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Background: Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between sodium-glucose cotransporter-2 inhibitor treatment, changes in metabolic pathways, and outcomes using targeted metabolomics. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis–defined metabolite clusters that changed differentially with treatment and examined the relationship between change in metabolite clusters and change in Kansas City Cardiomyopathy Questionnaire scores and NT-proBNP (N-terminal probrain natriuretic peptide). Models were adjusted for relevant clinical covariates and nominal P P Results: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short-chain acylcarnitine as well as medium-chain acylcarnitine principal components analysis–defined metabolite clusters compared with placebo (nominal P =0.01, false discovery rate–adjusted P =0.08 for both clusters). However, ketosis (β-hydroxybutyrate levels >500 μmol/L) was achieved infrequently (3 [2.5%] in dapagliflozin arm versus 1 [0.9%] in placebo arm) and supraphysiologic levels were not observed. Increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in Kansas City Cardiomyopathy Questionnaire scores (ie, worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of sodium-glucose cotransporter-2 inhibitors in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with sodium-glucose cotransporter-2 inhibitors in patients with HFrEF. Only physiologic levels of ketosis were observed. In addition, we identified several metabolic biomarkers associated with adverse HFrEF outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02653482.

Background: Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. Methods: Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. Results: Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6–7.5]; P P =0.01), >40 to ≤60 (4.9 points [95% CI, 0.8–9.0]; P =0.02) and >60% (6.8 points [95% CI, 1.5–12.1]; P =0.01; P interaction =0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously ( P interaction =0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all P interaction values nonsignificant). Conclusions: In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02653482 and NCT03030235.

Objectives This study sought to determine whether the increased use of telehealth was associated with a difference in outcomes for outpatients with heart failure. Background The COVID-19 pandemic led to dramatic changes in the delivery of outpatient care. It is unclear whether increased use of telehealth affected outcomes for outpatients with heart failure. Methods In March 2020, a large Midwestern health care system, encompassing 16 cardiology clinics, 16 emergency departments, and 12 hospitals, initiated a telehealth-based model for outpatient care in the setting of the COVID-19 pandemic. A propensity-matched analysis was performed to compare outcomes between outpatients seen in-person in 2018 and 2019 and via telemedicine in 2020. Results Among 8,263 unique patients with heart failure with 15,421 clinic visits seen from March 15 to June 15, telehealth was employed in 88.5% of 2020 visits but in none in 2018 or 2019. Despite the pandemic, more outpatients were seen in 2020 (n = 5,224) versus 2018 and 2019 (n = 5,099 per year). Using propensity matching, 4,541 telehealth visits in 2020 were compared with 4,541 in-person visits in 2018 and 2019, and groups were well matched. Mortality was similar for telehealth and in-person visits at both 30 days (0.8% vs 0.7%) and 90 days (2.9% vs 2.4%). Likewise, there was no excess in hospital encounters or need for intensive care with telehealth visits. Conclusions A telehealth model for outpatients with heart failure allowed for distanced encounters without increases in subsequent acute care or mortality. As the pressures of the COVID-19 pandemic abate, these data suggest that telehealth outpatient visits in patients with heart failure can be safely incorporated into clinical practice., Central Illustration

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.

Patients with heart failure and preserved ejection fraction (HFpEF) have a high burden of symptoms and functional limitations, and have a poor quality of life. By targeting cardiometabolic abmormalities, sodium glucose cotransporter 2 (SGLT2) inhibitors may improve these impairments. In this multicenter, randomized trial of patients with HFpEF (NCT03030235), we evaluated whether the SGLT2 inhibitor dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS), a measure of heart failure-related health status, at 12 weeks after treatment initiation. Secondary endpoints included the 6-minute walk test (6MWT), KCCQ Overall Summary Score (KCCQ-OS), clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin and systolic blood pressure. In total, 324 patients were randomized to dapagliflozin or placebo. Dapagliflozin improved KCCQ-CS (effect size, 5.8 points (95% confidence interval (CI) 2.3–9.2, P = 0.001), meeting the predefined primary endpoint, due to improvements in both KCCQ total symptom score (KCCQ-TS) (5.8 points (95% CI 2.0–9.6, P = 0.003)) and physical limitations scores (5.3 points (95% CI 0.7–10.0, P = 0.026)). Dapagliflozin also improved 6MWT (mean effect size of 20.1 m (95% CI 5.6–34.7, P = 0.007)), KCCQ-OS (4.5 points (95% CI 1.1–7.8, P = 0.009)), proportion of participants with 5-point or greater improvements in KCCQ-OS (odds ratio (OR) = 1.73 (95% CI 1.05–2.85, P = 0.03)) and reduced weight (mean effect size, 0.72 kg (95% CI 0.01–1.42, P = 0.046)). There were no significant differences in other secondary endpoints. Adverse events were similar between dapagliflozin and placebo (44 (27.2%) versus 38 (23.5%) patients, respectively). These results indicate that 12 weeks of dapagliflozin treatment significantly improved patient-reported symptoms, physical limitations and exercise function and was well tolerated in chronic HFpEF., In a multicenter, randomized trial, the SGLT2 inhibitor dapagliflozin improved the health status and exercise function of patients with heart failure with preserved ejection fraction (HFpEF), a condition for which effective treatments are lacking.

Summary Background COVID-19 can lead to multiorgan failure. Dapagliflozin, a SGLT2 inhibitor, has significant protective benefits for the heart and kidney. We aimed to see whether this agent might provide organ protection in patients with COVID-19 by affecting processes dysregulated during acute illness. Methods DARE-19 was a randomised, double-blind, placebo-controlled trial of patients hospitalised with COVID-19 and with at least one cardiometabolic risk factor (ie, hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease). Patients critically ill at screening were excluded. Patients were randomly assigned 1:1 to dapagliflozin (10 mg daily orally) or matched placebo for 30 days. Dual primary outcomes were assessed in the intention-to-treat population: the outcome of prevention (time to new or worsened organ dysfunction or death), and the hierarchial composite outcome of recovery (change in clinical status by day 30). Safety outcomes, in patients who received at least one study medication dose, included serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This study is registered with ClinicalTrials.gov , NCT04350593 . Findings Between April 22, 2020 and Jan 1, 2021, 1250 patients were randomly assigned with 625 in each group. The primary composite outcome of prevention showed organ dysfunction or death occurred in 70 patients (11·2%) in the dapagliflozin group, and 86 (13·8%) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·58–1·10; p=0·17). For the primary outcome of recovery, 547 patients (87·5%) in the dapagliflozin group and 532 (85·1%) in the placebo group showed clinical status improvement, although this was not statistically significant (win ratio 1·09, 95% CI 0·97–1·22; p=0·14). There were 41 deaths (6·6%) in the dapagliflozin group, and 54 (8·6%) in the placebo group (HR 0·77, 95% CI 0·52–1·16). Serious adverse events were reported in 65 (10·6%) of 613 patients treated with dapagliflozin and in 82 (13·3%) of 616 patients given the placebo. Interpretation In patients with cardiometabolic risk factors who were hospitalised with COVID-19, treatment with dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, but was well tolerated. Funding AstraZeneca.

Statins are recommended in heart transplant patients, but are sometimes poorly tolerated. Alternative agents are often considered including proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i). We sought to investigate the use of PCSK9i after heart transplantation.We identified patients who received a heart transplant from 1999 to 2019 and were started on PCSK9i at our institution. Clinical, laboratory, and coronary angiography with intravascular ultrasound results were compared. Among 65 patients initiated on PCSK9i (48 for statin intolerance and 17 for refractory hyperlipidemia), the median time from transplant was 5.5 years (interquartile range [IQR], 2.8-9.9 years) with a median PCSK9 treatment duration of 1.6 years (IQR, 0.8-3.2 years) and 80% still on treatment. Evolocumab was used in 73.8%, alirocumab in 12.3%, and both in 13.8% owing to insurance coverage. All patients required prior authorization; initial denial occurred in 18.5% and 32.3% had denials in subsequent years. The median low-density lipoprotein cholesterol decreased from 130 mg/dL (IQR, 102-148 mg/dL) to 55 mg/dL (IQR, 35-74 mg/dL) after starting PCSK9i (P.001), with 72% of patients achieving a low-density lipoprotein cholesterol of70 mg/dL after treatment. There were also significant reductions of total cholesterol, non-high-density lipoprotein cholesterol, total/high-density lipoprotein cholesterol ratio, and triglycerides, with a modest increase in high-density lipoprotein cholesterol. These changes were durable at latest follow-up. In 33 patients with serial coronary angiography and intravascular ultrasound, PCSK9i were associated with stable coronary plaque thickness and lumen area.Among heart transplant recipients, PCSK9i are effective in lowering cholesterol levels and stabilizing coronary intimal hyperplasia with minimal side effects. Despite favorable effects, access and affordability remain a challenge.

Type 2 diabetes mellitus (T2D) is a common comorbidity among patients who have undergone heart transplantation. Recently two classes of glucose-lowering medications (sodium-glucose cotransporter type-2 inhibitors [SGLT-2Is] and glucagon-like-peptide-1 receptor agonists [GLP-1RAs]), have been shown to significantly improve cardiovascular outcomes. There is a paucity of data regarding their use in immunosuppressed patients, with many studies specifically excluding this population. We retrospectively evaluated the safety and efficacy of GLP-1RAs and SGLT-2Is in patients who had undergone orthotopic heart transplant at a high-volume center. Among 21 patients, we found significant weight loss, reductions in insulin use, hemoglobin A1c, and low-density lipoprotein-cholesterol. Moreover, both SGLT-2Is and GLP-1RAs were well tolerated with no adverse events leading to discontinuation of either therapy. While larger studies of patients after solid organ transplant are needed, this small hypothesis-generating study demonstrates that SGLT-2Is and GLP-1RAs appear safe and effective therapies among patients with T2D after heart transplant.

Cardiogenic shock (CS) is associated with high mortality and often requires involvement of a multidisciplinary provider team to deliver timely care. Care coordination is more difficult on weekends, which may lead to a delay in care. We sought to assess the effect of weekend admissions on outcomes in patients admitted with CS. Patients admitted with CS were identified from 2005 to 2014 in the National Inpatient Sample using ICD9 code 785.51. Baseline demographics, in-hospital procedures, and outcomes were obtained and compared by day of admission. A multivariable model was used to assess the impact of weekend admission on in-hospital mortality. A total of 875,054 CS admissions were identified (age 67.4 ± 15.1 years, 40.2% female, 72.1% Caucasian), with 23% of patients being admitted on weekends. Baseline co-morbidities were similar between groups. Weekend admissions were associated with higher in-hospital mortality (40.6% vs 37.5%) and cardiac arrest (20.3% vs 18.1%, p < 0.001 for both) consistently over the study period. Use of temporary and permanent mechanical support devices and heart transplantation were slightly less common for weekend admissions. In a multivariable model adjusting for relevant confounders, weekend admission was associated with a 10% increased mortality in patients with CS. In conclusion, patients with CS admitted on weekends had higher in-hospital mortality and were slightly less likely to receive mechanical support and advanced therapies compared with those admitted on weekdays. Future studies and health system initiatives should focus on rectifying these disparities with around-the-clock multidisciplinary coordinated care for CS.

International audience; Aims: Treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors improves outcomes in patients with chronic heart failure (HF) with reduced ejection fraction. There is limited experience with the in-hospital initiation of SGLT2 inhibitors in patients with acute HF (AHF) with or without diabetes. EMPULSE is designed to assess the clinical benefit and safety of the SGLT2 inhibitor empagliflozin compared with placebo in patients hospitalized with AHF.Methods: EMPULSE is a randomized, double-blind, parallel-group, placebo-controlled multinational trial comparing the in-hospital initiation of empagliflozin (10 mg once daily) with placebo. Approximately 500 patients admitted for AHF with dyspnoea, signs of fluid overload, and elevated natriuretic peptides will be randomized 1:1 stratified to HF status (de-novo and decompensated chronic HF) to either empagliflozin or placebo at approximately 165 sites across North America, Europe and Asia. Patients will be enrolled regardless of ejection fraction and diabetes status and will be randomized during hospitalization and after stabilization (between 24 h and 5 days after admission), with treatment continued up to 90 days after initiation. The primary outcome is clinical benefit at 90 days, consisting of a composite of all-cause death, HF events, and ≥5 point change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), assessed using a 'win-ratio' approach. Secondary outcomes include assessments of safety, change in KCCQ-TSS from baseline to 90 days and change in natriuretic peptides from baseline to 30 days.Conclusion: The EMPULSE trial will evaluate the clinical benefit and safety of empagliflozin in patients hospitalized for AHF.

Aims Effective and safe decongestion remains a major goal for optimal management of patients with acute heart failure (AHF). The effects of the sodium–glucose cotransporter 2 inhibitor empagliflozin on decongestion-related endpoints in the EMPULSE trial (NCT0415775) were evaluated. Methods and results A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL), WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal pro-B-type natriuretic peptide levels, hemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points, adjusted mean differences (95% confidence interval) at Days 15, 30, and 90 were: for WL −1.97 (−2.86, −1.08), −1.74 (−2.73, −0.74); −1.53 (−2.75, −0.31) kg; for WL-adjusted: −2.31 (−3.77, −0.85), −2.79 (−5.03, −0.54), −3.18 (−6.08, −0.28) kg/40 mg furosemide i.v. or equivalent; respectively (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90 (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days) with the win ratio of 1.75 (95% confidence interval 1.37, 2.23; P < 0.0001). Conclusion Initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective and sustained decongestion which was associated with clinical benefit at Day 90.

Background: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized). Methods: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model. Results: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01–2.20], 1.37 [0.94–1.99], and 1.48 [1.00–2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32–8.59], P =0.03; 4.80 [95% CI, 0.00–9.61], P =0.05; 4.66 [95% CI, 0.32–9.01], P =0.04; 4.85 [95% CI, 0.77–8.92], P =0.02; and 4.40 points [95% CI, 0.33–8.48], P =0.03, respectively). Conclusions: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT0415775.

The sodium–glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09–1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

This study sought to describe the short-term health status benefits of angiotensin-neprilysin inhibitor (ARNI) therapy in patients with heart failure and reduced ejection fraction (HFrEF).Although therapy with sacubitril/valsartan, a neprilysin inhibitor, improved patients' health status (compared with enalapril) at 8 months in the PARADIGM-HF (Prospective Comparison of ARNI with ACE inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study, the early impact of ARNI on patients' symptoms, functions, and quality of life is unknown.Health status was assessed by using the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ) in 3,918 outpatients with HFrEF and left ventricular ejection fraction ≤40% across 140 U.S. centers in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry. ARNI therapy was initiated in 508 patients who were matched 1:2 to 1,016 patients who were not initiated on ARNI (no-ARNI), using a nonparsimonious time-dependent propensity score (6 sociodemographic factors, 23 clinical characteristics), prior KCCQ overall summary (KCCQ-OS) score, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker status.Multivariate linear regression demonstrated a greater mean improvement in KCCQ-OS in patients initiated on ARNI therapy (5.3 ± 19 vs. 2.5 ± 17.4, respectively; p 0.001) over a median (interquartile range [IQR]) of 57 (32 to 104) days. The proportions of ARNI versus no-ARNI groups with ≥10-point (large) and ≥20-point (very large) improvements in KCCQ-OS were 32.7% versus 26.9%, respectively, and 20.5% versus 12.1%, respectively, consistent with numbers needed to treat of 18 and 12, respectively.In routine clinical care, ARNI therapy was associated with early improvements in health status, with 20% experiencing a very large health status benefit compared with 12% who were not started on ARNI therapy. These findings support the use of ARNI to improve patients' symptoms, functions, and quality of life.

Type 2 Diabetes (T2D) is a growing public health threat that is evolving into a global pandemic with debilitating, expensive and often lethal complications. Even when hemoglobin A1c (HbA1C) levels are well controlled, and concomitant cardiovascular (CV) risk factors are effectively treated, two out of every three patients with T2D are destined to die from CV complications. Several large randomized controlled trials (RCT) indicate that two classes of glucose-lowering medications, oral sodium-glucose cotransporter type 2 inhibitors (SGLT2-i) and injectable glucagon-like peptide-1 receptor agonists (GLP-1RA), confer significant CV benefits, including reductions in: hospitalizations for heart failure (HF), progression of diabetic kidney disease, atherosclerotic CV events, and (with some agents) CV death. These CV benefits appear to be independent of the glucose-lowering effects of these agents. These compelling findings are triggering a fundamental paradigm shift in T2D management whereby the focus is no longer on HbA1c alone, but instead on implementing a comprehensive CV risk reduction strategy prioritizing the use of these evidence-based therapies (along with other evidence-based treatment strategies) with the objective of reducing the risk of morbid complications, and improving the quantity and quality of life of patients with T2D. Cardiologists are uniquely positioned to become more involved in the management of T2D and established CV disease, which at this time should include initiation (either by prescribing or by making recommendations) of agents proven to reduce CV risk. Specifically, SGLT2-is and/or GLP-1RA have now been shown to have a favorable risk-benefit balance, and are being increasingly emphasized by the practice guidelines as preferable treatment options in vulnerable patients with T2D. The cardiology community should collaborate with other care providers to ensure that when and where appropriate these new T2D therapies are used along with other evidence-based therapies to improve patient outcomes.

Objectives The aim of this study was to use a multicenter, observational outpatient registry of patients with heart failure with reduced ejection fraction (HFrEF) to describe the association between changes in patients’ medications with changes in health status. Background Alleviating symptoms and improving function and quality of life for patients with HFrEF are primary treatment goals and potential indicators of quality. Whether titrating medications in routine clinical care improves patients’ health status is unknown. Methods The association of any change in HFrEF medications with 3-month change in health status, as measured using the 12-item Kansas City Cardiomyopathy Questionnaire Overall Summary Scale, was determined in unadjusted and multivariate-adjusted (25 clinical characteristics, baseline health status) models using hierarchical linear regression. Results Among 3,313 outpatients with HFrEF from 140 centers, 21.9% had medication changes. Three months later, 23.7% and 46.4% had clinically meaningfully worse (≥5-point decrease) and improved (≥5-point increase) Kansas City Cardiomyopathy Questionnaire Overall Summary Scale scores. The 3-month median change in Kansas City Cardiomyopathy Questionnaire Overall Summary Scale score for patients whose HFrEF medications were changed was significantly larger (7.3 points; interquartile range: −3.1 to 20.8 points) than in patients whose medications were not changed (3.1 points; interquartile range: −4.7 to 12.5 points) (adjusted difference 3.0 points; 95% confidence interval: 1.4 to 4.6 points; p Conclusions In routine care of patients with HFrEF, changes in HFrEF medications were associated with significant improvements in patients’ health status, suggesting that health status–based performance measures can quantify the benefits of titrating medicines in patients with HFrEF.

Heart failure (HF) is emerging as one of the most common cardiovascular (CV) events in patients with type 2 diabetes (T2D), and the one associated with the worst prognosis. T2D and insulin resistance are strong predictors of incident HF, especially HF with preserved ejection fraction (HFpEF). Recent data suggest that even when all traditional risk factors for ASCVD are well controlled, patients with T2D continue to have a substantially greater risk of developing HF-indicating that traditional risk factor control is insufficient from a HF prevention standpoint, and highlighting the need for novel, more effective strategies for both prevention and treatment of heart failure in patients with T2D. Until recently, medications developed for glucose-lowering had, at best, neutral effect on heart failure outcomes in patients with T2D, while several classes of T2D medications had little data in regards to HF risk, and others actually increased the risk of HF hospitalization. Sodium glucose cotransporter type 2 inhibitors (SGLT-2i) have a novel and unique mechanism of action. By inhibiting sodium and glucose reabsorption in the proximal tubule, SGLT-2i result in a number of downstream effects, including glucosuria, weight loss, osmotic diuresis and natriuresis, which should theoretically be beneficial in HF. Three CVOTs of various SGLT-2i (EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58) enrolled markedly different patient populations in terms of ASCVD risk, but have demonstrated robust and consistent benefits in reduction of hospitalization for HF. In a meta-analysis of the three outcomes trials, SGLT-2i significantly reduced the risk of cardiovascular death or hospitalization for HF by 23% and hospitalization for HF by 31%. Although the declines in HF hospitalization with SGLT-2is are impressive, only a small proportion of patients with established HF were enrolled in these trials, and these benefits, therefore, represent primarily a HF prevention signal. Whether this prevention of HF benefit will translate to better outcomes for those patients with established HF (with or without diabetes), and whether it will extend across the spectrum of HF phenotypes (HFrEF and HFpEF) is yet to be determined, and is being actively investigated in several large ongoing trials.

Right ventricular (RV) failure is difficult to predict and is a major determinant of poor outcomes after left ventricular assist device (LVAD) implantation. We evaluated the associations of the following variables with severe RV failure in LVAD patients: tricuspid annular plane systolic excursion (TAPSE), pulmonary artery pulsatility index (PAPi), simplified RV contraction pressure index (sRVCPI), and HeartMate Risk Score (HMRS). We performed a retrospective case-control study on 216 patients who underwent continuous-flow LVAD implantation between 2008 and 2014. The primary analysis assessed the ability of HMRS, PAPi, sRVCPI, and TAPSE to predict severe RV failure. A secondary analysis evaluated the incremental benefit of combining predictive variables. Seventy-four patients developed severe RV failure (24%). Compared with the control group, the severe RV failure group had lower TAPSE (1.30 vs. 1.55; p < 0.001), lower PAPi (1.77 vs. 2.47; p = 0.001), lower sRVCPI (42.71 vs. 57.82; p < 0.001), and higher HMRS (2.12 vs. 1.65; p < 0.001). All four variables had similar receiver operating characteristic curves with modest area under the receiver operating characteristic curve (0.63-0.67, all p values < 0.001). In the evaluation of combined predictive variables, the combination of TAPSE with HMRS was found to be best for predicting severe RV failure. In summary, patients at risk for severe RV failure after LVAD implantation were successfully identified using TAPSE, PAPi, sRCPI, and HMRS. The combination of TAPSE and HMRS-incidentally, the least invasive and most readily available variables-proved to be superior to RV-centric metrics for predicting severe RV failure. The predictive and clinical use of these two variables should be tested prospectively.

Hyperkalaemia is a common electrolyte abnormality, associated with higher risk of morbid events, and increasing in prevalence—in part, due to increasing rates of comorbidities such as heart failure, chronic kidney disease, diabetes mellitus, and the use of renin-angiotensin-aldosterone system inhibitors (RAASi). In spite of this growing problem, the existing treatments for chronic hyperkalaemia have been limited, and are typically confined to dietary potassium restrictions and cessation or modification of RAASi, with latter option being potentially problematic given the known morbidity and mortality benefit of RAASi therapy in certain disease states, such as heart failure. The use of sodium polystyrene sulfonate (SPS/Kayexelate) for chronic hyperkalaemia has been low, due to poor tolerability, potential gastrointestinal safety concerns, and remaining uncertainty in regards to its efficacy. Given the shortcomings of existing therapies, novel treatments are clearly needed. There are now two novel treatment options, patiromer and sodium zirconium cyclosilicate (SZC), both approved by the FDA and EMA for treatment of chronic hyperkalaemia. These novel compounds have been demonstrated in multiple studies to be efficacious in achieving and maintaining normal serum potassium levels, over an extended time period, in patients with hyperkalaemia; and appear to be relatively safe and well-tolerated. Whether the correction of hyperkalaemia with these agents will allow optimization of RAASi, which could theoretically lead to improvement in clinical outcomes, especially in patients with heart failure, remains to be determined. Several clinical trials are ongoing to address these important knowledge gaps.

Background Cardiovascular and kidney complications of T2D are increasing, in part due to suboptimal implementation of guideline-directed therapies. The Saint Luke's Haverty Cardiometabolic Center (CMC) of Excellence implements team-based, patient-centered approach focused on comprehensive risk reduction for patients with T2D and CVD, including use of cardioprotective agents such as GLP-1RA and SGLT-2i. We assessed outcomes during the first two years of CMC. Methods We included consecutive patients with at least two CMC visits January 2019-December 2020. We compared change in outcomes of interest between baseline and last CMC visits. Results Among 382 patients, mean age was 64.8±10.8 years, 62% were men, 81% Caucasian, BMI was 35.8±7.3 kg/m2, 90% had T2D. At baseline, 52(14%) patients were on GLP-1RA [5(1%) on target dose], and 86(23%) on SGLT-2i. After median follow-up of 6.5(3.7-11.4) months, 338(89%) patients were receiving GLP-1RA [249(65%) on target dose], and 240(63%) SGLT-2i, with 222(58%) on both agents. During follow-up, patients experienced significant reductions in body weight (235.2±51.7 to 220.1±50.9 lbs.; p Conclusion CMC approach was associated with greater adoption of guideline-directed therapies and substantial reductions in key CVD risk factors. Treatments were generally well tolerated. Adoption of novel care models such as CMC is important for more effective implementation of guidelines into practice.

Aims We sought to analyse quality of life (QoL) measures derived from two questionnaires widely used in clinical trials, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQoL 5 dimensions (EQ‐5D), and to compare their prognostic value in men and women with heart failure and reduced ejection fraction (HFrEF). Methods and results From the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) we compared KCCQ and EQ‐5D at baseline and after 9 months in 1276 men and 373 women with new‐onset or worsening symptoms of HFrEF, who were sub‐optimally treated and in whom there was an anticipated up‐titration of guideline‐derived medical therapies. Women had significantly worse baseline QoL (median) as compared with men, both when assessed with KCCQ overall score (KCCQ‐OS, 44 vs. 53, P 0.2). Conclusion Amongst patients with HFrEF, women reported significantly worse QoL than men. QoL was independently associated with subsequent outcome, similarly in men and women. The KCCQ in general, and the KCCQ‐OS in particular, showed the strongest independent association with outcome., Sex differences in quality of life, in its relationship with outcomes, and predictive ability of different quality of life measures towards outcome. BIOSTAT‐CHF, BIOlogy Study to TAilored Treatment in Chronic Heart Failure; EQ‐5D, EuroQoL 5 dimensions; KCCQ, Kansas City Cardiomyopathy Questionnaire; OS, overall score; US, utility score; VAS, visual analogue scale.

Background Gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) are useful in acute rejection (AR) surveillance in orthotopic heart transplant (OHT) patients. We report a single-center experience of combined GEP and dd-cfDNA testing for AR surveillance. Methods GEP and dd-cfDNA are tested together starting at 2 months post-OHT. After 6 months, combined testing was obtained before scheduled endomyocardial biopsy (EMB), and EMB was canceled with a negative dd-cfDNA. This approach was compared to using a GEP-only approach, where EMB was canceled with a negative GEP. We evaluated for frequency of EMB cancellation with dd-cfDNA usage. Results A total of 153 OHT patients over a 13-month period underwent 495 combined GEP/dd-cfDNA tests. 82.2% of dd-cfDNA tests were below threshold. Above threshold results identified high-risk patients who developed AR. 378 combined tests ≥6 months post-OHT resulted in cancellation of 83.9% EMBs as opposed to 71.2% with GEP surveillance alone. There were 2 acute cellular and 2 antibody-mediated rejection episodes, and no significant AR ≥6 months. Conclusion Routine dd-cfDNA testing alongside GEP testing yielded a significant reduction in EMB volume by re-classifying GEP (+) patients into a lower risk group, without reduction in AR detection. The addition of dd-cfDNA identified patients at higher risk for AR.

Author(s): Thomas, Merrill; Khariton, Yevgeniy; Fonarow, Gregg C; Arnold, Suzanne V; Hill, Larry; Nassif, Michael E; Chan, Paul S; Butler, Javed; Thomas, Laine; DeVore, Adam D; Hernandez, Adrian F; Albert, Nancy M; Patterson, J Herbert; Williams, Fredonia B; Spertus, John A | Abstract: AimsImproving the health status (symptoms, function, and quality of life) of patients with heart failure with reduced ejection fraction (HFrEF) is a primary treatment goal. Angiotensin receptor neprilysin inhibitors (ARNI) improve short-term health status in clinical practice, but the sustainability of these improvements is unknown.Methods and resultsIn CHAMP-HF, a multicentre observational study of outpatients with HFrEF, patients initiated on ARNI were propensity score matched 1:2 to patients not using ARNI with Cox regression modelling time to ARNI initiation, adjusted for sociodemographic and clinical variables, medical history, medications, and baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Repeated measures models for the overall KCCQ score and each domain compared the health status trajectories of patients initiated on ARNI vs. not. Among 3930 participants, 746 (19.0%) began ARNI, of whom 576 were matched to 1152 non-ARNI patients. Prior to matching, participants initiated on ARNI were younger, non-Hispanic, had lower EFs, more commonly had a history of ventricular arrhythmia, were less likely to be taking an ACEI/ARB, and more likely to be treated with beta-blockers and mineralocorticoid receptor antagonists. There were no differences after matching. In the matched cohort, participants initiated on ARNI experienced improved health status by 3nmonths that persisted through 12nmonths [KCCQ Overall Summary Score (OSS)n=n73.4 vs. 70.8; Pnln0.001], with the largest benefit observed in the KCCQ Quality of Life domain (68.7 vs. 64.7; Pnln0.001). Similar health status benefits were noted through 18nmonths (KCCQ-OSSn=n73.9 vs. 71.3; Pnln0.001). A responder analysis showed that 12 patients would need to be initiated on ARNI for one to experience at least a large improvement (≥10 points) in health status benefit at 12nmonths.ConclusionsIn outpatient practice, ARNI therapy was associated with improved health status by 3nmonths and continued to 18nmonths after initiating therapy.

Background: Sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors) prevent heart failure (HF) hospitalizations in patients with type 2 diabetes and improve outcomes in those with HF and reduced ejection fraction, regardless of type 2 diabetes. Mechanisms of HF benefits remain unclear, and the effects of SGLT2 inhibitor on hemodynamics (filling pressures) are not known. The EMBRACE-HF trial (Empagliflozin Evaluation by Measuring Impact on Hemodynamics in Patients With Heart Failure) was designed to address this knowledge gap. Methods: EMBRACE-HF is an investigator-initiated, randomized, multicenter, double-blind, placebo-controlled trial. From July 2017 to November 2019, patients with HF (regardless of ejection fraction, with or without type 2 diabetes) and previously implanted pulmonary artery (PA) pressure sensor (CardioMEMS) were randomized across 10 US centers to empagliflozin 10 mg daily or placebo and treated for 12 weeks. The primary end point was change in PA diastolic pressure (PADP) from baseline to end of treatment (average PADP weeks 8–12). Secondary end points included health status (Kansas City Cardiomyopathy Questionnaire score), natriuretic peptides, and 6-min walking distance. Results: Overall, 93 patients were screened, and 65 were randomized (33 to empagliflozin, 32 to placebo). The mean age was 66 years; 63% were male; 52% had type 2 diabetes; 54% were in New York Heart Association class III/IV; mean ejection fraction was 44%; median NT-proBNP (N-terminal pro B-type natriuretic peptide) was 637 pg/mL; and mean PADP was 22 mm Hg. Empagliflozin significantly reduced PADP, with effects that began at week 1 and amplified over time; average PADP (weeks 8–12) was 1.5 mm Hg lower (95% CI, 0.2–2.8; P =0.02); and at week 12, PADP was 1.7 mm Hg lower (95% CI, 0.3–3.2; P =0.02) with empagliflozin versus placebo. Results were consistent for PA systolic and PA mean pressures. There was no difference in mean loop diuretic management (daily furosemide equivalents) between treatment groups. No significant differences between treatment groups were observed in Kansas City Cardiomyopathy Questionnaire scores, natriuretic peptide levels, and 6-min walking distance. Conclusions: In patients with HF and CardioMEMS PA pressure sensor, empagliflozin produced rapid reductions in PA pressures that were amplified over time and appeared to be independent of loop diuretic management. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03030222.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular death or worsening heart failure (HF), and improve symptom burden, physical function and quality of life in patients with HF and reduced ejection fraction. The mechanisms of the HF benefits of SGLT2 inhibitors, however, remain unclear. In this substudy of the DEFINE-HF trial, patients randomized to dapagliflozin or placebo had lung fluid volumes (LFVs) measured by remote dieletric sensing at baseline and after 12 weeks of therapy. A significantly greater proportion of dapagliflozin-treated patients (as compared with placebo) experienced improvement in LFVs and fewer dapagliflozin-treated patients had no change or deterioration in LFVs after 12 weeks of treatment. To our knowledge, this is the first study to suggest a direct effect of dapagliflozin (or any SGLT2 inhibitor) on more effective "decongestion", contributing in a meaningful way to the ongoing debate regarding the mechanisms of SGLT2 inhibitor HF benefits.

Author(s): Khariton, Yevgeniy; Fonarow, Gregg C; Hellkamp, Ann; Thomas, Laine; Nassif, Michael E; Butler, Javed; Duffy, Carol I; Albert, Nancy M; Spertus, John A | Abstract: AimsThe aim of our study was to investigate heterogeneity of health status treatment response of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).Methods and resultsWe leveraged data from CHAMP-HF, an observational registry of 140 US clinics and 5026 outpatients with chronic HFrEF, where health status was serially assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 Overall Summary Scale (range from 0 to 100; ≥20-point improvement is a very large improvement). In 334 patients newly initiated on sacubitril/valsartan, we used hierarchical multivariable logistic regression (13 patient-level characteristics as well as baseline KCCQ-12 score) to calculate the odds ratio (OR) of any characteristic being associated with a very large health status improvement. A total of 104/334 (31.1%) of patients achieved the primary endpoint, where only worse baseline health status [KCCQ-12 score of 0-60 points had an ORn=n0.86/5-point higher score (CI 0.79, 0.93)], and those with a KCCQ-12 score of 60-80 points had an ORn=n0.61/5-point higher score (0.45-0.82), which was associated with a very large benefit. No other patient characteristic was associated with a very large health status improvement (Pngn0.05).ConclusionsWe found that, after initiation of sacubitril/valsartan, only worse baseline health status was associated with very large health status improvement. Accordingly, a trial of therapy-particularly in those with worse symptoms, function, and quality of life-and assessing treatment response are likely to be the best prospective strategy.

Background: Optimal guideline-directed medical therapy is delivered to only 6.9% of patients with type 2 diabetes (T2D) and cardiovascular disease (CVD) nationally, despite guideline recommendations emphasizing aggressive comprehensive secondary risk reduction. While there are many potential explanations, lack of effective clinical care delivery models is a key contributor. The Haverty Cardiometabolic Center of Excellence at Saint Luke’s Mid America Heart Institute was designed to address this unmet need, by delivering a patient-centric, collaborative model of care which focuses on aggressive and comprehensive secondary risk reduction in patients with T2D and CVD. Patients are managed by a multidisciplinary team comprised of preventative cardiologists, advanced practice providers and nurses cross-trained in T2D and CVD management, certified diabetes educator, dietician, pharmacist, and other professionals, in close coordination with endocrinologists and primary care clinicians. We aimed to determine whether patients receiving care in the Center had experienced better intermediate outcomes with similar patients receiving routine care in conventional settings. Methods: We analyzed data from the initial 60 patients seen in the Center who had at least one follow-up visit, and propensity matched them 1:3 to similar patients with T2D and CVD treated in conventional care settings. Propensity model included age, sex, baseline weight, HbA1c, systolic blood pressure (SBP), history of CVD, and duration between visits. Linear mixed models with a random effect for matched groups was used to compare between-group differences for changes in weight, LDL-C, and HbA1c. Results: At baseline, patients in the Center weighed 241.3 lbs ± 51.0 and had HbA1c 7.4 ± 1.4 and LDL 68.0 ± 27.0 as compared to 245.5 lbs ± 55.3, HbA1c 7.5 ± 1.5, and LDL 79.1 ± 37.1 in controls. Average duration between follow up visits was 138.3 days ± 52.5 in patients seen in the Center and 138.9 days ± 54.7 in controls. Patients seen in the Center had greater degree of weight loss (12.3 lbs vs 3.8 lbs, p Conclusion: Patients with T2D and CVD, seen in a specialized, comprehensive Cardiometabolic Center experienced higher use of guideline-directed medical therapies and greater reduction in multiple CVD risk factors within ~4 months, as compared to those seen in the conventional setting. Although longer follow up is needed, these preliminary data suggest that such novel clinical care delivery models may improve the implementation of clinical practice guidelines.

Background: The primary indication for coronary revascularization in patients with stable ischemic heart disease (SIHD) is relief of angina and improvement in quality of life. In current clinical practice, the Canadian Cardiovascular Society Classification (CCSC) system is used to quantify angina. However, the CCSC is a subjective estimate of angina burden from the perspective of the physician, rather than the patient. Although previous studies have demonstrated discordance between physician-estimated and patient-reported assessment of angina, whether this discordance exists in patients undergoing percutaneous coronary intervention (PCI) is unknown. Methods: We prospectively collected the Seattle Angina Questionnaire Angina Frequency (SAQ AF) scores on 769 patients undergoing PCI for SIHD and 895 patients undergoing PCI for unstable angina (UA) between 2009-2011 across 10 U.S. hospitals, and compared the SAQ AF categories of daily (SAQ AF 0 - 30), weekly (SAQ AF 31 - 60), monthly (SAQ AF 61 - 99) and no angina (SAQ AF = 100) over the past 4 weeks with the CCSC as captured in the National Cardiovascular Data Registry (NCDR) for PCI (Table 1). Results: In patients with SIHD, 267 (35.2%) of 769 patients reported a SAQ AF score of 100 (no angina). Of those with no self-reported angina, 33 (12.4%) and 20 (7.5%) were assessed by physicians as having moderate (CCSC II) or severe (CCSC III or IV) angina, while 197 (73.8%) were reported to have no angina (CCSC 0). In patients with UA, 110 (12.3%) of 895 patients reported a SAQ AF of 100, despite being categorized as having unstable angina. Conclusions: These data suggest a discordance between patient-reported and physician-assessed angina burden among patients undergoing PCI and may impact ratings of procedural appropriateness in the NCDR. Collecting patient-reported outcome measures with the SAQ may be a useful clinical tool for selecting patients who are likely to experience quality of life benefit after coronary revascularization.

Cerebrovascular events (CVE) are among the most common and serious complications after implantation of continuous-flow left ventricular assist devices (CF-LVAD). We studied the incidence, subtypes, anatomical distribution, and pre- and post-implantation risk factors of CVEs as well as the effect of CVEs on outcomes after CF-LVAD implantation at our institution. Retrospective analysis of clinical and neuroimaging data of 372 patients with CF-LVAD between May 2005 and December 2013 using standard statistical methods. CVEs occurred in 71 patients (19%), consisting of 35 ischemic (49%), 26 hemorrhagic (37%), and 10 ischemic+hemorrhagic (14%) events. History of coronary artery disease and female gender was associated with higher odds of ischemic CVE (OR 2.84 and 2.5, respectively), and diabetes mellitus was associated with higher odds of hemorrhagic CVE (OR 3.12). While we found a higher rate of ischemic CVEs in patients not taking any antithrombotic medications, no difference was found between patients with ischemic and hemorrhagic CVEs. Occurrence of CVEs was associated with increased mortality (HR 1.62). Heart transplantation was associated with improved survival (HR 0.02). In patients without heart transplantation, occurrence of CVE was associated with decreased survival. LVADs are associated with high rates of CVE, increased mortality, and lower rates of heart transplantation. Further investigations to identify the optimal primary and secondary stroke prevention measures in post-LVAD patients are warranted.

Treatment of advanced heart failure with implantable LVADs is increasing, driven by profound unmet patient need despite potential serious complications: bleeding, infection, and thrombus. The experimental objective was to develop a sensitive imaging approach to assess early thrombus accumulation in LVADs under operational high flow and high shear rates. Methods: A monomeric bifunctional ligand with a fibrin-specific peptide, a short spacer, and 99mTc chelating amino acid sequence (F1A) was developed and compared to its tetrameric PEG analogue (F4A). Results:99mTc attenuation by LVAD titanium (1 mm) was 23%. 99mTc-F1A affinity to fibrin was Kd ~10 µM, whereas, the bound 99mTc-F4A probe was not displaced by F1A (120,000:1). Human plasma interfered with 99mTc-F1A binding to fibrin clot (p

Frail patients are more prone to adverse events after cardiac surgery, particularly after implantation of left ventricular assist devices. Thus, frailty assessment may help identify patients unlikely to benefit from left ventricular assist device therapy. The purpose was to establish a suitable measure of frailty in adults with end-stage heart failure. In a prospective cohort of 75 patients (age 58 ± 12 years) with end-stage heart failure, we assessed the association between frailty (5-component Fried criteria) and the composite primary outcome of inpatient mortality or prolonged length of stay, as well as extubation status, time on ventilator, discharge status, and long-term mortality. Fried frailty criteria were met in 44 (59%) patients, but there was no association with the primary outcome (p = 0.10). However, an abridged set of 3 criteria (exhaustion, inactivity, and grip strength) was predictive of the primary outcome (odds ratio 2.9, 95% confidence interval 1.1 to 7.4), and of time to extubation and time to discharge. In patients with advanced heart failure, the 5-component Fried criteria may not be optimally sensitive to clinical differences. In conclusion, an abridged set of 3 frailty criteria was predictive of the primary outcome and several secondary outcomes, and may therefore be a clinically useful tool in this population.

Introduction Sodium glucose cotransporter 2 inhibitors (SGLT2i) prevent heart failure (HF) in patients with Type 2 Diabetes (T2D), and reduce CV death or worsening HF in HF and reduced ejection fraction (HFrEF), regardless of T2D. Mechanisms of HF benefits are unclear, and effects of SGLT2i on filling pressures are not known. EMBRACE-HF was designed to address this knowledge gap. Methods EMBRACE-HF was an investigator-initiated, multi-center, double-blind, randomized trial. From July 2017 to November 2019, 65 patients with HF (regardless of EF, with or without T2D) and previously implanted pulmonary artery (PA) pressure sensor (CardioMEMS) were randomized across 10 US centers to empagliflozin (empa) 10 mg daily or placebo (pbo) and treated for 12 weeks. Primary endpoint was change in PA diastolic pressure (PADP) from baseline to end of treatment (average PADP weeks 8-12). Results 93 patients were screened, and 65 were randomized (33 empa, 32 pbo). Mean age was 66 yrs, 63% were male, 52% had T2D, 54% NYHA class III/IV; LVEF 44%, NTproBNP 1665 pg/mL and PADP 20 mmHg. Empa significantly reduced PADP, with effects beginning at week 1, and amplified over time (Figure 1). Average PADP (week 8-12) was 1.5 mmHg lower (95% CI: 0.2, 2.8; p = 0.02); and at week 12, PADP was 1.7 mmHg lower (95% CI: 0.3, 3.2; p = 0.02) with empa vs pbo. Results were consistent for PA systolic and PA mean pressures. There was no difference in loop diuretic dose (measured in daily furosemide equivalents) at baseline (90 mg empa, 85 mg pbo; p = 0.51), week 12 (92 mg empa, 86 mg pbo; p = 0.24), or any interim time point. Majority of patients in both groups (76% empa, 81% placebo; p = 0.89) had no change in loop diuretic dose during the study. Conclusion EMBRACE-HF is the first randomized controlled trial to show a direct beneficial effect of SGLT2i on decongestion in patients with HF (reduced or preserved EF), with rapid reductions in PA pressures that were amplified over time and appeared to be independent of loop diuretic management.

Introduction Improving the health status—symptoms, function, and quality of life - of patients with HFrEF is a primary goal of treatment. Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), improves short-term health status in clinical practice, but whether these improvements are sustained has not been assessed. Methods Using data from CHAMP-HF, a multicenter observational study of outpatients with HFrEF (EF ≤40%), patients initiated on ARNI were matched 1:2 to patients not started on ARNI using propensity score Cox models that included sociodemographic and clinical variables, medical history, medications, and baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) Symptom Frequency and Quality of Life scores. Five repeated measures models, one for the overall KCCQ score and one for each domain, were used to compare the health status trajectories of patients initiated on ARNI vs not. Results Among 3,930 patients, 746 (19.0%) were initiated on ARNI and 576 were matched to 1,152 patients not started on ARNI. Prior to matching, patients initiated on ARNI were more likely to be younger, non-Hispanic, have lower EF and a history of ventricular arrhythmia, and were less likely to be taking an ACEI or ARB, but were more likely to be on beta-blockers and mineralocorticoid receptor antagonists. Patients initiated on ARNI experienced improved quality of life by 3 months that persisted to 12 months, with the largest benefit observed in the KCCQ Quality of Life domain (Figure 1). Conclusion In a real-world setting, the health status benefits of ARNI therapy occur within 3 months and persists up to 12-months after initiating therapy.

Purpose Gene expression profile (GEP) testing has a high negative predictive value for Methods dd-cfDNA was drawn beginning at 2 mos post transplant and GEP was drawn at 2 mos or 30 days post prednisone wean Results Between 2/11-10/4/19, 121 pts (54.8±12.9 yrs; 79% men) between 2 mos-3 yrs post transplant had 324 visits with both GEP/dd-cfDNA. Table shows distribution of results. Only 6% were above threshold for both. This led to an additional 12 (60%) EMBs. 20% had positive GEP with negative dd-cfDNA (which would have led to an EMB without dd-cfDNA), EMB was cancelled for 46 (70%) of these visits. 8% of visits had only dd-cfDNA elevation. 13 (52%) of these had EMBs, but 10 (40%) EMBs were cancelled in favor of repeating dd-cfDNA at the next visit. 66% had both tests negative and EMB was cancelled for 156 (73%) of these visits. With the use of dd-cfDNA, an additional 13 EMBs were performed with negative GEP but 46 EMBs were avoided due to dd-cfDNA being negative with a positive GEP. For visits starting at 6 mos, 84% of EMBs were cancelled due to combined testing. Without dd-cfDNA, only 73% EMBs would have been cancelled for negative GEP. Conclusion Adding dd-cfDNA to GEP testing helped reclassify some GEP positive only pts into a lower risk group with an additional 11% of EMBs cancelled. Further evaluation of the utility of the combined use of GEP and dd-cfDNA is warranted.

An old fable, “Belling the Cat,” tells a story about a concerned group of mice that debate plans to nullify the threat of a menacing cat. One proposes placing a bell around its neck so that they are warned of its approach. The plan is met with applause, and the mice rejoice that their conundrum has been solved. This lasts until an old mouse asks, “That is all well, but who is to bell the cat?” All go on to make excuses why they cannot accomplish the task, and the cat continues to relentlessly hunt the mice. The moral of the fable is that it is one thing to say that something should be done but quite a different matter to actually do it. There is a parallel between the fable and our current approach to managing cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). For the first time ever, several classes of compounds initially developed for glucose lowering (oral sodium-glucose cotransporter type 2 inhibitors [SGLT2is] and injectable glucagon-like peptide-1 receptor agonists [GLP-1RAs]), have been shown to significantly improve cardiovascular outcomes, including reductions in cardiovascular mortality.1,2 These landmark developments have been celebrated by the cardiology community as major advancements in management. However, when the time comes to actually use these agents in clinical practice, it is all too common to hear excuses for why it is too cumbersome for cardiologist to prescribe these agents. The EMPA-REG OUTCOME ([Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation …

Background: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m 2 , and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. Results: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036–1238) vs 1191 pg/dL (95% CI 1089–1304), P =0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P =0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98–3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1–3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). Conclusions: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT 02653482.