scholarly journals Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction

Circulation ◽  
2020 ◽  
Vol 142 (17) ◽  
pp. 1623-1632 ◽  
Author(s):  
Kieran F. Docherty ◽  
Pardeep S. Jhund ◽  
Inder Anand ◽  
Olof Bengtsson ◽  
Michael Böhm ◽  
...  

Background: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and heart failure (HF) hospitalization. We examined the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events. Methods: Patients in New York Heart Association functional class II to IV, with a left ventricular ejection fraction ≤40% and elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide), were eligible. The primary outcome was the composite of an episode of worsening HF (HF hospitalization or an urgent HF visit requiring intravenous therapy) or cardiovascular death, whichever occurred first. An additional prespecified exploratory outcome was the primary outcome plus worsening HF symptoms/signs leading to the initiation of new, or the augmentation of existing, oral treatment. Results: Overall, 36% more patients experienced the expanded, in comparison with the primary, composite outcome. In the placebo group, 684 of 2371 (28.8%) patients and, in the dapagliflozin group, 527 of 2373 (22.2%) participants experienced the expanded outcome (hazard ratio, 0.73 [95% CI, 0.65–0.82]; P <0.0001). Each component of the composite was reduced significantly by dapagliflozin. Over the median follow-up of 18.2 months, the number of patients needed to treat with dapagliflozin to prevent 1 experiencing an episode of fatal or nonfatal worsening was 16. Among the 4744 randomly assigned patients, the first episode of worsening was outpatient augmentation of treatment in 407 participants (8.6%), an urgent HF visit with intravenous therapy in 20 (0.4%), HF hospitalization in 489 (10.3%), and cardiovascular death in 295 (6.2%). The adjusted risk of death from any cause (in comparison with no event) after an outpatient worsening was hazard ratio, 2.67 (95% CI, 2.03–3.52); after an urgent HF visit, the adjusted risk of death was hazard ratio, 3.00 (95% CI, 1.39–6.48); and after a HF hospitalization, the adjusted risk of death was hazard ratio, 6.21 (95% CI, 5.07–7.62). Conclusion: In DAPA-HF, outpatient episodes of HF worsening were common, were of prognostic importance, and were reduced by dapagliflozin. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT03036124.

Author(s):  
Eigir Einarsen ◽  
Dana Cramariuc ◽  
Edda Bahlmann ◽  
Helga Midtbo ◽  
John B. Chambers ◽  
...  

Background: Acceleration time (AT)/ejection time (ET) ratio is a marker of aortic valve stenosis (AS) severity and predicts outcome in moderate-severe AS. Methods: We explored the association of increased AT/ET ratio on prognosis in 1530 asymptomatic patients with presumably mild-moderate AS, normal ejection fraction, and without known diabetes or cardiovascular disease. Patients were part of the SEAS study (Simvastatin Ezetimibe Aortic Stenosis). Patients were grouped according to the optimal AT/ET ratio threshold to predict cardiovascular death and heart failure hospitalization. Low-gradient severe AS was identified as combined valve area ≤1.0 cm 2 and mean gradient <40 mm Hg. Outcome was assessed in Cox regression analyses, and results are reported as hazard ratio and 95% CI. Results: Higher AT/ET ratio was significantly associated with lower systolic blood pressure, lower left ventricular ejection fraction, lower stress-corrected midwall shortening, low flow, and with higher left ventricular mass and higher peak aortic jet velocity. AT/ET ratio ≥0.32 provided the optimal cutoff for predicting incident cardiovascular death and heart failure hospitalization in the total study sample. In patients with low-gradient severe AS, this threshold was >0.32. AT/ET ratio ≥0.32 had a 79% higher risk of cardiovascular death and heart failure hospitalization (hazard ratio, 1.79 [95% CI, 1.20–2.68]). In patients with low-gradient severe AS, AT/ET ratio >0.32 was associated with a 2-fold higher risk of cardiovascular death and heart failure hospitalization (hazard ratio, 2.15 [95% CI, 1.22–3.77]). Conclusions: In asymptomatic nonsevere AS and low-gradient severe AS, higher AT/ET ratio was associated with increased cardiovascular morbidity and mortality. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00092677.


Author(s):  
Akshay S. Desai ◽  
Muthiah Vaduganathan ◽  
John G. Cleland ◽  
Brian L. Claggett ◽  
Ebrahim Barkoudah ◽  
...  

Background: Patients with heart failure (HF) and preserved left ventricular ejection fraction comprise a heterogeneous group including some with mildly reduced EF. We hypothesized that mode of death differs by EF in ambulatory patients with HF and preserved left ventricular ejection fraction. Methods: PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor With Angiotensin-Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) compared clinical outcomes in 4796 patients with chronic HF and EF ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the mode of death in relation to baseline EF in logistic regression models and the effect of randomized treatment on cause-specific death in Cox regression models. Nonlinear relationships with continuous EF were modelled using quadratic and cubic terms. Results: Of 691 deaths during the trial, 416 (60%) were ascribed to cardiovascular, 220 (32%) to noncardiovascular, and 55 (8%) to unknown causes. Of cardiovascular deaths, 154 (37%) were due to sudden death, 118 (28%) were due to HF, 35 (8%) to stroke, 27 (6%) to myocardial infarction, and 82 (20%) to other cardiovascular causes. Rates of all-cause, cardiovascular, and sudden death were higher in those with lower left ventricular ejection fraction (all P <0.001), while rates of non-cardiovascular death were greater in patients with higher EF. Sacubitril/valsartan did not reduce overall death, cardiovascular death, or sudden death compared with valsartan, irrespective of baseline EF (all P for interaction >0.30). Conclusions: Among patients with HF and preserved left ventricular ejection fraction enrolled in PARAGON-HF, the proportion of cardiovascular and sudden death were higher in those with lower left ventricular EF, and the proportion of noncardiovascular death rose with EF. Regardless of EF, sacubitril/valsartan did not reduce death from any cause compared with valsartan. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.


2021 ◽  
Vol 1 (223) ◽  
pp. 2-14
Author(s):  
Gulmira Alipova ◽  
◽  
Anna Bazarova ◽  
Nazira Bazarova ◽  
Rimma Bazarbekova ◽  
...  

The article presents the results of the DAPA-HF study - evaluating the efficacy of dapagliflozin, used at a dose of 10 mg once a day, in addition to the standard treatment for patients with chronic heart failure with reduced left ventricular ejection fraction, compared to placebo. An analysis of current clinical recommendations related to this issue was carried out, the results of recent clinical studies and metaanalyses conducted were highlighted. Based on the results of the study, the need is postulated to optimize drug therapy of this category to patients with persistent symptoms of heart failure, despite standard therapy, with the addition of dapagliflozin to reduce the risk of cardiovascular death and hospitalizations for heart failure, improve the course of the disease. Keywords: chronic heart failure, dapagliflozin, low ejection fraction, effects of type 2 sodium-glucose co transporter inhibitors, diabetes mellitus.


Author(s):  
Masanori Asakura ◽  
Shin Ito ◽  
Takahisa Yamada ◽  
Yoshihiko Saito ◽  
Kazuo Kimura ◽  
...  

Abstract Aims A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated. Methods and results In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642–1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213–1.434). The safety profile for eplerenone was as expected. Conclusion The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power.


2020 ◽  
pp. 204748732092761
Author(s):  
Francesco Gentile ◽  
Paolo Sciarrone ◽  
Elisabet Zamora ◽  
Marta De Antonio ◽  
Evelyn Santiago ◽  
...  

Aims Obesity is related to better prognosis in heart failure with either reduced (HFrEF; left ventricular ejection fraction (LVEF) <40%) or preserved LVEF (HFpEF; LVEF ≥50%). Whether the obesity paradox exists in patients with heart failure and mid-range LVEF (HFmrEF; LVEF 40–49%) and whether it is independent of heart failure aetiology is unknown. Therefore, we aimed to test the prognostic value of body mass index (BMI) in ischaemic and non-ischaemic heart failure patients across the whole spectrum of LVEF. Methods Consecutive ambulatory heart failure patients were enrolled in two tertiary centres in Italy and Spain and classified as HFrEF, HFmrEF or HFpEF, of either ischaemic or non-ischaemic aetiology. Patients were stratified into underweight (BMI <18.5 kg/m2), normal-weight (BMI 18.5–24.9 kg/m2), overweight (BMI 25–29.9 kg/m2), mild-obese (BMI 30–34.9 kg/m2), moderate-obese (BMI 35–39.9 kg/m2) and severe-obese (BMI ≥40 kg/m2) and followed up for the end-point of five-year all-cause mortality. Results We enrolled 5155 patients (age 70 years (60–77); 71% males; LVEF 35% (27–45); 63% HFrEF, 18% HFmrEF, 19% HFpEF). At multivariable analysis, mild obesity was independently associated with a lower risk of all-cause mortality in HFrEF (hazard ratio, 0.78 (95% confidence interval (CI) 0.64–0.95), p = 0.020), HFmrEF (hazard ratio 0.63 (95% CI 0.41–0.96), p = 0.029), and HFpEF (hazard ratio 0.60 (95% CI 0.42–0.88), p = 0.008). Both overweight and mild-to-moderate obesity were associated with better outcome in non-ischaemic heart failure, but not in ischaemic heart failure. Conclusions Mild obesity is independently associated with better survival in heart failure across the whole spectrum of LVEF. Prognostic benefit of obesity is maintained only in non-ischaemic heart failure.


2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Calogero Falletta ◽  
Francesco Clemenza ◽  
Catherine Klersy ◽  
Valentina Agnese ◽  
Diego Bellavia ◽  
...  

Background. Risk stratification is a crucial issue in heart failure. Clinicians seek useful tools to tailor therapies according to patient risk. Methods. A prospective, observational, multicenter study on stable chronic heart failure outpatients with reduced left ventricular ejection fraction (HFrEF). Baseline demographics, blood, natriuretic peptides (NPs), high-sensitivity troponin I (hsTnI), and echocardiographic data, including the ratio between tricuspid annular plane excursion and systolic pulmonary artery pressure (TAPSE/PASP), were collected. Association with death for any cause was analyzed. Results. Four hundred thirty-one (431) consecutive patients were enrolled in the study. Fifty deaths occurred over a median follow-up of 32 months. On the multivariable Cox model analysis, TAPSE/PASP ratio, number of biomarkers above the threshold values, and gender were independent predictors of death. Both the TAPSE/PASP ratio ≥0.36 and TAPSE/PASP unavailable groups had a three-fold decrease in risk of death in comparison to the TAPSE/PASP ratio <0.36 group. The risk of death increased linearly by 1.6 for each additional positive biomarker and by almost two for women compared with men. Conclusions. In a HFrEF outpatient cohort, the evaluation of plasma levels of both NPs and hsTnI can contribute significantly to identifying patients who have a worse prognosis, in addition to the echocardiographic assessment of right ventricular-arterial coupling.


2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
H Hayama ◽  
T Uejima ◽  
J Cho ◽  
L Takahashi ◽  
H Hara ◽  
...  

Abstract Background Pulmonary hypertension (PH) is prevalent and is associated with adverse outcomes in heart failure. The pathophysiology of PH is heterogeneous, including pre-capillary PH and combined pre- and post-capillary PH. The latter PH has been reported in experimental studies to cause wave reflection in pulmonary circulation, putting additional burden on right ventricle. This study tested the hypothesis that separating wave reflection would enhance risk stratification in heart failure. Methods This study included 152 patients with clinical stable heart failure associated with PH who were referred to echocardiography for hemodynamic assessment (age = 72 ± 13 years old, ejection fraction = 49 ± 21%). Pulmonary arterial wave reflection was characterised by separating PA pressure waveform into forward (Pf) and backward pressure (Pb) waves, based on the concept of wave intensity. PA pressure waveform was estimated from continuous Doppler tracing of tricuspid regurgitation. Flow velocity was measured by pulse Doppler at right ventricular outflow tract. Outcome data was obtained by reviewing medical charts. The endpoint was hospitalization for worsening heart failure (WHF). Results Figure A compares PA pressure waveforms (total and separated waves) obtained from 2 patients with and without WHF event. The patient with event had higher total pressure associated with late peak than the patient without event. Pb appeared later than Pf; it was markedly higher in the patient with event than the patient without event, although Pf was similar between both patients. Kaplan-Meier analysis demonstrated a significant separation of survival curves stratified by Pb (chi-square = 25.1, p &lt; 0.001, figure B). During follow-up period of 1.5 ± 1.8 years, 65 patients (43%) experienced the endpoint. Sequential Cox analysis revealed that PASP remained significant after adjusted for left ventricular ejection fraction and E/e’ (hazard ratio = 1.017, p = 0.019). Pb also remained significant after the same adjustment (hazard ratio = 1.066, p = 0.003); the addition of Pb to a baseline model resulted in greater increase in predictive power than the addition of PASP (model chi-square: from 27.4 (baseline), to 37.6 (p = 0.004) for Pb, to 31.6 (p = 0.027) for PASP, figure C) Conclusions Pressure wave reflection in pulmonary artery is associated with early decompensation in heart failure. Abstract P1528 Figure.


2020 ◽  
Vol 16 ◽  
Author(s):  
Farah Hamad ◽  
Asim Ahmed Elnour ◽  
Abdelgadir Elamin ◽  
Sasha Mohamed ◽  
Isra Yousif ◽  
...  

Background: The major cardiovascular outcome trials on glucagon-like peptide one receptor agonist has examined its effect on hospitalization of subjects with heart failure, however, very limited trials has been conducted on subjects with reduced ejection fraction as primary outcome. Objective: We have conducted a systematic review on two major (FIGHT and LIVE) placebo-controlled trials of liraglutide and its clinical effect on ejection fraction of subjects with heart failure Method: Medline was retrieved for trials involving liraglutide from 2012 to 2020. The inclusion criteria for trials were: subjects with or without T2DM, subjects with heart failure with reduced left ventricular ejection fraction (rLVEF), major trials (phase II or III) on liraglutide, trials included liraglutide with defined efficacy primary outcome of patients with heart failure with rLVEF. The search was limited to the English language, whereby two trials [FIGHT and LIVE] have been included and have excluded two trials due to different primary outcomes. Participants (541) have been randomized for either liraglutide or placebo for 24 weeks. Results: In the FIGHT trial the primary intention-to-treat, sensitivity, and diabetes subgroup analyses have showed no significant between-group difference in the global rank scores (mean rank of 146 in the liraglutide group versus 156 in the placebo group; Wilcoxon rank-sum P=.31), in number of deaths, re-hospitalizations for heart failure, or the composite of death or in change in NT-pro BNP level (P= .94). In the LIVE trial, the change in LVEF from baseline to week 24 was not significantly different between treatment groups. The overall discontinuation rate of liraglutide was high in the FIGHT trial (29%, [86]) as compared to the LIVE trial (11.6%, [28]). Conclusion: The two trials FIGHT and LIVE have demonstrated that liraglutide use in subjects with heart failure and rLVEF was implicated with an increased adverse risk of heart failure-related outcomes.


2019 ◽  
Vol 8 (2) ◽  
pp. 262 ◽  
Author(s):  
Giuseppe Vitale ◽  
Giuseppe Romano ◽  
Antonino Di Franco ◽  
Giuseppa Caccamo ◽  
Cinzia Nugara ◽  
...  

Background. Sacubitril/valsartan in heart failure (HF) with reduced ejection fraction (HFrEF) was shown to be superior to enalapril in reducing the risk of death and hospitalization for HF. Our aim was to evaluate the cardiopulmonary effects of sacubitril/valsartan in patients with HFrEF. Methods. We conducted an observational study. Ninety-nine ambulatory patients with HFrEF underwent serial cardiopulmonary exercise tests (CPET) after initiation of sacubitril/valsartan in addition to recommended therapy. Results. At baseline, 37% of patients had New York Heart Association (NYHA) class III. After a median follow-up of 6.2 months (range 3–14.9 months) systolic blood pressure decreased from 117 ± 14 to 101 ± 12 mmHg (p < 0.0001), left ventricular ejection fraction (LVEF) increased from 27 ± 6 to 29.7 ± 7% (p < 0.0001), peak oxygen consumption (VO2) improved from 14.6 ± 3.3 (% of predicted = 53.8 ± 14.1) to 17.2 ± 4.7 mL/kg/min (% of predicted = 64.7 ± 17.8) (p < 0.0001), minute ventilation/carbon dioxide production relationship (VE/VCO2 Slope) decreased from 34.1 ± 6.3 to 31.7 ± 6.1 (p = 0.006), VO2 at anaerobic threshold increased from 11.3 ± 2.6 to 12.6 ± 3.5 mL/kg/min (p = 0.007), oxygen pulse increased from 11.5 ± 3.0 to 13.4 ± 4.3 mL/kg/min (p < 0.0001), and ∆VO2/∆Work increased from 9.2 ± 1.5 to 10.1 ± 1.8 mL/min/watt (p = 0.0002). Conclusion. Sacubitril/valsartan improved exercise tolerance, LVEF, peak VO2, and ventilatory efficiency at 6.2 months follow-up. Further studies are necessary to better clarify underlying mechanisms of this functional improvement.


2019 ◽  
Vol 8 (7) ◽  
pp. 623-633 ◽  
Author(s):  
Yu Sato ◽  
Akiomi Yoshihisa ◽  
Masayoshi Oikawa ◽  
Toshiyuki Nagai ◽  
Tsutomu Yoshikawa ◽  
...  

Introduction: Hyponatremia predicts adverse prognosis in patients with heart failure in particular with reduced ejection fraction. In contrast, it has recently been reported that hyponatremia on admission is not a predictor of post-discharge mortality in patients with heart failure with preserved ejection fraction. We investigated the prognostic impact of hyponatremia at discharge in patients with heart failure with preserved ejection fraction and its clinical characteristics. Methods and results: The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, prospective registration of consecutive Japanese patients hospitalised with heart failure with preserved ejection fraction and left ventricular ejection fraction of 50% or greater. Five hundred consecutive patients were enrolled in this analysis. We divided the patients into two groups based on their sodium serum levels at discharge: hyponatremia group (sodium <135 mEq/L, n=50, 10.0%) and control group (sodium ⩾135 mEq/L, n=450, 90.0%). This present analysis had two primary endpoints: all-cause death and all-cause death or rehospitalisation for heart failure. At discharge, the hyponatremia group had lower systolic blood pressure (110.0 mmHg vs. 114.5 mmHg, P=0.014) and higher levels of urea nitrogen (31.9 mg/dL vs. 24.2 mg/dL, P=0.032). In the Kaplan–Meier analysis, more patients in the hyponatremia group reached the primary endpoints than those in the control group (log rank <0.01, respectively). In the Cox proportional hazard analysis, hyponatremia at discharge was a predictor of the two endpoints (all-cause death, hazard ratio 2.708, 95% confidence interval 1.557–4.708, P<0.001; all-cause death or rehospitalisation for heart failure, hazard ratio 1.829, 95% confidence interval 1.203–2.780, P=0.005). Conclusions: Hyponatremia at discharge is associated with adverse prognosis in hospitalised patients with heart failure with preserved ejection fraction.


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