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

Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF

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 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. 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

Long-term exposure to transportation noise and risk of incident stroke:A pooled study of nine scandinavian cohorts

BACKGROUND: Transportation noise is increasingly acknowledged as a cardiovascular risk factor, but the evidence base for an association with stroke is sparse. OBJECTIVE: We aimed to investigate the association between transportation noise and stroke incidence in a large Scandinavian population. METHODS: We harmonized and pooled data from nine Scandinavian cohorts (seven Swedish, two Danish), totaling 135,951 participants. We identified residential address history and estimated road, railway, and aircraft noise for all addresses. Information on stroke incidence was acquired through link-age to national patient and mortality registries. We analyzed data using Cox proportional hazards models, including socioeconomic and lifestyle con-founders, and air pollution. RESULTS: During follow-up (median = 19:5 y), 11,056 stroke cases were identified. Road traffic noise (Lden ) was associated with risk of stroke, with a hazard ratio (HR) of 1.06 [95% confidence interval (CI): 1.03, 1.08] per 10-dB higher 5-y mean time-weighted exposure in analyses adjusted for indi-vidual-and area-level socioeconomic covariates. The association was approximately linear and persisted after adjustment for air pollution [particulate matter (PM) with an aerodynamic diameter of ≤2:5 lm (PM2:5 ) and NO2 ]. Stroke was associated with moderate levels of 5-y aircraft noise exposure (40–50 vs. ≤40 dB) (HR = 1:12; 95% CI: 0.99, 1.27), but not with higher exposure (≥50 dB, HR = 0:94; 95% CI: 0.79, 1.11). Railway noise was not associated with stroke. DISCUSSION: In this pooled study, road traffic noise was associated with a higher risk of stroke. This finding supports road traffic noise as an important cardiovascular risk factor that should be included when estimating the burden of disease due to traffic noise. https://doi.org/10.1289/EHP8949

Efficacy of dapagliflozin in heart failure with reduced ejection fraction according to body mass index

Background: 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 SGLT2 inhibitor according to baseline BMI in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). Methods and Results: BMI 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); class II (35.0-39.9 Kg/m2) and 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% CI) for the primary outcome with obesity category 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., HR 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 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 number NCT03036124 (https://clinicaltrials.gov/ct2/show/NCT03036124

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)

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

Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF)

Aims: Concern about hypotension often leads to withholding of beneficial therapy in patients with heart failure and reduced ejection fraction (HFrEF). We evaluated the efficacy and safety of dapagliflozin, which lowers systolic blood pressure (SBP),according to baseline SBP in Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Methods and results: Key inclusion criteria were: New York Heart Association Class II−IV, left ventricular ejection fraction ≤ 40%, elevated N-terminal pro-B-type natriuretic peptide level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening heart failure or cardiovascular death. The efficacy and safety of dapagliflozin were examined using SBP as both a categorical and continuous variable. A total of 1205 patients had a baseline SBP <110 mmHg; 981 ≥ 110 < 120; 1149 ≥ 120 < 130; and 1409 ≥ 130 mmHg. The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was −2.54 (−3.33 to −1.76) mmHg (P < 0.001), with a smaller between-treatment difference in patients in the lowest compared to highest SBP category. Patients in the lowest SBP category had a much higher rate (per 100 person-years) of the primary outcome [20.6, 95% confidence interval (95% CI) 17.6–24.2] than those in the highest SBP category (13.8, 11.7–16.4). The benefit and safety of dapagliflozin was consistent across the range of SBP; hazard ratio (95% CI) in each SBP group, lowest to highest: 0.76 (0.60–0.97), 0.76 (0.57–1.02), 0.81 (0.61–1.08), and 0.67 (0.51–0.87), P interaction = 0.78. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined. Conclusion: Dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF. Clinical Trial Registration: ClinicalTrials.gov NCT03036124

Non-steroidal anti-inflammatory drugs and blood pressure control in patients treated for hypertension: results from the Swedish primary care cardiovascular database

Purpose: The aim of this observational cohort study was to investigate blood pressure level and the possibility to reach target blood pressure during concomitant use of NSAID in hypertensive patients. Materials and methods: From the Swedish primary care cardiovascular database (SPCCD) a cohort of 5463 patients (2007 to 2008) with at least one prescription of NSAID dispensed 6 months prior to the last blood pressure measurement were included. Clinical data were extracted from computerized medical records and linked to the Prescribed Drug Register. Multivariable logistic regression models were used for analysis. Results: Patients with NSAID usage were younger, more often female, with lower creatinine concentrations, more musculoskeletal diagnosis and less cardiovascular comorbidity compared to patients without dispensed NSAID (p < .0001 for all). Regular dose of NSAID was not associated with a decreased possibility to reach target blood pressure. A correlation between the dose of naproxen and an increase in SBP of 7 mm Hg was found. Impairment in renal function did not influence the association between blood pressure control and NSAID (p = .27). Conclusion: In hypertensive patients with concomitant use of NSAID the chance to reach target blood pressure was not impaired. In intermediate and frequent users of NSAID there was a dose response relation with naproxen and SBP which was not found in diclofenac and ibuprofen

Risk of stroke in patients with heart failure and sinus rhythm: data from the Swedish Heart Failure Registry

Aims We investigated the 2 year rate of ischaemic stroke/transient ischaemic attack (IS) in patients with heart failure (HF) who were in sinus rhythm (HF-SR) and aimed to develop a score for stratifying risk of IS in this population. Methods and results A total of 15 425 patients (mean age 71.5 years, 39% women) with HF-SR enrolled in the Swedish Heart Failure Register were included; 28 815 age-matched and sex-matched controls, without a registered diagnosis of HF, were selected from the Swedish Population Register. The 2 year rate of IS was 3.0% in patients and 1.4% in controls. In the patient group, a risk score including age (1p for 65-74 years; 2p for 75-84 years; 3p for &amp;gt;= 85 years), previous IS (2p), ischaemic heart disease, diabetes, hypertension, kidney dysfunction, and New York Heart Association III/IV class (1p each) was generated. Over a mean follow-up of 20.1 (SD 7.5) months, the cumulative incidences (per 1000 person-years) of IS in patients with score 0 to &amp;gt;= 7 were 2.2, 5.3, 8.9, 13.2, 15.7, 20.4, 26.4, and 33.0, with hazard ratios for score 1 to &amp;gt;= 7 (with 0 as reference): 2.4, 4.1, 6.1, 7.2, 9.4, 12.2, and 15.3. The risk score performed modestly (area under the curve 63.7%; P = 0.4711 for lack of fit with a logistic model; P = 0.7062 with Poisson, scaled by deviance). Conclusions In terms of absolute risk, only 27.6% of patients had an annual IS incidence of &amp;lt;= 1%. To which extent this would be amenable to anticoagulant treatment remains conjectural. A score compiling age and specific co-morbidities identified HF-SR patients with increased risk of IS with modest discriminative ability.Funding Agencies|Swedish government [ALFGBG-717211]; County Councils Concerning Economic Support of Research and Education of Doctors [ALFGBG-717211]; Swedish Heart and Lung Foundation (Hjart-Lungfonden) [2015-0438, 2018-0366]; Swedish Research Council (Vetenskapsradet)Swedish Research Council [2013-05187, 2018-02527]</p

Rationale and design of switch Swedeheart : A registry-based, stepped-wedge, cluster-randomized, open-label multicenter trial to compare prasugrel and ticagrelor for treatment of patients with acute coronary syndrome

Background: European treatment guidelines recommend prasugrel over ticagrelor for treating patients with non–ST-elevation acute coronary syndrome (ACS), prompting several Swedish administrative regions to transition from ticagrelor to prasugrel as the preferred treatment for patients with ACS. We aim to systematically evaluate this transition to determine the relative efficacy of prasugrel versus ticagrelor in a real-world cohort of patients with ACS. Study design and objectives: The SWITCH SWEDEHEART trial is a prospective, multicenter, open-label, cross-sectional, stepped-wedge cluster-randomized clinical trial, in which administrative regions in Sweden will constitute the clusters. At the start of the study, all clusters will use ticagrelor as the P2Y12 inhibitor drug of choice for ACS. The order in which the clusters will implement the transition from ticagrelor to prasugrel will be randomly assigned. Every 9 months, 1 cluster will switch from ticagrelor to prasugrel as the P2Y12 inhibitor of choice for patients with ACS. The primary endpoint is the composite 1-year rate of the death, stroke, or myocardial infarction. Conclusions: The SWITCH SWEDEHEART study will provide an extensive randomized comparison between ticagrelor and prasugrel. Novel therapies are frequently costly and supported by evidence from few or small studies, and systematic evaluation after the introduction is rare. This study will establish an important standard for introducing and evaluating the effects of health care changes within our societies