| 1. |
- Lewis, Eldrin F., et al.
(författare)
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Health-Related Quality of Life Outcomes in PARADIGM-HF
- 2017
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Ingår i: Circulation: Heart Failure. - 1941-3289 .- 1941-3297. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 American Heart Association, Inc. Background Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only. Methods and Results Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29; P=0.008) and KCCQ overall summary score (+1.13 versus -0.14; P < 0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (≥5 points decrease) of both KCCQ scores (27% versus 31%; P=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months. Conclusions Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
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| 2. |
- Myhre, Peder L., et al.
(författare)
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Influence of NT-proBNP on Efficacy of Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction.
- 2022
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Ingår i: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 10:12, s. 902-913
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is used for diagnostic and prognostic evaluation in heart failure (HF). Previous clinical trials in heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF) have shown potential heterogeneity in the treatment response by baseline NT- proBNP levels. OBJECTIVES: The purpose of this study was to assess the treatment effect of dapagliflozin across baseline levels of NT-proBNP among patients with HFmrEF or HFpEF. METHODS: This was a post hoc analysis from DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure), a randomized, placebo-controlled trial of dapagliflozin in patients with HFmrEF or HFpEF. Elevated NT-proBNP was part of the inclusion criteria ($>$/=300 ng/L for non-atrial fibrillation or flutter [AFF]; $>$/=600 ng/L for AFF). Baseline NT-proBNP was categorized in quartiles and additionally analyzed continuously. The primary composite outcome was cardiovascular death or worsening HF events. RESULTS: Among the 6,262 included patients (mean: 71.7 years and 3,516 [56%] men), the median baseline concentration of NT- proBNP was 716 (Q1-Q3: 469-1,280) ng/L and 1,399 (Q1-Q3: 962-2,212) ng/L for non-AFF and AFF, respectively. Higher NT-proBNP levels were linearly associated with a greater risk of the primary outcome (adjusted HR for log2NTpro-BNP was 1.53 [95% CI: 1.46-1.62] and Q4 vs Q1: 3.46 [95% CI: 2.48-4.22]; P $<$ 0.001), with consistent results regardless of AFF status. The clinical benefit of dapagliflozin was present irrespective of baseline NT-proBNP concentration (P value for interaction = 0.40 by quartiles and = 0.19 continuously for the primary outcome) and the absolute risk reduction was, therefore, greater with higher NT-proBNP concentrations. The effect on health status and safety of dapagliflozin was similarly consistent across NT-proBNP quartiles. CONCLUSIONS: Dapagliflozin is safe and improves outcomes irrespective of baseline NT- proBNP concentrations in HFmrEF or HFpEF, with the greatest absolute benefit likely seen in patients with higher NT-proBNP concentrations. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
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| 3. |
- Srivastava, Pratyaksh K, et al.
(författare)
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Estimated 5-Year Number Needed to Treat to Prevent Cardiovascular Death or Heart Failure Hospitalization With Angiotensin Receptor-Neprilysin Inhibition vs Standard Therapy for Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of Data From the PARADIGM-HF Trial.
- 2018
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6591 .- 2380-6583. ; 77:4, s. 563-70
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Tidskriftsartikel (refereegranskat)abstract
- The addition of neprilysin inhibition to standard therapy, including a renin-angiotensin system blocker, has been demonstrated to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with standard therapy alone. The long-term absolute risk reduction from angiotensin receptor neprilysin inhibitor (ARNI) therapy, and whether it merits widespread use among diverse subpopulations, has not been well described.To calculate estimated 5-year number needed to treat (NNT) values overall and for different subpopulations for the Prospective Comparison of ARNI with Angiotensin-Converting Enzyme Inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) cohort.Overall and subpopulation 5-year NNT values were estimated for different end points using data from PARADIGM-HF, a double-blind, randomized trial of sacubitril-valsartan vs enalapril. This multicenter, international study included 8399 men and women with HFrEF (ejection fraction, ≤40%). The study began in December 2009 and ended in March 2014. Analyses began in March 2018.Random assignment to sacubitril-valsartan or enalapril.Cardiovascular death or HF hospitalization, cardiovascular death, and all-cause mortality.The final cohort of 8399 individuals included 1832 women (21.8%) and 5544 white individuals (66.0%), with a mean (SD) age of 63.8(11.4) years. The 5-year estimated NNT for the primary outcome of cardiovascular death or HF hospitalization with ARNI therapy incremental to ACEI therapy in the overall cohort was 14. The 5-year estimated NNT values were calculated for different clinically relevant subpopulations and ranged from 12 to 19. The 5-year estimated NNT for all-cause mortality in the overall cohort with ARNI incremental to ACEI was 21, with values ranging from 16 to 31 among different subgroups. Compared with imputed placebo, the 5-year estimated NNT for all-cause mortality with ARNI was 11. The 5-year estimated NNT values were also calculated for other HFrEF therapies compared with controls from landmark trials for all-cause mortality and were found to be 18 for ACEI, 24 for angiotensin receptor blockers, 8 for β-blockers, 15 for mineralocorticoid antagonists, 14 for implantable cardioverter defibrillator, and 14 for cardiac resynchronization therapy.The 5-year estimated NNT with ARNI therapy incremental to ACEI therapy overall and for clinically relevant subpopulations of patients with HFrEF are comparable with those for well-established HF therapeutics. These data further support guideline recommendations for use of ARNI therapy among eligible patients with HFrEF.
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| 4. |
- Bhatt, Ankeet S., et al.
(författare)
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Operational Challenges and Mitigation Measures during the COVID-19 Pandemic-Lessons from DELIVER.
- 2023
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Ingår i: American heart journal. ; 263, s. 133-140
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Catastrophic disruptions in care delivery threaten the operational efficiency and potentially the validity of clinical research efforts, in particular randomized clinical trials. Most recently, the COVID-19 pandemic affected essentially all aspects of care delivery and clinical research conduct. While consensus statements and clinical guidance documents have detailed potential mitigation measures, few real- world experiences detailing clinical trial adaptations to the COVID-19 pandemic exist, particularly among, large, global registrational cardiovascular trials. METHODS: We outline the operational impact of COVID-19 and resultant mitigation measures in the Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, one of the largest and most globally diverse experiences with COVID-19 of any cardiovascular clinical trial to date. Specifically, we address the needed coordination between academic investigators, trial leadership, clinical sites, and the supporting sponsor to ensure the safety of participants and trial staff, to maintain the fidelity of trial operations, and to prospectively adapt statistical analyses plans to evaluate the impact of COVID-19 and the pandemic at large on trial participants. These discussions included key operational issues such as ensuring delivery of study medications, adaptations to study visits, enhanced COVID-19 related endpoint adjudication, and protocol and analytical plan revisions. CONCLUSION: Our findings may have important implications for establishing consensus on prospective contingency planning in future clinical trials. CLINICALTRIAL: gov: NCT03619213. CLINICALTRIAL: GOV: NCT03619213.
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| 5. |
- Brown, Jenifer M., et al.
(författare)
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Cardiac Structure and Function Across the Spectrum of Aldosteronism: the Atherosclerosis Risk in Communities Study
- 2022
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Ingår i: Hypertension. - : LIPPINCOTT WILLIAMS & WILKINS. - 0194-911X .- 1524-4563. ; 79:9, s. 1984-1993
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aldosterone production and mineralocorticoid receptor activation are implicated in myocardial fibrosis and cardiovascular events. Methods: Cardiac structure and function were assessed in 4547 participants without prevalent heart failure (HF) in the ARIC study (Atherosclerosis Risk in Communities), with echocardiography, aldosterone, and plasma renin activity measurement (2011-2013). Subjects were characterized by plasma renin activity as suppressed (<= 0.5 ng/mL per hour) or unsuppressed (>0.5 ng/mL per hour). Cross-sectional relationships with cardiac structure and function, and longitudinal relationships with outcomes (HF hospitalization; HF and all-cause death; HF, death, myocardial infarction, and stroke; and incident atrial fibrillation) were assessed. Models were adjusted for demographic and anthropometric characteristics and additively, for blood pressure and antihypertensives. Results: Evidence of primary aldosteronism physiology was prevalent (11.6% with positive screen) and associated with echocardiographic parameters. Renin suppression was associated with greater left ventricular mass, left ventricular volumes, and left atrial volume index, and a lower E/A ratio (adjusted P<0.001 for all). Higher aldosterone was associated with greater left ventricular mass and lower global longitudinal strain and lateral E . The highest tertile of aldosterone was associated with a hazard ratio of 1.37 (95% CI, 1.06-1.77; 5.5-year follow-up) for incident atrial fibrillation relative to the lowest. Renin suppression was associated with HF (hazard ratio, 1.34 [95% CI, 1.05-1.72]; 7.3-year follow-up), although these relationships did not remain statistically significant after additional adjustment for hypertension. Conclusions: Renin suppression and aldosterone excess, consistent with primary aldosteronism pathophysiology, were associated with cardiac structural and functional alterations and may represent an early target for mitigation of fibrosis with mineralocorticoid receptor antagonists.
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| 6. |
- Butt, Jawad H., et al.
(författare)
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Efficacy and Safety of Dapagliflozin According to Frailty in Patients With Heart Failure : A Prespecified Analysis of the DELIVER Trial.
- 2022
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Ingår i: Circulation. ; 146:16, s. 1210-1224
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Frailty is increasing in prevalence. Because patients with frailty are often perceived to have a less favorable risk/benefit profile, they may be less likely to receive new pharmacologic treatments. We investigated the efficacy and tolerability of dapagliflozin according to frailty status in patients with heart failure with mildly reduced or preserved ejection fraction randomized in DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure). METHODS: Frailty was measured using the Rockwood cumulative deficit approach. The primary end point was time to a first worsening heart failure event or cardiovascular death. RESULTS: Of the 6263 patients randomized, a frailty index (FI) was calculable in 6258. In total, 2354 (37.6%) patients had class 1 frailty (FI $<$/=0.210; ie, not frail), 2413 (38.6%) had class 2 frailty (FI 0.211-0.310; ie, more frail), and 1491 (23.8%) had class 3 frailty (FI $>$/=0.311; ie, most frail). Greater frailty was associated with a higher rate of the primary end point (per 100 person-years): FI class 1, 6.3 (95% CI 5.7-7.1); class 2, 8.3 (7.5-9.1); and class 3, 13.4 (12.1-14.7; P$<$0.001). The effect of dapagliflozin (as a hazard ratio) on the primary end point from FI class 1 to 3 was 0.85 (95% CI, 0.68-1.06), 0.89 (0.74-1.08), and 0.74 (0.61-0.91), respectively (Pinteraction=0.40). Although patients with a greater degree of frailty had worse Kansas City Cardiomyopathy Questionnaire scores at baseline, their improvement with dapagliflozin was greater than it was in patients with less frailty: placebo-corrected improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score at 4 months in FI class 1 was 0.3 (95% CI, -0.9 to 1.4); in class 2, 1.5 (0.3-2.7); and in class 3, 3.4 (1.7-5.1; Pinteraction=0.021). Adverse reactions and treatment discontinuation, although more frequent in patients with a greater degree of frailty, were not more common with dapagliflozin than with placebo irrespective of frailty class. CONCLUSIONS: In DELIVER, frailty was common and associated with worse outcomes. The benefit of dapagliflozin was consistent across the range of frailty studied. The improvement in health-related quality of life with dapagliflozin occurred early and was greater in patients with a higher level of frailty. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03619213.
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| 7. |
- 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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| 8. |
- Jhund, Pardeep S., et al.
(författare)
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Dapagliflozin across the Range of Ejection Fraction in Patients with Heart Failure : A Patient-Level, Pooled Meta-Analysis of DAPA-HF and DELIVER.
- 2022
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:9, s. 1956-1964
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Tidskriftsartikel (refereegranskat)abstract
- Whether the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction ($<$/=40% and $>$40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)). A total of 11,007 participants with a mean ejection fraction of 44% (s.d. 14%) were included. Dapagliflozin reduced the risk of death from cardiovascular causes (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76-0.97; P = 0.01), death from any cause (HR 0.90, 95% CI 0.82-0.99; P = 0.03), total hospital admissions for heart failure (rate ratio 0.71, 95% CI 0.65-0.78; P $<$ 0.001) and MACEs (HR 0.90, 95% CI 0.81-1.00; P = 0.045). There was no evidence that the effect of dapagliflozin differed by ejection fraction. In a patient- level pooled meta-analysis covering the full range of ejection fractions in patients with heart failure, dapagliflozin reduced the risk of death from cardiovascular causes and hospital admissions for heart failure (PROSPERO: CRD42022346524).
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| 9. |
- 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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| 10. |
- Malachias, Marcus V. B., et al.
(författare)
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NT-proBNP by Itself Predicts Death and Cardiovascular Events in High-Risk Patients With Type 2 Diabetes Mellitus
- 2020
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Ingår i: Journal of the American Heart Association. - : Wiley-Blackwell Publishing Inc.. - 2047-9980. ; 9:19
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) improves the discriminatory ability of risk‐prediction models in type 2 diabetes mellitus (T2DM) but is not yet used in clinical practice. We assessed the discriminatory strength of NT‐proBNP by itself for death and cardiovascular events in high‐risk patients with T2DM.Methods and ResultsCox proportional hazards were used to create a base model formed by 20 variables. The discriminatory ability of the base model was compared with that of NT‐proBNP alone and with NT‐proBNP added, using C‐statistics. We studied 5509 patients (with complete data) of 8561 patients with T2DM and cardiovascular and/or chronic kidney disease who were enrolled in the ALTITUDE (Aliskiren in Type 2 Diabetes Using Cardiorenal Endpoints) trial. During a median 2.6‐year follow‐up period, 469 patients died and 768 had a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, stroke, or heart failure hospitalization). NT‐proBNP alone was as discriminatory as the base model for predicting death (C‐statistic, 0.745 versus 0.744, P=0.95) and the cardiovascular composite outcome (C‐statistic, 0.723 versus 0.731, P=0.37). When NT‐proBNP was added, it increased the predictive ability of the base model for death (C‐statistic, 0.779 versus 0.744, P<0.001) and for cardiovascular composite outcome (C‐statistic, 0.763 versus 0.731, P<0.001).ConclusionsIn high‐risk patients with T2DM, NT‐proBNP by itself demonstrated discriminatory ability similar to a multivariable model in predicting both death and cardiovascular events and should be considered for risk stratification.
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| 11. |
- Myhre, Peder Langeland, et al.
(författare)
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B-Type Natriuretic Peptide During Treatment With Sacubitril/Valsartan: ThePARADIGM-HFTrial.
- 2019
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 1558-3597 .- 0735-1097. ; 73:11, s. 1264-1272
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Tidskriftsartikel (refereegranskat)abstract
- Natriuretic peptides are substrates of neprilysin; hence, B-type natriuretic peptide (BNP) concentrations rise with neprilysin inhibition. Thus, the clinical validity of measuring BNP in sacubitril/valsartan-treated patients has been questioned, and use of N-terminal pro-B-type natriuretic peptides (NT-proBNP) has been preferred and recommended.The purpose of this study was to determine the prognostic performance of BNP measurements before and during treatment with sacubitril/valsartan.BNP and NT-proBNP were measured before and after 4 to 6weeks, 8 to 10weeks, and 9months of treatment with sacubitril/valsartan in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. We assessed the association of levels of these natriuretic peptides with the subsequent risk of cardiovascular death or hospitalization for HF.Median BNP concentration (before treatment: 202ng/l [Q1 to Q3: 126 to 335ng/l]) increased to 235ng/l (Q1to Q3: 128 to 422ng/l) after 8 to 10weeks of treatment. BNP concentrations doubled in 141 (18%) patients and tripled in 49 (6%) patients during the first 8 to 10weeks of sacubitril/valsartan. In contrast, such striking increases in NT-proBNP following the use of the neprilysin inhibitor were extremely rare. Treatment with sacubitril/valsartan causedarightward shift in the distribution of BNP when compared with NT-proBNP, but both peptides retained theirprognostic accuracy (C-statistics of 63% to 67% for BNP and C-statistics of 64% to 70% for NT-proBNP) with nodifference between the 2 biomarkers. Increases in both BNP and NT-proBNP during 8 to 10weeks of sacubitril/valsartanwere associated with worse outcomes (p=0.003 and p=0.005, respectively).Circulating levels of BNP may increase meaningfully early after initiation of sacubitril/valsartan. In comparison, NT-proBNP is not a substrate of neprilysin inhibition, and thus may lead to less clinical confusion when measured within 8 to 10weeks of drug initiation. However, during treatment, either biomarker predicts the risk of major adverse outcomes in patients treated with angiotensin receptor-neprilysin inhibitors. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255).
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| 12. |
- 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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| 13. |
- 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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| 14. |
- Platz, Elke, et al.
(författare)
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Prevalence and prognostic importance of precipitating factors leading to heart failure hospitalization: Recurrent hospitalizations and mortality
- 2018
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 20:2, s. 295-303
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 The Authors European Journal of Heart Failure. Aims: Hospitalizations for heart failure (HF) are common and are associated with significant morbidity, mortality and cost. However, precipitating factors leading to HF hospitalization and their importance with respect to subsequent outcomes are not well understood. Methods and results: The symptoms and signs present at admission and investigator-identified factors thought to have contributed to the first adjudicated HF hospitalization in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) programme were prospectively collected and stratified by ejection fraction (EF). Potential precipitants were collected using a specifically designed case report form and categorized according to the presence of cardiovascular (CV), non-CV and unknown factors. Associations between these factors and subsequent rehospitalization and mortality rates were examined. Of 1668 patients who experienced HF hospitalization, 1152 had reduced EF (≤40%) (HFrEF) and 516 had preserved EF (HFpEF). Overall, 54% had CV, 32% had non-CV and 14% had unknown factors thought to have precipitated HF, with similar proportions in the HFrEF and HFpEF groups. The most common precipitants were arrhythmia (15%), other non-CV factors (11%) and respiratory infection (10%). Subsequent CV readmission rates were highest in those whose initial HF hospitalization was precipitated by CV factors. However, mortality rates were similar among patients with any of the three categories of precipitating factors. Results were similar in HFrEF and HFpEF. Conclusions: Among chronic HF patients hospitalized for decompensation, the investigator-reported precipitating factor was not associated with the subsequent mortality rate, but was associated with type of readmission: readmissions for CV reasons were more likely when the index precipitant was CV.
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| 15. |
- Solomon, Scott D., et al.
(författare)
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Baseline Characteristics of Patients With HF With Mildly Reduced and Preserved Ejection Fraction : DELIVER Trial.
- 2022
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Ingår i: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 10:3, s. 184-197
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials. BACKGROUND: The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter-2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF). METHODS: Adults with symptomatic HF and LVEF $>$40%, with or without type 2 diabetes mellitus, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo. RESULTS: A total of 6,263 patients were randomized (mean age: 72 +/- 10 years; 44% women; 45% type 2 diabetes mellitus; 45% with body mass index $>$/=30 kg/m(2); and 57% with history of atrial fibrillation or flutter). Most participants had New York Heart Association functional class II symptoms (75%). Baseline mean LVEF was 54.2 +/- 8.8% and median NT-proBNP of 1,399 pg/mL (IQR: 962 to 2,210 pg/mL) for patients in atrial fibrillation/flutter compared with 716 pg/mL (IQR: 469 to 1,281 pg/mL) in those who were not. Patients in both hospitalized and ambulatory settings were enrolled, including 10% enrolled in-hospital or within 30 days of a hospitalization for HF. Eighteen percent of participants had HF with improved LVEF. CONCLUSIONS: DELIVER is the largest and broadest clinical trial of this population to date and enrolled high-risk, well-treated patients with HF with mildly reduced and preserved LVEF. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [NCT03619213]).
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| 16. |
- Solomon, Scott D., et al.
(författare)
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Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan : The DAPA-HF Trial.
- 2020
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Ingår i: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 8:10, s. 811-818
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: This study assessed the efficacy and safety of dapagliflozin in patients who were or were not taking sacubitril/valsartan at baseline in the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial. BACKGROUND: Both the angiotensin receptor neprilysin-inhibitor sacubitril/valsartan and the sodium glucose co-transporter 2 inhibitor dapagliflozin reduced cardiovascular death and heart failure (HF) hospitalization in patients with HF with reduced ejection fraction (HFrEF). Whether either of these classes of drugs influences the effectiveness or safety of the other remains unknown. METHODS: DAPA-HF was a 4,744 patient trial that compared dapagliflozin with placebo in patients with HFrEF. Patients were analyzed according to whether they were taking sacubitril/valsartan at randomization. The efficacy of dapagliflozin on the primary composite outcome (CV death or episode of worsening heart failure), its components, and all-cause death was examined according to sacubitril/valsartan and the interaction tested. Predefined safety outcomes were examined by sacubitril/valsartan group. RESULTS: A total of 508 patients (10.7%) enrolled in DAPA-HF were treated with sacubitril/valsartan at baseline. Patients prescribed sacubitril/valsartan were more likely to be from North America or Europe, to have lower ejection fractions and systolic and diastolic blood pressures, but were similar with respect to age, New York Heart Association functional class, history of diabetes, and use of other evidence-based HF therapies. The benefit of dapagliflozin compared with placebo was similar in patients taking sacubitril/valsartan (hazard ratio: 0.75; 95% confidence interval 0.50 to 1.13) compared with those not taking sacubitril/valsartan (hazard ratio: 0.74; 95% confidence interval 0.65 to 0.86) for the primary endpoint of cardiovascular death or worsening HF; similar findings were observed for secondary endpoints. All measures of safety, including episodes related to hypovolemia, were similar among patients randomized to dapagliflozin or placebo, whether they received background sacubitril/valsartan. CONCLUSIONS: Dapagliflozin was similarly efficacious and safe in patients who were and who were not taking sacubitril/valsartan in the DAPA-HF trial, which suggested that the use of both agents together could further lower morbidity and mortality in patients with HFrEF. (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure [DAPA-HF]; NCT03036124).
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| 17. |
- Solomon, Scott D, et al.
(författare)
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Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure.
- 2020
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 141:5, s. 352-361
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Tidskriftsartikel (refereegranskat)abstract
- Background: While disease modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin- system (RAS) inhibitor alone in two similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF (LVEF eligibility≤40%; n=8,399) and PARAGON-HF (LVEF eligibility≥45%; n=4,796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories:≤22.5% (n=1269), >22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality and non-cardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. Results: Among 13,195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of non-cardiovascular death, among patients in the highest vs. lowest groups. Overall sacubitril/valsartan was superior to RAS inhibition for first cardiovascular death or heart failure hospitalization (HR 0.84, 95% CI 0.78, 0.90), cardiovascular death (HR 0.84, 95% CI 0.76, 0.92), heart failure hospitalization (HR 0.84, 95% CI 0.77, 0.91), and all-cause mortality (HR 0.88, 95% CI 0.81, 0.96). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction p=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. Conclusions:The therapeutic effects of sacubitril/valsartan, compared with a RAS inhibitor alone, vary by LVEF, with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. Clinical Trial Registration: URL: https://clinicaltrials.gov PARAGON-HF Unique Identifier: NCT01920711. PARADIGM-HF Unique Identifier: NCT01035255.
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| 18. |
- Vaduganathan, Muthiah, et al.
(författare)
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Estimated Long-Term Benefit of Dapagliflozin in Patients With Heart Failure.
- 2022
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 80:19, s. 1775-1784
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recent guidelines support consideration of sodium-glucose cotransporter-2 inhibitors in the long-term management of heart failure (HF) with mildly reduced or preserved ejection fraction. Patients and clinicians may be interested in the expected lifetime benefits of sodium- glucose cotransporter-2 inhibitors in this population. OBJECTIVES: This study aimed to estimate event-free survival gains from long-term use of dapagliflozin in patients with HF with mildly reduced or preserved ejection fraction overall and in clinically relevant subgroups. METHODS: In this prespecified analysis of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), we applied validated nonparametric age-based methods to extrapolate potential gains in survival free from the primary endpoint (cardiovascular death or worsening HF event) from long-term use of dapagliflozin. Eligible participants had symptomatic HF, left ventricular ejection fraction $>$40%, elevated natriuretic peptide levels, and structural heart disease. For every year between the ages of 55 and 85 years, we estimated event-free survival using age at randomization rather than time from randomization as the time horizon. Residual lifespan free from a primary endpoint was estimated based on area under the survival curve in each arm. RESULTS: Among 6,263 participants, mean survival free from the primary endpoint for a 65-year-old participant was 12.1 years (95% CI: 11.0-13.2 years) with dapagliflozin and 9.7 years (95% CI: 8.8-10.7 years) with placebo, representing a 2.3-year (95% CI: 0.9-3.8 years) event-free survival gain (P = 0.002). Treatment gains in survival free from the primary endpoint ranged from 2.0 years (95% CI: -0.6 to 4.6 years) in a 55-year-old to 1.2 years (95% CI: -0.1 to 2.4 years) in a 75-year-old patient. Mean event-free survival was greater with dapagliflozin than with placebo across all 14 subgroups. CONCLUSIONS: Treatment with dapagliflozin is projected to extend event-free survival by up to 2.0 to 2.5 years among middle-aged and older individuals with HF with mildly reduced or preserved ejection fraction. (DELIVER [Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure]; NCT03619213).
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| 19. |
- Vaduganathan, Muthiah, et al.
(författare)
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Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction : A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial.
- 2022
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 7:12, s. 1259-1263
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Dapagliflozin was recently shown to reduce cardiovascular death or worsening heart failure (HF) events in patients with HF with mildly reduced or preserved ejection fraction in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. Objective: To evaluate the time course of benefits of dapagliflozin on clinically relevant outcomes in this population. Design, Setting, and Participants: The DELIVER trial was a global phase 3 clinical trial that randomized patients with HF with mildly reduced or preserved ejection fraction to dapagliflozin or matching placebo. Inclusion criteria included symptomatic HF, left ventricular ejection fraction greater than 40%, elevated natriuretic peptide levels, and evidence of structural heart disease. In this prespecified secondary analysis of the DELIVER trial, to examine the timeline to onset of clinical benefit with dapagliflozin, hazard ratios (HR) and 95% CIs were iteratively estimated for the primary composite end point and worsening HF events alone with truncated data at every day postrandomization. Time to first and sustained statistical significance of dapagliflozin for these end points were then examined. Participants were enrolled from August 2018 to December 2020, and for this secondary analysis, data were analyzed from April to September 2022. Interventions: Dapagliflozin, 10 mg, once daily or matching placebo. Main Outcomes and Measures: The primary outcome was time to first occurrence of cardiovascular death or worsening HF (hospitalization for HF or urgent HF visit requiring intravenous HF therapies). Results: Overall, 6263 patients were randomized across 350 centers in 20 countries. Of 6263 included patients, 2747 (43.9%) were women, and the mean (SD) age was 71.7 (9.6) years. During a median (IQR) of 2.3 (1.7-2.8) years’ follow- up, 1122 primary end point events occurred, with an incidence rate per 100 patient-years of 8.7 (95% CI, 8.2-9.2). Time to first nominal statistical significance for the primary end point was 13 days (HR, 0.45; 95% CI, 0.20-0.99; P = .046), and significance was sustained from day 15 onwards. First and sustained statistical significance was reached for worsening HF events (HR, 0.45; 95% CI, 0.21-0.96; P = .04) by day 16 after randomization. Significant benefits for the primary end point and worsening HF events were sustained at 30 days, 90 days, 6 months, 1 year, 2 years, and final follow-up (primary end point: HR, 0.82; 95% CI, 0.73-0.92; worsening HF events: HR, 0.79; 95% CI, 0.69-0.91). Conclusions and Relevance: In the DELIVER trial, dapagliflozin led to early and sustained reductions in clinical events in patients with HF with mildly reduced or preserved ejection fraction with statistically significant reductions observed within 2 weeks of treatment initiation. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.
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| 20. |
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| 21. |
- Wijkman, Magnus, 1978-, et al.
(författare)
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NT-proBNP versus routine clinical risk factors as a predictor of cardiovascular events or death in people with dysglycemia & ndash : A brief report from the ORIGIN trial
- 2021
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Ingår i: Journal of diabetes and its complications. - : ELSEVIER SCIENCE INC. - 1056-8727 .- 1873-460X. ; 35:7
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Tidskriftsartikel (refereegranskat)abstract
- In patients with diabetes and cardiovascular or renal comorbidities, circulating levels of the N-terminal fragment of prohormone B-type natriuretic peptide (NT-proBNP) have similar discriminatory ability as multivariate models for prediction of cardiovascular events or death. We validated this finding in patients with dysglycemia not selected for co-existing cardiorenal diseases. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
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| 22. |
- Wijkman, Magnus, et al.
(författare)
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Resistance to antihypertensive treatment and long-term risk: The Atherosclerosis Risk in Communities study
- 2021
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Ingår i: The Journal of Clinical Hypertension. - : Wiley. - 1524-6175 .- 1751-7176. ; 23:10, s. 1887-1896
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Tidskriftsartikel (refereegranskat)abstract
- More stringent blood pressure (BP) goals have led to greater prevalence of apparent resistant hypertension (ARH), yet the long-term prognostic impact of ARH diagnosed according to these goals in the general population remains unknown. We assessed the prognostic impact of ARH according to contemporary BP goals in 9612 participants of the Atherosclerosis Risk in Communities (ARIC) study without previous cardiovascular disease. ARH, defined as BP above goal (traditional goal <140/90 mmHg, more stringent goal <130/80 mmHg) despite the use of >= 3 antihypertensive drug classes or any BP with >= 4 antihypertensive drug classes (one of which was required to be a diuretic) was compared with controlled hypertension (BP at goal with 1-3 antihypertensive drug classes). Cox regression models were adjusted for age, sex, race, study center, BMI, heart rate, smoking, eGFR, LDL, HDL, triglycerides, and diabetes. Using the traditional BP goal, 133 participants (3.8% of the treated) had ARH. If the more stringent BP goal was instead applied, 785 participants (22.6% of the treated) were reclassified from controlled hypertension to uncontrolled hypertension (n = 725) or to ARH (n = 60). Over a median follow-up time of 19 years, ARH was associated with increased risk for a composite end point (all-cause mortality, hospitalization for myocardial infarction, stroke, or heart failure) regardless of whether traditional (adjusted HR 1.50, 95% CI: 1.23-1.82) or more stringent (adjusted HR 1.43, 95% CI: 1.20-1.70) blood pressure goals were applied. We conclude that in patients free from cardiovascular disease, ARH predicted long-term risk regardless of whether traditional or more stringent BP criteria were applied.
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