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Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains underused. Acute heart failure (HF) hospitalization represents a critical opportunity for rapid initiation of evidence-based medications. However, data on GDMT use at discharge are mostly derived from national quality improvement registries.

Guideline-directed medical therapy (GDMT) decisions may be less affected by single patient variables such as blood pressure or kidney function and more by overall risk profile. In STRONG-HF (Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure), high-intensity care (HIC) in the form of rapid uptitration of heart failure (HF) GDMT was effective overall, but the safety, tolerability and efficacy of HIC across the spectrum of HF severity is unknown. Evaluating this with a simple risk-based framework offers an alternative and more clinically translatable approach than traditional subgroup analyses.

Heart failure (HF) is a leading cause of hospitalization in the United States. Decongestion remains a central goal of inpatient management, but contemporary decongestion practices and associated weight loss have not been well characterized nationally.

Ischemic cardiomyopathy (ICM) is the most common underlying etiology of heart failure in the United States and is a significant contributor to deaths due to cardiovascular disease worldwide. The diagnosis and management of ICM has advanced significantly over the past few decades, and the evidence for medical therapy in ICM is both compelling and robust. This contrasts with evidence for coronary revascularization, which is more controversial and favors surgical approaches. This review will examine landmark clinical trial results in detail as well as provide a comprehensive overview of the current epidemiology, diagnostic approaches, and management strategies of ICM.

Polypharmacy is common among patients with heart failure with reduced ejection fraction (HFrEF). However, its impact on the use of optimal guideline-directed medical therapy (GDMT) is not well established.

Early recognition of heart failure (HF) can reduce morbidity, yet HF is often diagnosed only after symptoms require urgent treatment.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro–B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736)

This study compared the efficacy and safety of sacubitril/valsartan to enalapril in Black and non-Black Americans with acute decompensated heart failure (ADHF).

IMPORTANCE: In PIONEER-HF, among stabilized patients with acute decompensated heart failure (ADHF), the in-hospital initiation of sacubitril/valsartan was well tolerated and led to improved outcomes compared with enalapril. However, there are limited data comparing the strategies of in-hospital vs postdischarge initiation of sacubitril/valsartan. OBJECTIVE: To describe changes in N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels in patients recently hospitalized for ADHF and switching from taking enalapril to taking sacubitril/valsartan after discharge and compare clinical outcomes for patients randomized to receive in-hospital initiation of sacubitril/valsartan vs in-hospital initiation of enalapril who later switched to taking sacubitril/valsartan during an open-label extension phase. INTERVENTIONS: Sacubitril/valsartan titrated to 97/103 mg twice daily. DESIGN, SETTING, AND PARTICIPANTS: The PIONEER-HF trial was a multicenter, randomized, double-blind, active-controlled trial conducted at 129 US sites between May 2016 and May 2018 that compared the in-hospital initiation of sacubitril/valsartan vs enalapril (titrated to target dose, 10 mg twice daily) for 8 weeks among patients admitted for ADHF with reduced ejection fraction and hemodynamic stability. All patients were to continue in a 4-week, open-label study of sacubitril/valsartan; of 881 patients enrolled in PIONEER-HF, 832 (94%) continued in the open-label study. MAIN OUTCOMES AND MEASURES: Changes in NT-proBNP levels from week 8 to 12 as well as the exploratory composite of heart failure rehospitalization or cardiovascular death from randomization through week 12. RESULTS: Of 881 participants, 226 (27.7%) were women, 487 (58.5%) were white, 297 (35.7%) were black, 15 (1.8%) were Asian, and 73 (8.8%) were of Hispanic ethnicity; the mean (SD) age was 61 (14) years. For patients who continued to take sacubitril/valsartan, NT-proBNP levels declined −17.2% (95% CI, −3.2 to −29.1) from week 8 to 12. The NT-proBNP levels declined to a greater extent for those switching from taking enalapril to sacubitril/valsartan after the week 8 visit (−37.4%; 95% CI, −28.1 to −45.6; P < .001; comparing changes in 2 groups). Over the entire 12 weeks of follow-up, patients that began taking sacubitril/valsartan in the hospital had a lower hazard for the composite outcome compared with patients that initiated enalapril in the hospital and then had a delayed initiation of sacubitril/valsartan 8 weeks later (hazard ratio, 0.69; 95% CI 0.49-0.97). CONCLUSIONS AND RELEVANCE: Switching patients’ treatment from enalapril to sacubitril/valsartan at 8 weeks after randomization led to a further 37% reduction in NT-proBNP levels in patients with heart failure with reduced ejection fraction and a recent hospitalization for ADHF. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02554890.

IMPORTANCE: A deceleration in the rate of decrease of heart disease (HD) mortality between 2011 and 2014 has been reported. In the context of the rapid increase in the population of adults aged 65 years and older, extending the examination of HD mortality through 2017 has potentially important implications for public health and medical care. OBJECTIVE: To examine changes in the age-adjusted mortality rate and the number of deaths within subcategories of HD from 2011 to 2017 in conjunction with the change in the size of the US population during the same period. DESIGN, SETTING, AND PARTICIPANTS: In this quality improvement study, the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) data set was used to identify national changes in the US population aged 65 years and older and in the age-adjusted mortality rates and number of deaths that were listed with an underlying cause of HD, coronary heart disease (CHD), heart failure, and other HDs from January 1, 2011, to December 31, 2017. MAIN OUTCOMES AND MEASURES: Changes from 2011 to 2017 in the US population and in age-adjusted mortality rates and number of deaths that were listed with an underlying cause of HD, CHD, heart failure (both as an underlying and a contributing cause), and other HDs overall, by sex and race/ethnicity. RESULTS: The total size of this population of US adults aged 65 years and older increased 22.9% from 41.4 million to 50.9 million between January 1, 2011, and December 31, 2017, while the population of adults younger than 65 years increased by only 1.7%. During this period, the age-adjusted mortality rate decreased 5.0% for HD and 14.9% for CHD while increasing 20.7% for heart failure and 8.4% for other HDs. The number of deaths increased 8.5% for HD, 38.0% for heart failure, and 23.4% for other HDs while decreasing 2.5% for CHD. A total of 80% of HD deaths occurred in the group of adults aged 65 years and older. CONCLUSIONS AND RELEVANCE: The substantial increase in the growth rate of the group of adults aged 65 years and older who have the highest risk of HD was associated with an increase in the number of HD deaths in this group despite a slowly declining HD mortality rate in the general population. With the number of adults aged 65 years and older projected to increase an additional 44% from 2017 to 2030, innovative and effective approaches to prevent and treat HD, particularly the substantially increasing rates of heart failure, are needed.

Limited data exist on the epidemiology, evaluation, and prognosis of otherwise unexplained anaemia of the elderly in heart failure (HF). Thus, we aimed to determine the incidence of anaemia, to characterize diagnostic testing patterns for potentially reversible causes of anaemia, and to evaluate the independent association between incident anaemia and long-term morbidity and mortality.

Acute heart failure (HF) patients with renal insufficiency and risk factors for diuretic resistance may be most likely to derive incremental improvement in congestion with the addition of spironolactone.

IMPORTANCE: Over the past decade, reducing 30-day readmission rates has been emphasized in the United States (including via the implementation of the Hospital Readmissions Reduction Program) but not Canada. OBJECTIVE: To examine changes that occurred from April 1, 2005, to December 31, 2015, in the United States and Canada for hospitalization length of stay and 30-day readmission rates of patients with heart failure. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients admitted with a primary diagnosis of heart failure to Canadian and US hospitals between April 1, 2005, and December 31, 2015, using International Classification of Diseases, Ninth Revision code 428.xx and Tenth Revision code I50. The study examined secular trends in length of stay and readmissions in both countries and tested for changes after implementation of the Hospital Readmissions Reduction Program using segmented regression models and the association between length of stay and readmissions using patient-level and hospital-level multivariable logistic regression models. Data analysis was completed from February 2018 to August 2018. MAIN OUTCOMES AND MEASURES: Thirty-day readmissions. RESULTS: Between 2005 and 2015, mean length of stay declined marginally in Canadian hospitals (from a mean [SD] of 7.5 [5.7] to 7.3 [5.6] days; P < .001) but remained stable in US hospitals (mean [SD], 4.9 [3.7] days to 4.9 [3.5] days). Thirty-day readmission rates declined similarly in Canada (from 4088 of 20 758 patients [19.7%] to 3823 of 21 733 patients [17.6%] for all-cause readmissions; P < .001; and from 1743 of 20 758 patients [8.4%] to 1490 of 21 733 patients [6.9%] for heart failure–specific readmissions; P < .001) and the United States (from 21.2% to 18.5% for all-cause readmissions; from 7.6% to 5.7% for heart failure–specific readmissions; both P < .001). There were small but statistically significant positive correlations between length of stay and 30-day readmissions in both Canada (odds ratio, 1.01 [95% CI, 1.01-1.01]) and the United States (odds ratio, 1.01 [95% CI, 1.01-1.01]). Interrupted time-series analysis comparing readmission rates before and after the Hospital Readmissions Reduction Program implementation revealed no significant difference in either country for all-cause readmission rates before and after October 2012. There was also no change in the slope of the temporal trends; in Canada, all-cause readmissions were decreasing 1.1% per year before implementation and 1.3% after implementation (P = .84 for slope change) compared with 1.6% per year in the United States before implementation and 1.8% per year after October 2012 (P = .60 for slope change). CONCLUSIONS AND RELEVANCE: Both Canada and the United States exhibited similar temporal declines in 30-day all-cause readmissions over the past decade. These findings suggest that the Hospital Readmissions Reduction Program did not appear to be associated with this secular trend or length of stay for heart failure in the United States.

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Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke.

With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.

As the largest acute heart failure (AHF) trial conducted to date, the global ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial database presented an opportunity to systematically describe the relationship among time of hospital presentation, clinical profile, inpatient management, and outcomes among patients admitted with AHF.

Transcatheter aortic valve replacement (TAVR) may be used to urgently or emergently treat severe aortic stenosis, but outcomes for this high-risk population have not been well-characterized. We sought to describe the incidence, clinical characteristics, and outcomes of patients undergoing urgent or emergent vs. elective TAVR.

This study sought to examine the relationships between in-hospital and post-discharge body weight changes and outcomes among patients hospitalized for acute heart failure (AHF).

The aim of this study was to characterize the association between decongestion therapy and 30-day outcomes in patients hospitalized for heart failure (HF).

Heart failure (HF) is a major and increasing global public health problem. In Asia, aging populations and recent increases in cardiovascular risk factors have contributed to a particularly high burden of HF, with outcomes that are poorer than those in the rest of the world. Representation of Asians in landmark HF trials has been variable. In addition, HF patients from Asia demonstrate clinical differences from patients in other geographic regions. Thus, the generalizability of some clinical trial results to the Asian population remains uncertain. In this article, we review differences in HF phenotype, HF management, and outcomes in patients from East and Southeast Asia. We describe lessons learned in Asia from recent HF registries and clinical trial databases and outline strategies to improve the potential for success in future trials. This review is based on discussions among scientists, clinical trialists, industry representatives, and regulatory representatives at the CardioVascular Clinical Trialist Asia Forum in Singapore on July 4, 2014.

The eligibility and potential benefit of transcatheter edge-to-edge repair (TEER) in addition to guideline-directed medical therapy to treat moderate-severe or severe secondary mitral regurgitation (MR) has not been reported in a contemporary heart failure (HF) population. In this study 50,841 adults with HF identified between 2013-2018 were screened for TEER eligibility based on the Food and Drug Administration (FDA) labeling. After applying the FDA eligibility criteria, 2,461 of these patients (4.8%) qualified for TEER (FDA+). These patients had higher natriuretic peptide levels and were more likely to have had a prior 1-year HF hospitalization. The estimated number needed to treat to prevent or postpone all-cause hospitalization was 4.4, 8.8 for HF hospitalization, and 5.3 for all-cause death at 24 months. The low prevalence of FDA eligibility for TEER treatment was primarily due to absence of moderate-severe or severe MR. Additional research is necessary to validate the scope of eligibility and comparative effectiveness of TEER.

Although the prognosis of ambulatory heart failure (HF) has improved dramatically there have been few advances in the management of acute HF (AHF). Despite regional differences in patient characteristics, background therapy, and event rates, AHF clinical trial enrollment has transitioned from North America and Western Europe to Eastern Europe, South America, and Asia-Pacific where regulatory burden and cost of conducting research may be less prohibitive. It is unclear if the results of clinical trials conducted outside of North America are generalizable to US patient populations. This article uses AHF as a paradigm and identifies barriers and practical solutions to successfully conducting site-based research in North America.

Hospitalized heart failure (HHF) patients carry a prognosis comparable to many cancers and constitute more than 1 million hospital admissions annually in the United States. To date, North Americans have comprised a minority of those included in prior hospitalized HF trials and have been repeatedly shown to differ from patients in other areas of the world in terms of clinical characteristics, length of hospital stay, therapy utilization, and post-discharge outcomes. Recognizing the varying patient profiles and outcomes of North Americans enrolled in prior HHF trial programs is critical to optimizing design of future drug development programs and maximizing chances of bringing a novel therapeutic agent to the bedside.

Background:Low serum albumin level is associated with increased morbidity and mortality in numerous chronic diseases, but the relationship between albumin and outcomes in heart failure (HF) and secondary mitral regurgitation (SMR) has not been previously described.Methods:The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial was a multicenter, randomized, controlled, parallel-group, open-label study that evaluated the efficacy and safety of transcatheter edge-to-edge repair (TEER) with the MitraClip + guideline-directed medical therapy (GDMT) versus GDMT alone in patients with symptomatic HF and moderate-to-severe or severe SMR. Baseline serum albumin level was obtained at enrollment.Results:Among 614 patients enrolled in COAPT, 559 (91.0%) had a baseline albumin level (median 4.0 g/dL [interquartile range: 3.7-4.2 g/dL]). Patients with albumin <4.0 g/dL compared with ≥4.0 g/dL were older (mean 73.7 years vs. 70.6), more likely to have ischemic cardiomyopathy (65.0% vs. 555.2%) and a hospitalization within the prior year (72.9% vs. 62.9%). After multivariable adjustment, patients with albumin <4.0 g/dL compared to ≥4.0 g/dL had higher 2-year rates of all-cause mortality (41.7% vs. 28.8%; HR 1.46, 95% CI 1.06-2.02; p=0.022; Figure Panel A), but no significant differences in the composite of all-cause mortality or hospitalization for HF (HHF), HHF alone, or all-cause hospitalizations (all p>0.05; Figure Panel B). There were no significant interactions between albumin and the relative efficacy of TEER + GDMT versus GDMT alone with respect to clinical outcomes (all p-interactions >0.05; Figure Panel B).Conclusions:In patients with HF and severe SMR enrolled in the COAPT trial, low serum albumin levels were common and were an independent predictor of mortality. MitraClip treatment provided a similar benefit regardless of baseline albumin level.

Background:Prior risk models in patients with heart failure (HF) have focused on hospitalizations for worsening HF (WHF) and have not evaluated for differences in predictors by left ventricular ejection fraction (LVEF). We used natural language processing (NLP) and machine learning methods with access to longitudinal electronic health record (EHR) data to develop risk prediction models for WHF events across practice settings and by LVEF category.Methods:We identified all adults with HF and known LVEF on January 1stof each year from 2011-2019 in an integrated health care system. WHF events within 1 year were defined as any hospitalization, emergency department, or outpatient encounter with ≥1 symptom, ≥2 objective findings including ≥1 sign, and ≥1 change in HF-related therapy. Signs and symptoms were ascertained using rule-based NLP. We conducted boosted decision tree-based ensemble models for any WHF event within each LVEF category: HF with reduced EF (HFrEF; LVEF ≤40%), HF with mildly reduced EF (HFmrEF; LVEF 41-49%), and HF with preserved EF (HFpEF; LVEF ≥50%). We evaluated model discrimination using area under the curve (AUC) and model calibration using Brier scores.Results:Among 359,298 patients from 2011-2019, 65,838 (18%) had HFrEF, 52,491 (15%) had HFmrEF, and 240,969 (67%) had HFpEF. Mean age was 75±12, 47% were women, and 37% were minorities including 10% Black, 11% Asian/Pacific Islander, and 12% of Hispanic ethnicity. WHF events occurred in 22% of patients with HFrEF, 17% with HFmrEF, and 16% with HFpEF. The models displayed an AUC of 0.75 and Brier score of 0.15 for HFrEF and an AUC of 0.77 and Brier scores of 0.12 for both HFmrEF and HFpEF. Clinical predictors were similar across LVEF categories (Table).Conclusions:Longitudinal EHR data can be leveraged using NLP and machine learning for accurate risk estimation that reliably identifies clinical predictors across a range of LVEF. These findings may provide novel insight into the natural history of HF.

Anemia has been associated with worse outcomes in patients with chronic heart failure (HF). We aimed to characterize the clinical profile and postdischarge outcomes of hospitalized HF patients with anemia at admission or discharge.

Background: Transaminases are commonly elevated in both the inpatient and ambulatory settings in heart failure (HF).Aims: To determine the prevalence and degree of elevated transaminase levels at admission and to evaluate the association between transaminase levels and in-hospital morbidity and mortality.Methods: Over a 12-month period, the Romanian Acute Heart Failure Syndromes (RO-AHFS) registry enrolled consecutive patients hospitalized for HF at 13 medical centres. A post-hoc analysis of the 489 patients (15.2%) with alanine transaminase (ALT) and aspartate transaminase (AST) (upper limits of normal 31 IU/l and 32 IU/l, respectively) measured at baseline was performed. In-hospital mortality was compared across quartiles using multivariable Cox regression models.Results: The prevalences of elevated ALT and AST were 28% and 24% and the medians (interquartile range) were 22 (16–47) and 23 (16–37 IU/L). Patients with elevated transaminases more commonly had right HF, cardiogenic shock, or an ejection fraction <45%. Patients with an ALT in the highest quartile were more likely to present with hypotension and a low pulse pressure, to have electrocardiographic evidence of left ventricular dyssynchrony and echocardiographic findings including increased left ventricular dimensions, reduced left ventricular ejection fraction, and valvular heart disease, to require inotropic or vasopressor support during hospitalization, and to report lower ß-blocker and angiotensin-converting enzyme inhibitor utilization. After adjusting for potential confounders, ALT was directly associated with BUN increases =10 mg/dl, necessity for intensive care unit admission, and longer length of stay. Patients in the highest quartile of ALT experienced significantly higher rates of all-cause mortality.Conclusions: In patients hospitalized for HF, there is a graded relationship between admission transaminase levels and surrogates for in-hospital morbidity, while more pronounced elevations of ALT predict in-hospital mortality independent of known prognostic indicators.

Patients hospitalized for heart failure (HF) have a high risk of postdischarge rehospitalization or mortality. Phase III trials of HF drugs have failed to show safety or efficacy, despite encouraging results from phase II studies. Muthiah Vaduganathan and colleagues overview five drug development programs for HF and discuss the importance of choosing the 'right' drug, target population, and clinical end points to optimize trial design.

Arginine vasopressin (AVP) levels are elevated in proportion to heart failure severity and are associated with higher cardiovascular mortality in ambulatory patients. However, the relationship between baseline and trends in AVP with outcomes in patients hospitalized for worsening heart failure with reduced ejection fraction is unclear.

Low lymphocyte count has been shown to be an independent prognostic marker in heart failure (HF) in the outpatient setting. Limited data exist regarding whether relative lymphocyte count correlates with postdischarge outcomes in patients hospitalized for HF.

Introduction:It has been > 25 years since it was first discovered that arginine vasopressin levels are elevated in heart failure and this elevation is proportional to the severity of heart failure. Tolvaptan is an oral nonpeptide V2-selective antagonist and has been shown to induce free water excretion without increasing urine sodium, an effect termed ‘‘aquaresis’’.Areas covered:This paper aims to review the physiology, chemistry, pharmacokinetics, clinical efficacy and safety of tolvaptan in HF. A PubMed literature search was performed using ‘‘tolvaptan’’ and the MeSH term ‘‘heart failure’’, yielding 89 references.Expert opinion:Clinical trials conducted in ambulatory and hospitalized patients with HF have found treatment with tolvaptan causes rapid and sustained body weight reductions concurrent with increases in urine output, improves and/or normalizes serum sodium in hyponatremic patients, reduces signs and symptoms of congestion and increases thirst. However, tolvaptan has not been shown to decrease HF re-hospitalization or mortality. As an adjunct to standard therapy, tolvaptan is unique in that it is virtually the only novel agent tested in patients hospitalized for acute heart failure syndrome (AHFS) to reach its primary end point for short-term efficacy without causing deleterious side effects. There is theoretical concern that chronic V2receptor blockade may cause harmful long-term side effects via enhanced V1areceptor activation, potentially offsetting any favorable effects on congestion and hyponatremia. The ‘‘vaptan’’ class of drugs is an active and promising area for clinical investigation and future research is necessary to clarify the therapeutic role of selective and nonselective vasopressin inhibition in chronic HF and AHFS.

Patients with risk factors for or established atherosclerotic cardiovascular disease (ASCVD) remain at high risk for subsequent ischemic events despite statin therapy. Triglyceride (TG) levels may contribute to residual ASCVD risk, and the performance of global risk assessment calculators across a broad range of TG levels is unknown.

Background:More data is needed on the cardiovascular impact of discontinuing versus continuing renin-angiotensin aldosterone system inhibitors (RAASi) among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection (COVID-19).Methods:The McGill RAAS-COVID-19 trial was a randomized, open label trial in adult patients hospitalized with COVID-19, who were previously treated with RAASi (angiotensin converting enzyme inhibitors [ACEi]/angiotensin receptor blocker [ARB]) (NCT04508985; 10/2020-03/2021). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]). All analyses were conducted using the intention-to-treat principle.Results:Overall, 21 participants were randomized to discontinue RAASi and 25 to continue. Patients’ mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a similar mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); p= 0.60), but the negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.7 [95% CI 1.1 to 2.6]; p=0.03). Particularly, RAASi discontinuation increased brain natriuretic peptide (BNP) levels (% change from baseline: +16.7% vs. -27.5%; p= 0.02) and increased the incidence of acute heart failure (33% vs. 4.2%, p=0.03).Conclusion:Discontinuation of RAASi increased BNP levels and risk of acute heart failure in participants hospitalized with COVID-19; where possible, RAASi should be continued.

Randomized clinical trials are the foundation of evidence-based medicine and central to practice guidelines and patient care decisions. Nonetheless, randomized trials in heart failure (HF) populations have become increasingly difficult to conduct and are frequently associated with slow patient enrollment, highly selected populations, extensive data collection, and high costs. The traditional model for HF trials has become particularly difficult to execute in the United States, where challenges to site-based research have frequently led to modest U.S. representation in global trials. In this context, the TRANSFORM-HF (Torsemide Comparison with Furosemide for Management of Heart Failure) trial aims to overcome traditional trial challenges and compare the effects of torsemide versus furosemide among patients with HF in the United States. Loop diuretic agents are regularly used by most patients with HF and practice guidelines recommend optimal use of diuretic agents as key to a successful treatment strategy. Long-time clinical experience has contributed to dominant use of furosemide for loop diuretic therapy, although preclinical and small clinical studies suggest potential advantages of torsemide. However, due to the lack of appropriately powered clinical outcome studies, there is insufficient evidence to conclude that torsemide should be routinely recommended over furosemide. Given this gap in knowledge and the fundamental role of loop diuretic agents in HF care, the TRANSFORM-HF trial was designed as a prospective, randomized, event-driven, pragmatic, comparative-effectiveness study to definitively compare the effect of a treatment strategy of torsemide versus furosemide on long-term mortality, hospitalization, and patient-reported outcomes among patients with HF. (TRANSFORM-HF: ToRsemide compArisoN With furoSemide FORManagement of Heart Failure [TRANSFORM-HF]; NCT03296813).

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Background:Congestion remains the most common reason for hospitalization among patients with acute decompensated heart failure (ADHF). How treatment with sacubitril/valsartan (S/V) affects outcomes in patients hospitalized for ADHF and with residual congestion is unknown.Methods:PIONEER-HFwas a multicenter, randomized, double-blind trial of in-hospital initiation of S/V vs. enalapril in patients stabilized during a hospitalization for ADHF. For this analysis, a congestion score (CS) was developed based on the presence and severity of orthopnea, rales and edema at randomization. We then compared changes in the time-averaged proportional change in NT-proBNP from randomization through weeks 4 and 8 as well the rates of a composite of HF rehospitalization or cardiovascular (CV) death. Key safety endpoints included symptomatic hypotension, hyperkalemia, and worsening renal function.Results:Among 764 randomized patients with complete data, 244 patients (32%) had a CS=0-1, 303 (40%) had CS=2-3, and 217 (28%) had CS ?4. Patients with a higher CS were older and with more comorbidities than patients with lower CS. The time-averaged reduction in the NT-proBNP concentration was greater with S/V vs enalapril across varying levels of congestion (interaction p-value=0.35). The rates of HF rehospitalization and CV death were also lower with S/V vs enalapril across varying levels of congestion (interaction p-value=0.21), including in those with the highest CS (Figure,10.0% vs 21.5%, HR 0.43, 95% CI 0.21 to 0.87). The incidence of symptomatic hypotension, hyperkalemia, and worsening renal failure was similar with S/V vs enalapril irrespective of CS (interaction p-value=NS for each safety endpoint).Conclusions:In PIONEER-HF, S/V was well-tolerated and improved clinical outcomes regardless of baseline congestion. These data support the in-hospital initiation of S/V in patients stabilized during a hospitalization for ADHF regardless of residual congestion.