| 1. |
- Teerlink, John R., et al.
(författare)
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Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure
- 2021
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Ingår i: New England Journal of Medicine. - Waltham, MA, United States : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 384:2, s. 105-116
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Tidskriftsartikel (refereegranskat)abstract
- Among patients with heart failure and a reduced ejection fraction, those who received the cardiac myosin activator omecamtiv mecarbil had a lower incidence of a composite of heart-failure events or cardiovascular death at a median of 22 months than those who received placebo. Background The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. Methods We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. Results During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P=0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. Conclusions Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, ; EudraCT number, 2016-002299-28.)
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| 2. |
- Teerlink, John R., et al.
(författare)
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Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC-HF baseline characteristics and comparison with contemporary clinical trials
- 2020
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Ingår i: European Journal of Heart Failure. - : WILEY. - 1388-9842 .- 1879-0844. ; 22:11, s. 2160-2171
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Tidskriftsartikel (refereegranskat)abstract
- Aims The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials. Methods and results Adults with established HFrEF, New York Heart Association (NYHA) functional class >= II, ejection fraction <= 35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m(2) (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594). Conclusions GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation.
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| 3. |
- Cunningham, Jonathan W., et al.
(författare)
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Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction.
- 2022
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 80:14, s. 1302-1310
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death. OBJECTIVES: The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization. METHODS: The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF $>$40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death. RESULTS: Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P $<$ 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients. CONCLUSIONS: Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
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| 4. |
- Kosiborod, Mikhail N., et al.
(författare)
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Effect of Dapagliflozin on Health Status in Patients With Preserved or Mildly Reduced Ejection Fraction.
- 2023
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 81:5, s. 460-473
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) experience a high burden of symptoms, physical limitations, and poor quality of life; improving health status is a key goal of management. OBJECTIVES: In a prespecified analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, we examine effects of dapagliflozin on health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ). METHODS: The DELIVER trial randomized patients with symptomatic HFmrEF/HFpEF to dapagliflozin 10 mg or placebo. KCCQ was evaluated at randomization, 1, 4, and 8 months; KCCQ Total Symptom Score (TSS) was a key secondary endpoint. Patients were stratified by KCCQ-TSS tertiles; Cox models examined effects of dapagliflozin on clinical outcomes. We evaluated the effects of dapagliflozin on KCCQ-TSS, Physical Limitations (PLS), Clinical Summary (CSS), and Overall Summary (OSS) domains. Responder analyses compared proportions of dapagliflozin vs placebo-treated patients with clinically meaningful changes in KCCQ. RESULTS: A total of 5,795 patients had baseline KCCQ (median KCCQ-TSS 72.9). The effects of dapagliflozin on reducing cardiovascular death/worsening HF appeared more pronounced in patients with greater baseline symptom burden (lowest-to-highest KCCQ-TSS tertile: HR: 0.70 [95% CI: 0.58-0.84]; 0.81 [95% CI: 0.65-1.01]; 1.07 [95% CI: 0.83-1.37]; Pinteraction = 0.026). Dapagliflozin improved KCCQ-TSS, -PLS, -CSS, and -OSS at 8 months (2.4, 1.9, 2.3, and 2.1 points higher vs placebo; P $<$ 0.001 for all). Dapagliflozin-treated patients experienced improvements in KCCQ-TSS regardless of EF (Pinteraction = 0.85). Fewer dapagliflozin- treated patients had deterioration, and more had improvements in all KCCQ domains at 8 months. CONCLUSIONS: The clinical benefits of dapagliflozin in HFmrEF/HFpEF appear especially pronounced in those with greater baseline symptom impairment. Dapagliflozin improved all KCCQ domains and the proportion of patients experiencing clinically meaningful changes in health status. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
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| 5. |
- Ostrominski, John W., et al.
(författare)
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Dapagliflozin and New York Heart Association Functional Class in Heart Failure with Mildly Reduced or Preserved Ejection Fraction : The DELIVER Trial.
- 2022
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:10, s. 1892-1901
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: This pre-specified analysis of the DELIVER trial examined whether clinical benefits of dapagliflozin in heart failure (HF) with left ventricular ejection fraction (LVEF) $>$40% varied by baseline New York Heart Association (NYHA) class and examined the treatment effects on NYHA class over time. METHODS AND RESULTS: Treatment effects of dapagliflozin by baseline NYHA class II (n = 4713) versus III/IV (n = 1549) were examined on the primary endpoint (cardiovascular death or worsening HF event) and key secondary endpoints. Effects of dapagliflozin on change in NYHA class at 4, 16, and 32 weeks were also evaluated. Higher baseline NYHA class was associated with older age, female sex, greater comorbidity burden, lower LVEF, and higher natriuretic peptide levels. Participants with baseline NYHA class III/IV, as compared with II, were independently more likely to experience the primary endpoint (adjusted hazard ratio [HR] 1.16 [95% confidence interval, 1.02-1.33]) and all-cause death (adjusted HR 1.22 [1.06-1.40]). Dapagliflozin consistently reduced the risk of the primary endpoint compared with placebo, irrespective of baseline NYHA class (HR 0.81 [0.70-0.94] for NYHA class II vs. HR 0.80 [0.65-0.98] for NYHA class III/IV; pinteraction = 0.921). Participants with NYHA class III/IV had greater improvement in Kansas City Cardiomyopathy Questionnaire total symptom scores between baseline and 32 weeks (+4.8 [2.5-7.1]) versus NYHA class II (+1.8 [0.7-2.9]; pinteraction = 0.011). Dapagliflozin was associated with higher odds of any improvement in NYHA class (odds ratio [OR] 1.32 [1.16-1.51]), as well as improvement to NYHA class I (OR 1.43 [1.17-1.75]), versus placebo at 32 weeks, with benefits seen as early as 4 weeks. CONCLUSIONS: Among symptomatic patients with HF and LVEF $>$40%, treatment with dapagliflozin provided clinical benefit irrespective of baseline NYHA class and was associated with early and sustained improvements in NYHA class over time.
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| 6. |
- Peikert, Alexander, et al.
(författare)
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Efficacy and Safety of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction According to Age : The DELIVER Trial.
- 2022
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Ingår i: Circulation. Heart failure. ; 15:10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The prevalence of heart failure with mildly reduced or preserved ejection fraction markedly increases with age, with older individuals disproportionately facing excess risk for mortality and hospitalization. METHODS: The DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) randomized patients with New York Heart Association functional class II-IV and left ventricular ejection fraction $>$40% to either dapagliflozin or placebo for a median follow-up period of 2.3 years. We examined efficacy and safety outcomes by age categories ($<$55, 55-64, 65-74, and $>$/=75 years) and across age as a continuous measure. RESULTS: Among 6263 randomized patients (aged 40-99 years, mean age 71.7+/-9.6 years), 338 (5.4%) were $<$55 years, 1007 (16.1%) were 55-64 years, 2326 (37.1%) were 65 to 74 years, and 2592 (41.4%) were $>$/=75 years. Dapagliflozin reduced the risk of the primary composite outcome compared with placebo in all age categories (Pinteraction=0.95) and across the age spectrum as a continuous function (Pinteraction=0.76). Similar benefits were observed for the components of the primary outcome, with no significant interaction between randomized treatment and age category. Adverse events occurred more frequently with increasing age, but there were no significant differences in predefined safety outcomes between patients randomized to dapagliflozin and placebo across all age categories. CONCLUSIONS: In patients with heart failure and mildly reduced or preserved ejection fraction enrolled in DELIVER, dapagliflozin reduced the combined risk of cardiovascular death or worsening heart failure events across the spectrum of age, with a consistent safety profile, including among the traditionally under-treated older segment of patients $>$/=75 years. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03619213.
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| 7. |
- Rossignol, Patrick, et al.
(författare)
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Impact of eplerenone on cardiovascular outcomes in heart failure patients with hypokalaemia
- 2017
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 19:6, s. 792-799
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Tidskriftsartikel (refereegranskat)abstract
- © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology Aims: Although hypokalaemia is common among patients with heart failure (HF), the prognostic significance of baseline hypokalaemia and hypokalaemia during follow-up in HF patients receiving a mineralocorticoid receptor antagonist (MRA) remains uncertain. Methods and results: Results of the EMPHASIS-HF trial in patients (n = 2737) with HF and reduced EF with mild symptoms, randomized to eplerenone or placebo, were analysed with regard to the presence or occurrence of hypokalaemia (serum K + < 4.0 mmol/L) and the risk of cardiovascular death or hospitalization for HF (primary endpoint). Median follow-up was 21 months. Baseline hypokalaemia and hypokalaemia during follow-up were common occurrences (19.6% and 40.6%, respectively). Hypokalaemia during follow-up was associated with worse outcomes in multivariable analyses [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.05–1.52, P = 0.01] without evidence of interaction with eplerenone. In contrast, baseline hypokalaemia was associated with outcomes in the placebo group (HR 1.37, 95% CI 1.05–1.79, P = 0.02) but not in the eplerenone group (HR 0.87, 95% CI 0.62–1.23, P = 0.44; P for interaction = 0.04). Concurrently, eplerenone was found to be more protective in patients with baseline hypokalaemia vs. patients without baseline hypokalaemia compared with placebo (HR 0.44, 95% 0.30–0.64, P < 0.0001 vs. 0.69, 95% CI 0.57–0.83, P = 0.0001; P for interaction = 0.04). In patients without baseline hypokalaemia, eplerenone use decreased the rate of hypokalaemia during follow-up (HR 0.69, 95% CI 0.59–0.80, P < 0.001). A potassium level > 4.0 mmol/L at 1 month after randomization mediated 26.0% (0.6–51.4%) of the eplerenone treatment effect (P = 0.04). Conclusion: In HF patients receiving optimal therapy but not treated with eplerenone, baseline hypokalaemia was associated with worse outcomes. Conversely, hypokalaemia amplified the treatment effect of eplerenone.
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| 8. |
- Adamson, Carly, et al.
(författare)
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Dapagliflozin for Heart Failure According to Body Mass Index : The DELIVER Trial.
- 2022
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Ingår i: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 43:41, s. 4406-4417
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Obesity is common and associated with unique phenotypic features in heart failure with preserved ejection fraction (HFpEF). Therefore, understanding the efficacy and safety of new therapies in HFpEF patients with obesity is important. The effects of dapagliflozin were examined according to body mass index (BMI) among patients in the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure trial. METHODS AND RESULTS: Body mass index was analysed by World Health Organization (WHO) categories and as a continuous variable using restricted cubic splines. Body mass index ranged from 15.2 to 50 kg/m2 with a mean value of 29.8 (standard deviation +/- 6.1) kg/m2. The proportions, by WHO category, were: normal weight 1343 (21.5%); overweight 2073 (33.1%); Class I obesity 1574 (25.2%); Class II obesity 798 (12.8%); and Class III obesity 415 (6.6%). Compared with placebo, dapagliflozin reduced the risk of the primary outcome to a similar extent across these categories: hazard ratio (95% confidence interval): 0.89 (0.69-1.15), 0.87 (0.70-1.08), 0.74 (0.58-0.93), 0.78 (0.57-1.08), and 0.72 (0.47-1.08), respectively (P-interaction = 0.82). The placebo-corrected change in Kansas City Cardiomyopathy Questionnaire total symptom score with dapagliflozin at 8 months was: 0.9 (-1.1, 2.8), 2.5 (0.8, 4.1), 1.9 (-0.1, 3.8), 2.7 (-0.5, 5.8), and 8.6 (4.0, 13.2) points, respectively (P-interaction = 0.03). The placebo-corrected change in weight at 12 months was: -0.88 (-1.28, -0.47), -0.65 (-1.04, -0.26), -1.42 (-1.89, -0.94), -1.17 (-1.94, -0.40), and -2.50 (-4.4, -0.64) kg (P-interaction = 0.002). CONCLUSIONS: Obesity is common in patients with HFpEF and is associated with higher rates of heart failure hospitalization and worse health status. Treatment with dapagliflozin improves cardiovascular outcomes across the spectrum of BMI, leads to greater symptom improvement in patients with obesity, compared with those without, and has the additional benefit of causing modest weight loss.
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| 9. |
- Adamson, Carly, et al.
(författare)
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IGFBP-7 and Outcomes in Heart Failure With Reduced Ejection Fraction : Findings From DAPA-HF.
- 2023
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Ingår i: JACC. Heart failure. - : Elsevier BV. - 2213-1779 .- 2213-1787. ; 11:3, s. 291-304
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Insulin-like growth factor-binding protein-7 (IGFBP-7) has been proposed as a potential prognostic biomarker in heart failure (HF), but the association between elevation in IGFBP-7 and HF outcomes in ambulant patients with heart failure with reduced ejection fraction (HFrEF) is unknown. OBJECTIVES: The authors addressed this question in a post hoc analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. METHODS: The primary outcome was a composite of cardiovascular death or a worsening HF event. The risk of adverse outcome was compared across tertiles of IGFBP-7 concentration by means of Cox proportional hazard models adjusted for N-terminal pro-B- type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT). The efficacy of randomized treatment across IGFBP-7 tertiles was assessed. Change in IGFBP-7 at 12 months was compared with the use of geometric means. RESULTS: A total of 3,158 patients had IGFBP-7 measured at baseline, and 2,493 had a repeated measure at 12 months. Patients in the highest tertile of IGFBP-7 had evidence of more advanced HFrEF. The adjusted HR for the primary endpoint in tertile 3, compared with tertile 1, was 1.48 (95% CI: 1.17-1.88). There was no modification of the benefit of dapagliflozin by baseline IGFBP-7 (P interaction = 0.34). Dapagliflozin did not change IGFBP-7 levels over 1 year (P = 0.34). CONCLUSIONS: Higher IGFBP-7 in patients with HFrEF was associated with worse clinical profile and an increased risk of adverse clinical outcomes. IGFBP-7 provided prognostic information incremental to clinical variables, NT-proBNP, and hsTnT. The benefit of dapagliflozin was not modulated by IGFBP-7 level. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124).
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| 10. |
- Adamson, Carly, et al.
(författare)
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Liver Tests and Outcomes in Heart Failure with Reduced Ejection Fraction : Findings from DAPA-HF.
- 2022
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:10, s. 1856-1868
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Reflecting both increased venous pressure and reduced cardiac output, abnormal liver tests are common in patients with severe heart failure and are associated with adverse clinical outcomes. We aimed to investigate the prognostic significance of abnormal liver tests in ambulatory patients with heart failure with reduced ejection fraction (HFrEF), explore any treatment interaction between bilirubin and sodium- glucose cotransporter 2 (SGLT2) inhibitors and examine change in liver tests with SGLT2 inhibitor treatment. METHODS AND RESULTS: We explored these objectives in the Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF) trial, with focus on bilirubin. We calculated the incidence of cardiovascular death or worsening heart failure by bilirubin tertile. Secondary cardiovascular outcomes were examined, along with the change in liver tests at the end-of-study visit. Baseline bilirubin was available in 4720 patients (99.5%). Participants in the highest bilirubin tertile (T3) have more severe HFrEF (lower left ventricular ejection fraction, higher N-terminal pro-B-type natriuretic peptide [NT-proBNP] and worse New York Heart Association class), had a greater burden of atrial fibrillation but less diabetes. Higher bilirubin (T3 vs. T1) was associated with worse outcomes even after adjustment for other predictive variables, including NT-proBNP and troponin T (adjusted hazard ratio for the primary outcome 1.73 [95% confidence interval 1.37-2.17], p $<$ 0.001; and 1.52 [1.12-2.07], p = 0.01 for cardiovascular death). Baseline bilirubin did not modify the benefits of dapagliflozin. During follow-up, dapagliflozin had no effect on liver tests. CONCLUSION: Bilirubin concentration was an independent predictor of worse outcomes but did not modify the benefits of dapagliflozin in HFrEF. Dapagliflozin was not associated with change in liver tests. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03036124.
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