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Clinical practice guidelines support sustained use of renin-angiotensin-aldosterone-system (RAAS) inhibitors over time in heart failure with reduced ejection fraction, yet few data are available regarding the frequency, timing or predictors of early treatment discontinuation in clinical practice.Among prevalent or new users of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs) in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry, we estimated the frequency and independent predictors of treatment discontinuation during follow-up. Among sites with5 users of a given RAAS inhibitor, we evaluated practice variation in the proportion of patients with treatment discontinuation.Over median follow-up of 18 months, frequency of drug discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.7% (444 of 3509 users), 10.4% (140 of 1352 users), and 20.4% (435 of 2129 users), respectively. An additional, 149 (11.0%) of ARNI users were switched to ACEis/ARBs, and 447 (12.7%) of ACEi/ARB users were switched to ARNIs during follow-up. Across sites, the median proportion of discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.5% (25th-75th percentiles 6.9%-18.9%), 18.8% (25th-75th percentiles 12.5%-28.6%), and 19.6% (25th-75th percentiles 10.7%-27.0%), respectively. Chronic kidney disease was the only independent predictor of increased risk of discontinuation of each of the RAAS inhibitor classes (P0.02 for all). Higher Kansas City Cardiomyopathy Questionnaire overall summary scores independently predicted lower risk of discontinuation of ACEis/ARBs and ARNIs (both P0.001) but not of MRAs. Investigator clinical experience was predictive of lower risks of discontinuation of ACEis/ARBs and MRAs (P0.02) but not of ARNIs. All other independent predictors of discontinuation were unique to individual therapeutic classes.One in 10 patients discontinue ACEis/ARBs or ARNIs, and 1 in 5 discontinue MRAs in routine clinical practice of heart failure with reduced ejection fraction. Unique patient-level and clinician/practice-level factors are associated with premature discontinuation of individual RAAS inhibitors, which may help to guide structured efforts to promote treatment persistence in clinical care.

To determine the trends in hospitalizations for heart failure (HF), acute myocardial infarction (AMI), and stroke in the United States (US).A retrospective analysis of the National Inpatient Sample weighted data between January 1, 2004 and December 31, 2018 which included hospitalized adults ≥18 years with a primary discharge diagnosis of HF, AMI, or stroke using International Classification of Diseases-9/10 administrative codes. Main outcomes were hospitalization for HF, AMI, and stroke per 1000 United States adults, length of stay, and in-hospital mortality. There were 33.4 million hospitalizations for HF, AMI, and stroke, with most being for HF (48%). After the initial decline in HF hospitalizations (5.3 hospitalizations/1000 US adults in 2004 to 4 hospitalizations/1000 US adults in 2013, P.001), there was a progressive increase in HF hospitalizations between 2013 and 2018 (4.0 hospitalizations/1000 US adults in 2013 to 4.9 hospitalizations/1000 US adults in 2018; P .001). Hospitalization for AMI decreased (3.1 hospitalizations/1000 US adults in 2004 to 2.5 hospitalizations/1000 US adults in 2010, P.001) and remained stable between 2010 and 2018. There was no significant change for hospitalization for stroke between 2004 and 2011 (2.3 hospitalizations/1000 US adults in 2004 vs 2.3 hospitalizations per 1000 US adults in 2011, P = .614); however, there was a small but significant increase in hospitalization for stroke after 2011 that reached 2.5 hospitalizations/1000 US adults in 2018. Adjusted length of stay and in-hospital mortality decreased for HF, AMI, and stroke hospitalizations.In contrast to the trend of AMI and stroke hospitalizations, a progressive increase in hospitalizations for HF has occurred since 2013. From 2004 to 2018, in-hospital mortality has decreased for HF, AMI, and stroke hospitalizations.

AIMS To evaluate the performance of the WATCH-DM risk score, a clinical risk score for heart failure (HF), in patients with dysglycaemia and in combination with natriuretic peptides (NPs). METHODS AND RESULTS Adults with diabetes/pre-diabetes free of HF at baseline from four cohort studies (ARIC, CHS, FHS, and MESA) were included. The machine learning- [WATCH-DM(ml)] and integer-based [WATCH-DM(i)] scores were used to estimate the 5-year risk of incident HF. Discrimination was assessed by Harrell's concordance index (C-index) and calibration by the Greenwood-Nam-D'Agostino (GND) statistic. Improvement in model performance with the addition of NP levels was assessed by C-index and continuous net reclassification improvement (NRI). Of the 8938 participants included, 3554 (39.8%) had diabetes and 432 (4.8%) developed HF within 5 years. The WATCH-DM(ml) and WATCH-DM(i) scores demonstrated high discrimination for predicting HF risk among individuals with dysglycaemia (C-indices = 0.80 and 0.71, respectively), with no evidence of miscalibration (GND P ≥0.10). The C-index of elevated NP levels alone for predicting incident HF among individuals with dysglycaemia was significantly higher among participants with low/intermediate (

Sodium-glucose cotransporter-2 inhibitor therapy is well suited for initiation during the heart failure hospitalization, owing to clinical benefits that accrue rapidly within days to weeks, a strong safety and tolerability profile, minimal to no effects on blood pressure, and no excess risk of adverse kidney events. There is no evidence to suggest that deferring initiation to the outpatient setting accomplishes anything beneficial. Instead, there is compelling evidence that deferring in-hospital initiation exposes patients to excess risk of early postdischarge clinical worsening and death. Lessons from other heart failure with reduced ejection fraction therapies highlight that deferring initiation of guideline-recommended medications to the U.S. outpatient setting carries a >75% chance they will not be initiated within the next year. Recognizing that 1 in 4 patients hospitalized for worsening heart failure die or are readmitted within 30 days, clinicians should embrace the in-hospital period as an optimal time to initiate sodium-glucose cotransporter-2 inhibitor therapy and treat this population with the urgency it deserves.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management., Central Illustration

Aims Associations between growth differentiation factor‐15 (GDF‐15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP‐1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps. Methods and results FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF‐15 and change in GDF‐15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF‐15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF‐15 were more likely to be male and have more co‐morbidities. After adjustment, an increase in GDF‐15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF‐15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF‐15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF‐15 levels remained stable among participants randomized to liraglutide. Conclusions An increase in GDF‐15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF‐15 trajectory in informing risk of heart failure disease progression.

Background Treatment guidelines for prediabetes primarily focus on glycemic control and lifestyle management. Few evidence-based cardiovascular and kidney risk-reduction strategies are available in this population. Objectives This study sought to characterize cardiovascular and kidney outcomes across the glycemic spectrum. Methods Among participants in the UK Biobank without prevalent type 1 diabetes, cardiovascular disease, or kidney disease, Cox models tested the association of glycemic exposures (type 2 diabetes [T2D], prediabetes, normoglycemia) with outcomes (atherosclerotic cardiovascular disease [ASCVD], chronic kidney disease [CKD], and heart failure), adjusting for demographic, lifestyle, and cardiometabolic risk factors. Results Among 336,709 individuals (mean age: 56.3 years, 55.4% female), 46,911 (13.9%) had prediabetes and 12,717 (3.8%) had T2D. Over median follow-up of 11.1 years, 6,476 (13.8%) individuals with prediabetes developed ≥1 incident outcome, of whom only 802 (12.4%) developed T2D prior to an incident diagnosis. Prediabetes and T2D were independently associated with ASCVD (prediabetes: adjusted HR [aHR]: 1.11; 95% CI: 1.08-1.15; P Conclusions Prediabetes and T2D were associated with ASCVD, CKD, and heart failure, but a substantial gradient of risk was observed across HbA1c levels below the threshold for diabetes. These findings highlight the need to design risk-reduction strategies across the glycemic spectrum.

Background : N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known. Objective : To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations. Methods : In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels ( 3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors. Results : A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months. Conclusions : The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

Background Maintaining a steady medication supply during a public health crisis is a major health priority. We leveraged a large U.S. pharmacy-claims database to understand the use of evidence-based therapies in heart failure (HF) care during the coronavirus disease-2019 (COVID-19) pandemic. Methods We analyzed 27,027,650 individual claims from an all-payer pharmacy-claims database across 56,155 chain, independent and mail-order pharmacies in 14,164 zip codes in 50 states. Prescriptions dispensed (in 2-week intervals) of evidence-based HF therapies in 2020 were indexed to comparable timeframes in 2019. We normalized these year-to-year changes in HF medical therapies relative to those observed with a stable basket of drugs. Results Fills of losartan, lisinopril, carvedilol, and metoprolol all peaked in the weeks of March 2020 and demonstrated trajectories thereafter that were relatively consistent with the reference set of drugs. Fills of spironolactone (+4%) and eplerenone (+18%) showed modest trends toward increased relative use during 2020. Fills of empagliflozin (+75%), dapagliflozin (+65%) and sacubitril/valsartan (+61%) showed striking longitudinal increases throughout 2020 that deviated substantially from year-to-year trends of the overall basket of drugs. For all 3 therapies, fills of all quantity sizes increased relatively throughout 2020. For both generic and brand-name therapies, prescription fill patterns from mail-order pharmacies increased substantially over expected trends beginning in March 2020 Conclusion Prescription fills of most established generic therapies used in HF care were maintained, whereas those of sacubitril/valsartan and the sodium-glucose cotransporter-2 inhibitors steeply increased during the COVID-19 pandemic. These nationwide pharmacy claims data provide reassurance about therapeutic access, during a public health crisis, to evidence-based medications used in HF care.

Background Limited real-world data exist on healthcare resource utilization (HCRU) and associated costs of patients with heart failure (HF) with reduced ejection fraction (HFrEF) and preserved EF (HFpEF), including urgent HF visits, which are assumed to be less burdensome than HF hospitalizations (hHFs)Hypothesis This study aimed to quantify the economic burden of HFrEF and HFpEF, via a retrospective, longitudinal cohort study, using IBM(R) linked claims/electronic health records (Commercial and Medicare Supplemental data only).Methods Adult patients, indexed on HF diagnosis (ICD-10-CM: I50.x) from July 2012 through June 2018, with 6-month minimum baseline period and varying follow-up, were classified as HFrEF (I50.2x) or HFpEF (I50.3x) according to last-observed EF-specific diagnosis. HCRU/costs were assessed during follow-up.Results About 109 721 HF patients (22% HFrEF, 31% HFpEF, 47% unclassified EF; median 18 months' follow-up) were identified. There were 3.2 all-cause outpatient visits per patient-month (HFrEF, 3.3; HFpEF, 3.6); 69% of patients required inpatient stays (HFrEF, 80%; HFpEF, 78%). Overall, 11% of patients experienced hHFs (HFrEF, 23%; HFpEF, 16%), 9% experienced urgent HF visits (HFrEF, 15%; HFpEF, 12%); 26% were hospitalized less than 30 days after first urgent HF visit versus 11% after first hHF. Mean monthly total direct healthcare cost per patient was $9290 (HFrEF, $11 053; HFpEF, $7482).Conclusions HF-related HCRU is substantial among contemporary real-world HF patients in US Commercial or Medicare supplemental health plans. Patients managed in urgent HF settings were over twice as likely to be hospitalized within 30 days versus those initially hospitalized, suggesting urgent HF visits are important clinical events and quality improvement targets.

BACKGROUND The incidence of pneumonia and subsequent outcomes has not been compared in patients with heart failure and reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF).OBJECTIVES This study aimed to examine the rate and impact of pneumonia in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction) trials.METHODS The authors analyzed the incidence of investigator-reported pneumonia and the rates of HF hospitalization, cardiovascular death, and all-cause death before and after the occurrence of pneumonia, and estimated risk after the first occurrence of pneumonia in unadjusted and adjusted analyses (the latter including N-terminal pro-B-type natriuretic peptide).RESULTS In PARADIGM-HF, 528 patients (6.3%) developed pneumonia after randomization, giving an incidence rate of 29 (95% CI: 27 to 32) per 1,000 patient-years. In PARAGON-HF, 510 patients (10.6%) developed pneumonia, giving an incidence rate of 39 (95% CI: 36 to 42) per 1,000 patient-years. The subsequent risk of all trial outcomes was elevated after the occurrence of pneumonia. In PARADIGM-HF, the adjusted hazard ratio (HR) for the risk of death from any cause was 4.34 (95% CI: 3.73 to 5.05). The corresponding adjusted HR in PARAGON-HF was 3.76 (95% CI: 3.09 to 4.58).CONCLUSIONS The incidence of pneumonia was high in patients with HF, especially HFpEF, at around 3 times the expected rate. A first episode of pneumonia was associated with 4-fold higher mortality. (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF], NCT01035255; Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ARB [Angiotensin Receptor Blocker] Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF], NCT01920711) (J Am Coll Cardiol 2021;77:1961-73) (c) 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Type 2 diabetes is a heterogeneous disease process with variable trajectories of CVD risk. We aimed to evaluate four phenomapping strategies and their ability to stratify CVD risk in individuals with type 2 diabetes and to identify subgroups who may benefit from specific therapies. Participants with type 2 diabetes and free of baseline CVD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial were included in this study (N = 6466). Clustering using Gaussian mixture models, latent class analysis, finite mixture models (FMMs) and principal component analysis was compared. Clustering variables included demographics, medical and social history, laboratory values and diabetes complications. The interaction between the phenogroup and intensive glycaemic, combination lipid and intensive BP therapy for the risk of the primary outcome (composite of fatal myocardial infarction, non-fatal myocardial infarction or unstable angina) was evaluated using adjusted Cox models. The phenomapping strategies were independently assessed in an external validation cohort (Look Action for Health in Diabetes [Look AHEAD] trial: n = 4211; and Bypass Angioplasty Revascularisation Investigation 2 Diabetes [BARI 2D] trial: n = 1495). Over 9.1 years of follow-up, 789 (12.2%) participants had a primary outcome event. FMM phenomapping with three phenogroups was the best-performing clustering strategy in both the derivation and validation cohorts as determined by Bayesian information criterion, Dunn index and improvement in model discrimination. Phenogroup 1 (n = 663, 10.3%) had the highest burden of comorbidities and diabetes complications, phenogroup 2 (n = 2388, 36.9%) had an intermediate comorbidity burden and lowest diabetes complications, and phenogroup 3 (n = 3415, 52.8%) had the fewest comorbidities and intermediate burden of diabetes complications. Significant interactions were observed between phenogroups and treatment interventions including intensive glycaemic control (p-interaction = 0.042) and combination lipid therapy (p-interaction

Patients with chronic cardiovascular or metabolic diseases, including diabetes, hypertension, obesity, and heart failure, often have comorbid kidney disease. Indeed, long-term outcomes are worse in the setting of both cardiac and kidney disease compared with either disease in isolation. In addition, the clinical presentations of certain acute cardiovascular events (such as heart failure) and worsening kidney function are overlapping and may be challenging to distinguish. Recently, certain novel treatments have demonstrated beneficial effects on both cardiac and kidney outcomes. Sodium-glucose cotransporter-2 inhibitors have exhibited concordant risk reduction and clinically important benefits in chronic kidney disease with and without diabetes, diabetes and established cardiovascular disease or multiple atherosclerotic vascular disease risk factors, and heart failure with reduced ejection fraction with and without diabetes mellitus. In addition, primary trial results have revealed that sacubitril-valsartan therapy improves cardiovascular outcomes in patients with chronic heart failure with reduced ejection fraction and post-hoc analyses suggest favorable kidney effects. A concordant pattern of kidney benefit with sacubitril-valsartan has also been observed in chronic heart failure with preserved ejection fraction. Given the complex interplay between cardiac and kidney disease and the possibility that treatments may show concordant cardio-kidney benefits, there has been recent interest to acknowledge formally, define, and utilize composite cardio-kidney outcomes in future cardiovascular trials. This review describes potential challenges in utilization of such outcomes that should be considered and addressed prior to their incorporation into such trials.

Objectives This study investigates the prevalence and prognostic significance of mitral regurgitation (MR) in acute decompensated heart failure (ADHF) patients. Background Few studies characterize the burden of MR in heart failure. Methods The ARIC (Atherosclerosis Risk In Communities) study surveilled ADHF hospitalizations for residents ≥55 years of age in 4 U.S. communities. ADHF cases were stratified by left ventricular ejection fraction (LVEF): Results From 2005 to 2014, there were 17,931 weighted ADHF hospitalizations of which 49.2% had an LVEF Conclusions Patients with ADHF have a significant MR burden that varies with sex and race. In ADHF patients with an LVEF

Background Morbidity and mortality associated with COVID-19 has increased exponentially, and patients with cardiovascular (CV) disease are at risk for poor outcomes. Several lines of evidence suggest a potential role for CV therapies in COVID-19 treatment. Characteristics of clinical trials of CV therapies related to COVID-19 registered on ClinicalTrials.gov have not been described. Methods ClinicalTrials.gov was queried on August 7, 2020 for COVID-19 related trials. Studies evaluating established CV drugs, other fibrinolytics (defibrotide), and extracorporeal membrane oxygenation were included. Studies evaluating anti-microbial, convalescent plasma, non-colchicine anti-inflammatory, and other therapies were excluded. Trial characteristics were tabulated from study-specific entries. Results A total of 2,935 studies related to COVID-19 were registered as of August 7, 2020. Of these, 1,645 were interventional studies, and the final analytic cohort consisted of 114 studies evaluating 10 CV therapeutic categories. Antithrombotics (32.5%; n = 37) were most commonly evaluated, followed by pulmonary vasodilators (14.0%; n = 16), renin-angiotensin-aldosterone system-related therapies (12.3%; n = 14), and colchicine (8.8%; n = 10). Trials evaluating multiple CV therapy categories and CV therapies in combination with non-CV therapies encompassed 4.4% (n = 5) and 9.6% (n = 11) of studies, respectively. Most studies were designed for randomized allocation (87.7%; n = 100), enrollment of less than 1000 participants (86.8%; n = 99), single site implementation (55.3%; n = 63), and had a primary outcome of mortality or a composite including mortality (56.1%; n = 64). Most study populations consisted of patients hospitalized with COVID-19 (81.6%; n = 93). At the time of database query, 28.9% (n = 33) of studies were not yet recruiting and the majority were estimated to be completed after December 2020 (67.8%; n = 78). Most lead sponsors were located in North America (43.9%; n = 50) or Europe (36.0%; n = 41). Conclusions A minority (7%) of clinical trials related to COVID-19 registered on ClinicalTrials.gov plan to evaluate CV therapies. Of CV therapy studies, most were planned to be single center, enroll less than 1000 inpatients, sponsored by European or North American academic institutions, and estimated to complete after December 2020. Collectively, these findings underscore the need for a network of sites with a platform protocol for rapid evaluation of multiple therapies and generalizability to inform clinical care and health policy for COVID-19 moving forward.

Background Sacubitril/valsartan reduces the risk of hospitalizations and death among patients with heart failure (HF) with reduced ejection fraction; its use is poised to increase worldwide. As bradykinin is a substrate of neprilysin, angioedema was a theoretical concern potentiated by neprilysin inhibition. Methods We explored angioedema in clinical trials and real-world pharmacovigilance data. We conducted a trial-level random-effects meta-analysis of 5 RCTs studying the effects of sacubitril/valsartan in heart failure. FDA Adverse Event Reporting System (FAERS) provided real-world pharmacovigilance data in the US. Results The 5 trials enrolled 14,841 patients with follow-up ranging from 2 to 27 months. The collective rate of angioedema in RCTs was 0.5% in sacubitril/valsartan arms vs. 0.3% in control arms (pooled odds ratio of 1.35; 95% confidence interval − 0.45 to 4.1; P = .59) with moderate heterogeneity (I2 55.2.%). These relative effects were driven by the larger PARADIGM-HF and PARAGON-HF experiences. FAERS pharmacovigilance data identified 426 angioedema cases over the last 5 years out of 40,559 adverse events reported related to sacubitril/valsartan. Conclusions Rates of angioedema with sacubitril/valsartan are reported to be low in RCTs and real-world clinical practice.

Objective: The aim of the study was to determine patterns and predictors of utilization of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs) in patients with acute heart failure (AHF) and changes in kidney function at admission, hospitalization, and discharge in relation to clinical outcomes. Methods: This retrospective analysis of the Veterans’ Health Administration data (2016) included patients with heart failure (HF) with reduced ejection fraction who were hospitalized. Patients with an estimated glomerular filtration 3/min/1.73 m2 and those on dialysis were excluded. Patients were categorized based on the use of ACEI/ARB as continued, initiated, discontinued, or no therapy. Multivariable logistic regression evaluated predictors of being discharged home on an ACEI/ARB. Cox regression analysis evaluated outcomes (30 and 180-day mortality/HF readmissions). Results: 3,652 patients were included, of which 37% of patients hospitalized for AHF had ACEI/ARB discontinued on admission, or not initiated. After adjusting for age, blood pressure, and serum potassium, a per-unit increase in admission serum creatinine (SCr) was independently associated with lower rates of continuation or initiation of ACEI/ARB odds ratio 0.51 95% confidence interval (CI) (0.46–0.57). Discharge on ACEI/ARB was independently associated with lower odds of 30- and 180-day mortality hazard ratio (HR) 0.36 95% CI (0.25–0.52), and HR 0.23 95% CI (0.19–0.27), respectively. Conclusion: Higher SCr at admission is an important determinant of ACEI/ARB being discontinued or withheld in patients admitted with AHF. ACEI/ARB at discharge was associated with lower mortality in patients with AHF.

Treatment of patients with heart failure with reduced ejection fraction (HFrEF) with currently available therapies reduces morbidity and mortality. However, implementation of these therapies is a problem with only few patients achieving guideline-recommended maximal doses of therapy. In an effort to improve guideline adherence and uptitration, several trials have investigated a biomarker-guided strategy (using natriuretic peptide targets in specific), but although conceptually promising, these trials failed to show a consistent beneficial effect on outcomes. In this review, we discuss different methodological issues that may explain the failure of these trials and offer potential solutions. Moreover, alternative approaches to increase heart failure guideline adherence are evaluated.

The treatment of heart failure with reduced ejection fraction (HFrEF) has changed considerably over time, particularly with the sequential development of therapies aimed at antagonism of maladaptive biologic pathways, including inhibition of the sympathetic nervous system and the renin-angiotensin aldosterone system. The sequential nature of earlier HFrEF trials allowed the integration of new therapies tested against the background therapy of the time. More recently, multiple heart failure therapies are being evaluated simultaneously, and the number of therapeutic choices for treating HFrEF has grown considerably. In addition, implementation science has lagged behind discovery science in heart failure. Furthermore, given there are currently >200 ongoing clinical trials in heart failure, further complexities are anticipated. In an effort to provide a decision-making framework in the current era of expanding therapeutic options in HFrEF, the Heart Failure Collaboratory convened a multi-stakeholder group, including patients, clinicians, clinical investigators, the U.S. Food and Drug Administration, industry, and payers who met at the U.S. Food and Drug Administration campus on March 6, 2020. This paper summarizes the discussions and expert consensus recommendations.

Background The burden of amyloidosis among hospitalized patients is increasing over time. However, amyloidosis remains an underdiagnosed cause of heart failure (HF) hospitalization among older adults. Objectives We investigated the prevalence and prognostic implications of amyloidosis among patients hospitalized with HF. Methods All hospitalizations for primary diagnosis of HF between January 1, 2010, and August 31, 2015, identified in the Nationwide Readmissions Database were categorized into those with and without a secondary diagnosis of amyloidosis. HF hospitalizations with amyloidosis were then matched in a 3:1 fashion to HF hospitalizations without amyloidosis using the year of admission, discharge quarter, age, sex, and Charlson comorbidity index. Primary outcomes were inpatient mortality and 30-day readmission. Multivariable logistic regression was used to estimate the association between HF with amyloidosis and clinical outcomes. Results Of 1,593,360 HF hospitalizations that met inclusion criteria, 2,846 (0.18%) had HF with a secondary diagnosis of amyloidosis and were matched to 8,515 hospitalizations for HF without amyloidosis. Hospitalizations for HF with amyloidosis were associated with higher prevalence of kidney disease (56% vs. 45%), malignancy (20% vs. 4%), and higher inpatient mortality (6% vs. 3%) as compared with HF without amyloidosis. In adjusted analyses, HF with amyloidosis was associated with higher odds of in-hospital mortality (odds ratio: 1.46; 95% confidence interval [CI]: 1.17 to 1.82), 30-day readmission (odds ratio: 1.17; 95% CI: 1.05 to 1.31), and longer mean length of stay (least-squares mean difference: 1.46; 95% CI: 1.12 to 1.80). Conclusions In patients hospitalized with decompensated HF, presence of amyloidosis was associated with higher risk of inpatient mortality and 30-day readmission., Central Illustration

The coronavirus disease-2019 (COVID-19) pandemic has profoundly changed clinical care and research, including the conduct of clinical trials, and the clinical research ecosystem will need to adapt to this transformed environment. The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory and the Academic Research Consortium, composed of academic investigators from the United States and Europe, patients, the U.S. Food and Drug Administration, the National Institutes of Health, and industry members. A series of meetings were convened to address the challenges caused by the COVID-19 pandemic, review options for maintaining or altering best practices, and establish key recommendations for the conduct and analysis of clinical trials for cardiovascular disease and heart failure. This paper summarizes the discussions and expert consensus recommendations., Central Illustration, Highlights • The COVID-19 pandemic has profoundly affected patient care and the conduct of clinical trials. • HF-ARC scientific expert panel developed recommendations for the conduct and analysis of heart failure trials during the pandemic. • The HF-ARC consensus recommendations support ongoing clinical trials and strengthen the clinical trial ecosystem, which should have sustained benefits in the future.

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms among patients with chronic heart failure with reduced ejection fraction compared to enalapril, the gold standard angiotensin-converting enzyme inhibitor. In the 5 years since the publication of the results of PARADIGM-HF, further insight has been gained into integrating a neprilysin inhibitor into a comprehensive multidrug regimen, including a renin-angiotensin aldosterone system (RAS) blocker. This paper reviews the current understanding of the effects of sacubitril/valsartan and highlights expected developments over the next 5 years, including potential new indications for use. Additionally, a practical, evidence-based approach is provided to the clinical integration of sacubitril/valsartan among patients with heart failure with reduced ejection fraction.

Objectives The purpose of this study was to investigate the effect of sacubitril/valsartan therapy on sudden cardiac death (SCD) according to the use of and eligibility for an implantable ...

Sodium-glucose cotransport protein-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to reduce cardiovascular events in high-risk patients with type 2 diabetes mellitus (T2DM). We examined real-world use of these agents at a US academic medical center in the state of Mississippi. Prescriptions, provider specialty, and insurance status of users of SGLT2is and GLP-1RAs in patients with T2DM, and T2DM and cardiovascular disease (CVD) seen from 1st January 2013 to 30th June 2019 were obtained by electronic health records review. We identified 21,173 patients with T2DM and CVD. Overall, 306 (1.4%) and 349 (1.6%) patients received a SGLT2i and GLP-1RA, respectively. After the US Food and Drug Administration (FDA) expanded empagliflozin and liraglutide indications, a mean difference of 19.2 and 12.7 greater quarterly new prescriptions was noted, respectively, whereas no such rise in canagliflozin was observed. Primary care physicians accounted for 53.4% SGLT2i prescriptions, endocrinology for 30.3%, and cardiology for 6.0%. Primary care physicians accounted for 45.1% GLP-1RA prescriptions, endocrinology for 45.0%, and cardiology for 1.4%. Prescription patterns did not largely differ by patient insurance status. In conclusion, prescription of evidence-based therapies to improve CVD outcomes in high-risk patients with T2DM remains very low after several years of evidence generation. Low uptake was evident across insurance types. Modest increases in use were observed after regulatory expansions in labeling; however, cardiologists rarely engaged in prescription, underscoring the need for widespread implementation strategies across health care systems.

Depression is a recognized predictor of adverse outcomes in patients with heart failure (HF) and is associated with poor quality of life, functional limitation, increased morbidity and mortality, decreased adherence to treatment, and increased rehospitalization. To understand the impact of depression on HF readmission, we conducted a retrospective cohort study using the Nationwide Readmission Database (NRD) 2010-2014.We identified all patients with the primary discharge diagnosis of HF by ICD-9-CM codes. The primary outcome of the study was to identify 30-day all-cause readmission and causes of readmission in patients with and without depression. Multivariate Cox regression analysis was used to estimate the adjusted hazard ratio for the primary and secondary outcomes.Among, 3,500,570 patients admitted with HF, 9.7% had concomitant depression. Patients with depression were more likely to be readmitted within 30 days (19.7% vs. 18.5%; P 0.001). Concomitant depression was associated with higher risk of all-cause readmissions within 30 days and 90 days [P 0.001] but was not associated with increased readmissions due to cardiovascular (CV) cause at 30 days and 90 days. The hazard of psychiatric causes of readmission was higher in patients with depression, both at 30 days [P 0.001], and 90 days [P 0.001]. Most of the readmissions were due to CV causes, with HF being the most common cause.Among patients hospitalized with HF, the presence of depression is associated with increased all-cause readmission driven mainly by psychiatric causes but not CV-related readmission. Standard interventions targeted toward HF are unlikely to modify this portion of all-cause readmission.

Objectives The authors investigated the relationship between past or incident myocardial infarction (MI) and cardiovascular (CV) events in heart failure with preserved ejection fraction (HFpEF). Background MI and HFpEF share some common risk factors. The prognostic significance of MI in patients with HFpEF is uncertain. Methods The authors pooled data from 3 trials—CHARM Preserved (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity), I-Preserve (Irbesartan in Heart Failure With Preserved Systolic Function), and the Americas region of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) (N = 8,916)—and examined whether MI before or following enrollment independently predicted CV death and heart failure (HF) hospitalization. Results At baseline, 2,668 patients (30%) had history of MI. Prior MI was independently associated with greater risk of CV death (4.7 vs. 3.5 events/100 patient-years [py], adjusted hazard ratio [HR]: 1.42 [95% confidence interval (CI): 1.23 to 1.64]; p Conclusions Prior MI in HFpEF is associated with greater CV and sudden death but similar risk of HF outcomes. Patients with HFpEF who experience MI are at high risk of subsequent CV death and HF hospitalization. These data highlight the importance of primary and secondary prevention of MI in patients with HFpEF. (Candesartan Cilexietil in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM Preserved]; NCT00634712; Irbesartan in Heart Failure With Preserved Systolic Function [I-Preserve]; NCT00095238; and Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist [TOPCAT]; NCT00094302)

Background: Patients with heart failure (HF) have multiple coexisting comorbidities. The temporal trends in the burden of comorbidities and associated risk of mortality among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not well established. Methods: HF-related hospitalizations were sampled by stratified design from 4 US areas in 2005 to 2014 by the community surveillance component of the ARIC study (Atherosclerosis Risk in Communities). Acute decompensated HF was classified by standardized physician review and a previously validated algorithm. An ejection fraction Results: A total of 5460 hospitalizations (24 937 weighted hospitalizations) classified as acute decompensated HF had available ejection fraction data (53% female, 68% white, 53% HFrEF, 47% HFpEF). The average number of comorbidities was higher for patients with HFpEF versus HFrEF, both for women (5.53 versus 4.94; P P P -trendP for interaction by HF type=0.02). The associated mortality risk per 1 higher comorbidity also increased significantly over time for patients with HFpEF and HFrEF, as well ( P for interaction with time=0.002 and 0.02, respectively) Conclusions: The burden of comorbidities among hospitalized patients with acute decompensated HFpEF and HFrEF has increased over time, as has its associated mortality risk. Higher burden of comorbidities is associated with higher risk of mortality, with a stronger association noted among patients with HFpEF versus HFrEF.

PURPOSE OF REVIEW: There has been a recent resurgence of diabetes-related cardiovascular complications after years of steady improvement. This review highlights established and emerging contemporary secondary prevention approaches that lower the risk of atherosclerotic and non-atherosclerotic cardiovascular disease events among patients with diabetes. RECENT FINDINGS: Secondary prevention therapies modify residual risk targets, including cardiometabolic pathways, lipoproteins, thrombosis, and inflammation. Large-scale clinical trials of sodium-glucose cotransporter-2 inhibitors have demonstrated significant reductions in hospitalization for heart failure. Glucagon-like peptide-1 receptor agonists have reduced the risk of major adverse cardiovascular events. Recent clinical trials provide evidence supporting the use of non-statin lipid-lowering therapies, novel antiplatelet and anticoagulant strategies, and anti-inflammatory strategies in select cases. SUMMARY: Therapeutic approaches targeting multiple distinct pathways have been shown to improve cardiometabolic risk in diabetes. Individual patient characteristics and consideration of residual risk targets may help guide selection of comprehensive secondary prevention approaches.

Objectives The purpose of this study was to characterize the clinical profile, treatment patterns, and clinical outcomes of patients with comorbid diabetes mellitus (DM) and heart failure with reduced ejection fraction (HFrEF) in a contemporary, real-world U.S. outpatient registry in the context of evolving treatment strategies. Background Specific antihyperglycemic classes have differential risks and benefits with respect to HF. Limited data are available evaluating contemporary treatment patterns and outcomes of patients with comorbid DM and HFrEF. Methods Among 4,970 patients with chronic HFrEF (≤40%) across 152 U.S. sites in the CHAMP-HF prospective, observational registry (2015 to 2017), we examined therapies and clinical outcomes by DM status. Results Median age was 68 (58 to 75) years of age; 29% were women; 73.5% were white; and 64% had coronary artery disease. Overall, 42% (n = 2,085) had comorbid DM with a median hemoglobin A1c (HbA1c) level of 7.2% (interquartile range [IQR]: 6.4% to 8.3%). One-fourth of DM patients (24%) were not treated with an antihyperglycemic therapy. Most patients with DM were taking 1 (46%) or 2 (23%) antihyperglycemic therapies: metformin (40%), insulin (33%); sulfonylureas (24%); dipeptidyl peptidase-4 inhibitors (10%); glucagon-like peptide (GLP)-1 receptor agonists (4%); sodium-glucose cotransporter (SGLT)-2 inhibitors (2%); and thiazolidinediones (2%). Among patients with DM, 62%, 16%, 80%, and 33.5% were receiving any angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitor (ARNI), β-blockers, or mineralocorticoid receptor antagonists (MRAs) at baseline, respectively. Among patients without DM, corresponding baseline rates were 65%, 15%, 80%, and 37%, respectively. Patients with or without DM were infrequently treated with guideline-directed HFrEF therapies at target doses (≤27% across classes). During median 15-month follow-up, patients with DM experienced higher rates of all-cause mortality or HF hospitalization (30% vs. 23%, respectively), independent of 11 pre-specified covariates (adjusted hazard ratio: 1.35 (95% confidence interval: 1.21 to 1.52); p Conclusions Despite higher risk-adjusted clinical event rates in patients with comorbid HFrEF and DM, guideline-directed medical therapies for both disease states are incomplete and represent an important target for quality improvement through multidisciplinary care pathways.

Highlights •BNP and NT-proBNP are used as inclusion criteria in several HF clinical trials. •Despite widespread use, there is inconsistency in how BNP and NT-proBNP are utilized. •We call for standardization of natriuretic peptide inclusion criteria across HF trials.

OBJECTIVES: The authors sought to evaluate the prognostic significance of baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP), whether NT-proBNP modified the treatment response to sacubitril/valsartan, and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in key subgroups. BACKGROUND: Sacubitril/valsartan reduces NT-proBNP in heart failure (HF) with both reduced and preserved ejection fraction (EF), but did not significantly reduce total HF hospitalizations and cardiovascular death compared with valsartan in patients with HF with preserved EF (HFpEF). METHODS: In the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial, 4,796 patients with HFpEF and elevated NT-proBNP were randomized to sacubitril/valsartan or valsartan. NT-proBNP was measured at screening in all patients and at 5 subsequent times in >2,700 patients: before, between, and after sequential valsartan and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-randomization. RESULTS: Median NT-proBNP was 911 pg/ml (interquartile range: 464 to 1,613 pg/ml) at screening. Screening NT-proBNP was strongly associated with the primary endpoint, total HF hospitalizations and cardiovascular death (rate ratio [RR]: 1.68 per log increase in NT-proBNP, 95% confidence interval [CI]: 1.53 to 1.85; p 57% (18%). Decreases in NT-proBNP predicted lower subsequent risk of the primary endpoint. CONCLUSIONS: Baseline NT-proBNP predicted HF events but did not modify the sacubitril/valsartan treatment effect in patients with HFpEF. Sacubitril/valsartan reduced NT-proBNP consistently in men and women, and in patients with lower or higher EF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711). ispartof: JACC-HEART FAILURE vol:8 issue:5 pages:372-381 ispartof: location:United States status: published

There is a wage gap among men and women practicing cardiology. Differences in industry funding can be both a consequence of and a contributor to gender differences in salaries. We sought to determine whether gender differences exist in the distribution, types, and amounts of industry payments among men and women in cardiology.In this cross-sectional analysis, we used the Centers for MedicareMedicaid Services Open Payment program database to obtain 2016 industry payment data for US cardiologists. We also used UK Disclosure data to obtain 2016 industry payments to UK cardiologists. Outcomes included the proportions of male and female cardiologists receiving industry funding and the mean industry payment amounts received by male and female cardiologists. Where possible, we also assessed 2014 and 2015 data in both locations.Of the 22,848 practicing Centers for MedicareMedicaid Services US cardiologists in 2016, 20,037 (88%) were men and 2,811 (12%) were women. Proportionally more men than women received industry payments in 2016 (78.0% vs 68.5%, respectively; P .001). Men received higher overall mean industry payments than women ($6,193.25 vs. $2,501.55, P .001). Results were similar in 2014 and 2015. Among UK cardiologists, more men (24.4%) than women (13.5%) received industry payments in 2016 (P .001). However, although the difference in overall industry payments was numerically larger among men compared to women, this did not achieve statistical significance (£2,348.31 vs £1,501.37, respectively, P = .35).Industry payments to cardiologists are common, and there are gender differences in these payments on both sides of the Atlantic.

Aims The primary objective of this systematic review was to estimate the prevalence and temporal changes in chronic comorbid conditions reported in heart failure (HF) clinical trials. Methods and results We searched MEDLINE for HF trials enrolling more than 400 patients published between 2001 and 2016.Trials were divided into HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), or trials enrolling regardless of ejection fraction. The prevalence of baseline chronic comorbid conditions was categorized according to the algorithm proposed by the Chronic Conditions Data Warehouse, which is used to analyse Medicare data. To test for a trend in the prevalence of comorbid conditions, linear regression models were used to evaluate temporal trends in prevalence of comorbidities. Overall, 118 clinical trials enrolling a cumulative total of 215 508 patients were included. Across all comorbidities examined, data were reported in a mean of 35% of trials, without significant improvement during the study period. Reporting of comorbidities was more common in HFrEF trials (51%) compared with HFpEF trials (27%). Among trials reporting data, hypertension (63%), ischaemic heart disease (44%), hyperlipidaemia (48%), diabetes (33%), chronic kidney disease (25%) and atrial fibrillation (25%) were the major comorbidities. The prevalence of comorbidities including hypertension, atrial fibrillation and chronic kidney disease increased over time while the prevalence of smoking decreased in HFrEF trials. Conclusion Many HF trials do not report baseline comorbidities. A more rigorous, systematic, and standardized framework needs to be adopted for future clinical trials to ensure adequate comorbidity reporting and improve recruitment of multi-morbid HF patients.

Aims The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin–angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF). Methods and results We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45–0.65] for the recurrent primary endpoint compared with putative placebo (P Conclusion This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%.

BACKGROUND: While left atrial (LA) mechanical dysfunction in heart failure with preserved ejection fraction (HFpEF) is associated with poor clinical outcomes, the influence of LA myopathy on temporal changes in cardiovascular biomarkers is unclear. METHODS AND RESULTS: We evaluated biomarker correlates of LA myopathy, as defined by reduced LA strain, and the associations of LA strain with longitudinal changes in biomarkers among participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. LA speckle-tracking was performed on baseline echocardiograms of RELAX participants to measure LA reservoir and LA contractile strain. Of the 216 RELAX participants, 169 (78%) had measurable LA strain and biomarker data. Participants with LA reservoir strain below median (13.5%, interquartile range: 10–22.5%) were older, more likely to have atrial fibrillation, and had higher jugular venous pressure (P

Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin-aldosterone–system inhibitor alone in 2 similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8399) and PARAGON-HF (LVEF eligibility≥45%; n=4796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories: ≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), and >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality, and noncardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. Results: Among 13 195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of noncardiovascular death, among patients in the highest versus the lowest groups. Overall sacubitril/valsartan was superior to renin-angiotensin-aldosterone–system inhibition for first cardiovascular death or heart failure hospitalization (Hazard Ratio [HR] 0.84 [95% CI, 0.78–0.90]), cardiovascular death (HR 0.84 [95% CI, 0.76–0.92]), heart failure hospitalization (HR 0.84 [95% CI, 0.77–0.91]), and all-cause mortality (HR 0.88 [95% CI, 0.81–0.96]). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction P =0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. Conclusions: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone–system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifiers: NCT01920711 (PARAGON-HF), NCT01035255 (PARADIGM-HF).

Marijuana use is increasing as more states are legalizing cannabis for both medicinal and recreational purposes. National survey data estimate that >2 million Americans with established cardiovascular diseases currently use or have used marijuana in its variety of forms, including inhalation and vaping. Cannabinoid receptors are distributed in multiple tissue beds and cells, including platelets, adipose tissue, and myocytes. Observational data suggest associations between marijuana and a broad range of adverse cardiovascular risks. Marijuana is becoming increasingly potent, and smoking marijuana carries many of the same cardiovascular health hazards as smoking tobacco. Synthetic cannabinoids have been linked to more sustained and deleterious pharmacodynamic effects. Marijuana is classified as a Schedule I substance, thus limiting its rigorous study for cardiovascular health effects. This review summarizes cardiovascular considerations related to marijuana use, pharmacological interactions, and future steps to provide clearer guidance regarding its cardiovascular safety. Screening for marijuana use is encouraged, especially in young patients presenting with cardiovascular disease.

Background: Risk for atherosclerotic cardiovascular disease was a novel consideration for antihypertensive medication initiation in the 2017 American College of Cardiology/American Heart Association Blood Pressure (BP) guideline. Whether biomarkers of chronic myocardial injury (high-sensitivity cardiac troponin T ≥6 ng/L] and stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥100 pg/mL) can inform cardiovascular (CV) risk stratification and treatment decisions among adults with elevated BP and hypertension is unclear. Methods: Participant-level data from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were pooled, excluding individuals with prevalent CV disease and those taking antihypertensive medication at baseline. Participants were analyzed according to BP treatment group from the 2017 American College of Cardiology/American Heart Association BP guideline and those with high BP (120 to 159/ Results: The study included 12 987 participants (mean age, 55 years; 55% women; 21.5% with elevated high-sensitivity cardiac troponin T; 17.7% with elevated NT-proBNP) with 825 incident CV events over 10-year follow-up. Participants with elevated BP or hypertension not recommended for antihypertensive medication with versus without either elevated high-sensitivity cardiac troponin T or NT-proBNP had a 10-year CV incidence rate of 11.0% and 4.6%, with a 10-year number needed to treat to prevent 1 event for intensive BP lowering of 36 and 85, respectively. Among participants with stage 1 or stage 2 hypertension recommended for antihypertensive medication with BP Conclusions: Elevations in high-sensitivity cardiac troponin T or NT-proBNP identify individuals with elevated BP or hypertension not currently recommended for antihypertensive medication who are at high risk for CV events. The presence of nonelevated biomarkers, even in the setting of stage 1 or stage 2 hypertension, was associated with lower risk. Incorporation of biomarkers into risk assessment algorithms may lead to more appropriate matching of intensive BP control with patient risk.

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

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Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P P P Conclusions Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711 .

Background: Patients with heart failure (HF) and preserved left ventricular ejection fraction comprise a heterogeneous group including some with mildly reduced EF. We hypothesized that mode of death differs by EF in ambulatory patients with HF and preserved left ventricular ejection fraction. Methods: PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor With Angiotensin-Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) compared clinical outcomes in 4796 patients with chronic HF and EF ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the mode of death in relation to baseline EF in logistic regression models and the effect of randomized treatment on cause-specific death in Cox regression models. Nonlinear relationships with continuous EF were modelled using quadratic and cubic terms. Results: Of 691 deaths during the trial, 416 (60%) were ascribed to cardiovascular, 220 (32%) to noncardiovascular, and 55 (8%) to unknown causes. Of cardiovascular deaths, 154 (37%) were due to sudden death, 118 (28%) were due to HF, 35 (8%) to stroke, 27 (6%) to myocardial infarction, and 82 (20%) to other cardiovascular causes. Rates of all-cause, cardiovascular, and sudden death were higher in those with lower left ventricular ejection fraction (all P P for interaction >0.30). Conclusions: Among patients with HF and preserved left ventricular ejection fraction enrolled in PARAGON-HF, the proportion of cardiovascular and sudden death were higher in those with lower left ventricular EF, and the proportion of noncardiovascular death rose with EF. Regardless of EF, sacubitril/valsartan did not reduce death from any cause compared with valsartan. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.

Background: Bedside evaluation of congestion is a mainstay of heart failure (HF) management. Whether detected physical examination signs have changed over time as obesity prevalence has increased in HF populations, or if the associated prognosis differs for HF with reduced or preserved ejection fraction (HFrEF or HFpEF) is uncertain. Methods: From 2005 to 2014, the ARIC study (Atherosclerosis Risk in Communities) conducted adjudicated hospital surveillance of acute decompensated HF. We analyzed trends in physical examination findings, imaging signs, and symptoms related to congestion, both over time and by obesity class, and associated 28-day mortality risks. Results: Of 24 937 weighted hospitalizations for acute decompensated HF (mean age 75 years, 53% women, 32% Black), 47% had HFpEF. The prevalence of obesity increased from 2005 to 2014 for both HF types. With increasing obesity category, detected edema increased, while jugular venous distension decreased, and rales remained stable. Detected edema also increased over time, for both HF types. Associations between 28-day mortality and individual signs and symptoms of congestion were similar for HFpEF and HFrEF; however, the adjusted mortality risk with all 3 (edema, rales, and jugular venous distension) versus P for interaction by HF type =0.02. Conclusions: In patients hospitalized with acute decompensated HF, detected physical examination findings differ both temporally and by obesity. Combined findings from the physical examination are more prognostic of 28-day mortality for patients with HFpEF than HFrEF.

A U-shaped association between serum potassium (s-potassium) and short-term mortality has been reported for patients with hypertension. Less is known about the long-term prognostic implications of s-potassium and whether this relationship is modified by intensive blood pressure (BP) control. SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized, controlled trial of 9361 high-risk patients aged ≥50 years without diabetes, who were allocated to intensive versus standard BP control. We investigated associations between baseline and on-treatment s-potassium and death, using Cox proportional hazards regression (including s-potassium as a time-dependent covariate) and restricted cubic splines. We further explored the effects of intensive BP control across the s-potassium spectrum. Baseline s-potassium was available in 9336 individuals, and 8473 had a measurement at 12 months. Mean baseline s-potassium was similar between the 2 treatment groups (intensive 4.21 mmol/L versus standard 4.20 mmol/L; P =0.74), but on-treatment s-potassium was lower in the intensive group (4.14 mmol/L versus 4.18 mmol/L; P =0.001). Median follow-up was 3.3 years, with 365 all-cause deaths (3.9%) and 102 cardiovascular deaths (1.1%). Baseline s-potassium had a linear association with both types of death events ( P P =0.04) but not with cardiovascular death ( P =0.13). None of the associations remained significant after multivariable adjustment ( P ≥0.05). S-potassium did not modify the effect of intensive BP control ( P ≥0.05). In SPRINT, neither baseline nor on-treatment s-potassium levels were independently associated with death, and the effect of intensive BP control was not modified by s-potassium. Careful monitoring of patients on antihypertensive medications may eliminate the risks associated with abnormal s-potassium. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01206062

Purpose of review Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF), with diabetic cardiomyopathy (DbCM) referring to abnormal heart structure in the absence of other driving cardiac factors such as hypertension, coronary artery disease (CAD), and valvular heart disease. Stage B DbCM is commonly asymptomatic and represents a form of stage B HF; DbCM thus represents a transitional phenotype prior to onset of symptomatic HF. The pathogenesis of DbCM is not fully elucidated but involves hyperglycemia, insulin resistance, increased free fatty acids (FFA), lipotoxicity, oxidative stress, advanced glycation end product (AGE) formation, activation of the renin-angiotensin-aldosterone system (RAAS) with an increase in angiotensin II, and dyshomeostasis of calcium, which all contribute to left ventricular hypertrophy (LVH) and cardiac systolic and diastolic dysfunction. Although DbCM is an established pathogenic process, it is underrecognized clinically due to its commonly asymptomatic nature. Raising awareness to identify high-risk individuals with stage B HF due to DbCM, who may subsequently progress to overt HF (stage C/D HF), as well as identifying new pharmacological agents and approaches to prevent functional decline, may help reduce this global health problem. The aim of this review is to focus on stage B DbCM; provide data on diagnostic approaches, current therapies, and potential therapies under investigation; and highlight the need to raise awareness and interdisciplinary dialogue among clinicians and researchers. Recent findings There are no currently approved therapeutic strategies to treat or prevent progression of stage B DbCM, but multiple attempts are being made to target different pathogenic mechanisms involved in the development of DbCM. Recent cardiovascular (CV) outcome trials (CVOTs) have identified newer therapeutic agents with CV benefit, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors that reduce hospitalization for HF and glucagon-like peptide-1 (GLP-1) receptor agonists that reduce major adverse CV events (MACE), though without consistent effect on HF outcomes. Recent clinical practice guidelines recommend screening patients at high risk for HF. Further definition and interdisciplinary discussion of high-yield populations to screen, appropriate subsequent evaluation and intervention are needed to advance this area. DbCM is a complex entity that results from multiple pathogenic mechanisms triggered by impairment of glucose and lipid metabolism over many years. DbCM is commonly asymptomatic and represents a form of stage B HF. It is an underrecognized process that may progress to functional decline and overt HF. Although newer medications approved for the treatment of T2D may play an important role in reducing the risk of HF complications, less focus has been placed on earlier recognition and treatment of DbCM while asymptomatic. Additional efforts should be made to further study and target this stage in order to decrease the overall burden of HF.