-
1.
Effect of Canagliflozin on Heart Failure Hospitalization in Diabetes According to Baseline Heart Failure Risk.
Khan, MS, Segar, MW, Usman, MS, Patel, KV, Van Spall, HGC, DeVore, AD, Vaduganathan, M, Lam, CSP, Zannad, F, Verma, S, et al
JACC. Heart failure. 2023;(7):825-835
Abstract
BACKGROUND In the CANVAS (Canagliflozin Cardiovascular Assessment Study) program, canagliflozin reduced the risk of heart failure (HF) hospitalization among individuals with type 2 diabetes mellitus (T2DM). OBJECTIVES The purpose of this study was to evaluate heterogeneity in absolute and relative treatment effects of canagliflozin on HF hospitalization according to baseline HF risk as assessed by diabetes-specific HF risk scores (WATCH-DM [Weight (body mass index), Age, hyperTension, Creatinine, HDL-C, Diabetes control (fasting plasma glucose) and QRS Duration, MI and CABG] and TRS-HFDM [TIMI Risk Score for HF in Diabetes]). METHODS Participants in the CANVAS trial were categorized into low, medium, and high risk for HF using the WATCH-DM score (for participants without prevalent HF) and the TRS-HFDM score (for all participants). The outcome of interest was time to first HF hospitalization. The treatment effect of canagliflozin vs placebo for HF hospitalization was compared across risk strata. RESULTS Among 10,137 participants with available HF data, 1,446 (14.3%) had HF at baseline. Among participants without baseline HF, WATCH-DM risk category did not modify the treatment effect of canagliflozin (vs placebo) on HF hospitalization (P interaction = 0.56). However, the absolute and relative risk reduction with canagliflozin was numerically greater in the high-risk group (cumulative incidence, canagliflozin vs placebo: 8.1% vs 12.7%; HR: 0.62 [95% CI: 0.37-0.93]; P = 0.03; number needed to treat: 22) than in the low- and intermediate-risk groups. When overall study participants were categorized according to the TRS-HFDM score, a statistically significant difference in the treatment effect of canagliflozin across risk strata was observed (P interaction = 0.04). Canagliflozin significantly reduced the risk of HF hospitalization by 39% in the high-risk group (HR: 0.61 [95% CI: 0.48-0.78]; P < 0.001; number needed to treat: 20) but not in the intermediate- or low-risk groups. CONCLUSIONS Among participants with T2DM, the WATCH-DM and TRS-HFDM can reliably identify those at high risk for HF hospitalization and most likely to benefit from canagliflozin.
-
2.
Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.
Mann, DL, Givertz, MM, Vader, JM, Starling, RC, Shah, P, McNulty, SE, Anstrom, KJ, Margulies, KB, Kiernan, MS, Mahr, C, et al
JAMA cardiology. 2022;(1):17-25
-
-
Free full text
-
Abstract
IMPORTANCE The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. OBJECTIVE To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. DESIGN, SETTING, AND PARTICIPANTS A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. INTERVENTION Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. MAIN OUTCOMES AND MEASURES The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. RESULTS Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns. CONCLUSIONS AND RELEVANCE The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02816736.
-
3.
Pharmacologic Therapy for Heart Failure with Preserved Ejection Fraction.
Peters, AE, DeVore, AD
Cardiology clinics. 2022;(4):473-489
Abstract
The management of heart failure with preserved ejection fraction (HFpEF) is rapidly evolving. The pharmacologic treatment of patients with HFpEF includes symptom management with diuretics and optimization of comorbidities, including hypertension, obesity, diabetes mellitus, and atrial fibrillation. Specific therapies, including angiotensin II receptor blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors, are well tolerated and can reduce the risk of HF hospitalization, particularly in those on the lower end of the HFpEF left ventricular ejection fraction spectrum. Ongoing trials should continue to inform optimal therapy in this evolving field.
-
4.
Association between sacubitril/valsartan initiation and real-world health status trajectories over 18 months in heart failure with reduced ejection fraction.
Thomas, M, Khariton, Y, Fonarow, GC, Arnold, SV, Hill, L, Nassif, ME, Chan, PS, Butler, J, Thomas, L, DeVore, AD, et al
ESC heart failure. 2021;(4):2670-2678
Abstract
AIMS: Improving 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 RESULTS In 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 3 months that persisted through 12 months [KCCQ Overall Summary Score (OSS) = 73.4 vs. 70.8; P < 0.001], with the largest benefit observed in the KCCQ Quality of Life domain (68.7 vs. 64.7; P < 0.001). Similar health status benefits were noted through 18 months (KCCQ-OSS = 73.9 vs. 71.3; P < 0.001). 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 12 months. CONCLUSIONS In outpatient practice, ARNI therapy was associated with improved health status by 3 months and continued to 18 months after initiating therapy.
-
5.
Efficacy and Safety of Sacubitril/Valsartan in High-Risk Patients in the PIONEER-HF Trial.
Berg, DD, Samsky, MD, Velazquez, EJ, Duffy, CI, Gurmu, Y, Braunwald, E, Morrow, DA, DeVore, AD
Circulation. Heart failure. 2021;(2):e007034
-
-
Free full text
-
Abstract
BACKGROUND In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile. METHODS PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mm Hg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate <60 mL/minute per 1.73 m2 (n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219). RESULTS The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups (P interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup (P interaction=NS for each). CONCLUSIONS In high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated.
-
6.
Angiotensin Receptor-Neprilysin Inhibition Based on History of Heart Failure and Use of Renin-Angiotensin System Antagonists.
Ambrosy, AP, Braunwald, E, Morrow, DA, DeVore, AD, McCague, K, Meng, X, Duffy, CI, Rocha, R, Velazquez, EJ, ,
Journal of the American College of Cardiology. 2020;(9):1034-1048
Abstract
BACKGROUND The PIONEER-HF (comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode) trial demonstrated the efficacy and safety of sacubitril/valsartan (S/V) in stabilized patients with acute decompensated heart failure (HF) and reduced ejection fraction. OBJECTIVES The study sought to determine whether and how prior HF history and treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) affected the results. METHODS The PIONEER-HF trial was a prospective, multicenter, double-blind, randomized clinical trial enrolling 881 patients with an ejection fraction ≤40%. Patients were randomly assigned 1:1 to in-hospital initiation of S/V (n = 440) versus enalapril (n = 441). Pre-specified subgroup analyses were performed based on prior HF history (i.e., de novo HF vs. worsening chronic HF) and treatment with an ACE inhibitor or ARB (i.e., ACE inhibitor or ARB-yes vs. ACE inhibitor or ARB-no) at admission. RESULTS At enrollment, 303 (34%) patients presented with de novo HF and 576 (66%) patients with worsening chronic HF. A total of 421 (48%) patients had been treated with an ACE inhibitor or ARB, while 458 (52%) had not been treated with an ACE inhibitor or ARB. N-terminal pro-B-type natriuretic peptide declined significantly in all 4 subgroups (p < 0.001), with greater decreases in the S/V versus the enalapril arm (p < 0.001). There was no interaction between prior HF history (p = 0.350) or ACE inhibitor or ARB treatment (p = 0.880) and the effect of S/V versus enalapril on cardiovascular death or rehospitalization for HF. The incidences of adverse events were comparable between S/V and enalapril across all 4 subgroups. CONCLUSIONS Among patients admitted for acute decompensated HF, S/V was safe and well tolerated, led to a significantly greater reduction in N-terminal pro-B-type natriuretic peptide, and improved clinical outcomes compared with enalapril irrespective of previous HF history or ACE inhibitor or ARB treatment. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).
-
7.
Eligibility of sodium-glucose co-transporter-2 inhibitors among patients with diabetes mellitus admitted for heart failure.
Sharma, A, Wu, J, Ezekowitz, JA, Felker, GM, Udell, JA, Heidenreich, PA, Fonarow, GC, Mahaffey, KW, Hernandez, AF, DeVore, AD
ESC heart failure. 2020;(1):274-278
Abstract
AIMS: Sodium-glucose co-transporter (SGLT)-2 inhibitors have been shown to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with type 2 diabetes mellitus (DM) and high cardiovascular risk in two large clinical outcome trials: empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS. The scope of eligibility for SGLT-2 inhibitors (empagliflozin and canagliflozin) among patients with type 2 DM and HF, based on clinical trial criteria and current US Food and Drug Administration (FDA) labelling criteria, remains unknown. METHODS AND RESULTS Using data from the US Get With The Guidelines (GWTG)-Heart Failure registry, we evaluated the proportion of patients with DM and HF eligible for SGLT-2 inhibitor therapy based on the clinical trial criteria and the US FDA labelling criteria. The GWTG-HF registry is a quality improvement registry of patients admitted in hospital with HF in the USA. We included GWTG-HF registry participants meeting eligibility criteria hospitalized between August 2014 and 30 June 2017 from sites fully participating in the registry. The initial inclusion time point reflects when both drugs had FDA approval. Among the 139 317 patients (out of 407 317) with DM hospitalized with HF (in 460 hospitals; 2014 to 2017), the median age was 71 years, 47% (n = 65 685) were female, and 43% (n = 59 973) had HF with reduced ejection fraction. Overall, 43% (n = 59 943) were eligible for the EMPA-REG OUTCOME trial, 45% (n = 62 818) were eligible for the CANVAS trial, and 34% (n = 47 747) of patients were eligible for either SGLT-2 inhibitors based on the FDA labelling criteria. Among the FDA-eligible patients, 91.5% (n = 43 708) were eligible for either the EMPA-REG OUTCOME trial or the CANVAS trial. Patients who were FDA eligible, compared with those who were not, were younger (70.0 vs. 72.0 years of age), more likely to be male (57.7 vs. 50.3%), and had less burden of co-morbidities. CONCLUSIONS The majority of patients with DM who are hospitalized with HF are not eligible for SGLT-2 inhibitor therapies. Ongoing studies evaluating the safety and efficacy of SGLT-2 inhibitors among patients with HF may potentially broaden the population that may benefit from these therapies.
-
8.
Contemporary Treatment Patterns and Clinical Outcomes of Comorbid Diabetes Mellitus and HFrEF: The CHAMP-HF Registry.
Vaduganathan, M, Fonarow, GC, Greene, SJ, DeVore, AD, Kavati, A, Sikirica, S, Albert, NM, Duffy, CI, Hill, CL, Patterson, JH, et al
JACC. Heart failure. 2020;(6):469-480
Abstract
OBJECTIVES The purpose of this study was to characterize the clinical profile, treatment patterns, and clinical outcomes of patients with comorbid diabetes mellitus (DM) and heart failure with reduced ejection fraction (HFrEF) in a contemporary, real-world U.S. outpatient registry in the context of evolving treatment strategies. BACKGROUND Specific antihyperglycemic classes have differential risks and benefits with respect to HF. Limited data are available evaluating contemporary treatment patterns and outcomes of patients with comorbid DM and HFrEF. METHODS Among 4,970 patients with chronic HFrEF (≤40%) across 152 U.S. sites in the CHAMP-HF prospective, observational registry (2015 to 2017), we examined therapies and clinical outcomes by DM status. RESULTS Median age was 68 (58 to 75) years of age; 29% were women; 73.5% were white; and 64% had coronary artery disease. Overall, 42% (n = 2,085) had comorbid DM with a median hemoglobin A1c (HbA1c) level of 7.2% (interquartile range [IQR]: 6.4% to 8.3%). One-fourth of DM patients (24%) were not treated with an antihyperglycemic therapy. Most patients with DM were taking 1 (46%) or 2 (23%) antihyperglycemic therapies: metformin (40%); insulin (33%); sulfonylureas (24%); dipeptidyl peptidase-4 inhibitors (10%); glucagon-like peptide (GLP)-1 receptor agonists (4%); sodium-glucose cotransporter (SGLT)-2 inhibitors (2%); and thiazolidinediones (2%). Among patients with DM, 62%, 16%, 80%, and 33.5% were receiving any angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitor (ARNI), β-blockers, or mineralocorticoid receptor antagonists (MRAs) at baseline, respectively. Among patients without DM, corresponding baseline rates were 65%, 15%, 80%, and 37%, respectively. Patients with or without DM were infrequently treated with guideline-directed HFrEF therapies at target doses (≤27% across classes). During median 15-month follow-up, patients with DM experienced higher rates of all-cause mortality or HF hospitalization (30% vs. 23%, respectively), independent of 11 pre-specified covariates (adjusted hazard ratio: 1.35 (95% confidence interval: 1.21 to 1.52); p < 0.001). CONCLUSIONS Despite higher risk-adjusted clinical event rates in patients with comorbid HFrEF and DM, guideline-directed medical therapies for both disease states are incomplete and represent an important target for quality improvement through multidisciplinary care pathways.
-
9.
Representativeness of the PIONEER-HF Clinical Trial Population in Patients Hospitalized With Heart Failure and Reduced Ejection Fraction.
Fudim, M, Sayeed, S, Xu, H, Matsouaka, RA, Heidenreich, PA, Velazquez, EJ, Yancy, CW, Fonarow, GC, Hernandez, AF, DeVore, AD
Circulation. Heart failure. 2020;(4):e006645
-
-
Free full text
-
Abstract
BACKGROUND In PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-pro BNP in Patients Stabilized From an Acute Heart Failure Episode), the in-hospital initiation of sacubitril/valsartan in patients hospitalized for acute decompensated heart failure (ADHF) was well-tolerated and led to improved outcomes. We aim to determine the representativeness of the PIONEER-HF trial among patients hospitalized for ADHF using real-world data. METHODS The study population was derived from all patients discharged alive for ADHF in the Get With The Guidelines-HF registry from 2006 to 2018 with HF with reduced ejection fraction (HFrEF; all HFrEF with ADHF). We then determined the proportion of patients meeting PIONEER-HF eligibility criteria (PIONEER-HF eligible) and those meeting a set of limited eligibility criteria (actionable cohort). Rates of HF readmissions and all-cause mortality were then compared between the all HFrEF with ADHF, PIONEER-HF eligible, and actionable cohorts using linked Medicare claims data. RESULTS A total of 99 767 patients with HFrEF in Get With The Guidelines-HF were hospitalized for ADHF. PIONEER-HF inclusion criteria were met by 71 633 (71.8%) patients, and both inclusion and exclusion criteria were met by 20 704 (20.8%) patients. Further, 68 739 (68.9%) patients met the criteria for the actionable cohort. Among the Centers for Medicare and Medicaid-linked patients, the HF rehospitalization rate at 1 year was 35.1% (95% CI, 34.5-35.8) for all HFrEF with ADHF patients, 32.6% (95% CI, 31.3-33.9) for the PIONEER-HF eligible cohort, and 33.1% (95% CI, 32.3-33.9) for the actionable cohort. The 1-year all-cause mortality was 36.7% (95% CI, 36.1-7.4) for all HFrEF with ADHF patients, 31.6% (95% CI, 30.3-32.9) for the PIONEER-HF eligible cohort, and 32.2% (95% CI, 31.4-33.0) for the actionable cohort. CONCLUSIONS Patient characteristics and clinical outcomes for patients eligible for PIONEER-HF only modestly differ when compared with those encountered in routine practice, suggesting that the in-hospital initiation of sacubitril/valsartan should be routinely considered for patients with HFrEF hospitalized for ADHF.
-
10.
Angiotensin-Neprilysin Inhibition in Black Americans: Data From the PIONEER-HF Trial.
Berardi, C, Braunwald, E, Morrow, DA, Mulder, HS, Duffy, CI, O'Brien, TX, Ambrosy, AP, Chakraborty, H, Velazquez, EJ, DeVore, AD, et al
JACC. Heart failure. 2020;(10):859-866
Abstract
OBJECTIVES This study compared the efficacy and safety of sacubitril/valsartan to enalapril in Black and non-Black Americans with acute decompensated heart failure (ADHF). BACKGROUND Black patients have a different response to treatment with angiotensin-converting enzyme inhibitors compared with other racial and ethnic groups. How Black patients with ADHF respond to sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, is unclear. PIONEER-HF was a double-blind randomized clinical trial of sacubitril/valsartan versus enalapril in hospitalized patients with ADHF following hemodynamic stabilization. METHODS In a pre-specified subgroup analysis, we examined changes in N-terminal pro-B-type natriuretic peptide, clinical outcomes, and safety according to race. RESULTS The study population, all enrolled in the United States, included 316 (36%) Black participants, 515 (58%) White participants, and 50 (5.7%) participants of other racial groups. The reduction in N-terminal pro-B-type natriuretic peptide concentration at weeks 4 and 8 was significantly greater with sacubitril/valsartan than enalapril in both Black (ratio of change with sacubitril/valsartan vs. enalapril: 0.71; 95% confidence interval [CI]: 0.58 to 0.88) and non-Black patients (ratio of change: 0.71; 95% CI: 0.61 to 0.83; interaction p = 1.00). Compared with enalapril, sacubitril/valsartan also reduced the pre-specified exploratory composite of cardiovascular death or HF rehospitalization in both Black (hazard ratio: 0.47; 95% CI: 0.24 to 0.93) and non-Black patients (hazard ratio: 0.65; 95% CI: 0.40 to 1.06; interaction p = 0.44). CONCLUSIONS Among Black patients admitted with ADHF in the United States, the in-hospital initiation of sacubitril/valsartan was more effective than enalapril in reducing natriuretic peptide levels and the composite of cardiovascular death or HF rehospitalization. The effect of sacubitril/valsartan did not differ by race. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890).