Effect of Torsemide Versus Furosemide on Symptoms and Quality of Life Among Patients Hospitalized for Heart Failure: The TRANSFORM-HF Randomized Clinical Trial.

BACKGROUND: Loop diuretics are a primary therapy for the symptomatic treatment of heart failure (HF), but whether torsemide improves patient symptoms and quality of life better than furosemide remains unknown. As prespecified secondary end points, the TRANSFORM-HF trial (Torsemide Comparison With Furosemide for Management of Heart Failure) compared the effect of torsemide versus furosemide on patient-reported outcomes among patients with HF. METHODS: TRANSFORM-HF was an open-label, pragmatic, randomized trial of 2859 patients hospitalized for HF (regardless of ejection fraction) across 60 hospitals in the United States. Patients were randomly assigned in a 1:1 ratio to a loop diuretic strategy of torsemide or furosemide with investigator-selected dosage. This report examined effects on prespecified secondary end points, which included Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; assessed as adjusted mean difference in change from baseline; range, 0-100 with 100 indicating best health status; clinically important difference, ≥5 points) and Patient Health Questionnaire-2 (range, 0-6; score ≥3 supporting evaluation for depression) over 12 months. RESULTS: Baseline data were available for 2787 (97.5%) patients for KCCQ-CSS and 2624 (91.8%) patients for Patient Health Questionnaire-2. Median (interquartile range) baseline KCCQ-CSS was 42 (27-60) in the torsemide group and 40 (24-59) in the furosemide group. At 12 months, there was no significant difference between torsemide and furosemide in change from baseline in KCCQ-CSS (adjusted mean difference, 0.06 [95% CI, -2.26 to 2.37]; P=0.96) or the proportion of patients with Patient Health Questionnaire-2 score ≥3 (15.1% versus 13.2%: P=0.34). Results for KCCQ-CSS were similar at 1 month (adjusted mean difference, 1.36 [95% CI, -0.64 to 3.36]; P=0.18) and 6-month follow-up (adjusted mean difference, -0.37 [95% CI, -2.52 to 1.78]; P=0.73), and across subgroups by ejection fraction phenotype, New York Heart Association class at randomization, and loop diuretic agent before hospitalization. Irrespective of baseline KCCQ-CSS tertile, there was no significant difference between torsemide and furosemide on change in KCCQ-CSS, all-cause mortality, or all-cause hospitalization. CONCLUSIONS: Among patients discharged after hospitalization for HF, a strategy of torsemide compared with furosemide did not improve symptoms or quality of life over 12 months. The effects of torsemide and furosemide on patient-reported outcomes were similar regardless of ejection fraction, previous loop diuretic use, and baseline health status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03296813.

Clinical trajectory of patients with a worsening heart failure event and reduced ventricular ejection fraction.

BACKGROUND: Recent data suggest that patients with heart failure with reduced ejection fraction (HFrEF) and worsening heart failure (WHF) have potential for greater benefit from newer HF therapies. We investigated characteristics and outcomes of patients with HFrEF and WHF by severity of left ventricular dysfunction. METHODS: We identified patients with chronic symptomatic HFrEF (left ventricular ejection fraction [LVEF] ≤35%) and evidence of WHF (emergency department visit or hospitalization for acute HF within 12 months of index echocardiogram) treated at Duke University between 1/2009 and 12/2018. Patients were stratified by LVEF≤25% or 26% to35%. Cox models were used to estimate cause-specific hazard ratios and 5-year event incidence of death and hospitalization across the range of LVEF. RESULTS: Of 2823 patients with HFrEF and WHF, 1620 (57.4%) had an LVEF≤25% and 1203 (42.6%) had an LVEF 26% to35%. Compared to patients with LVEF 26% to35%, those with LVEF≤25% were younger and more commonly men with a lower cardiovascular comorbidity burden. Patients with LVEF≤25% were less commonly on beta blockers (85.9% vs 90.5%) but more commonly treated with mineralocorticoid receptor antagonists (49.3% vs 41.1%) and implantable defibrillators (41.3% vs 28.2%). Patients with LVEF≤25% had significantly higher hazards for death (HR 1.24 [95% CI 1.11 - 1.38]), all-cause hospitalization (HR 1.21 [95% CI 1.10 - 1.33]), and HF hospitalization (HR 1.25 [95% CI 1.1 - 1.38]) through 5-years. CONCLUSIONS: More than half of patients with chronic HFrEF and WHF have severe LV dysfunction. Important differences in comorbidities, HF therapies, and outcomes exist between those with LVEF≤25% and those with LVEF 26% to35%.

Health System-Level Performance in Prescribing Guideline-Directed Medical Therapy for Patients With Heart Failure With Reduced Ejection Fraction: Results From the CONNECT-HF Trial.

BACKGROUND: Health system-level interventions to improve use of guideline-directed medical therapy (GDMT) often fail in the acute care setting. We sought to identify factors associated with high performance in adoption of GDMT among health systems in CONNECT-HF. METHODS AND RESULTS: Site-level composite quality scores were calculated at discharge and last follow-up. Site performance was defined as the average change in score from baseline to last follow-up and analyzed by performance tertile using a mixed-effects model with baseline performance as a fixed effect and site as a random effect. Among 150 randomized sites, the mean 12-month improvement in GDMT was 1.8% (-26.4% to 60.0%). Achievement of 50% or more of the target dose for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, and beta-blockers at 12 months was modest, even at the highest performing sites (median 29.6% [23%, 41%] and 41.2% [29%, 50%]). Sites achieving higher GDMT scores had care teams that included social workers and pharmacists, as well as patients who were able to afford medications and access medication lists in the electronic health record. CONCLUSIONS: Substantial gaps in site-level use of GDMT were found, even among the highest performing sites. The failure of hospital-level interventions to improve quality metrics suggests that a team-based approach to care and improved patient access to medications are needed for postdischarge success.

Drugs of Abuse and Heart Failure.

Substance use is common among those with heart failure (HF) and is associated with worse clinical outcomes. Alcohol, tobacco, cannabis, and cocaine are commonly abused substances that can contribute to the development and worsening of HF. Heavy alcohol consumption can lead to dilated cardiomyopathy, whereas moderate intake may decrease incident HF. Tobacco increases the risk of HF through coronary artery disease and coronary artery disease-independent mechanisms. Continued smoking worsens outcomes for those with HF and cessation is associated with an improved risk of major adverse cardiac events. Cannabis has complex interactions on the cardiovascular system depending on the method of consumption, amount consumed, and content of cannabinoids. Delta-9-tetrahydrocannabinol can increase sympathetic tone, cause vascular dysfunction, and may increase the risk of myocardial infarction. Cannabidiol is cardioprotective in preclinical studies and is a potential therapeutic target. Cocaine increases sympathetic tone and is a potent proarrhythmogenic agent. It increases the risk of myocardial infarction and can also lead to a dilated cardiomyopathy. The use of beta-blockers in those with HF and cocaine use is likely safe and effective. Future studies are needed to further elucidate the impact of these substances both on the development of HF and their effects on those who have HF.

Making Sense of Hypertension Guidelines.

Hypertension is a leading risk factor for heart disease, stroke, kidney failure, and diabetes and is a predisposing risk factor for most cardiovascular chronic illnesses. The risk for major cardiovascular events drops significantly when guideline-based blood pressure targets are achieved. Several different societies and organizations have released guidelines during the past 6 years, and significant clinical trial data have been recently released. Here, we summarize existing guidelines and recent pertinent clinical trial data to assist practitioners in identifying optimal treatment strategies for the successful management of hypertension.

Results of the Chronic Heart Failure Intervention to Improve MEdication Adherence study: A randomized intervention in high-risk patients.

BACKGROUND: Poor adherence to evidence-based medications in heart failure (HF) is a major cause of avoidable hospitalizations, disability, and death. To test the feasibility of improving medication adherence, we performed a randomized proof-of-concept study of a self-management intervention in high-risk patients with HF. METHODS: Patients with HF who screened positively for poor adherence (<6 Morisky Medication Adherence Scale 8-item) were randomized to either the intervention or attention control group. In the intervention group (n = 44), a nurse conducted self-management training before discharge that focused on identification of medication goals, facilitation of medication-symptom associations, and use of a symptom response plan. The attention control group (n = 42) received usual care; both groups received follow-up calls at 1 week. However, the content of follow-up calls for the attention control group was unrelated to HF medications or symptoms. General linear mixed models were used to evaluate the magnitude of change in adherence and symptom-related events at 3-, 6-, and 12-month follow-up clinic visits. Efficacy was measured as improved medication adherence using nurse-assessed pill counts at each time point. RESULTS: Pooled over all time points, patients in the intervention group were more likely to be adherent to medications compared with patients in the attention control group (odds ratio 3.92, t = 3.51, P = .0007). CONCLUSIONS: A nurse-delivered, self-care intervention improved medication adherence in patients with advanced HF. Further work is needed to examine whether this intervention can be sustained to improve clinical outcomes.

Use of antiarrhythmic drug therapy and clinical outcomes in older patients with concomitant atrial fibrillation and coronary artery disease.

AIMS: Atrial fibrillation (AF) and coronary artery disease (CAD) are common in older patients. We aimed to describe the use of antiarrhythmic drug (AAD) therapy and clinical outcomes in these patients. METHODS AND RESULTS: We analysed AAD therapy and outcomes in 1738 older patients (age ≥65) with AF and CAD in the Duke Databank for cardiovascular disease. The primary outcomes were mortality and rehospitalization at 1 and 5 years. Overall, 35% of patients received an AAD at baseline, 43% were female and 85% were white. Prior myocardial infarction (MI, 31%) and heart failure (41%) were common. Amiodarone was the most common AAD (21%), followed by pure Class III agents (sotalol 6.3%, dofetilide 2.2%). Persistence of AAD was low (35% at 1 year). After adjustment, baseline AAD use was not associated with 1-year mortality [adjusted hazard ratio (HR) 1.23, 95% confidence interval (CI) 0.94-1.60] or cardiovascular mortality (adjusted HR 1.27, 95% CI 0.90-1.80). However, AAD use was associated with increased all-cause rehospitalization (adjusted HR 1.20, 95% CI 1.03-1.39) and cardiovascular rehospitalization (adjusted HR 1.20, 95% CI 1.01-1.43) at 1 year. This association did not persist at 5 years; however, these patients were at very high risk of death (55% for those >75 and on AAD) and all-cause rehospitalization (87% for those >75 and on AAD) at 5 years. CONCLUSIONS: In older patients with AF and CAD, antiarrhythmic therapy was associated with increased rehospitalization at 1 year. Overall, these patients are at high risk of longer-term hospitalization and death. Safer, better-tolerated, and more effective therapies for symptom control in this high-risk population are warranted.

The pharmacology of novel oral anticoagulants.

Anticoagulation for the prevention of stroke is an important aspect of the management of atrial fibrillation. Novel anticoagulants including oral factor Xa inhibitors rivaroxaban and apixaban and the direct thrombin inhibitor dabigatran have emerged as important therapeutic treatment options for prevention of stroke in non-valvular atrial fibrillation. These agents offer practical advantages over traditional vitamin K antagonists, however an understanding of their individual pharmacokinetic and other agent-specific differences is essential for identifying appropriate candidates for therapy, and for selecting the appropriate agent that will be effective and safe. Here, we review the pharmacokinetic process of oral medication use, summarize the newer anticoagulants, their pharmacology, individual pharmacokinetic features, and explore possible explanations for the differences in bleeding outcomes observed in the clinical trials.

Anabolic androgenic steroids and cardiomyopathy: an update.

Anabolic androgenic steroids (AAS) include endogenously produced androgens like testosterone and their synthetic derivatives. Their influence on multiple metabolic pathways across organ systems results in an extensive side effect profile. From creating an atherogenic and prothrombotic milieu to direct myocardial injury, the effects of AAS on the heart may culminate with patients requiring thorough cardiac evaluation and multi-disciplinary medical management related to cardiomyopathy and heart failure (HF). Supraphysiological doses of AAS have been shown to induce cardiomyopathy via biventricular dysfunction. Advancement in imaging including cardiac magnetic resonance imaging (MRI) and additional diagnostic testing have facilitated the identification of AAS-induced left ventricular dysfunction, but data regarding the impact on right ventricular function remains limited. Emerging studies showed conflicting data regarding the reversibility of AAS-induced cardiomyopathy. There is an unmet need for a systematic long-term outcomes study to empirically evaluate the clinical course of cardiomyopathy and to assess potential targeted therapy as appropriate. In this review, we provide an overview of the epidemiology, pathophysiology and management considerations related to AAS and cardiomyopathy.

Management of Heart Failure With Reduced Ejection Fraction.

Heart failure with reduced ejection fraction (HFrEF) is a complex and progressive clinical condition characterized by dyspnea and functional impairment. HFrEF has a high burden of mortality and readmission rate making it one of the most significant public health challenges. Basic treatment strategies include diuretics for symptom relief and use of quadruple therapy (Angiotensin receptor blocker/neprilysin inhibitors, evidence-based beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors) for reduction in hospitalizations, all-cause mortality, and cardiovascular mortality. Despite compelling evidence of clinical benefit, guideline directed medical therapy is vastly underutilized in the real-world clinical practice. Other medications such as intravenous iron, ivabradine, hydralazine/nitrates and vericiguat may also have a role in certain subgroup of HFrEF patients. Specific groups of patients with HFrEF may also be candidates for various device therapies such as implanted cardioverter defibrillators, cardiac resynchronization therapy and trans catheter mitral valve repair. This review provides a comprehensive overview of drug and device management approaches for patients with HFrEF, recommendations for initiation and titrations of therapies, and challenges associated with guideline directed medical therapy in the management of patients with HFrEF (Graphical abstract).

Patients hospitalized with acute heart failure, worsening renal function, and persistent congestion are at high risk for adverse outcomes despite current medical therapy.

INTRODUCTION: Approximately 1/3 of patients with acute decompensated heart failure (ADHF) are discharged with persistent congestion. Worsening renal function (WRF) occurs in approximately 50% of patients hospitalized for ADHF and the combination of WRF and persistent congestion are associated with higher risk of mortality and HF readmissions. METHODS: We designed a multicenter, prospective registry to describe current treatments and outcomes for patients hospitalized with ADHF complicated by WRF (defined as a creatinine increase ≥0.3 mg/dL) and persistent congestion at 96 h. Study participants were followed during the hospitalization and through 90-day post-discharge. Hospitalization costs were analyzed in an economic substudy. RESULTS: We enrolled 237 patients hospitalized with ADHF, who also had WRF and persistent congestion. Among these, the average age was 66 ± 13 years and 61% had a left ventricular ejection fraction (LVEF) ≤ 40%. Mean baseline creatinine was 1.7 ± 0.7 mg/dL. Patients with persistent congestion had a high burden of clinical events during the index hospitalization (7.6% intensive care unit transfer, 2.1% intubation, 1.7% left ventricular assist device implantation, and 0.8% dialysis). At 90-day follow-up, 33% of patients were readmitted for ADHF or died. Outcomes and costs were similar between patients with reduced and preserved LVEF. CONCLUSIONS: Many patients admitted with ADHF have WRF and persistent congestion despite diuresis and are at high risk for adverse events during hospitalization and early follow-up. Novel treatment strategies are urgently needed for this high-risk population.

Bending the Cardiovascular Event Curve by Evaluating the Potential Impact of Achieving Low-Density Lipoprotein Cholesterol Goal Across a Large Health System Among Secondary Prevention Patients.

Guidelines recommend aggressive low-density lipoprotein cholesterol (LDL-C) lowering in patients with atherosclerotic cardiovascular disease (ASCVD). However, the recommended threshold of LDL-C ≤70 mg/dL is often not achieved. We used data from the Duke University Health System electronic health record to characterize patterns of lipid levels and lipid management in patients with ASCVD to estimate the number of clinical events that could be prevented by achieving LDL-C ≤70 mg/dL . A multivariable logistic regression model was developed to predict the 1-year composite of all-cause mortality, myocardial infarction, stroke, or coronary revascularization and was validated through bootstrapping. The number needed to treat to prevent an event was then determined. Among 56,230 patients with ASCVD, the median (quartile 1, quartile 3) age was 68.6 years (59.9, 76.2), 47% were women, and 27% were non-Hispanic Black. LDL-C was >70 mg/dL in 39,566 of patients (70%); these patients were more frequently female (51% vs 36%), non-Hispanic Black (28% vs 23%), and less frequently on statin therapy (67% vs 91%) than those with LDL-C ≤70 mg/dL . A predictive model with reasonable discrimination (c-index 0.77, 95% confidence interval 0.760 to 0.77) and calibration (slope 0.99) determined that if the overall population achieved an LDL-C ≤70 mg/dL, 734 clinical events (455 myocardial infarctions, 186 strokes, and 93 coronary revascularizations) could be prevented in a year. Achieving LDL-C ≤70 mg/dL in patients with ASCVD across a health system could prevent significant clinical events within a single year. In conclusion, this study quantifies the potential benefit of a system-wide effort to achieve guideline-based LDL-C goals.

An evaluation of torsemide in patients with heart failure and renal disease.

INTRODUCTION: Torsemide is a loop diuretic that inhibits the Na+/K+/2Cl- cotransporter type 2 in the thick ascending loop of Henle, leading to increased excretion of urinary sodium and chloride and associated diuresis. While furosemide remains the dominant diuretic utilized in current practice, increasing evidence supports potential advantages of torsemide in heart failure (HF) and/or renal disease. AREAS COVERED: This narrative review covers the evidence for use of torsemide in HF and renal disease. Comparative effectiveness with regards to clinical outcomes is reviewed, as well as the ongoing multicenter trial, TRANSFORM-HF, comparing the effect of torsemide versus furosemide among patients with HF. EXPERT OPINION: Compared with furosemide, torsemide has favorable pharmacodynamics/pharmacokinetics including higher bioavailability, longer duration of effect, minor renal excretion, decreased kaliuresis, and enhanced natriuresis/diuresis. These properties may be further supported by differential effects on RAAS regulation and fibrosis modulation as compared with other diuretics. The limited current body of evidence indicates that torsemide may be superior to furosemide with respect to improving HF functional status and reducing HF hospitalization, and there are mixed data regarding effect on reducing overall cardiovascular hospitalizations/mortality. Further, randomized data are necessary to definitively determine if torsemide can reduce risk of mortality and hospitalization among patients with HF.

Body surface area and medication dosing in patients with heart failure with reduced ejection fraction.

Multiple medications are proven to reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), but data regarding personalized approaches to optimize medication dosing remain limited. Current treatment guidelines recommend up-titration to target or maximally tolerated doses of these medications, yet use and dosing remain suboptimal in clinical practice. Body surface area (BSA) is a readily available clinical metric, used for dosing many medications, closely associated with blood pressure, renal function, and vascular congestion, and may influence efficacy, safety, and tolerability of HFrEF medications. In this review, we examine the rationale, strengths/weaknesses, and potential utility of BSA as a means of optimizing HFrEF medication use and dosing.

Anticoagulants: Pharmacokinetics, Mechanisms of Action, and Indications.

Anticoagulant medications are used widely for a variety of medical and surgical diseases, disorders, and conditions associated with thrombosis and thromboembolism. This review highlights labeled indications, mechanisms of action, potential drug interactions, and specific pharmacokinetic characteristics of available anticoagulants as an essential foundation for guiding selection and management of therapies for patients undergoing neurosurgical procedures.

Achieving a Maximally Tolerated ß-Blocker Dose in Heart Failure Patients: Is There Room for Improvement?

Heart failure (HF) is associated with significant morbidity and mortality. Although initially thought to be harmful in HF, beta-adrenergic blockers (ß-blockers) have consistently been shown to reduce mortality and HF hospitalization in chronic HF with reduced ejection fraction. Proposed mechanisms include neurohormonal blockade and heart rate reduction. A new therapeutic agent now exists to target further heart rate lowering in patients who have been stable on a "maximally tolerated ß-blocker dose," but this definition and how to achieve it are incompletely understood. In this review, the authors summarize published reports on the mechanisms by which ß-blockers improve clinical outcomes. The authors describe differences in doses achieved in landmark clinical trials and those observed in routine clinical practice. They further discuss reasons for intolerance and the evidence behind using ß-blocker dose and heart rate as therapeutic targets. Finally, the authors offer recommendations for clinicians actively initiating and up-titrating ß-blockers that may aid in achieving maximally tolerated doses.

Vasopressin receptor antagonists. Therapeutic potential in the management of acute and chronic heart failure.

Despite the use of ACE inhibitors and beta-blockers, the morbidity and mortality of patients with chronic heart failure remains quite high. This has stimulated the development of new therapies, many based on the neurohormonal hypothesis. There are now multiple agents being developed for the treatment of heart failure designed to block many of the neurohormones that are increased in these patients. One of the hormones that is increased in chronic heart failure is vasopressin. Vasopressin reduces free water secretion and at high concentrations, causes vasoconstriction in the peripheral vasculature. Antagonists to vasopressin will promote free water excretion (aquaresis) and vasodilatation with a subsequent reduction in afterload. In theory, these agents would be beneficial for both acute exacerbations of heart failure (free water excretion) and chronic heart failure (neurohormonal blockade). We review the potential uses of these antagonists for these two conditions and the promising results of small, hemodynamic trials with the new vasopressin antagonists that have already been performed.

Comparison of safety of sotalol versus amiodarone in patients with atrial fibrillation and coronary artery disease.

Sotalol is a commonly prescribed antiarrhythmic drug (AAD) used for maintaining sinus rhythm in patients with atrial fibrillation (AF). Although randomized studies have found that sotalol can significantly delay time to AF recurrence, its association with mortality is less clear, particularly among those with coronary artery disease. We examined outcomes of 2,838 patients with coronary artery disease and AF. Using Cox proportional hazards modeling, landmark analysis, and time-dependent covariates for drug therapy, we compared cumulative survival among patients treated with sotalol (n = 226), amiodarone (n = 856), or no AAD (n = 1,756). Median follow-up was 4.2 years (interquartile range [IQR] 2.0-7.4). The median age was 68 years (IQR 60-75). Compared with those treated with amiodarone or no AAD, patients treated with sotalol were less likely to be black (6% vs 13% vs 13%) and have a previous myocardial infarction (35% vs 51% vs 48%) or a left ventricular ejection fraction <40% (13% vs 26% vs 21%). In follow-up, persistence of sotalol was limited; 97% of patients treated with sotalol were treated for <25% of the follow-up period. In adjusted analysis accounting for time on therapy, sotalol use was associated with an increased risk of all-cause death compared with no drug (hazard ratio 1.53, 95% confidence interval 1.19 to 1.96, p = 0.0009), but a decreased risk of death compared with amiodarone (hazard ratio 0.72, 95% confidence interval 0.55 to 0.91, p = 0.0141). In conclusion, sotalol therapy was more frequently used in patients with fewer co-morbidities, often discontinued early in follow-up, and was associated with increased mortality compared with no AAD but decreased mortality relative to amiodarone.

Cardiohepatic interactions in heart failure: an overview and clinical implications.

Heart failure (HF) is a major public health problem leading to frequent hospitalizations, impaired quality of life, and shortened life expectancy. Heart failure leads to a chronic inability to meet metabolic requirements of end organs or skeletal muscle. Current literature lacks comprehensive descriptions of HF effects on hepatic function. In this review paper, we summarize the literature that is available in hopes of highlighting the key differences in clinical presentation, histological findings, and biochemical profiles of patients who present with both acute and chronic liver injury secondary to HF. We further discuss the use of liver function tests as prognostic markers in patients with HF, as well as the implications of liver injury on drug metabolism in this patient population. Finally, we provide recommendations regarding the management of both types of liver injury in HF patients.