Dapagliflozin: A Review in Symptomatic Heart Failure with Reduced Ejection Fraction.
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SUBMITTER: Blair HA
PROVIDER: S-EPMC8639555 | biostudies-literature | 2021 Nov
REPOSITORIES: biostudies-literature
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Dapagliflozin: A Review in Symptomatic Heart Failure with Reduced Ejection Fraction.
American journal of cardiovascular drugs : drugs, devices, and other interventions 20211015 6
Dapagliflozin [Farxiga<sup>®</sup> (USA); Forxiga<sup>®</sup> (EU)], a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was recently approved in the USA and the EU for the treatment of adults with symptomatic heart failure with reduced ejection fraction (HFrEF). The cardiovascular (CV) benefits of dapagliflozin were first observed in the DECLARE-TIMI 58 trial, in which dapagliflozin 10 mg/day significantly reduced the risk of CV death or hospitalization for HF in patients with type 2 diabetes m ...[more]
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Project description:ImportanceHeart failure with reduced ejection fraction produces substantial morbidity, mortality, and health care costs. Dapagliflozin is the first sodium-glucose cotransporter 2 inhibitor approved for the treatment of heart failure with reduced ejection fraction.ObjectiveTo examine the cost-effectiveness of adding dapagliflozin to guideline-directed medical therapy for heart failure with reduced ejection fraction in patients with or without diabetes.Design, setting, and participantsThis economic evaluation developed and used a Markov cohort model that compared dapagliflozin and guideline-directed medical therapy with guideline-directed medical therapy alone in a hypothetical cohort of US adults with similar clinical characteristics as participants of the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial. Dapagliflozin was assumed to cost $4192 annually. Nonparametric modeling was used to estimate long-term survival. Deterministic and probabilistic sensitivity analyses examined the impact of parameter uncertainty. Data were analyzed between September 2019 and January 2021.Main outcomes and measuresLifetime incremental cost-effectiveness ratio in 2020 US dollars per quality-adjusted life-year (QALY) gained.ResultsThe simulated cohort had a starting age of 66 years, and 41.8% had diabetes at baseline. Median (interquartile range) survival in the guideline-directed medical therapy arm was 6.8 (3.5-11.3) years. Dapagliflozin was projected to add 0.63 (95% uncertainty interval [UI], 0.25-1.15) QALYs at an incremental lifetime cost of $42 800 (95% UI, $37 100-$50 300), for an incremental cost-effectiveness ratio of $68 300 per QALY gained (95% UI, $54 600-$117 600 per QALY gained; cost-effective in 94% of probabilistic simulations at a threshold of $100 000 per QALY gained). Findings were similar in individuals with or without diabetes but were sensitive to drug cost.Conclusions and relevanceIn this study, adding dapagliflozin to guideline-directed medical therapy was projected to improve long-term clinical outcomes in patients with heart failure with reduced ejection fraction and be cost-effective at current US prices. Scalable strategies for improving uptake of dapagliflozin may improve long-term outcomes in patients with heart failure with reduced ejection fraction.
| S-EPMC8317009 | biostudies-literature
Project description:BackgroundPatients with heart failure (HF) and reduced ejection fraction will experience multiple hospitalizations for heart failure during the course of their disease. We assessed the efficacy of dapagliflozin on reducing the rate of total (ie, first and repeat) hospitalizations for heart failure in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure).MethodsThe total number of HF hospitalizations and cardiovascular deaths was examined by using the proportional-rates approach of Lei-Wei-Yang-Ying and a joint frailty model for each of recurrent HF hospitalizations and time to cardiovascular death. Variables associated with the risk of recurrent hospitalizations were explored in a multivariable Lei-Wei-Yang-Ying model.ResultsOf 2371 participants randomly assigned to placebo, 318 experienced 469 hospitalizations for HF; of 2373 assigned to dapagliflozin, 230 patients experienced 340 admissions. In a multivariable model, factors associated with a higher risk of recurrent HF hospitalizations included higher heart rate, higher N-terminal pro-B-type natriuretic peptide, and New York Heart Association class. In the Lei-Wei-Yang-Ying model, the rate ratio for the effect of dapagliflozin on recurrent HF hospitalizations or cardiovascular death was 0.75 (95% CI, 0.65-0.88), P=0.0002. In the joint frailty model, the rate ratio for total HF hospitalizations was 0.71 (95% CI, 0.61-0.82), P<0.0001, whereas, for cardiovascular death, the hazard ratio was 0.81 (95% CI, 0.67-0.98), P=0.0282.ConclusionsDapagliflozin reduced the risk of total (first and repeat) HF hospitalizations and cardiovascular death. Time-to-first event analysis underestimated the benefit of dapagliflozin in HF and reduced ejection fraction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
| S-EPMC8126492 | biostudies-literature
Project description:AimsIn 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 resultsBody mass index was examined using standard categories, i.e. underweight (<18.5 kg/m2 ); normal weight (18.5-24.9 kg/m2 ); overweight (25.0-29.9 kg/m2 ); obesity class I (30.0-34.9 kg/m2 ); obesity class II (35.0-39.9 kg/m2 ); and obesity class III (≥40 kg/m2 ). 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).ConclusionWe confirmed an 'obesity survival paradox' in HFrEF. We showed that dapagliflozin was beneficial across the wide range of BMI studied.Clinical trial registrationClinicalTrials.gov NCT03036124.
| S-EPMC9292627 | biostudies-literature
Project description:ImportanceIn the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, dapagliflozin was shown to reduce cardiovascular mortality and hospitalizations due to heart failure while improving patient-reported health status. However, the cost-effectiveness of adding dapagliflozin therapy to standard of care (SOC) is unknown.ObjectiveTo estimate the cost-effectiveness of dapagliflozin therapy among patients with chronic heart failure with reduced ejection fraction (HFrEF).Design, setting, and participantsThis Markov cohort cost-effectiveness model used estimates of therapy effectiveness, transition probabilities, and utilities from the DAPA-HF trial and other published literature. Costs were derived from published sources. Patients with HFrEF included subgroups based on diabetes status and health status impairment due to heart failure. We compiled parameters from the literature including DAPA-HF, on which our model is based, and many other sources from December 2019 to February 27, 2021. We performed our analysis in February 2021.ExposuresDapagliflozin or SOC.Main outcomes and measuresHospitalizations for heart failure, life-years, quality-adjusted life-years (QALYs), costs, and the cost per QALY gained (incremental cost-effectiveness ratio).ResultsIn the model, dapagliflozin therapy yielded a mean of 0.78 additional life-years and 0.46 additional QALYs compared with SOC at an incremental cost of $38 212, resulting in a cost per QALY gained of $83 650. The cost per QALY was similar for patients with or without diabetes and for patients with mild or moderate impairment of health status due to heart failure. The cost-effectiveness was most sensitive to estimates of the effect on mortality and duration of therapy effectiveness. If the cost of dapagliflozin decreased from $474 to $270 (43% decline), the cost per QALY gained would drop below $50 000.Conclusions and relevanceThese findings suggest that dapagliflozin provides intermediate value compared with SOC, based on American College of Cardiology/American Heart Association benchmarks. Additional data regarding the magnitude of mortality reduction would improve the precision of cost-effectiveness estimates.
| S-EPMC8156166 | biostudies-literature
Project description:ObjectivesThis study was aimed to systematically review published economic studies to determine whether dapagliflozin, a sodium-glucose co-transporter inhibitor, plus standard care therapy (SCT) is cost-effective in heart failure with reduced ejection fraction (HFrEF).MethodWe searched relevant keywords in PubMed, Scopus, Web of science, and Google Scholar to find related articles. Costs, QALYs, ICERs were extracted from eligible studies.ResultsTen studies finally included in the systematic review. The results of quality assessment of the study showed that a reasonable quality of all studies. Incremental QALYs were in favor of dapagliflozin plus SCT treatment regimen. In all the studies, the incremental costs per QALY was below the willingness-to-pay (WTP) threshold with the exception of one study in United Kingdom which the ICER and WTP were $83,650 and $50,000. All the studies determined the National Health Care perspective. The highest and lowest ICERs were $83,650 and $1991 per QALY in United Kingdom and Thailand, respectively.ConclusionResults of cost-effectiveness analyses showed that adjunct dapagliflozin plus SCT is cost-effective compared to SCT alone despite the additional costs of the drug. Finally it can be concluded that dapagliflozin is a worldwide cost-effective as an adjunct medicine in HFrEF management.
| S-EPMC9714165 | biostudies-literature
Project description:BackgroundIn 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.MethodsWe 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.ResultsOf 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.ConclusionsThe efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.
| S-EPMC7664959 | biostudies-literature
Project description:BackgroundPatients with heart failure with reduced ejection fraction (HFrEF) in Asia exhibit many differences from those in other parts of the world.ObjectivesThis study sought to investigate the efficacy and safety of dapagliflozin, compared with placebo, in HFrEF patients in Asia, compared with those elsewhere, enrolled in the DAPA-HF (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure) trial.MethodsPatients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and elevated N-terminal pro-B-type natriuretic peptide were eligible for the DAPA-HF trial. The primary outcome in the DAPA-HF trial was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.ResultsOf the 4,744 patients in the DAPA-HF trial, 1,096 (23.1%) were enrolled in Asia; 721 (15.2% overall, 65.8% of patients in Asia) were enrolled in East Asia (237 in China, 343 in Japan, and 141 in Taiwan), 138 (2.9% overall, 12.6% in Asia) in South-East Asia (Vietnam), and 237 (5.0% overall, 21.6% in Asia) in South Asia (India). Patients from Asia had similar rates of worsening HF events and mortality compared with patients elsewhere. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients from Asia (HR: 0.65; 95% CI: 0.49 to 0.87) as elsewhere (HR: 0.77; 95% CI: 0.66 to 0.89) (P for interaction = 0.32). Consistent benefits were observed for the other prespecified outcomes and among the regions of Asia. Study drug discontinuation and prespecified adverse events did not differ between regions.ConclusionsDapagliflozin, compared with placebo, reduced the risk of worsening HF events and cardiovascular death to the same extent in Asian patients as elsewhere. (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).
| S-EPMC9627879 | biostudies-literature
Project description:Circulating antigen carbohydrate 125 (CA125) has emerged as a proxy of fluid overload in heart failure. This study aimed to evaluate the effect of dapagliflozin on short-term CA125 levels in patients with stable heart failure with reduced ejection fraction (HFrEF) and whether these changes mediated the effects on peak oxygen consumption (peakVO2). This study is a post-hoc sub-analysis of a randomized, double-blinded clinical trial in which 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin or placebo to evaluate change in peakVO2 (NCT04197635). We used linear mixed regression analysis to compare changes in the natural logarithm of CA125 (logCA125) and percent changes from baseline (Δ%CA125). We used the "rwrmed" package to perform mediation analyses. CA125 was available in 87 patients (96.7%). LogCA125 significantly decreased in patients on treatment with dapagliflozin [1-month: Δ - 0.18, (CI 95% = - 0.33 to - 0.22) and 3-month: Δ - 0.23, (CI 95% = - 0.38 to - 0.07); omnibus p-value = 0.012]. Δ%CA125 decreased by 18.4% and 31.4% at 1 and 3-month, respectively (omnibus p-value = 0.026). Changes in logCA125 mediated the effect on peakVO2 by 20.4% at 1 month (p < 0.001). We did not find significant changes for natural logarithm of NTproBNP (logNT-proBNP) [1-month: Δ - 0.03, (CI 95% = - 0.23 to 0.17; p = 0.794), and 3-month: Δ 0.73, (CI 95% = - 0.13 to 0.28; p-value 0.489), omnibus p-value = 0.567]. In conclusion, in patients with stable HFrEF, dapagliflozin resulted in a significant reduction in CA125. Dapagliflozin was not associated with short-term changes in natriuretic peptides. These changes mediated the effects on peakVO2.
| S-EPMC10313805 | biostudies-literature
Project description:AimsDapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure with mildly reduced or preserved ejection fraction. In this study, the safety and efficacy of dapagliflozin according to background diuretic therapy and the influence of dapagliflozin on longitudinal diuretic use were evaluated.Methods and resultsIn this pre-specified analysis of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial, the effects of dapagliflozin vs. placebo were assessed in the following subgroups: no diuretic, non-loop diuretic, and loop diuretic furosemide equivalent doses of <40, 40, and >40 mg, respectively. Of the 6263 randomized patients, 683 (10.9%) were on no diuretic, 769 (12.3%) were on a non-loop diuretic, and 4811 (76.8%) were on a loop diuretic at baseline. Treatment benefits of dapagliflozin on the primary composite outcome were consistent by diuretic use categories (Pinteraction = 0.64) or loop diuretic dose (Pinteraction = 0.57). Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. Dapagliflozin reduced new initiation of loop diuretics by 32% [hazard ratio (HR) 0.68; 95% confidence interval (CI): 0.55-0.84, P < 0.001] but did not influence discontinuations/disruptions (HR 0.98; 95% CI: 0.86-1.13, P = 0.83) in follow-up. First sustained loop diuretic dose increases were less frequent, and sustained dose decreases were more frequent in patients treated with dapagliflozin: net difference of -6.5% (95% CI: -9.4 to -3.6; P < 0.001). The mean dose of loop diuretic increased over time in the placebo arm, a longitudinal increase that was significantly attenuated with treatment with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5, -3.7, P < 0.001).ConclusionIn patients with heart failure with mildly reduced or preserved ejection fraction, the clinical benefits of dapagliflozin relative to placebo were consistent across a wide range of diuretic categories and doses with a similar safety profile. Treatment with dapagliflozin significantly reduced new loop diuretic requirement over time.
| S-EPMC10484057 | biostudies-literature
Project description:BackgroundData about real-world effects of combined therapy with sacubitril/valsartan plus dapagliflozin in patients affected by heart failure (HF) with reduced ejection fraction (HFrEF) has not been widely reported. In this article, the benefits of dapagliflozin and sacubitril/valsartan respect to improvements of cardiac function in patients with HFrEF would be investigated.MethodsHF patients prescribed sacubitril/valsartan between January 2020 and January 2022 in a tertiary teaching hospital were selected using the Computerized Patient Record System. Patients were divided into two groups according to whether they were taking dapagliflozin. Clinical parameters at baseline and during follow-up were retrospectively collected and analyzed.ResultsTotal of 136 consecutive patients were recruited for this study. 72 patients treated with sacubitril/valsartan and dapagliflozin were assigned to Group A, and another 64 patients receiving sacubitril/valsartan monotherapy were assigned to Group B. After treatment with sacubitril/valsartan plus dapagliflozin for a median follow-up period of 189 days (IQR, 180-276), significant improvements of cardiac function were achieved in Group A. Median N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was significantly decreased from 2585 pg/ml (1014-3702.5) to 1260.5 pg/ml (439.8-2214.3) (P < 0.001). Mean left ventricular ejection fraction (LVEF) improved from 34.7 ± 4.6% to 39.2 ± 7.5% (P < 0.001). Mean daily dose of loop diuretics decreased from 37.1 ± 17.3 mg/day to 25.9 ± 18.5 mg/day (P < 0.001). Regarding safety, both systolic blood pressure (P = 0.002) and diastolic blood pressure (P = 0.002) significantly decreased. For patients in Group B, significant improvements in mean LVEF (P < 0.001), decreases in mean daily dose of loop diuretics (P = 0.001) and reductions in diastolic blood pressure (P = 0.023) were observed. Strikingly, both median Δ NT-proBNP (P = 0.04) and median Δ LAD (P = 0.006) in Group A were more pronounced in comparison with those seen in Group B.ConclusionsThe combined use of sacubitril/valsartan and dapagliflozin was associated with improved cardiac function in patents with HFrEF, and led to greater reductions in LAD and NT-proBNP levels compared to sacubitril/valsartan monotherapy. These findings suggest that the combination therapy may offer more potent cardiovascular benefits.
| S-EPMC10073490 | biostudies-literature