Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

Impact of empagliflozin on decongestion in acute heart failure: the EMPULSE trial.

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.

Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF.

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<0.05 with false discovery rate-adjusted P<0.10 was used to determine statistical significance. 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 (ß-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.

Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial.

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.

Association Between Change in Ambulatory Pulmonary Artery Pressures and Natriuretic Peptides in Patients with Heart Failure: Results From the EMBRACE-HF Trial.

BACKGROUND: Remote monitoring of pulmonary artery (PA) pressures and serial N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements guide heart failure (HF) treatment, but their association has yet to be described. METHODS AND RESULTS: In the Empagliflozin Evaluation by Measuring the Impact on Hemodynamics in Patients with Heart Failure (EMBRACE-HF) trial, patients with HF and a remote PA pressure monitoring device were randomized to empagliflozin vs placebo. PA diastolic pressures (PADP) and NT-proBNP levels were obtained at baseline and 6 and 12 weeks. We used linear mixed models to examine the association between change in PADP and change in NT-proBNP, adjusting for baseline covariates. Of 62 patients, the mean patient age was 66.2 years, and 63% were male. The mean baseline PADP was 21.8 ± 6.4 mm Hg, and the mean NT-proBNP was 1844.6 ± 2767.7 pg/mL. The mean change between baseline and averaged 6- and 12-week PADP was -0.4 ± 3.1 mm Hg, and the mean change between baseline and averaged 6- and 12-week NT-proBNP was -81.5 ± 878.6 pg/mL. In adjusted analyses, every 2-mm Hg decrease in PADP was associated with an NT-proBNP reduction of 108.9 pg/mL (95% confidence interval -4.3 to 222.0, P = .06). CONCLUSIONS: We observed that short-term decreases in ambulatory PADP seem to be associated with decreases in NT-proBNP. This finding may provide additional clinical context when tailoring treatment for patients with HF.

Empagliflozin Effects on Pulmonary Artery Pressure in Patients With Heart Failure: Results From the EMBRACE-HF Trial.

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.

Influence of Donor Transmitted and Rapidly Progressive Coronary Vascular Disease on Long-Term Outcomes After Heart Transplantation: A Contemporary Intravascular Ultrasound Analysis.

BACKGROUND: Donor-transmitted atherosclerosis (DTA) and rapidly progressive cardiac allograft vasculopathy (CAV) at 1 year are intravascular ultrasound (IVUS)-derived measures shown to predict adverse cardiovascular outcomes in the setting of early generation immunosuppressive agents. Given the paucity of data on the prognostic value of IVUS-derived measurements in the current era, we sought to explore their association with adverse outcomes after heart transplantation. METHODS AND RESULTS: This is a retrospective cohort analysis of patients who underwent heart transplantation at our center between January 2009 and June 2016 with baseline and 1-year IVUS. Five IVUS sections were prospectively analyzed for intimal thickness and lumen area. DTA was defined as maximum intimal thickness of 0.5 mm or greater at baseline, and rapidly progressive CAV as an increase in maximum intimal thickness by 0.5 mm or more at 1 year. Our primary analysis assessed the relationship of IVUS and other clinical data on a composite outcome: coronary intervention, CAV stage 2 or 3 (defined by the International Society for Heart and Lung Transplantation 2010 nomenclature), or cardiovascular death. Among 249 patients (mean age 51.0 ± 12.2 years and 74.3% male) included in the analysis, DTA was detected in 118 patients (51.4%). Over a median follow-up of 6.1 years (interquartile range 4.2-8.0 years), 45 patients met the primary end point (23 percutaneous coronary intervention, 11 CAV 2 or 3, and 11 cardiovascular deaths as first event). DTA and rapidly progressive CAV were not associated with the primary end point, all-cause mortality, or retransplantation. In an additional analysis including post-transplant events, incident rejection was strongly associated with poor outcomes, although cytomegalovirus infection was not. CONCLUSIONS: In this contemporary cohort, IVUS-derived DTA and rapidly progressive CAV were not associated with medium- to long-term adverse events after heart transplantation.

PCSK9 Inhibitors in Heart Transplant Patients: Safety, Efficacy, and Angiographic Correlates.

BACKGROUND: 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. METHODS AND RESULTS: 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 of <70 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. CONCLUSIONS: 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.

Dapagliflozin effects on lung fluid volumes in patients with heart failure and reduced ejection fraction: Results from the DEFINE-HF trial.

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.

Single-center utilization of donor-derived cell-free DNA testing in the management of heart transplant patients.

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.

Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.

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/1.73m2, 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: NCT02653482.

Effects of sodium glucose cotransporter type 2 inhibitors on heart failure.

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.

New frontiers for management of hyperkalaemia: the emergence of novel agents.

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.

Cerebrovascular Events After Continuous-Flow Left Ventricular Assist Devices.

BACKGROUND: 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. METHODS: Retrospective analysis of clinical and neuroimaging data of 372 patients with CF-LVAD between May 2005 and December 2013 using standard statistical methods. RESULTS: 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. CONCLUSIONS: 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.

Use of adenosine diphosphate receptor inhibitor prior to left ventricular assist device implantation is not associated with increased bleeding.

Current guidelines recommend adenosine diphosphate receptor inhibitors (ADPRi) be discontinued 5-7 days prior to cardiac surgery due to increased bleeding events, rates of re-exploration, and transfusions. However, the risks of left ventricular assist device (LVAD) implantation in patients taking an ADPRi have not previously been studied. We retrospectively identified 134 eligible patients with ischemic cardiomyopathy that underwent LVAD implantation between July 2009 and August 2013. The cohorts received an ADPRi ≤5 days of surgery (n = 25) versus >5 days prior or not at all (n = 109). Subgroup analyses adjusted for differences in frequency of redo sternotomy between cohorts, excluded patients that received an ADPRi >1 year prior to surgery, and excluded patients with a redo sternotomy. The ADPRi and control groups did not have significant differences in the primary outcomes, intraoperative PRBC units transfused (3.0 vs. 4.0, p = 0.12) or chest tube output within 24 h of surgery (1.66 L vs. 1.80 L, p = 0.61). After adjusting for differences in frequency of redo sternotomy (ADPRi vs. control, 12 vs. 52%, p ≤ 0.001), no significant difference in PRBC units transfused (3.1 vs. 3.5, p = 0.59) or chest tube output (2.04 L vs. 2.04 L, p = 0.98) was seen. No significant difference in 30-day mortality (8.0 vs. 11.0%, p = 0.63), 90-day mortality (16.4 vs. 23.3%, p = 0.42), or length of stay (29.0 vs. 28.0, p = 0.61) was seen. In this single-center experience, use of an ADPRi ≤5 days prior to LVAD implantation was not associated with increased bleeding, length of stay, or mortality.

Treatment effects of empagliflozin in hospitalized heart failure patients across the range of left ventricular ejection fraction - Results from the EMPULSE trial.

AIM: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium-glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41-49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all-cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41-49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], pinteraction = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint. CONCLUSION: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in-hospital initiation of empagliflozin regardless of LVEF.

Time from admission to randomization and the effect of empagliflozin in acute heart failure: A post-hoc analysis from EMPULSE.

AIMS: Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization. METHODS AND RESULTS: The EMPULSE population was dichotomized by median time from hospital admission to randomization (1-2 days vs. 3-5 days). The primary outcome was a hierarchical composite endpoint of time to all-cause death, number of HF events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3-5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1-2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3-5 days: WR 1.69, 95% confidence interval [CI] 1.26-2.25) but was attenuated in patients randomized earlier (1-2 days: WR 1.04, 95% CI 0.74-1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all-cause hospitalizations (interaction p < 0.1 for both). The reduction of N-terminal pro-B-type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004). CONCLUSIONS: Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3-5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1-2 days). These findings should be confirmed in future studies before clinical application.