Abstract
Aims
The aim of this study was to examine the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection ...fraction (HFrEF).
Methods and results
In a post hoc analysis of DAPA-HF, we examined serious adverse event reports related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF (ventricular fibrillation in 15 patients, ventricular tachycardia in 86, ‘other’ ventricular arrhythmia/tachyarrhythmia in 12, and torsade de pointes in 2 patients). A total of 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Eight patients survived resuscitation from cardiac arrest. Independent predictors of the composite outcome (first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest or sudden death), ranked by chi-square value, were log-transformed N-terminal pro-B-type natriuretic peptide, history of ventricular arrhythmia, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 140/2373 patients (5.9%) experienced the composite outcome compared with 175/2371 patients (7.4%) in the placebo group hazard ratio 0.79 (95% confidence interval 0.63–0.99), P = 0.037, and the effect was consistent across each of the components of the composite outcome.
Conclusions
Dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF.
Clinical trial registration
ClinicalTrials.gov unique identifier: NCT03036124 (DAPA-HF).
Graphical Abstract
DAPA-HF: trial design and main findings. BMI, body mass index; BP, blood pressure; CI, confidence interval; HF, heart failure; HFrEF, heart failure and reduced ejection fraction; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NT-proBNP, N-terminal pro-B-type natriuretic peptide.
SGLT2 inhibitors are strongly recommended in guidelines to treat patients with heart failure with reduced ejection fraction, but their clinical benefits at higher ejection fractions are less well ...established. Two large-scale trials, DELIVER and EMPEROR-Preserved, in heart failure with mildly reduced or preserved ejection fraction have been done, providing power to examine therapeutic effects on cardiovascular mortality and in patient subgroups when combined with the earlier trials in reduced ejection fraction.
We did a prespecified meta-analysis of DELIVER and EMPEROR-Preserved, and subsequently included trials that enrolled patients with reduced ejection fraction (DAPA-HF and EMPEROR-Reduced) and those admitted to hospital with worsening heart failure, irrespective of ejection fraction (SOLOIST-WHF). Using trial-level data with harmonised endpoint definitions, we did a fixed-effects meta-analysis to estimate the effect of SGLT2 inhibitors on various clinical endpoints in heart failure The primary endpoint for this meta-analysis was time from randomisation to the occurrence of the composite of cardiovascular death or hospitalisation for heart failure. We assessed heterogeneity in treatment effects for the primary endpoint across subgroups of interest. This study is registered with PROSPERO, CRD42022327527.
Among 12 251 participants from DELIVER and EMPEROR-Preserved, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalisation for heart failure (hazard ratio 0·80 95% CI 0·73-0·87) with consistent reductions in both components: cardiovascular death (0·88 0·77-1·00) and first hospitalisation for heart failure (0·74 0·67-0·83). In the broader context of the five trials of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalisation for heart failure (0·77 0·72-0·82), cardiovascular death (0·87 0·79-0·95), first hospitalisation for heart failure (0·72 0·67-0·78), and all-cause mortality (0·92 0·86-0·99). These treatment effects for each of the studied endpoints were consistently observed in both the trials of heart failure with mildly reduced or preserved ejection fraction and across all five trials. Treatment effects on the primary endpoint were generally consistent across the 14 subgroups examined, including ejection fraction.
SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalisations for heart failure in a broad range of patients with heart failure, supporting their role as a foundational therapy for heart failure, irrespective of ejection fraction or care setting.
None.
Glucagon-like peptide-1 (GLP-1) receptor agonists differ in their structure and duration of action and have been studied in trials of varying sizes and with different patient populations, with ...inconsistent effects on cardiovascular outcomes reported. We aimed to synthesise the available evidence by doing a systematic review and meta-analysis of cardiovascular outcome trials of these drugs.
We searched MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials for eligible placebo-controlled trials reporting major adverse cardiovascular events (MACE; ie, cardiovascular death, stroke, or myocardial infarction) up to June 15, 2019. We did a meta-analysis using a random-effects model to estimate overall hazard ratios (HRs) for MACE, its components, death from any cause, hospital admission for heart failure, kidney outcomes, and key safety outcomes (severe hypoglycaemia, pancreatitis, and pancreatic cancer). We also examined MACE in several subgroups based on patient characteristics (history of cardiovascular disease, BMI, age, baseline HbA1c, and baseline estimated glomerular filtration rate), trial duration, treatment dosing interval, and structural homology.
Of 27 publications screened, seven trials, with a combined total of 56 004 participants, were included: ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide). Overall, GLP-1 receptor agonist treatment reduced MACE by 12% (HR 0·88, 95% CI 0·82-0·94; p<0·0001). There was no statistically significant heterogeneity across the subgroups examined. HRs were 0·88 (95% CI 0·81-0·96; p=0·003) for death from cardiovascular causes, 0·84 (0·76-0·93; p<0·0001) for fatal or non-fatal stroke, and 0·91 (0·84-1·00; p=0·043) for fatal or non-fatal myocardial infarction. GLP-1 receptor agonist treatment reduced all-cause mortality by 12% (0·88, 0·83-0·95; p=0·001), hospital admission for heart failure by 9% (0·91, 0·83-0·99; p=0·028), and a broad composite kidney outcome (development of new-onset macroalbuminuria, decline in estimated glomerular filtration rate or increase in creatinine, progression to end-stage kidney disease, or death attributable to kidney causes) by 17% (0·83, 0·78-0·89; p<0·0001), mainly due to a reduction in urinary albumin excretion. There was no increase in risk of severe hypoglycaemia, pancreatitis, or pancreatic cancer.
Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes.
None.
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).
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.
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;
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;
<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;
<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;
<0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score).
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.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.
Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, ...even those without diabetes.
To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes.
Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019.
Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy.
The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%.
Among 4744 patients randomized (mean age, 66 years; 1109 23% women; 2605 55% without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 95% CI, 0.60-0.88). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 95% CI, 0.63-0.90) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 95% CI, 0.47-0.96). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 95% CI, 0.59-0.94) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes.
In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status.
ClinicalTrials.gov Identifier: NCT03036124.
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