| 1. |
- 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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| 2. |
- McDowell, Kirsty, et al.
(författare)
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Prognostic Models for Mortality and Morbidity in Heart Failure with Preserved Ejection Fraction
- 2024
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Ingår i: JAMA Cardiology. - 2380-6583.
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. Objective: To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Design, Setting, and Participants: Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Exposures: Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Results: Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P <.001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P <.001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. Conclusions and Relevance: In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF..
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| 3. |
- Adamson, Carly, et al.
(författare)
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Efficacy of Dapagliflozin in Heart Failure with Reduced Ejection Fraction According to Body Mass Index.
- 2021
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:10, s. 1662-1672
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: In heart failure with reduced ejection fraction (HFrEF), there is an ’obesity paradox’, where survival is better in patients with a higher body mass index (BMI) and weight loss is associated with worse outcomes. We examined the effect of a sodium-glucose co-transporter 2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse- outcomes in Heart Failure trial (DAPA-HF). METHODS AND RESULTS: Body mass index was examined using standard categories, i.e. underweight ($<$18.5 kg/m(2) ); normal weight (18.5-24.9 kg/m(2) ); overweight (25.0-29.9 kg/m(2) ); obesity class I (30.0-34.9 kg/m(2) ); obesity class II (35.0-39.9 kg/m(2) ); and obesity class III ($>$/=40 kg/m(2) ). The primary outcome in DAPA-HF was the composite of worsening heart failure or cardiovascular death. Overall, 1348 patients (28.4%) were under/normal- weight, 1722 (36.3%) overweight, 1013 (21.4%) obesity class I and 659 (13.9%) obesity class II/III. The unadjusted hazard ratio (95% confidence interval) for the primary outcome with obesity class 1, the lowest risk group, as reference was: under/normal-weight 1.41 (1.16-1.71), overweight 1.18 (0.97-1.42), obesity class II/III 1.37 (1.10-1.72). Patients with class I obesity were also at lowest risk of death. The effect of dapagliflozin on the primary outcome and other outcomes did not vary by baseline BMI, e.g. hazard ratio for primary outcome: under/normal-weight 0.74 (0.58-0.94), overweight 0.81 (0.65-1.02), obesity class I 0.68 (0.50-0.92), obesity class II/III 0.71 (0.51-1.00) (P-value for interaction = 0.79). The mean decrease in weight at 8 months with dapagliflozin was 0.9 (0.7-1.1) kg (P $<$ 0.001). CONCLUSION: We confirmed an ’obesity survival paradox’ in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03036124.
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| 4. |
- 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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| 5. |
- Berg, David D., et al.
(författare)
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Serial Assessment of High-Sensitivity Cardiac Troponin and the Effect of Dapagliflozin in Patients With Heart Failure With Reduced Ejection Fraction : An Analysis of the DAPA-HF Trial.
- 2022
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Ingår i: Circulation. ; 145:3, s. 158-169
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction. Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels. METHODS: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with New York Heart Association class II to IV symptoms and left ventricular ejection fraction $<$/=40% (median follow-up, 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3112 patients and at 1 year in 2506 patients. The primary end point was adjudicated worsening heart failure or cardiovascular death. Clinical end points were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical end points with dapagliflozin versus placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored. RESULTS: Median baseline hsTnT concentration was 20.0 (25th-75th percentile, 13.7-30.2) ng/L. Over 1 year, 67.9% of patients had a $>$/=10% relative increase or decrease in hsTnT concentrations, and 43.5% had a $>$/=20% relative change. A stepwise gradient of higher risk for the primary end point was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio Q4 versus Q1, 3.44 [95% CI, 2.46-4.82]). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary end point. The relative reduction in the primary end point with dapagliflozin was consistent across quartiles of baseline hsTnT (P-interaction=0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5% [95% CI, 1.0%-14.0%]). Dapagliflozin tended to attenuate the increase in hsTnT over time compared with placebo (relative least squares mean reduction, -3% [-6% to 0%]; P=0.076). CONCLUSIONS: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary end point, irrespective of baseline hsTnT levels. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
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| 6. |
- Brum, Wagner S., et al.
(författare)
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Effect of Neprilysin Inhibition on Alzheimer Disease Plasma Biomarkers : A Secondary Analysis of a Randomized Clinical Trial
- 2024
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Ingår i: JAMA Neurology. - 2168-6149. ; 81:2, s. 197-200
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-β (Aβ) accumulation is critical in Alzheimer disease (AD), and neprilysin is involved in physiologically clearing Aβ. Concerns exist regarding long-term use of sacubitril/valsartan, a neprilysin inhibitor and angiotensin receptor blocker used for heart failure, and its potential to increase AD risk. We evaluated neprilysin inhibition’s effect on AD blood biomarkers in patients with coronary heart disease.
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| 7. |
- Butt, Jawad H., et al.
(författare)
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Efficacy and Safety of Dapagliflozin According to Frailty in Heart Failure With Reduced Ejection Fraction : A Post Hoc Analysis of the DAPA- HF Trial.
- 2022
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Ingår i: Annals of internal medicine. ; 175:6, s. 820-830
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Frailty may modify the risk-benefit profile of certain treatments, and frail patients may have reduced tolerance to treatments. OBJECTIVE: To investigate the efficacy of dapagliflozin according to frailty status, using the Rockwood cumulative deficit approach, in DAPA- HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). DESIGN: Post hoc analysis of a phase 3 randomized clinical trial. (ClinicalTrials.gov: NCT03036124). SETTING: 410 sites in 20 countries. PATIENTS: Patients with symptomatic heart failure (HF) with a left ventricular ejection fraction of 40% or less and elevated natriuretic peptide. INTERVENTION: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. MEASUREMENTS: The primary outcome was worsening HF or cardiovascular death. RESULTS: Of the 4744 patients randomly assigned in DAPA-HF, a frailty index (FI) was calculable in 4742. In total, 2392 patients (50.4%) were in FI class 1 (FI $<$/=0.210; not frail), 1606 (33.9%) in FI class 2 (FI 0.211 to 0.310; more frail), and 744 (15.7%) in FI class 3 (FI $>$/=0.311; most frail). The median follow-up time was 18.2 months. Dapagliflozin reduced the risk for worsening HF or cardiovascular death, regardless of FI class. The differences in event rate per 100 person-years for dapagliflozin versus placebo from lowest to highest FI class were -3.5 (95% CI, -5.7 to -1.2), -3.6 (CI, -6.6 to -0.5), and -7.9 (CI, -13.9 to -1.9). Consistent benefits were observed for other clinical events and health status, but the absolute reductions were generally larger in the most frail patients. Study drug discontinuation and serious adverse events were not more frequent with dapagliflozin than placebo, regardless of FI class. LIMITATION: Enrollment criteria precluded the inclusion of very high-risk patients. CONCLUSION: Dapagliflozin improved all outcomes examined, regardless of frailty status. However, the absolute reductions were larger in more frail patients. PRIMARY FUNDING SOURCE: AstraZeneca.
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| 8. |
- Butt, Jawad H., et al.
(författare)
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Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to N-Terminal Pro-B-Type Natriuretic Peptide : Insights From the DAPA-HF Trial.
- 2021
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Ingår i: Circulation. Heart failure. ; 14:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Effective therapies for HFrEF usually reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and it is important to establish whether new treatments are effective across the range of NT- proBNP. METHODS: We evaluated both these questions in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction $<$/=40% and a NT-proBNP level $>$/=600 pg/mL ($>$/=600 ng/L; $>$/=400 pg/mL if hospitalized for HF within the previous 12 months or $>$/=900 pg/mL if atrial fibrillation/flutter) were eligible. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. RESULTS: Of the 4744 randomized patients, 4742 had an available baseline NT-proBNP measurement (median, 1437 pg/mL [interquartile range, 857-2650 pg/mL]). Compared with placebo, treatment with dapagliflozin significantly reduced NT-proBNP from baseline to 8 months (absolute least-squares mean reduction, -303 pg/mL [95% CI, -457 to -150 pg/mL]; geometric mean ratio, 0.92 [95% CI, 0.88-0.96]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of baseline NT-proBNP quartile; the hazard ratio for dapagliflozin versus placebo, from lowest to highest quartile was 0.43 (95% CI, 0.27-0.67), 0.77 (0.56-1.04), 0.78 (0.60-1.01), and 0.78 (0.64-0.95); P for interaction=0.09. Consistent benefits were observed for all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement ($>$/=5 points) in Kansas City Cardiomyopathy Questionnaire total symptom score (P for interaction=0.99) and decreased the proportion with a deterioration $>$/=5 points (P for interaction=0.87) across baseline NT-proBNP quartiles. CONCLUSIONS: In patients with HFrEF, dapagliflozin reduced NT-proBNP by 300 pg/mL after 8 months of treatment compared with placebo. In addition, dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, across the spectrum of baseline NT-proBNP levels included in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
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| 9. |
- Butt, Jawad H., et al.
(författare)
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Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction : A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.
- 2021
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Ingår i: JAMA cardiology. - : American Medical Association (AMA). - 2380-6583 .- 2380-6591. ; 6:6, s. 678-689
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Women may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men. Objective: To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Design, Setting, and Participants: Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B- type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021. Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy. Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. Results: A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of $>$/=5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of $>$/=5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women. Conclusions and Relevance: Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex. Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.
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| 10. |
- Dewan, Pooja, et al.
(författare)
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Effects of Dapagliflozin in Heart Failure with Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease : An Analysis of DAPA-HF.
- 2021
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Ingår i: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:4, s. 632-643
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Chronic obstructive pulmonary disease (COPD) is an important comorbidity in heart failure (HF) with reduced ejection fraction (HFrEF), associated with worse outcomes and often suboptimal treatment because of under-prescription of beta-blockers. Consequently, additional effective therapies are especially relevant in patients with COPD. The aim of this study was to examine outcomes related to COPD in a post hoc analysis of the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial. METHODS AND RESULTS: We examined whether the effects of dapagliflozin in DAPA-HF were modified by COPD status. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. Overall, 585 (12.3%) of the 4744 patients randomized had a history of COPD. Patients with COPD were more likely to be older men with a history of smoking, worse renal function, and higher baseline N-terminal pro B-type natriuretic peptide, and less likely to be treated with a beta-blocker or mineralocorticoid receptor antagonist. The incidence of the primary outcome was higher in patients with COPD than in those without [18.9 (95% confidence interval 16.0-22.2) vs. 13.0 (12.1-14.0) per 100 person-years; hazard ratio (HR) for COPD vs. no COPD 1.44 (1.21-1.72); P $<$ 0.001]. The effect of dapagliflozin, compared with placebo, on the primary outcome, was consistent in patients with [HR 0.67 (95% confidence interval 0.48-0.93)] and without COPD [0.76 (0.65-0.87); interaction P-value 0.47]. CONCLUSIONS: In DAPA-HF, one in eight patients with HFrEF had concomitant COPD. Participants with COPD had a higher risk of the primary outcome. The benefit of dapagliflozin on all pre-specified outcomes was consistent in patients with and without COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03036124.
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