a complement activation inhibitor and a purinergic receptor antagonist failed during the randomized control trials in the patients undergoing the CABG surgery. It further informs that there is a requirement of a fully functional therapy for this.

Abstract: Background: Older age is an independent predictor of all-cause mortality in patients with mild to moderate heart failure (HF). Whether older age is also an independent predictor of mortality in patients with more advanced HF is unknown. Methods: Of the 2707 Beta-Blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF (New York Heart Association class III/IV and left ventricular ejection fraction <35%), 1091 were elderly (≥65years). Propensity scores for older age, estimated for each of the 2707 patients, were used to assemble a cohort of 603 pairs of younger and older patients, balanced on 66 baseline characteristics. Results: All-cause mortality occurred in 33% and 36% of younger and older matched patients respectively during 4years of follow-up (hazard ratio {HR} associated with age ≥65years, 1.05; 95% confidence interval {CI}, 0.87–1.27; P =0.614). HF hospitalization occurred in 38% and 40% of younger and older matched patients respectively (HR, 1.01; 95% CI, 0.84–1.21; P =0.951). Among 603 pairs of unmatched and unbalanced patients, all-cause mortality occurred in 28% and 36% of younger and older patients respectively (HR, 1.34; 95% CI, 1.10–1.64; P =0.004) and HF hospitalization occurred in 34% and 40% of younger and older unmatched patients respectively (HR, 1.24; 95% CI, 1.03–1.50; P =0.024). Conclusion: Significant bivariate associations suggest that older age is a useful marker of poor outcomes in patients with advanced chronic systolic HF. However, lack of significant independent associations suggests that older age per se has no intrinsic effect on outcomes in these patients. [Copyright &y& Elsevier]

Abstract: Background: Compared with serum potassium levels 4–5.5 mEq/L, those <4 mEq/L have been shown to increase mortality in chronic heart failure (HF). Expert opinions suggest that serum potassium levels >5.5 mEq/L may be harmful in HF. However, little is known about the safety of serum potassium 5–5.5 mEq/L. Methods: Of the 7788 chronic HF patients in the Digitalis Investigation Group trial, 5656 had serum potassium 4–5.5 mEq/L. Of these, 567 had mild hyperkalemia (5–5.5 mEq/L) and 5089 had normokalemia (4–4.9 mEq/L). Propensity scores for mild hyperkalemia were used to assemble a balanced cohort of 548 patients with mild hyperkalemia and 1629 patients with normokalemia. Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for association between mild hyperkalemia and mortality during a median follow-up of 38 months. Results: All-cause mortality occurred in 36% and 38% of matched patients with normokalemia and mild hyperkalemia respectively (HR, 1.07; 95% CI, 0.90–1.26; P =0.458). Unadjusted, multivariable-adjusted, and propensity-adjusted HRs for mortality associated with mild hyperkalemia were 1.33 (95% CI, 1.15–1.52; P <0.0001), 1.16 (95% CI, 1.01–1.34; P =0.040) and 1.13 (95% CI, 0.98–1.31; P =0.091) respectively. Mild hyperkalemia had no association with cardiovascular or HF mortality or all-cause or cardiovascular hospitalization. Conclusion: Serum potassium 4–4.9 mEq/L is optimal and 5–5.5 mEq/L appears relatively safe in HF. Despite lack of an intrinsic association , the bivariate association of mild-hyperkalemia with mortality suggests that it may be useful as a biomarker of poor prognosis in HF. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hypokalemia is common in heart failure (HF) and is associated with increased mortality. Potassium supplements are commonly used to treat hypokalemia and maintain normokalemia. However, their long-term effects on outcomes in chronic HF are unknown. We used a public-use copy of the Digitalis Investigation Group (DIG) trial dataset to determine the associations of potassium supplement use with outcomes using a propensity-matched design. Methods: Of the 7788 DIG participants with chronic HF, 2199 were using oral potassium supplements at baseline. We estimated propensity scores for potassium supplement use for each patient and used them to match 2131 pairs of patients receiving and not receiving potassium supplements. Matched Cox regression models were used to estimate associations of potassium supplement use with mortality and hospitalization during 40 months of median follow-up. Results: All-cause mortality occurred in 818 (rate, 1327/10,000 person-years) and 802 (rate, 1313/10,000 person-years) patients respectively receiving and not receiving potassium supplements (hazard ratio {HR} when potassium supplement use was compared with nonuse, 1.05; 95% confidence interval {CI}, 0.94–1.18; P =0.390). All-cause hospitalizations occurred in 1516 (rate, 4777/10,000 person-years) and 1445 (rate, 4120/10,000 person-years) patients respectively receiving and not receiving potassium supplements (HR, 1.15; 95% CI, 1.05–1.26; P =0.004). HRs (95% CI) for hospitalizations due to cardiovascular causes and worsening HF were respectively 1.19 (95% CI, 1.08–1.32; P =0.001) and 1.27 (1.12–1.43; P <0.0001). Conclusion: The use of potassium supplements in chronic HF was not associated with mortality. However, their use was associated with increased hospitalization due to cardiovascular causes and progressive HF. [Copyright &y& Elsevier]

Aims: To test the hypothesis that an earlier post-acute myocardial infarction (AMI) eplerenone initiation in patients with left ventricular systolic dysfunction (LVSD) and heart failure (HF) is associated with better long-term outcomes. [ABSTRACT FROM PUBLISHER]

Abstract: Background: There is minimal evidence that HMG-CoA reductase inhibitors (statins) are beneficial in patients with chronic heart failure (CHF). Treatment with statins may lead to a lower mortality in CHF, independent of cholesterol levels, CHF etiology and clinical status. Methods: In a first study, we included 3132 patients with CHF from the ELITE 2 study in whom information on body mass index (BMI) and statin use at baseline were available. In a second study, we pooled the databases of 5 tertiary referral centers with 2068 CHF patients. In this cohort 705 patients were on a statin (34%), 585 of 1202 (49%) patients with ischemic etiology, and 120 of 866 (14%) patients with non-ischemic etiology (established by coronary angiography). Findings: Patients in ELITE 2 who received statin therapy at baseline (n =397, 13%) had lower mortality (hazard ratio [HR] 0.61, 95% CI 0.45–0.83; p =0.0007). In univariate analysis, increasing age, NYHA class, creatinine, and decreasing BMI, LVEF, and cholesterol, as well as lack of beta-blocker treatment and ischemic etiology (all p <0.002) related to higher mortality. In multivariable analysis, statin therapy related to lower mortality independently of all these variables (adjusted HR 0.66, 95% CI 0.47–0.93; p =0.017). In the second study CHF patients on statins had lower mortality (adjusted HR 0.58, 95% CI 0.44–0.77; p =0.0001). Both in patients with ischemic (p <0.0001) and non-ischemic etiology (p =0.028) statin treatment related to better survival. Interpretation: In chronic heart failure, treatment with statins is related to lower mortality, independent of cholesterol levels, disease etiology and clinical status. [Copyright &y& Elsevier]

Background: The efficacy of mineralocorticoid receptor antagonists or aldosterone antagonists in heart failure with reduced ejection fraction (HFrEF) is well known. Less is known about their effectiveness in real-world older patients with HFrEF.Methods: Of the 8206 patients with heart failure and ejection fraction ≤35% without prior spironolactone use in the Medicare-linked OPTIMIZE-HF registry, 6986 were eligible for spironolactone therapy based on serum creatinine criteria (men ≤2.5 mg/dL, women ≤2.0 mg/dL) and 865 received a discharge prescription for spironolactone. Using propensity scores for spironolactone use, we assembled a matched cohort of 1724 (862 pairs) patients receiving and not receiving spironolactone, balanced on 58 baseline characteristics (Creatinine Cohort: mean age, 75 years, 42% women, 17% African American). We repeated the above process to assemble a secondary matched cohort of 1638 (819 pairs) patients with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 (eGFR Cohort: mean age, 75 years, 42% women, 17% African American).Results: In the matched Creatinine Cohort, spironolactone-associated hazard ratios (95% confidence intervals) for all-cause mortality, heart failure readmission, and combined endpoint of heart failure readmission or all-cause mortality were 0.92 (0.81-1.03), 0.87 (0.77-0.99), and 0.87 (0.79-0.97), respectively. Respective hazard ratios (95% confidence intervals) in the matched eGFR Cohort were 0.87 (0.77-0.98), 0.92 (0.80-1.05), and 0.91 (0.82-1.02).Conclusions: These findings provide evidence of consistent, albeit modest, clinical effectiveness of spironolactone in older patients with HFrEF regardless of renal eligibility criteria used. Additional strategies are needed to improve the effectiveness of aldosterone antagonists in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Severe chronic obstructive pulmonary disease (COPD) predicts worse outcomes in heart failure (HF). The impact of milder pulmonary disease not requiring oral steroids or home O2 on outcomes in HF with preserved ejection fraction (HFpEF) is less well characterized. Objectives: We quantified the prognostic relevance of obstructive pulmonary disease for cardiovascular outcomes, and determined alterations in cardiac structure and function associated with pulmonary disease, in HFpEF. Methods: Among 1765 patients enrolled in TOPCAT in the Americas, pulmonary disease (COPD or asthma; patients using oral steroids or home O2 excluded from enrollment) was reported in 416 at baseline. Multivariable Cox regression models were used to compare outcomes in patients with and without (n=1349) pulmonary disease. Cardiac structure and function were also quantified in 653 patients in an echocardiography sub-study. Results: Patients with pulmonary disease were more likely to be non-white, current smokers, with prior PCI, lower beta-blocker use, higher heart rate, BMI and NYHA class. During a median follow up of 2.4 years, pulmonary disease was independently associated with a higher risk for the composite outcome (cardiovascular mortality, HF hospitalization and aborted cardiac arrest), HF hospitalization alone, and all-cause hospitalization alone, but not for mortality in multivariable analysis (TABLE). In the echo cohort, pulmonary disease was associated with higher LVEF (61±6% with vs. 59±8% without pulmonary disease; p<0.01) and smaller LA volume index (28±10 vs. 32±14 mL/m2; p<0.01), without differences in RV fractional area change (49±8 vs. 49±9%, p=0.77) or pulmonary pressure (RV-RA gradient 32±11 vs. 33±11mmHg, p=0.93). Conclusion: In TOPCAT, pulmonary disease was independently associated with greater risk of HF hospitalization and all-cause hospitalization, but not mortality. Pulmonary disease was not associated with prominent differences in cardiac structure and function, suggesting an important role for extracardiac factors in mediating observed risks. [ABSTRACT FROM AUTHOR]