Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: insights from DAPA-HF

Background: The DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) showed that dapagliflozin added to other guideline-recommended therapies reduced the risk of mortality and heart failure hospitalization and improved symptoms in patients with heart failure and reduced ejection fraction. We examined the effects of dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly. Methods: Patients in New York Heart Association functional class II or greater with a left ventricular ejection fraction ≤40% and a modest elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide) were eligible. Key exclusion criteria included systolic blood pressure <95 mm Hg and estimated glomerular filtration rate <30 mL·min−1·1.73 m−2. The primary outcome was the composite of an episode of worsening heart failure (heart failure hospitalization or urgent heart failure visit) or cardiovascular death, whichever occurred first. Results: A total of 4744 patients 22 to 94 years of age (mean age, 66.3 [SD 10.9] years) were randomized: 636 patients (13.4%) were <55 years of age, 1242 (26.2%) were 55 to 64 years of age, 1717 (36.2%) were 65 to 74 years of age, and 1149 (24.2%) were ≥75 years of age. The rate of the primary outcome (per 100 person-years, placebo arm) in each age group was 13.6 (95% CI, 10.4–17.9), 15.7 (95% CI, 13.2–18.7), 15.1 (95% CI, 13.1–17.5), and 18.0 (95% CI, 15.2–21.4) with corresponding dapagliflozin/placebo hazard ratios of 0.87 (95% CI, 0.60–1.28), 0.71 (95% CI, 0.55–0.93), 0.76 (95% CI, 0.61–0.95), and 0.68 (95% CI, 0.53–0.88; P for interaction=0.76). Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and symptoms. Although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group. Conclusions: Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of age studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals

Estimating the prevalence of obstetric fistula: a systematic review and meta-analysis.

BACKGROUND: Obstetric fistula is a severe condition which has devastating consequences for a woman's life. The estimation of the burden of fistula at the population level has been impaired by the rarity of diagnosis and the lack of rigorous studies. This study was conducted to determine the prevalence and incidence of fistula in low and middle income countries. METHODS: Six databases were searched, involving two separate searches: one on fistula specifically and one on broader maternal and reproductive morbidities. Studies including estimates of incidence and prevalence of fistula at the population level were included. We conducted meta-analyses of prevalence of fistula among women of reproductive age and the incidence of fistula among recently pregnant women. RESULTS: Nineteen studies were included in this review. The pooled prevalence in population-based studies was 0.29 (95% CI 0.00, 1.07) fistula per 1000 women of reproductive age in all regions. Separated by region we found 1.57 (95% CI 1.16, 2.06) in sub Saharan Africa and South Asia, 1.60 (95% CI 1.16, 2.10) per 1000 women of reproductive age in sub Saharan Africa and 1.20 (95% CI 0.10, 3.54) per 1000 in South Asia. The pooled incidence was 0.09 (95% CI 0.01, 0.25) per 1000 recently pregnant women. CONCLUSIONS: Our study is the most comprehensive study of the burden of fistula to date. Our findings suggest that the prevalence of fistula is lower than previously reported. The low burden of fistula should not detract from their public health importance, however, given the preventability of the condition, and the devastating consequences of fistula

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

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

Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists An Analysis of DAPA-HF

OBJECTIVES The purpose of this study was to assess the efficacy and safety of dapagliflozin in patients taking or not taking an mineralocorticoid receptor antagonist (MRA) at baseline in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial. BACKGROUND MRAs and sodium glucose co-transporter 2 inhibitors each have diuretic activity, lower blood pressure, and reduce glomerular filtration rate (GFR). Therefore, it is important to investigate the safety, as well as efficacy, of their combination. METHODS A total of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) were randomized to placebo or dapagliflozin 10mg daily. The efficacy of dapagliflozin on the primary composite outcome (cardiovascular death or episode of worsening heart failure) and its components was examined according to MRA use, as were predefined safety outcomes. RESULTS A total of 3,370 patients (71%) were treated with an MRA and they were younger (65 vs. 69 years of age), less often from North America (9% vs. 26%), had worse New York Heart Association functional class (35% vs. 25% in class III/ IV), lower left ventricular ejection fraction (30.7% vs. 31.9%) and systolic blood pressure (120.3 vs. 125.5 mm Hg), but higher estimated GFR (67.1 vs. 62.6 ml/min/1.73 m(2)), than patients not taking an MRA. The benefit of dapagliflozin compared with placebo was similar in patients taking or not taking an MRA: hazard ratio: 0.74 (95% confidence interval [CI]: 0.63 to 0.87) versus 0.74 (95% CI: 0.57 to 0.95), respectively, for the primary endpoint (p value for interaction - 0.97); similar findings were observed for secondary endpoints. In both MRA subgroups, safety outcomes were similar in patients randomized to dapagliflozin or placebo. CONCLUSIONS Dapagliflozin was similarly efficacious and safe in patients with HFrEF taking or not taking an MRA, supporting the use of both drugs together. (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) (C)2021 Published by Elsevier on behalf of the American College of Cardiology Foundation

Dapagliflozin in patients with heart failure and reduced ejection fraction

Background: In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes. Methods: In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. Results: Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups. Conclusions: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.

Effects of dapagliflozin in DAPA-HF according to background heart failure therapy

Aims 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. Methods and results 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). Conclusion The benefit of dapagliflozin was consistent regardless of background therapy for HF

Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction A Prespecified Analysis of DAPA-HF

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 RESULTS: Overall, 36% more patients experienced the expanded, in comparison with the primary, composite outcome. In the placebo group, 684 of 2371 (28.8%) patients and, in the dapagliflozin group, 527 of 2373 (22.2%) participants experienced the expanded outcome (hazard ratio, 0.73 [95% CI, 0.65-0.82]; P CONCLUSION: In DAPA-HF, outpatient episodes of HF worsening were common, were of prognostic importance, and were reduced by dapagliflozin

Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure:pooled analysis of the DAPA-CKD and DAPA-HF trials

Background: Chronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials. Methods: This study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials. Participants with no history of diabetes and HbA1c less than 6·5% (48 mmol/mol) at baseline were included in this pooled analysis. New-onset type 2 diabetes was a prespecified exploratory endpoint in both DAPA-CKD and DAPA-HF trials and is the focus of this analysis. New-onset type 2 diabetes was identified by serial trial measurements of HbA1c (two consecutive values ≥6·5% [≥48 mmol/mol]) or following a clinical diagnosis of diabetes between trial visits. Time to new-onset type 2 diabetes was analysed in a Cox proportional Hazards model from random assignment to end of treatment. Findings: 4003 participants (1398 [34·9%] from the DADA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) were included in our analysis: 1995 (49·8%) had received dapagliflozin and 2008 (50·2%) had received placebo. Over a median follow-up of 21·2 months (IQR 16·0 to 25·4), 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed type 2 diabetes (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). There was no heterogeneity between studies (p interaction 0·77) and there was no clear evidence that the effect of dapagliflozin varied in prespecified subgroups including sex, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use. More than 90% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5·7% to 6·4% [39 to 46 mmol/mol]). Mean HbA1c remained unchanged (placebo-adjusted change in the dapagliflozin group of −0·01% [95% CI −0·03 to 0·01], −0·1 mmol/mol [95% CI −0·3 to 0·1] at 12 months). Interpretation: Treatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes in participants with chronic kidney disease and HF without a reduction in HbA1c. Funding: AstraZeneca