| 1. |
- Adamson, Carly, et al.
(author)
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Dapagliflozin for Heart Failure According to Body Mass Index : The DELIVER Trial.
- 2022
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In: European heart journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 43:41, s. 4406-4417
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Journal article (peer-reviewed)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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| 2. |
- Adamson, Carly, et al.
(author)
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Efficacy of Dapagliflozin in Heart Failure with Reduced Ejection Fraction According to Body Mass Index.
- 2021
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In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:10, s. 1662-1672
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Journal article (peer-reviewed)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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| 3. |
- Adamson, Carly, et al.
(author)
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IGFBP-7 and Outcomes in Heart Failure With Reduced Ejection Fraction : Findings From DAPA-HF.
- 2023
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In: JACC. Heart failure. - : Elsevier BV. - 2213-1779 .- 2213-1787. ; 11:3, s. 291-304
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Journal article (peer-reviewed)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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| 4. |
- Adamson, Carly, et al.
(author)
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Liver Tests and Outcomes in Heart Failure with Reduced Ejection Fraction : Findings from DAPA-HF.
- 2022
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In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:10, s. 1856-1868
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Journal article (peer-reviewed)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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| 5. |
- Bhatt, Ankeet S., et al.
(author)
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Operational Challenges and Mitigation Measures during the COVID-19 Pandemic-Lessons from DELIVER.
- 2023
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In: American heart journal. ; 263, s. 133-140
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Journal article (peer-reviewed)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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| 6. |
- Butt, Jawad H., et al.
(author)
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Atrial Fibrillation and Dapagliflozin Efficacy in Patients With Preserved or Mildly Reduced Ejection Fraction.
- 2022
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 80:18, s. 1705-1717
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Journal article (peer-reviewed)abstract
- BACKGROUND: Atrial fibrillation (AF) is common in heart failure (HF), is associated with worse outcomes compared with sinus rhythm, and may modify the effects of therapy. OBJECTIVES: This study examined the effects of dapagliflozin according to the presence or not of AF in the DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trial. METHODS: A total of 6,263 patients with HF with New York Heart Association functional class II-IV, left ventricular ejection fraction $>$40%, evidence of structural heart disease, and elevated N-terminal pro-B-type natriuretic peptide levels were randomized to dapagliflozin or placebo. Clinical outcomes and the effect of dapagliflozin, according to AF status, were examined. The primary outcome was a composite of cardiovascular death or worsening HF. RESULTS: Of the 6,261 patients with data on baseline AF, 43.3% had no AF, 18.0% had paroxysmal AF, and 38.7% had persistent/permanent AF. The risk of the primary endpoint was higher in patients with AF, especially paroxysmal AF, driven by a higher rate of HF hospitalization: no AF, HF hospitalization rate per 100 person-years (4.5 [95% CI: 4.0-5.1]), paroxysmal AF (7.5 [95% CI: 6.4-8.7]), and persistent/permanent AF (6.4 [95% CI: 5.7-7.1]) (P $<$ 0.001). The benefit of dapagliflozin on the primary outcome was consistent across AF types: no AF, HR: 0.89 (95% CI: 0.74-1.08); paroxysmal AF, HR: 0.75 (95% CI: 0.58-0.97); persistent/permanent AF, HR: 0.79 (95% CI: 0.66-0.95) (Pinteraction = 0.49). Consistent effects were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the KCCQ- TSS. CONCLUSIONS: In DELIVER, the beneficial effects of dapagliflozin compared with placebo on clinical events and symptoms were consistent, irrespective of type of AF at baseline. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. [DELIVER]; NCT03619213).
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| 7. |
- Butt, Jawad H., et al.
(author)
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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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In: Annals of internal medicine. ; 175:6, s. 820-830
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Journal article (peer-reviewed)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.
(author)
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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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In: Circulation. ; 146:16, s. 1210-1224
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Journal article (peer-reviewed)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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| 9. |
- Butt, Jawad H., et al.
(author)
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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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In: Circulation. Heart failure. ; 14:12
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Journal article (peer-reviewed)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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| 10. |
- Cunningham, Jonathan W., et al.
(author)
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Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction.
- 2022
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 80:14, s. 1302-1310
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Journal article (peer-reviewed)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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| 11. |
- Dewan, Pooja, et al.
(author)
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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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In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 23:4, s. 632-643
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Journal article (peer-reviewed)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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| 12. |
- Docherty, Kieran F., et al.
(author)
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Effect of Dapagliflozin, Compared With Placebo, According to Baseline Risk in DAPA-HF.
- 2022
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In: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 10:2, s. 104-118
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Journal article (peer-reviewed)abstract
- OBJECTIVES: The authors sought to examine the effect of dapagliflozin across the spectrum of risk in patients enrolled in DAPA-HF. BACKGROUND: In the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin decreased the risk of worsening HF events and cardiovascular death in patients with HF and reduced ejection fraction. METHODS: The MAGGIC (Meta-analysis Global Group in Chronic Heart Failure) and the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) PREDICT-HF (Risk of Events and Death in the Contemporary Treatment of Heart Failure) risk models were used to categorize patients according to risk score quintiles. The authors analyzed rates of the primary composite outcome of a worsening HF event or cardiovascular death, its components, and all-cause mortality according to risk quintile and whether risk modified the effect of dapagliflozin. RESULTS: The MAGGIC score was available for 4,740 of 4,744 patients in DAPA-HF (median score 22 [IQR: 18-25]). A1-point increase was associated with an 8.2% (95% CI: 6.9%-9.4%) higher relative risk of the primary endpoint (P $<$ 0.001). The benefit of dapagliflozin over placebo for the primary endpoint was similar across the spectrum of MAGGIC risk score (interaction P = 0.71). Applying the overall relative risk reduction (26%) with dapagliflozin added to standard therapy resulted in 7 fewer patients in the highest MAGGIC risk quintile experiencing a primary outcome, compared with 2 in the lowest quintile, per 100 person-years of treatment. The findings with PREDICT-HF were similar, although this model led to better risk discrimination. CONCLUSIONS: The benefits of dapagliflozin were consistent across the broad spectrum of baseline risk in DAPA-HF.
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| 13. |
- Docherty, Kieran F., et al.
(author)
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Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction : A Prespecified Analysis of DAPA- HF.
- 2020
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In: Circulation. ; 142:17, s. 1623-1632
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Journal article (peer-reviewed)abstract
- BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure), dapagliflozin, added to guideline-recommended therapies, reduced the risk of mortality and heart failure (HF) hospitalization. We examined the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events. METHODS: Patients in New York Heart Association functional class II to IV, with a left ventricular ejection fraction
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| 14. |
- Docherty, Kieran F, et al.
(author)
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Effects of dapagliflozin in DAPA-HF according to background heart failure therapy.
- 2020
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In: European heart journal. - : Oxford University Press (OUP). - 1522-9645 .- 0195-668X. ; 41:25, s. 2379-2392
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Journal article (peer-reviewed)abstract
- In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure (HF) and death in patients with HF and reduced ejection fraction. We examined whether this benefit was consistent in relation to background HF therapy.In this post hoc analysis, we examined the effect of study treatment in the following yes/no subgroups: diuretic, digoxin, mineralocorticoid receptor antagonist (MRA), sacubitril/valsartan, ivabradine, implanted cardioverter-defibrillating (ICD) device, and cardiac resynchronization therapy. We also examined the effect of study drug according to angiotensin-converting enzyme inhibitor/angiotensin receptor blocker dose, beta-blocker (BB) dose, and MRA (≥50% and <50% of target dose). We analysed the primary composite endpoint of cardiovascular death or a worsening HF event. Most randomized patients (n=4744) were treated with a diuretic (84%), renin-angiotensin system (RAS) blocker (94%), and BB (96%); 52% of those taking a BB and 38% taking a RAS blocker were treated with ≥50% of the recommended dose. Overall, the dapagliflozin vs. placebo hazard ratio (HR) was 0.74 [95% confidence interval (CI) 0.65-0.85] for the primary composite endpoint (P<0.0001). The effect of dapagliflozin was consistent across all subgroups examined: the HR ranged from 0.57 to 0.86 for primary endpoint, with no significant randomized treatment-by-subgroup interaction. For example, the HR in patients taking a RAS blocker, BB, and MRA at baseline was 0.72 (95% CI 0.61-0.86) compared with 0.77 (95% CI 0.63-0.94) in those not on all three of these treatments (P-interaction 0.64).The benefit of dapagliflozin was consistent regardless of background therapy for HF.
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| 15. |
- Docherty, Kieran F., et al.
(author)
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Efficacy of Dapagliflozin in Black Versus White Patients With Heart Failure and Reduced Ejection Fraction.
- 2022
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In: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 10:1, s. 52-64
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Journal article (peer-reviewed)abstract
- OBJECTIVES: This study sought to investigate the efficacy and safety of dapagliflozin in Black and White patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in 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). BACKGROUND: Black patients may respond differently to certain treatments for HFrEF than White patients. METHODS: Patients with New York Heart Association functional class II to IV with an ejection fraction of $<$/=40% and elevated N-terminal pro-B-type natriuretic peptide were eligible for DAPA-HF. Because $>$99% of Black patients were randomized in the Americas, this post hoc analysis considered Black and White patients enrolled only in North and South America. The primary outcome was the composite of a worsening HF event (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death. RESULTS: Of the 4,744 patients randomized in DAPA-HF, 1,494 (31.5%) were enrolled in the Americas. Of these, 1,181 (79.0%) were White, and 225 (15.1%) were Black. Black patients had a higher rate of worsening HF events, but not mortality, compared with White patients. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint similarly in Black patients (HR: 0.62; 95% CI: 0.37-1.03) and White patients (HR: 0.68; 95% CI: 0.52-0.90; P-interaction = 0.70). Consistent benefits were observed for other prespecified outcomes, including the composite of total (first and repeat) HF hospitalizations and cardiovascular death (P-interaction = 0.43) and Kansas City Cardiomyopathy Questionnaire total symptom score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either Black or White patients. CONCLUSIONS: Dapagliflozin reduced the risk of worsening HF and cardiovascular death, and it improved symptoms, similarly in Black and White patients without an increase in adverse events. (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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| 16. |
- Heerspink, Hiddo J. L., et al.
(author)
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Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers
- 2019
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In: Diabetes, obesity and metabolism. - : Wiley-Blackwell Publishing Inc.. - 1462-8902 .- 1463-1326. ; 21:3, s. 720-725
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Journal article (peer-reviewed)abstract
- The sodium glucose co-transporter-2 inhibitor dapagliflozin has been shown to decrease urinary albumin-to-creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/d in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24 weeks, whereas UACR non-response was defined as ≤30% reduction at 24 weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24 weeks, the UACR-adjusted mean change from baseline was −71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in estimated glomerular filtration rate and systolic blood pressure versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic variables. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined.
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| 17. |
- Jackson, Alice M., et al.
(author)
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Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF.
- 2020
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In: Circulation. - 1524-4539. ; 142:11, s. 1040-1054
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Journal article (peer-reviewed)abstract
- BACKGROUND: In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo. METHODS: We examined the effects of study treatment in the following subgroups: no diuretic and diuretic dose equivalent to furosemide $<$40, 40, and $>$40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms. RESULTS: Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on $<$40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking $>$40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroups: hazard ratios were 0.57 (95% CI, 0.36-0.92), 0.83 (95% CI, 0.63-1.10), 0.77 (95% CI, 0.60-0.99), and 0.78 (95% CI, 0.63-0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68-0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow- up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization. CONCLUSIONS: The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
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| 18. |
- Jhund, Pardeep S., et al.
(author)
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Dapagliflozin across the Range of Ejection Fraction in Patients with Heart Failure : A Patient-Level, Pooled Meta-Analysis of DAPA-HF and DELIVER.
- 2022
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In: Nature medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:9, s. 1956-1964
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Journal article (peer-reviewed)abstract
- Whether the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction ($<$/=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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| 19. |
- Kosiborod, Mikhail N., et al.
(author)
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Effect of Dapagliflozin on Health Status in Patients With Preserved or Mildly Reduced Ejection Fraction.
- 2023
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 81:5, s. 460-473
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Journal article (peer-reviewed)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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| 20. |
- Kosiborod, Mikhail N., et al.
(author)
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Effects of Dapagliflozin on Symptoms, Function, and Quality of Life in Patients With Heart Failure and Reduced Ejection Fraction : Results From the DAPA-HF Trial.
- 2020
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In: Circulation. ; 141:2, s. 90-99
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse- Outcomes in Heart Failure), sodium-glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ). METHODS: KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months. RESULTS: A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 [interquartile range, 58.3-91.7]). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertile: hazard ratio, 0.70 [95% CI, 0.57-0.86]; hazard ratio, 0.77 [95% CI, 0.61-0.98]; hazard ratio, 0.62 [95% CI, 0.46-0.83]; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P$<$0.0001 for all). Fewer patients treated with dapagliflozin had a deterioration in KCCQ-TSS (odds ratio, 0.84 [95% CI, 0.78-0.90]; P$<$0.0001); and more patients had at least small, moderate, and large improvements (odds ratio, 1.15 [95% CI, 1.08-1.23]; odds ratio, 1.15 [95% CI, 1.08-1.22]; odds ratio, 1.14 [95% CI, 1.07-1.22]; number needed to treat=14, 15, and 18, respectively; P$<$0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score). CONCLUSIONS: Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.
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| 21. |
- McDowell, Kirsty, et al.
(author)
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Dapagliflozin Reduces Uric Acid Concentration, an Independent Predictor of Adverse Outcomes in DAPA-HF.
- 2022
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In: European journal of heart failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:6, s. 1066-1076
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Journal article (peer-reviewed)abstract
- AIMS: Blood uric acid (UA) levels are frequently elevated in patients with heart failure and reduced ejection fraction (HFrEF), may lead to gout and are associated with worse outcomes. Reduction in UA is desirable in HFrEF and sodium-glucose cotransporter 2 inhibitors may have this effect. We aimed to examine the association between UA and outcomes, the effect of dapagliflozin according to baseline UA level, and the effect of dapagliflozin on UA in patients with HFrEF in the DAPA-HF trial. METHODS AND RESULTS: The association between UA and the primary composite outcome of cardiovascular death or worsening heart failure, its components, and all-cause mortality was examined using Cox regression analyses among 3119 patients using tertiles of UA, after adjustment for other prognostic variables. Change in UA from baseline over 12 months was also evaluated. Patients in tertile 3 (UA $>$/=6.8 mg/dl) versus tertile 1 ($<$5.4 mg/dl) were younger (66.3 +/- 10.8 vs. 68 +/- 10.2 years), more often male (83.1% vs. 71.5%), had lower estimated glomerular filtration rate (58.2 +/- 17.4 vs. 70.6 +/- 18.7 ml/min/1.73 m(2) ), and more often treated with diuretics. Higher UA was associated with a greater risk of the primary outcome (adjusted hazard ratio tertile 3 vs. tertile 1: 1.32, 95% confidence interval [CI] 1.06-1.66; p = 0.01). The risk of heart failure hospitalization and cardiovascular death increased by 7% and 6%, respectively per 1 mg/dl unit increase of UA (p = 0.04 and p = 0.07). Spline analysis revealed a linear increase in risk above a cut-off UA value of 7.09 mg/dl. Compared with placebo, dapagliflozin reduced UA by 0.84 mg/dl (95% CI -0.93 to -0.74) over 12 months (p $<$ 0.001). Dapagliflozin improved outcomes, irrespective of baseline UA concentration. CONCLUSION: Uric acid remains an independent predictor of worse outcomes in a well-treated contemporary HFrEF population. Compared with placebo, dapagliflozin reduced UA and improved outcomes irrespective of UA concentration.
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| 22. |
- McDowell, Kirsty, et al.
(author)
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Prognostic Models for Mortality and Morbidity in Heart Failure with Preserved Ejection Fraction
- 2024
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In: JAMA Cardiology. - 2380-6583.
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Journal article (peer-reviewed)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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| 23. |
- McMurray, John J V, et al.
(author)
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A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF).
- 2019
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In: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 21:5, s. 665-675
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of incident heart failure hospitalization in individuals with type 2 diabetes who have, or are at high risk of, cardiovascular disease. Most patients in these trials did not have heart failure at baseline and the effect of SGLT2 inhibitors on outcomes in individuals with established heart failure (with or without diabetes) is unknown.DESIGN AND METHODS: The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) is an international, multicentre, parallel group, randomized, double-blind, study in patients with chronic heart failure, evaluating the effect of dapagliflozin 10 mg, compared with placebo, given once daily, in addition to standard care, on the primary composite outcome of a worsening heart failure event (hospitalization or equivalent event, i.e. an urgent heart failure visit) or cardiovascular death. Patients with and without diabetes are eligible and must have a left ventricular ejection fraction ≤ 40%, a moderately elevated N-terminal pro B-type natriuretic peptide level, and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 . The trial is event-driven, with a target of 844 primary outcomes. Secondary outcomes include the composite of total heart failure hospitalizations (including repeat episodes), and cardiovascular death and patient-reported outcomes. A total of 4744 patients have been randomized.CONCLUSIONS: DAPA-HF will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in a broad spectrum of patients with heart failure and reduced ejection fraction.
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| 24. |
- Myhre, Peder L., et al.
(author)
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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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In: JACC. Heart failure. - : Elsevier BV. - 2213-1779. ; 10:12, s. 902-913
-
Journal article (peer-reviewed)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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| 25. |
- Neeland, Ian J, et al.
(author)
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The Impact of Empagliflozin on Obstructive Sleep Apnea and Cardiovascular and Renal Outcomes: An Exploratory Analysis of the EMPA-REG OUTCOME Trial.
- 2020
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In: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 1935-5548 .- 0149-5992. ; 43:12, s. 3007-3015
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Journal article (peer-reviewed)abstract
- To explore the effects of empagliflozin on the incidence of obstructive sleep apnea (OSA) and its effects on metabolic, cardiovascular (CV), and renal outcomes among participants with or without OSA in the EMPA-REG OUTCOME trial.Participants with diabetes and CV disease were randomized to empagliflozin (10 and 25 mg) or placebo daily in addition to standard of care. OSA was assessed by investigator report using Medical Dictionary for Regulatory Activities version 18.0, and CV outcomes were independently adjudicated. Analyses were performed using multivariable-adjusted Cox regression models.OSA was reported in 391 of 7,020 (5.6%) participants at baseline. Those with OSA were more likely to be male (83% vs. 71%) and to have moderate to severe obesity (BMI ≥35 kg/m2; 55% vs. 18%). Over a median of 3.1 years, empagliflozin had similar placebo-adjusted reductions in HbA1c, waist circumference, and systolic blood pressure, regardless of OSA status, but a larger effect on weight (adjusted mean ± SE difference at week 52: OSA vs. no OSA -2.9 ± 0.5 vs. -1.9 ± 0.1 kg). Incidence of 3-point major adverse CV events, CV death, heart failure hospitalization, and incident or worsening nephropathy in the placebo group was 1.2- to 2.0-fold higher for those with baseline OSA compared with those without. Empagliflozin significantly reduced the risk for outcomes regardless of OSA status (P-interaction all >0.05). Fifty patients reported a new diagnosis of OSA through 7 days after medication discontinuation, and this occurred less often with empagliflozin treatment (hazard ratio 0.48 [95% CI 0.27, 0.83]).In EMPA-REG OUTCOME, participants with OSA had greater comorbidity and higher frequency of CV and renal events. Empagliflozin had favorable effects on risk factors and CV and renal outcomes regardless of preexisting OSA and may also reduce the risk for new-onset OSA.
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