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The TOPCAT trial investigated spironolactone vs placebo in patients with heart failure with preserved ejection fraction (HFpEF). Although the primary endpoint was not statistically significant, treatment with spironolactone did reduce heart failure hospitalizations compared with placebo. TOPCAT's impact on prescribing patterns in the United States is not well-characterized. We performed a retrospective analysis of discharge prescribing data in the Get With The Guidelines-Heart Failure Registry among patients with left ventricular ejection fraction ≥50% discharged between January 2009 and December 2016 to assess prescribing trends upon dissemination of TOPCAT results. Of 142,201 patients included in the study, 18,581 (13.1%) were prescribed mineralocorticoid receptor antagonists (MRAs) at discharge. Compared with those not prescribed MRAs, patients discharged on MRAs were generally younger (75 vs 78 years), and report white race (76.7% vs 72.0%), more likely to have had prior heart failure hospitalizations (75.5% vs 65.7%), lower brain natriuretic peptide levels (492 vs 545 pg/mL), but similar serum creatinine levels (1.2 vs 1.2 mg/dL) upon admission. MRA prescribing modestly increased over time (p <0.0001), without significant change in the overall trend of prescribing rate for MRAs after TOPCAT results were presented (p =0.17). In conclusion, our findings suggest that for patients with HFpEF, the use of MRAs at hospital discharge is low, with only modest increases over time and no discernible change in the rate of MRA use after the TOPCAT results were released. There remains an important need for more clinical trials to better establish the efficacy and safety of MRAs for the treatment of HFpEF., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We aimed to evaluate the impact of diabetes mellitus (DM) and insulin treatment on clinical outcomes in patients with heart failure and preserved left ventricular ejection fraction enrolled in the TOPCAT study. We investigated the influence of DM status (insulin-treated [ITDM], non-insulin treated [NITDM], and no diabetes [non-DM]) at baseline on time to development of the primary end point, a composite of cardiovascular (CV) mortality, heart failure hospitalization, and aborted cardiac arrest. Secondary end points included the individual components of the primary end point, myocardial infarction, stroke, all-cause mortality, hyperkalemia, and worsened renal function. Due to marked regional differences in characteristics and outcomes of the TOPCAT patients, with much lower events in patients enrolled in Russia/Georgia, we restricted our analyses on findings from patients enrolled from the Americas. Compared to patients without DM, patients with ITDM had approximately 2-fold increased risk for the primary end point, heart failure hospitalization, and myocardial infarction (hazard ratios: 1.80, 1.97, and 2.27, respectively) and approximately 50% increases in all-cause and CV mortality. The risks for these outcomes were also increased in patients with ITDM in comparison to patients with NITDM as well (hazard ratios: 1.63, 1.65, and 2.73, respectively, and approximately 40% increases in all-cause and CV mortality). Patients with NITDM had similar risks for the primary end point and all secondary end points as patients without DM. In conclusion, the apparent increased risk of adverse outcomes in patients with heart failure and preserved left ventricular ejection fraction and ITDM merits future research to improve the prognosis of these high-risk patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Higher serum bilirubin has been associated with poorer prognosis in patients with heart failure (HF). We examined the association between serum bilirubin and clinical outcomes in patients with clinical signs of HF and/or left ventricular systolic dysfunction after acute myocardial infarction (MI). A total of 7,467 patients from the High-Risk Myocardial Infarction Database Initiative with an available baseline total bilirubin concentration were studied. The association between baseline bilirubin concentrations and the composite outcome of cardiovascular mortality (CVM), nonfatal stroke, nonfatal MI or hospitalization for HF, CVM, and all-cause mortality were assessed using Cox proportional hazards models. An interaction with time was observed with associations present only in the first 90 days after randomization. The median (percentile 25-75 ) baseline total bilirubin concentration was 11 (8 to 14) µmol/L and was above the "normal" range (>17.1 µmol/L) in 1,053 (14.1%) patients. In multivariable analysis, with adjustment for baseline characteristics (demographic, co-morbidities, Killip score, left ventricular ejection fraction, and laboratory variables), patients with a bilirubin concentration of >17.1 µmol/L had a significantly higher risk of all the studied outcomes at 90 days (e.g., CVM: adjusted hazard ratio 1.45, 95% confidence interval 1.14 to 1.86, p = 0.003). The addition of bilirubin to a validated survival model modestly improved the risk reclassification to predict 90-day events (continuous net reclassification improvement for CVM 6.4%, 95% confidence interval 0.7% to 9.6%, p = 0.04). In patients with MI complicated with HF and/or systolic dysfunction, bilirubin concentration is an independent predictor of mortality and may improve risk stratification., (Copyright © 2018. Published by Elsevier Inc.)

Acute heart failure (AHF) is a complex syndrome with presentations ranging from hypotensive cardiogenic shock to hypertensive emergency with pulmonary edema. Most patients with AHF present with worsening of chronic HF signs and symptoms over days to weeks, and significant heterogeneity exists. It can, therefore, be challenging to characterize the overall population. The complexity of defining the AHF phenotype has been cited as a contributing cause for neutral results in most pharmacologic trials in patients with AHF. Dyspnea has been a routine inclusion criterion for AHF for over a decade, but the utility of current instruments for dyspnea assessment has been called into question. Furthermore, the threshold of clinical severity that prompts patient admission of an HF clinic visit may vary substantially across regions in global trials. Therefore, the inclusion of cardiac-specific biomarkers has been incorporated into AHF trials as 1 strategy to support inclusion of the target patient population and potentially enrich the population with patients at risk for clinical outcomes. In conclusion, we discuss strategies to support appropriate patient selection in AHF trials with an emphasis on using biomarker criteria that may improve the likelihood of success with future AHF clinical trials., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The aim of our study is to investigate the effect of spironolactone on 30-day outcomes in patients with acute heart failure (AHF) and the association between treatment and outcomes stratified by biomarkers. We conducted a secondary analysis of the biomarker substudy of the multicenter COACH (Co-ordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure) trial involving 534 AHF patients for 30-day mortality and HF rehospitalizations. Spironolactone therapy was initiated and terminated at the discretion of the treating physician; 30-day outcomes were compared between patients who were treated with spironolactone and those who were not. Outcomes with spironolactone therapy were explored based on N-terminal pro-B-type natriuretic peptide, ST2, galectin-3, and creatinine levels. Spironolactone was prescribed to 297 (55.6%) patients at discharge (158 new and 139 continued). There were 19 deaths and 30 HF rehospitalizations among 46 patients by 30 days. Patients discharged on spironolactone had significantly less 30-day event (hazard ratio 0.538, p = 0.039) after adjustment for multiple risk factors. Initiation of spironolactone in patients who were not on spironolactone before admission was associated with a significant reduction in event rate (hazard ratio 0.362, p = 0.027). The survival benefit of spironolactone was more prominent in patient groups with elevations of creatinine, N-terminal pro-B-type natriuretic peptide, ST2, or galectin-3. In conclusion, AHF patients who received spironolactone during hospitalization had significantly fewer 30-day mortality and HF rehospitalizations, especially in high-risk patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The associations of a history of hypertension with subsequent outcomes after acute myocardial infarction have not been examined in propensity-matched studies. Of the 6,632 patients with acute myocardial infarctions and left ventricular systolic dysfunction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), 4,407 had histories of hypertension. Propensity scores for a history of hypertension, estimated for each patient using 64 baseline characteristics, were used to match 1,990 pairs of patients with and without hypertension. Matched Cox regression models were used to estimate associations between hypertension and outcomes during a mean of 16 months of follow-up. Heart failure (HF) hospitalization occurred in 11.9% and 8.8% of patients, respectively, with and without hypertension (hazard ratio [HR] for hypertension vs no hypertension 1.36, 95% confidence interval [CI] 1.10 to 1.68, p = 0.004). The association between a history of hypertension and HF hospitalization was significant only in patients without previous HF (n = 3,495, HR 1.48, 95% CI 1.18 to 1.84, p = 0.001), but not in those with previous HF (n = 485, HR 1.09, 95% CI 0.73 to 1.62, p = 0.688, p for interaction = 0.179). A history of hypertension was not associated with all-cause mortality (HR 1.02, 95% CI 0.86 to 1.22, p = 0.790) or cardiovascular hospitalization (HR 1.08, 95% CI 0.92 to 1.27, p = 0.339). In conclusion, a history of hypertension was associated with subsequent HF hospitalization after acute myocardial infarction, especially in patients without histories of HF, suggesting that hypertension increased the risk for hospitalization with incident HF but did not affect hospitalization for worsening HF symptoms in those with prevalent HF.

Post hoc analyses of the Digitalis Investigation Group (DIG) trial indicate that digoxin at low (0.5 to 0.9 ng/ml) serum digoxin concentration (SDC) reduces mortality, which is eliminated at higher (>or=1 ng/ml) SDC, and that low-dose digoxin (

Heart failure continues to significantly impact morbidity and mortality after acute myocardial infarction (AMI), especially when associated with left ventricular systolic dysfunction (LVSD). Therefore, routine use of optimal therapy for patients with heart failure after AMI is needed in the future. Data from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) has demonstrated that addition of eplerenone to standard therapy in patients with LVSD and clinical heart failure post-AMI significantly improves outcomes in these patients, providing the basis for acceptance of aldosterone blockade as an integral component of therapy. However, further studies are needed to more broadly explore the usefulness of aldosterone blockade in heart failure therapy. As research clarifies the many complex pathophysiologic processes involved in post-AMI remodeling, treatment should continue to move beyond symptom-targeted therapies to disease- and mechanism-targeted therapies that will further improve outcomes in the setting of heart failure post-AMI and beyond.

Although angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and beta-blockers have been proved to reduce mortality in patients with heart failure post-acute myocardial infarction (AMI), studies show that these agents are consistently underused in this population. Further, morbidity and mortality remain high even when standard-of-care therapies are applied. Thus, new strategies have been sought to better counteract the maladaptive effects of neurohormonal stimulation in post-AMI heart failure. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone, when used in addition to standard therapy, results in significant incremental improvements in survival and morbidity and is safe and well tolerated in this setting. Based on this, major therapeutic guidelines in the United States and Europe now strongly recommend that all eligible patients with concomitant heart failure post-AMI be treated with an aldosterone blocker in addition to an ACE inhibitor (or an ARB) and a beta-blocker. To achieve needed improvements in outcomes in this population, early and consistent initiation of these evidence-based, guideline-recommended therapies in all eligible patients is crucial.

The myocardial contractile protein myosin light chain 1 isoform (MLC-1) is released into the circulation during myocyte necrosis and could thus be a marker of low-grade myocardial damage and of poor prognosis in patients with heart failure. Two hundred eighteen patients with stable heart failure (ejection fraction [EF] <35%) and in New York Heart Association (NYHA) class III to IV had MLC-1 measured at baseline and 1 month after being randomized to the direct vasodilator flosequinan or placebo. Patients were followed a mean of 302 +/- 142 days. The prognostic value of an increase in MLC-1 above the 98th percentile of normal controls was compared with that of conventional prognostic variables in heart failure. MLC-1 was increased in over half of patients at baseline and 1 month, and this was associated with increased age, NYHA class IV, and renal insufficiency. By Kaplan-Meier survival analysis, patients with a baseline increase in MLC-1 had a greater mortality (26%) than those without an increase (15%) (p = 0.043). A significant interaction among MLC-1, survival, and treatment was found (p = 0.043). In the placebo group, MLC-1 was associated with increased mortality (29% vs 12%, p = 0.025), whereas there was no significant difference among patients receiving flosequinan. In a multivariate logistic regression model including age, treatment, and left ventricular (LV) ejection fraction, the MLC-1 chain was most predictive of mortality (p = 0.049). Thus, circulating MLC-1 is elevated in over half of patients with stable severe heart failure, and this increase is associated with a poor prognosis. Flosequinan treatment eliminates this association, highlighting the complexity of the relation between cardiac myocyte damage, drug treatment, and mortality.