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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.

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.

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.

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.

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.

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.

Fear of high local recurrence rate associated with immediate breast reconstruction (IBR) following total mastectomy for breast cancer might be a contributing factor to the low rate of immediate reconstruction performed in Quebec. The aim of this study was to demonstrate the oncological safety of total mastectomy with immediate breast reconstruction. A retrospective chart review of all patients who underwent total mastectomy with immediate breast reconstruction at the University of Montreal Hospital Center between 2006 and 2015 was performed. 375 patients (420 cases) met the inclusion criteria. The mean age was 51.5 years (25-77). The median follow-up was 45.6 months (0.4-115.2). Clinical cancer staging was done according to the American Joint Committee on Cancer (AJCC) criteria. 349 cases (83.1%) were classified as Stage < cIIb and 71 cases (16.9%) as ≥ cIIb. 73 patients (19.5%) received neoadjuvant chemotherapy, 113 (30.1%) received adjuvant chemotherapy and 91 (21.7%) received postoperative radiotherapy. Only 4 patients (3.5%) had a significant delay in receiving adjuvant chemotherapy and 4 patients (4.4%) had a delay in initiation of radiotherapy. In total, there were 12 (2.6%) local recurrences and 29 (7.7%) distant recurrences. The results of this study demonstrate a low rate of local recurrence that is comparable to the current litterature. Total mastectomy in association with immediate breast reconstruction is therefore an oncologically safe approach for the treatment of breast cancer and should be more widely adopted by medical centers throughout Quebec. Citation Format: Younan RJ, Al Khaldi M, Maalouf C, Guez M, Boulva K, robidoux A, Nassif E, Poljicak M, BouMerhi J, Bernier C, Patocskai E. Total mastectomy and immediate breast reconstruction for breast cancer: A ten-year Canadian single institution experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-14-13.

The purpose of this study is to examine the association of sarcopenia as measured by psoas muscle area and outcomes in patients undergoing left ventricular assist device (LVAD) implantation. We retrospectively examined 333 consecutive patients who underwent implantation of a HeartMate II LVAD at our institution from June 2008 to August 2013. Patients were included if they had a perioperative computed tomography that spanned the L3-L4 vertebrae. Sarcopenia was defined as having the lowest tertile psoas muscle area by gender. The primary end point was the composite of inpatient death or prolonged length of stay of >30 days. One hundred patients met inclusion criteria. The psoas muscle area cut-off values for the lowest tertiles were 12.0 cm 2 for men and 6.5 cm 2 for women, resulting in 32 sarcopenic patients (32%). The primary outcome of inpatient death or prolonged length of stay occurred in 81% of patients in the sarcopenic versus 60% in the nonsarcopenic group (p = 0.043). There was a trend toward prolonged length of stay in sarcopenic patients but no difference in overall mortality. This demonstrates that sarcopenia as measured by psoas muscle area is associated with increased composite length of stay and mortality after LVAD implantation and may serve as correlate for frailty.

Aims Heart failure (HF) has been defined classically as a condition in which the heart is unable to deliver sufficient oxygen to match the needs of the metabolizing tissues. Surprisingly, this definition has never been validated. The goal of this study was to determine the prevalence of elevated lactate levels in a cohort of patients with advanced heart failure. Methods and results We retrospectively analysed the arterio-venous oxygen difference (A–V O2), haemodynamics, and plasma lactate levels in stage D heart failure patients who were being evaluated for a left ventricular assist device (LVAD). We identified 359 patients with a right heart catheterization (RHC) performed prior to LVAD implantation. Plasma lactate was available for 96 patients. RHC showed that 93% of the patients had an A–V O2 above the upper limit of normal (>5 mL/100 mL). Among patients with measured lactate levels, the prevalence of elevated lactate (>2.1 mmol/L) was 25% (95% confidence interval 16.7–34.9). The A–V O2 was widened in all patients with elevated lactate, but plasma lactate did not correlate with A–V O2 (r = 0.02) and only 27% of patients with increased A–V O2 had elevated plasma lactate. Conclusions Lactate levels were normal in ∼75% of the patients with advanced heart failure and a widened A–V O2, suggesting that the cardiac output was sufficient to meet the metabolic needs of the peripheral metabolizing tissues. Given that ∼4% of heart failure patients are in NYHA class IV, these findings suggest that the classic definition of heart failure pertains to ∼1% of patients with HF.

Background Type 2 diabetes mellitus (T2D) is common in post-heart transplant patients. Commonly used T2D medications, especially insulin, can promote weight gain and are not associated with cardiovascular (CV) benefits. Glucagon-like Peptide-1 receptor agonists (GLP-1 RA) and Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i) are two drug classes that produce CV benefits in T2D and promote weight loss with minimal risk of hypoglycemia. Their use has not been previously evaluated in this particular group, and there have been theoretical concerns about safety in immunosuppressed patients. Methods Patients with T2D are sequentially referred by the Heart Transplant program to the Cardiometabolic Center of Excellence (CMCE) at our institution, allowing minimal selection bias. CMCE provides treatment algorithms that emphasize the use of cardioprotective T2D medications. We analyzed this initial series of transplant patients with T2D who have been on GLP-1 RA and/or SGLT-2i with at least two visits at CMCE. Results Among 15 patients, the mean age was 59.4 ± 2.6 years, 66.7% were males, 73.3% were Caucasians, 33.3% had history of ischemic cardiomyopathy and baseline eGFR was 53.5 ± 7.9 mL/min/1.73m2. The median time from transplant was 4.6 (1.6 - 10.5) years. The median follow-up time at CMCE was 5.4 (2.8 - 10.9) months. At baseline, 73% were on insulin, 40% on Metformin, 13% on Sulfonylurea, 13% on Dipeptidyl peptidase-4 inhibitors, and 7% on Thiazolidinediones. Following initiation of therapy at CMCE, 86.7% of patients were on a combination of GLP-1 RA and SGLT-2i, while the rest were taking only GLP-1 RA. Overall, the median total daily insulin requirements decreased substantially from 94 (40.5 - 124) to 34 (5 - 60) units at latest clinic visit; p = 0.003. Further, median hemoglobin A1c dropped from 7.7% (7.3 - 9.5) to 6.6% (6 - 8.5); p = 0.007. There was also a significant reduction in mean body weight (241.9 ± 35.8 at baseline vs. 217.1 ± 34.2 lbs at follow-up; p = 0.001), and mean body mass index (34.9 ± 4.5 vs. 31.1 ± 3.7; p = 0.001). Only one patient experienced side effects as one episode of severe nausea with Liraglutide that resolved when switched to Semaglutide. No infectious complications (including urinary tract or genital mycotic infections) were observed. Conclusions In this limited case series, combination therapy with GLP-1 RA and SGLT-2i was well tolerated in heart transplant patients and associated with favorable results in insulin requirement, hemoglobin A1c, and body weight.

PET Myocardial Perfusion Imaging (MPI) uniquely measures myocardial blood flow in addition to perfusion and function. The prevalence of abnormal PET MPI, if it helps guide treatment and its relation to outcomes among asymptomatic patients (pts) with diabetes (DM) is not well understood. We included

Patient-reported outcome measures (PROMs) are relevant independent outcomes in heart failure (HF) care and are predictive of subsequent hospitalization and death in HF. The Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) are the 2 most widely adopted PROMs specific to HF. We compared their prognostic abilities in a prospective cohort of HF patients. A prospective cohort of subjects from a single-center registry was analyzed with regard to baseline KCCQ and MLHFQ scores and the outcomes of death, transplant, or left ventricular assist device implantation and hospitalization. A total of 516 subjects with reduced left ventricular ejection fraction (HFrEF) and 151 subjects with preserved left ventricular ejection fraction (HFpEF) were included. Discrimination was assessed using c-statistics based on time-to-event analyses and receiver-operator curves. The additive contribution of MLHFQ was assessed through the change in c-statistic, incremental discrimination index, and category-free net reclassification index. Overall, KCCQ was superior to MLHFQ for predicting death/transplant/ventricular assist device (c-statistic 0.702 [0.666 to 0.738] and 0.658 [0.621 to 0.695] respectively, p value for difference

Background: Although a key treatment goal for patients with heart failure with reduced ejection fraction is to optimize their health status (their symptoms, function, and quality of life), the variability across outpatient practices in achieving this goal is unknown. Methods and Results: In the CHAMP-HF (Change the Management of Patients With Heart Failure) registry, associations between baseline practice characteristics and Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary (OS) and Symptom Frequency (SF) scores were assessed in 3494 patients across 140 US practices using hierarchical regression after accounting for 23 patient and 11 treatment characteristics. We then calculated an adjusted median odds ratio to quantify the average difference in likelihood that a patient would have excellent (KCCQ-OS, ≥75) health status or minimal (monthly or fewer) symptoms (KCCQ-SF, ≥75) when treated at one practice versus another, at random. The mean (±SD) KCCQ-OS and KCCQ-SF were 64.2±24 and 68.9±25.6, with 40% (n=1380) and 50% (n=1760) having KCCQ scores ≥75, respectively. The adjusted median odds ratio across practices, for KCCQ-OS ≥75, was 1.70 (95% confidence interval, 1.54–1.99; P P =0.001). Conclusions: In a large, contemporary registry of outpatients with chronic heart failure with reduced ejection fraction, we observed significant practice-level variability in patients’ health status. Quantifying patients’ health status as a measure of quality should be explored as a foundation for improving care. Clinical Trial Registration: URL: https://www.centerwatch.com . Unique identifier: TX144901.

Background Three large cardiovascular outcome trials of patients with type 2 diabetes (T2D) found a reduction in hospitalizations for heart failure (HF) in patients treated with SGLT2i. However, a majority of patients in these trials did not have manifest HF, and those that did were not well characterized. Consequently, the effects of SGLT-2i in patients with established HF, specifically HF with reduced ejection fraction (HFrEF), including those with and without T2DM, have not been examined in a dedicated trial. Methods The effects of dapagliflozin on biomarkers, symptoms, and functional status in patients with HFrEF (DEFINE-HF) is a 12-week multi-center, randomized, double-blind, placebo-controlled trial. From March 2016 to March 2019, 263 patients from 26 US centers were randomized 1:1 to dapagliflozin 10 mg or matching placebo. Patients with or without T2D, with LVEF ≤40%, EGFR ≥30 mL/min/m2, and NTproBNP ≥400 pg/mL were eligible for inclusion. Co-primary end points were (1) change in NTproBNP and (2) composite of proportion of patients with ≥ 5point increase in the HF disease-specific health status (assessed using KCCQ) or ≥ 20% decrease in NTproBNP over 12 weeks. Key secondary endpoints included functional status based on 6-minute walk test, and change in KCCQ. Exploratory endpoints included hospitalizations for HF and urgent HF visits. Results Enrollment in DEFINE-HF was completed in March 2019, with last visit scheduled in June. Baseline characteristics are consistent with other trials of high risk HFrEF patients, and are shown in the Table. Topline study results will be available in July 2019, in time for presentation at HFSA 2019. Conclusion DEFINE-HF is the first dedicated multi-center randomized double-blind placebo-controlled trial of SGLT-2i in patients with established HFrEF with and without T2D. It will assess whether the SGLT2i dapagliflozin improves HF biomarkers, symptoms and functional status in this high-risk patient population.

Objectives This study sought to determine whether severe right ventricular (RV) dysfunction in the pre-operative setting is associated with an increased risk of gastrointestinal bleeding (GIB) post-left ventricular assist device (LVAD). Background GIB is a significant complication in patients supported with continuous-flow LVADs. The impact of RV dysfunction on the risk of GIB has not been investigated. Methods We retrospectively identified 212 patients who survived index hospitalization after implantation of HeartMate II (Thoratec Corp., Pleasanton, California) or Heartware HVAD (HeartWare Corp., Framingham, Massachusetts) from June 2009 to April 2013. Patients with severe RV dysfunction on pre-LVAD echocardiogram (n = 37) were compared to patients without severe RV dysfunction (n = 175). The primary outcome was freedom from GIB. Results The majority of patients were male (79%) with a median INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profile of 2 at LVAD implantation. There were no significant differences between cohorts with respect to demographics, comorbidities, device type, international normalization ratio, or aspirin strategy. During follow-up, 81 patients had GIB events: 23 of 37 (62%) in the severe RV dysfunction group versus 58 of 175 (33%) in the control group (p = 0.001). After adjustment for age and ischemic cardiomyopathy, severe RV dysfunction was associated with increased risk of GIB (hazard ratio: 1.799, 95% confidence interval: 1.089 to 2.973, p = 0.022). Conclusions In this single-center sample of patients supported with continuous-flow LVADs, severe RV dysfunction on pre-LVAD echocardiogram was associated with an increased risk of GIB. Further studies are needed to investigate possible mechanisms by which RV dysfunction increases the risk of GIB and to identify patient populations who may benefit from alterations in antithrombotic strategies.

Background— After left ventricular assist device (LVAD) placement for advanced heart failure, increased cerebral perfusion should result in improved cognitive function. However, stroke (a well-known LVAD complication) and subclinical cerebral ischemia may result in transient or permanent cognitive decline. We sought to describe the incidence and predictors of cognitive decline after LVAD using a valid, sensitive assessment tool. Methods and Results— Among 4419 patients in the Interagency Registry for Mechanically Assisted Circulatory Support who underwent LVAD implantation between May 2012 and December 2013, cognitive function was assessed in 1173 patients with the Trail Making B Test before LVAD and at 3, 6, and 12 months. The test detects several forms of cognitive impairment, including subclinical stroke. Cognitive decline was defined as a clinically important increase during follow-up using a moderate Cohen d effect size of 0.5×baseline SD (32 s). The cumulative incidence of cognitive decline in the year after LVAD implantation, treating death and transplantation as competing risks, was 29.2%. In adjusted analysis, older age (≥70 versus P trend Conclusions— Cognitive decline occurs commonly in patients in the year after LVAD and is associated with older age and destination therapy. These results could have important implications for patient selection and improved communication of risks before LVAD implantation. Additional studies are needed to explore the association between cognitive decline and subsequent stroke, health status, and mortality in patients after LVAD.

Objectives This study evaluated the Heartmate Risk Score (HMRS) and its potential benefits in clinical practice. Background The HMRS has been shown to correlate with mortality in the cohort of patients enrolled in the Heartmate II trials, but its validity in unselected, “real world” populations remains unclear. Methods This study identified a cohort of 269 consecutive patients who received a Heartmate II left ventricular assist device at our institution, the Barnes-Jewish Hospital in St. Louis, Missouri, between June 2005 and June 2013. Ninety-day and 2-year mortality rates, as well as frequency of several morbid events, were compared by retrospectively assigned HMRS category groups. The analysis was repeated within the subgroup of INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) class 1 patients. Results Receiver operating curve analysis showed that the HMRS correlated with 90-day mortality with an area under the curve of 0.70. Stratification in low, mid, and high HMRS groups identified patients with increasing hazard of 90-day mortality, increasing long-term mortality, increasing rate of gastrointestinal bleeding events, and increasing median number of days spent in the hospital in the first year post implant. Within INTERMACS class 1 patients, those in the highest HMRS group were found to have a relative risk of 90-day mortality 5.7 times higher than those in the lowest HMRS group (39.1% vs. 6.9%, p = 0.029). Conclusions HMRS is a valid clinical tool to stratify risk of morbidity and mortality after implant of Heartmate II devices in unselected patients and can be used to predict short-term mortality risk in INTERMACS class 1 patients.

Background Stroke is a significant complication in patients supported with continuous-flow left ventricular assist devices (CF-LVAD) and hypertension is a significant risk factor for stroke, but the association between blood pressure and stroke in LVAD patients is not well characterized. Methods We identified 275 consecutive patients who survived implant hospitalization between January 2005 and April 2013. Patients were grouped according to systolic blood pressure (SBP) as above a median and below a median of 100 mm Hg by their averaged systolic blood pressure during the 48 hours before discharge from implantation hospitalization. The groups were compared for the primary outcome of time to stroke. Results The above-median SBP group had mean SBP of 110 mm Hg and the below-median SBP group had mean SBP of 95 mm Hg. There were no significant between-group differences in body mass index, smoking, vascular disease, hypertension, atrial fibrillation, or prior stroke. During a mean follow-up of 16 months, stroke occurred in 16% of the above-median SBP group vs in 7% of the below-median SBP group (hazard ratio, 2.38; 95% confidence interval, 1.11–5.11), with a similar proportion of hemorrhagic and ischemic strokes in each group. In Cox proportional hazard models adjusting for age, diabetes, or prior stroke, the hazard ratio remained statistically significant. SBP as a continuous variable predictor of stroke had an area under the curve of 0.64 in a receiver operating characteristic curve analysis. Conclusions In this large, CF-LVAD cohort, elevated SBP was independently associated with a greater risk of subsequent stroke. These results identify management of hypertension as a potential modifiable risk factor for reducing the incidence of stroke in patients supported by CF-LVAD.

Summary Introduction Secondary pulmonary hypertension (PH) and right ventricular dysfunction are common and associated with poor prognosis in HF patients with left ventricular assist devices (LVADs). The role of pulmonary vasodilator therapy for these patients is currently unclear. Aims We sought to evaluate the safety and clinical course of patients treated with bosentan, an endothelin receptor antagonist, after the implementation of a LVAD. Results Between 10/2008 and 5/2011, 50 consecutive patients with mean PAP >25 mmHg were treated with bosentan after LVAD implantation for a mean duration of 15.7 (±12.4) months. Ten patients discontinued the drug for possible side effects, including three for LFT abnormalities. Comparison of baseline to 6-month follow-up data revealed laboratory evidence for decongestion with a decrease in bilirubin (2.3–0.6, P

Heart failure is one of the most common comorbidities of diabetes mellitus. Glucose-lowering therapies that can prevent heart failure or improve outcomes in patients with established heart failure are of critical importance among those with type 2 diabetes. Several types of glucose-lowering drugs have been assessed in this setting. Metformin has been shown to modestly improve the outcomes of patients with heart failure, whereas the effect of insulin in those with established heart failure is less clear. The effect of sulfonylureas on improving heart failure is controversial; observational reports have suggested that they are harmful in these patients, but these data have not been confirmed in randomized, controlled trials. Thiazolidinediones are contraindicated in patients with established heart failure and have also been known to cause heart failure. Furthermore, certain dipeptidyl peptidase 4 inhibitors seem to increase heart failure hospitalization. The effects of glucagon-like peptide 1 receptor agonists might differ in patients with or without established heart failure, particularly those with decompensated heart failure with a reduced ejection fraction. However, perhaps the most important finding has been that sodium/glucose cotransporter 2 (SGLT2; also known as SLC5A2) inhibitors reduce heart failure hospitalizations and, in the case of empagliflozin, markedly reduce the rate of cardiovascular death. Given the known neutral (or even harmful) effects of other glucose-lowering drugs on heart failure outcomes, SGLT2 inhibitors might well be considered the drug class of choice in patients with diabetes and heart failure, or in those at high risk of developing heart failure.

This study evaluated clinical outcomes associated with erythropoiesis stimulating agent (ESA) use in left ventricular assist devices (LVAD)-supported patients.Use of ESAs in patients with LVADs may minimize blood transfusions and decrease allosensitization. ESAs increase thrombotic events, which is concerning because LVADs are sensitive to pump thrombosis (PT).We retrospectively reviewed 221 patients at our center who received a HeartMate II (Thoratec Corp., Pleasanton, California) LVAD between January 1, 2009 and June 6, 2013. Patients were divided into those who received ESAs during index admission (n = 121) and those who did not (n = 100). Suspected PT was defined as evidence of thrombus in the LVAD or severe hemolysis (lactate dehydrogenase1,000 mg/dl or plasma-free hemoglobin40 mg/dl). Outcomes were compared between cohorts using inverse probability-weighted analyses.During a mean follow-up of 14.2 ± 11.9 months, suspected PT occurred in 37 patients (ESA 23%, no ESA 12%; p =0.03). The ESA cohort received ESAs 13.9 ± 60.9 days after LVAD implantation. At 180 days, event-free rates for suspected PT were ESA 78.6% versus no ESA 94.5% (p 0.001). ESA use had higher rates of suspected PT (hazard ratio [HR]: 2.35; 95% confidence interval [CI]: 1.38 to 4.00; p = 0.002). For every 100-unit increase in cumulative ESA dosage, the hazard of suspected PT increased by 10% (HR: 1.10; 95% CI: 1.04 to 1.16; p 0.001). After inverse probability weighting, ESA use was associated with a significantly higher rate of all-cause mortality (HR: 1.62; 95% CI: 1.12 to 2.33; p = 0.01).ESA use in LVAD patients is associated with higher rates of suspected PT.

An inflammatory response after cardiac surgery is associated with worse clinical outcomes, but recent trials to attenuate it have been neutral. We evaluated the association between systemic inflammatory response syndrome (SIRS) and mortality after transcatheter (TAVR) and surgical aortic valve replacement (SAVR) for aortic stenosis (AS) and evaluated whether diabetes influenced this relationship.Patients (n=747) with severe AS treated with TAVR (n=264) or SAVR (n=483) between January 2008 and December 2013 were included and 37% had diabetes mellitus. SIRS was defined by four criteria 12-48 h after aortic valve replacement (AVR): (1) white blood cell count4 or12; (2) heart rate90; (3) temperature36 or38°C; or (4) respiratory rate20. Severe SIRS was defined as meeting all four criteria. The primary endpoint was 6-month all-cause mortality (60 deaths occurred by 6 months). Inverse probability weighting (IPW) was performed on 44 baseline and procedural variables to minimise confounding.Severe SIRS developed in 6% of TAVR patients and 11% of SAVR patients (p=0.02). Six-month mortality tended to be higher in those with severe SIRS (15.5%) versus those without (7.4%) (p=0.07). After adjustment, severe SIRS was associated with higher 6-month mortality (IPW adjusted HR 2.77, 95% CI 2.04 to 3.76, p0.001). Moreover, severe SIRS was more strongly associated with increased mortality in diabetic (IPW adjusted HR 4.12, 95% CI 2.69 to 6.31, p0.001) than non-diabetic patients (IPW adjusted HR 1.74, 95% CI 1.10 to 2.73, p=0.02) (interaction p=0.007). The adverse effect of severe SIRS on mortality was similar after TAVR and SAVR.Severe SIRS was associated with a higher mortality after SAVR or TAVR. It occurred more commonly after SAVR and had a greater effect on mortality in diabetic patients. These findings may have implications for treatment decisions in patients with AS, may help explain differences in outcomes between different AVR approaches and identify diabetic patients as a high-risk subgroup to target in clinical trials with therapies to attenuate SIRS.

While there is increasing emphasis on incorporating patient-reported outcome measures in routine care for patients with heart failure (HF), how best to interpret longitudinally collected patient-reported outcome measures is unknown.To examine the strength of association between prior, current, or a change in Kansas City Cardiomyopathy Questionnaire (KCCQ) scores with death and hospitalization in patients with HF with preserved (HFpEF) and reduced (HFrEF) ejection fractions.Secondary analyses of the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial of 1372 patients with HFpEF, conducted between August 2006 and January 2012, and the HF-ACTION trial that included 1669 patients with HFrEF, conducted between April 2003 and February 2007.Prior, current, and change in KCCQ Overall Summary scores (KCCQ-os) in 5-point increments (higher scores indicate better health status).Time to cardiovascular death/first HF hospitalization (primary outcome) and all-cause death (secondary outcome).Of 1767 eligible TOPCAT participants, 882 were women (49.9%), and the mean (SD) age was 71.5 (9.7) years. Of 2130 eligible HF-ACTION participants, 599 were women (28.1%), and the mean age was 58.6 (12.7) years. Each 5-point difference in prior or current KCCQ-os scores was associated with a 6% (95% CI, 4%-8%; P .001) to 9% (95% CI, 7%-11%; P .001) lower risk for subsequent cardiovascular death/first HF hospitalization in patients with HFpEF and 6% (95% CI, 4%-9%; P .001) to 8% (95% CI, 5%-10%; P .001) lower risk for subsequent cardiovascular death/first HF hospitalization in patients with HRpEF and HFrEF in unadjusted analyses. Results were similar for change in KCCQ-os. In models with the prior and current KCCQ-os, only the current KCCQ-os was significantly associated with 10% (95% CI, 7%-12%; P.001) and 7% (95% CI, 3%-11%; P.001) lower risk for subsequent cardiovascular death/first HF hospitalization in patients with HFpEF and HFrEF, respectively. Similar results were observed when the current and Δ KCCQ-os were considered together, when adjusted for important patient and treatment characteristics, when including 3 sequential KCCQ-os scores, and when examining all-cause death as the outcome.In serial health status evaluations of patients with HF, the most recent KCCQ score was most strongly associated with subsequent death and cardiovascular hospitalization in HFpEF and HFrEF. Measuring serial patient-reported outcome measures in the clinical care of patients with HF can provide an updated assessment of prognosis.clinicaltrials.gov Identifier: NCT00094302 (TOPCAT) and NCT00047437 (HF-ACTION).

Background: Clinical trials have established the average benefit of cardiac resynchronization therapy (CRT), but estimating benefit for individual patients remains difficult because of the heterogeneity in treatment response. Accordingly, we created a multivariable model to predict changes in quality of life (QoL) with and without CRT. Methods and Results: Patient-level data from 5 randomized trials comparing CRT with no CRT were used to create a prediction model of change in QoL at 3 months using a partial proportional odds model for no change, small, moderate, and large improvement, or deterioration of any magnitude. The C statistics for not worsening or obtaining at least a small, moderate, and large improvement were calculated. Among the 3614 patients, regardless of assigned treatment, 33.3% had a deterioration in QoL, 9.2% had no change, 9.2% had a small improvement, 13.5% had a moderate improvement, and the remaining 34.9% had a large improvement. Patients undergoing CRT were less likely to have a decrement in their QoL (28.2% versus 38.9%; P P Conclusions: There is marked heterogeneity of treatment benefit of CRT that can be predicted based on baseline QoL, age, and QRS duration.

Study subjects were French-Canadian women with ductal carcinoma in situ (DCIS) or invasive breast cancer (incident or prevalent) who were treated and followed at a single breast cancer clinic affiliated with the Research Center of University of Montreal (CRCHUM), who were either aged less than 50 years at diagnosis or who were 50 years or older and with at least two affected first- or second-degree relatives. Subjects were tested for six founder mutations (three in BRCA1 and three in BRCA2); 1093 eligible cases were tested. Of these, 56 women (5.1%) were mutation carriers, including 43 BRCA2 carriers and 13 BRCA1 carriers. The prevalence of mutations was 5.3% for unselected women aged 50 and less and was 4.6% for familial cases over age 50. The prevalence of mutations was 3.3% for women with DCIS and was 5.3% for women with invasive cancer. It is rational to offer genetic testing to all French-Canadian women diagnosed recently or in the past with either DCIS or invasive breast cancer before age 50 or with familial breast cancer above age 50.

Acute myocardial infarction (AMI) is an underrecognized phenomenon in patients with continuous-flow left ventricular assist devices (CF-LVAD). Previously, there has been an optimistic expectation of a benign clinical course; however, AMI in LVAD-supported patients can result in profound consequences and management remains controversial. We describe a case series of AMI in four CF-LVAD patients, each with a different presentation, clinical course, treatment, and outcome. The clinical variability and mixed outcomes of these patients highlights the unique challenges in diagnosis and management of AMI in this population, particularly the uncertain role of percutaneous intervention (PCI), and underscores the potentially poor prognosis of this entity. Several key points emerge from this review. First, LVAD-supported patients frequently have underlying abnormalities on the electrocardiogram (ECG) that obscure the diagnosis of AMI. Second, clinicians should have a high degree of suspicion for AMI in the presence of suggestive clinical features, elevated cardiac biomarkers, or new-onset ventricular arrhythmias. Third, the decision to proceed with PCI requires careful evaluation of the risk of hemorrhage, and strong consideration should be given to the use of bleeding avoidance strategies during and after PCI.