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1.
Eur J Heart Fail ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594755

RESUMO

AIMS: We examined the efficacy and safety of dapagliflozin, compared with placebo, according to aetiology in patients with heart failure (HF) with reduced ejection fraction (HFrEF) enrolled in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). METHODS AND RESULTS: Aetiology was investigator-reported and categorized as ischaemic or non-ischaemic. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. A total of 4,744 patients were randomised in DAPA-HF, of whom 2,674 (56.4%) patients had an ischaemic aetiology. Participants with an ischaemic aetiology had a higher risk of cardiovascular mortality (hazard ratio [HR] 1.35 [95%CI 1.13-1.63]), but lower risk of HF hospitalisation (0.83 [0.70-0.98]) than non-ischaemic patients. Compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death to a similar extent in both patients with ischaemic and non-ischaemic aetiology (HR 0.77 [95%CI 0.65-0.92] and 0.71 [0.58-0.87], respectively, P for interaction=0.55). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Dapagliflozin, as compared with placebo, increased the proportion of patients with an improvement of KCCQ-TSS of ≥5 points (P for interaction=0.32) and decreased the proportion with a deterioration in KCCQ-TSS of ≥5 points (P for interaction=0.76), irrespective of aetiology. Study drug discontinuation and serious adverse events were similar according to treatment groups, irrespective of aetiology. CONCLUSIONS: Dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, similarly in patients with ischaemic and non-ischaemic aetiology. In addition, dapagliflozin was safe and well-tolerated, irrespective of aetiology.

2.
JAMA Cardiol ; 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33595593

RESUMO

Importance: Dapagliflozin has been shown to reduce the risk of cardiovascular death or worsening heart failure (HF) in patients with chronic HF and reduced ejection fraction (HFrEF). However, clinical inertia often underlies deferred initiation of effective therapies. Objective: To examine timing of onset of clinical benefit with dapagliflozin and magnitude as a function of proximity to prior HF hospitalization. Design, Setting, and Participants: This is a secondary analysis of a completed multinational trial. The Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure trial was a double-blind, placebo-controlled randomized clinical trial of dapagliflozin in patients with chronic HFrEF (n = 4744). From February 2017 to August 2018, the study enrolled patients in New York Heart Association classes II through IV and with left ventricular ejection fraction of 40% or less; the median (range) follow-up time was 18.2 (0-27.8) months. Hazard ratios (HRs) were calculated for the primary efficacy outcome with dapagliflozin vs placebo by time following randomization. Efficacy and safety of dapagliflozin were assessed according to the timing of the most recent HF hospitalization prior to trial enrollment. Exposures: None. Main Outcomes and Measures: Composite of cardiovascular death or worsening HF. Results: A total of 4744 patients were included (1109 women [23.4%]; mean [SD] age, 66.3 [10.9] years). The reduction in the primary outcome with dapagliflozin was rapidly apparent, with a sustained statistically significant benefit by 28 days after randomization (HR at 28 days, 0.51 [95% CI, 0.28-0.94]; P = .03). A total of 2251 patients (47.4%) had been previously hospitalized for HF, and 1301 (27.4%) had been hospitalized within 12 months prior to enrollment. Among patients treated with placebo, there was a stepwise gradient of risk for the primary outcome according to timing of most recent HF hospitalization, with 2-year Kaplan-Meier rates of 21.1%, 25.3%, and 33.8% (adjusted P = .003) for patients with a prior HF hospitalization never, more than 12 months ago, and 12 or fewer months ago, respectively. Across these subgroups, dapagliflozin reduced the relative risk of the primary outcome by 16% (HR, 0.84 [95% CI, 0.69-1.01]), 27% (HR, 0.73 [95% CI, 0.54-0.99]), and 36% (HR, 0.64 [95% CI, 0.51-0.80]), respectively (P = .07 for trend). Accordingly, patients with a more recent HF hospitalization tended to experience greater absolute risk reductions with dapagliflozin at 2 years: 2.1% (95% CI, -1.9% to 6.1%), 4.1% (95% CI, -3.6% to 11.7%), and 9.9% (95% CI, 3.3%-16.5%), respectively (P = .05 for trend). Conclusions and Relevance: In this study, treatment with dapagliflozin was associated with rapid reduction in the risk of cardiovascular death or worsening HF, with a sustained statistically significant benefit emerging very early after randomization. Patients with a more recent HF hospitalization were at particularly high risk and experienced greater relative and absolute risk reductions with dapagliflozin. Trial Registration: ClinicalTrials.gov Identifier NCT03036124.

3.
Diabetes Obes Metab ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33606902

RESUMO

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes (T2D) in both the 'established CV disease' (CVD) and 'CV risk factor' subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD than REWIND. This post hoc analysis assessed the effect of semaglutide on major adverse cardiovascular events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% versus 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR], 95% confidence interval [CI]: 0.74 [0.59, 0.92]) and non-significantly lower in the CV risk factor subgroup (HR, 95% CI: 0.84 [0.55, 1.28]) (P-interaction=0.60). These results suggest that the CV effects of semaglutide may extend to patients with T2D across the CV risk continuum. This article is protected by copyright. All rights reserved.

4.
Acta Diabetol ; 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33483855

RESUMO

PURPOSE: A recent large cardiovascular outcome trial in patients with type 2 diabetes (T2DM) demonstrated excess heart failure hospitalization with saxagliptin. We sought to evaluate the impact of saxagliptin on cardiac structure and function using cardiac magnetic resonance imaging (CMR) in patients with T2DM without pre-existing heart failure. METHODS: In this prospective study, patients with T2DM without heart failure were prescribed saxagliptin as part of routine guideline-directed management. Clinical assessment, CMR imaging and biomarkers were assessed in a blinded fashion and compared following 6 months of continued treatment. The primary outcome was the change in left ventricular (LV) ejection fraction (LVEF) after 6 months of therapy. Key secondary outcomes included changes in LV and right ventricular (RV) end-diastolic volume, ventricular mass, LV global strain and cardiac biomarkers [N terminal pro B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP)] over 6 months. RESULTS: The cohort (n = 16) had a mean age of 59.9 years with 69% being male. The mean hemoglobin A1c (HbA1c) was 8.3%. Mean baseline LVEF was 57% ± 3.4, with no significant change over 6 months (- 0.2%, 95% CI - 2.5, 2.1, p = 0.86). Detailed CMR analyses that included LV/RV volumes, LV mass, and feature tracking-derived strain showed no significant change (all p > 0.50). NT-proBNP and hsCRP levels did not significantly change (p > 0.20). CONCLUSIONS: In this cohort of stable ambulatory patients with T2DM without heart failure, saxagliptin treatment was not associated with adverse ventricular remodeling over 6 months as assessed using CMR and biomarkers.

5.
Can J Cardiol ; 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33450364

RESUMO

The role of SGLT2 inhibitors in preventing heart failure (HF) in people with type-2 diabetes (T2DM) is now part of current treatment recommendations. Two large clinical trials (DAPA-HF and EMPEROR-Reduced) have recently highlighted the important impact of SGLT2 inhibitors in patients with HF and a reduced ejection fraction (HFrEF) with significant outcome benefits on HF hospitalizations and cardiovascular mortality, and comparable effects in patients with and without T2DM. These benefits were observed on top of excellent background HF therapy, and there were no treatment interactions between SGLT2 inhibitors and background HF therapy. There were no increases in adverse events of interest in the SGLT2 inhibitor arm, including volume depletion, adverse renal events, hypoglycemia, amputation and ketoacidosis, demonstrating the favorable safety profile of this treatment in HFrEF. Approximately 40-50% of patients with HFrEF have CKD, and the recently reported results of the DAPA-CKD trial indicate that dapagliflozin can prevent renal and cardiovascular outcomes in patients with established CKD, whether diabetes is present or not. Although the mechanisms of action of SGLT2 inhibitors are not fully understood, the hypotheses that have been proposed for their HF outcome benefits include a reduction of preload via osmotic diuresis, lowering of afterload, reduction in myocardial mass, alteration of myocardial energy substrate toward a more efficient glucose metabolism, modulation of renal sympathetic afferent tone, and increased erythropoiesis. We here present a summary of the evidence, as well as a practical perspective on prescribing SGLT2 inhibitors in patients with HFrEF, with or without diabetes.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33454272

RESUMO

OBJECTIVES: This study sought to evaluate the effects of empagliflozin on extracellular volume (ECV) in individuals with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). BACKGROUND: Empagliflozin has been shown to reduce left ventricular mass index (LVMi) in patients with T2DM and CAD. The effects on myocardial ECV are unknown. METHODS: This was a prespecified substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes) CardioLink-6 trial in which 97 participants were randomized to receive empagliflozin 10 mg daily or placebo for 6 months. Data from 74 participants were included: 39 from the empagliflozin group and 35 from the placebo group. The main outcome was change in left ventricular ECV from baseline to 6 months determined by cardiac magnetic resonance (CMR). Other outcomes included change in LVMi, indexed intracellular compartment volume (iICV) and indexed extracellular compartment volume (iECV), and the fibrosis biomarkers soluble suppressor of tumorgenicity (sST2) and matrix metalloproteinase (MMP)-2. RESULTS: Baseline ECV was elevated in the empagliflozin group (29.6 ± 4.6%) and placebo group (30.6 ± 4.8%). Six months of empagliflozin therapy reduced ECV compared with placebo (adjusted difference: -1.40%; 95% confidence interval [CI]: -2.60 to -0.14%; p = 0.03). Empagliflozin therapy reduced iECV (adjusted difference: -1.5 ml/m2; 95% CI: -2.6 to -0.5 ml/m2; p = 0.006), with a trend toward reduction in iICV (adjusted difference: -1.7 ml/m2; 95% CI: -3.8 to 0.3 ml/m2; p = 0.09). Empagliflozin had no impact on MMP-2 or sST2. CONCLUSIONS: In individuals with T2DM and CAD, 6 months of empagliflozin reduced ECV, iECV, and LVMi. No changes in MMP-2 and sST2 were seen. Further investigation into the mechanisms by which empagliflozin causes reverse remodeling is required. (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes [EMPA-HEART]; NCT02998970).

7.
Artigo em Inglês | MEDLINE | ID: mdl-33431580

RESUMO

Embryogenesis in seed plants is the process during which a single cell develops into a mature multicellular embryo that encloses all the modules and primary patterns necessary to build the architecture of the new plant after germination. This process involves a series of cell divisions and coordinated cell fate determinations resulting in the formation of an embryonic pattern with a shoot-root axis and cotyledon(s). The phytohormone auxin profoundly controls pattern formation during embryogenesis. Auxin functions in the embryo through its maxima/minima distribution, which acts as an instructive signal for tissue specification and organ initiation. In this review, we describe how disruptions of auxin biosynthesis, transport, and response severely affect embryo development. Also, the mechanism of auxin action in the development of the shoot-root axis and the three-tissue system is discussed with recent findings. Biological tools that can be implemented to study the auxin function during embryo development are presented, as they may be of interest to the reader.

8.
Curr Opin Cardiol ; 36(2): 117-124, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33394711

RESUMO

PURPOSE OF REVIEW: Transcatheter aortic valve replacement (TAVR) has expanded as a treatment option for severe aortic stenosis throughout the surgical risk spectrum. Decreasing procedural risk and inclusion of lower risk population has shifted the focus to optimization of postprocedural management and balancing the thrombotic and bleeding complications. In this review, we outline various patient and procedure related factors affecting choice of antithrombotic therapy post TAVR and provide an update of recent development in this area. RECENT FINDINGS: Multiple studies have confirmed the high incidence of both ischemic and bleeding complications in the early to midterm post-TAVR. In addition, new data has emerged for the role of high resolution computed tomography to detect decreased leaflet mobility and leaflet micro thrombi associated with implications for bioprosthetic valve dysfunction and cerebrovascular events post TAVR. Randomized clinical trials have reported increased bleeding with dual antiplatelet therapy (DAPT) and oral anticoagulation (OAC) plus antiplatelet therapy. These findings suggest that aspirin monotherapy or OAC monotherapy likely provides the appropriate balance for antithrombotic protection and risk of bleeding. SUMMARY: Majority of patients undergoing TAVR have multiple comorbidities and are at increased risk of ischemic and bleeding complications. In the absence of robust clinical evidence, there is significant variability among guideline recommendations and antithrombotic therapy post TAVR across institutions. The available evidence confirms a high rate of bleeding with more potent and prolonged antithrombotic regimens without a documented benefit for clinical endpoints. The authors favor a conservative anti thrombotic approach and suggest monotherapy with aspirin or systemic anticoagulation based upon an individual's risk of thromboembolic complications. DAPT is reserved for patients with recent stenting and OAC plus aspirin is prescribed for patients with established CAD in the post TAVR setting.

9.
Curr Opin Cardiol ; 36(2): 125-129, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33395077

RESUMO

PURPOSE OF REVIEW: To provide a critical review of the application and outcomes of surgical edge-to-edge (E2E) or Alfieri repair for mitral valvulopathy. RECENT FINDINGS: The E2E repair is a surgical technique to address mitral regurgitation, particularly suited when the responsible mechanism is bileaflet prolapse combined with enlarged annular area. It can also be used for a range of mitral valve pathologies. Surgically, the technique has been employed as a bailout for unsuccessful repair including residual mitral regurgitation because of systolic anterior motion (SAM). E2E repair should be accompanied by a ring annuloplasty for long-term repair durability. The simplicity of this approach makes it an ideal strategy during minimally-invasive mitral valve repair. It may also be performed via a transaortic approach at the time of aortic valve surgery to address less-than-severe mitral regurgitation or to address residual SAM following myectomy for hypertrophic obstructive cardiomyopathy. We review the surgical indication, potential complications including risk of mitral stenosis and the long-term outcomes of E2E repair. SUMMARY: The E2E surgical repair is a simple and effective surgical strategy to address a wide range of mitral regurgitation. This is an important technique in the surgical armamentarium especially in cases of minimally-invasive mitral valve surgery.

10.
Eur Heart J ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33420498

RESUMO

AIMS: In this secondary analysis of the EMPEROR-Reduced trial, we sought to evaluate whether the benefits of empagliflozin varied by baseline health status and how empagliflozin impacted patient-reported outcomes in patients with heart failure with reduced ejection fraction. METHODS AND RESULTS: Health status was assessed by the Kansas City Cardiomyopathy Questionnaires-clinical summary score (KCCQ-CSS). The influence of baseline KCCQ-CSS (analyzed by tertiles) on the effect of empagliflozin on major outcomes was examined using Cox proportional hazards models. Responder analyses were performed to assess the odds of improvement and deterioration in KCCQ scores related to treatment with empagliflozin. Empagliflozin reduced the primary outcome of cardiovascular death or heart failure hospitalization regardless of baseline KCCQ-CSS tertiles [hazard ratio (HR) 0.83 (0.68-1.02), HR 0.74 (0.58-0.94), and HR 0.61 (0.46-0.82) for <62.5, 62.6-85.4, and ≥85.4 score tertiles, respectively; P-trend = 0.10]. Empagliflozin improved KCCQ-CSS, total symptom score, and overall summary score at 3, 8, and 12 months. More patients on empagliflozin had ≥5-point [odds ratio (OR) 1.20 (1.05-1.37)], 10-point [OR 1.26 (1.10-1.44)], and 15-point [OR 1.29 (1.12-1.48)] improvement and fewer had ≥5-point [OR 0.75 (0.64-0.87)] deterioration in KCCQ-CSS at 3 months. These benefits were sustained at 8 and 12 months and were similar for other KCCQ domains. CONCLUSION: Empagliflozin improved cardiovascular death or heart failure hospitalization risk across the range of baseline health status. Empagliflozin improved health status across various domains, and this benefit was sustained during long-term follow-up. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03057977.

11.
Diabetes Obes Metab ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33502090

RESUMO

AIM: To determine the relationship between polyvascular disease and risk of hospitalization for heart failure (HHF) and cardiovascular (CV) death in the EMPA-REG OUTCOME population, and the relationship of kidney dysfunction co-existent with polyvascular disease on CV/heart failure (HF) outcomes. MATERIALS AND METHODS: Patients with type 2 diabetes and atherosclerotic CV (ASCVD) received empagliflozin 10, 25 mg or placebo. Post hoc, subgroups were analyzed by one versus two or more vascular beds, and the estimated glomerular filtration rate ([eGFR] < vs. ≥60 mL/min/1.73 m2 ) at baseline. The empagliflozin arms were pooled. Time to CV death, HHF, CV death (excluding fatal stroke) or HHF, all-cause mortality (ACM) and 3-point major adverse CV events (3P-MACE) were assessed using multivariable Cox regression models. RESULTS: Baseline characteristics (N = 6959) within subgroups were balanced between treatment groups. In the placebo group, two or more versus one vascular bed increased HHF risk (1.59 [95% confidence interval 1.02, 2.49]), CV death (2.17 [1.52, 3.09]), CV death/HHF (1.79 [1.32, 2.43]), ACM (1.95 [1.44, 2.64]) and 3P-MACE (1.76 [1.36, 2.27]). Hazard ratios for those with polyvascular disease/kidney dysfunction (vs. 1 vascular bed/eGFR ≥60 mL/min/1.73 m2 ) were HHF 2.80 (1.46, 5.36), CV death 3.10 (1.87, 5.13), CV death/HHF 2.71 (1.74, 4.23), ACM 2.59 (1.67, 4.02) and 3P-MACE 2.62 (1.82, 3.77). Empagliflozin reduced the risk of all outcomes across subgroups. CONCLUSIONS: Polyvascular disease with/without kidney dysfunction markedly increases the risk of HF/CV events. Empagliflozin consistently reduces risk, regardless of vascular bed and kidney function status.

12.
Diabetes Care ; 44(2): 586-594, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33355302

RESUMO

OBJECTIVE: The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. This report explores the effect of dapagliflozin on incident type 2 diabetes (T2D) in the cohort without diabetes enrolled in the trial. RESEARCH DESIGN AND METHODS: The subgroup of 2,605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and an HbA1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new-onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model. RESULTS: At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93 of 1,307 patients (7.1%) in the placebo group and 64 of 1,298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (hazard ratio 0.68, 95% CI 0.50-0.94; P = 0.019). More than 95% of the participants who developed T2D had prediabetes at baseline (HbA1c 5.7-6.4%). Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not. CONCLUSIONS: In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure.

13.
Diabetes Obes Metab ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33269511

RESUMO

BACKGROUND: The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM ) risk stratifies patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk for heart failure (HF) hospitalization. The utility of TRS-HFDM in risk stratification for HF outcomes requires further validation. MATERIALS AND METHODS: We used data from the control group of The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD) trial (n=5123; mean follow up 4.8 years). The TRS-HFDM includes: prior HF (2 points), atrial fibrillation (1 point), coronary artery disease (1 point), estimated glomerular filtration rate < 60 mL/min/1.73 m2 (1 point), and urine albumin-to-creatinine ratio (> 300 mg/g; 2 point and 30-300 mg/g; 1 point). We evaluated discrimination (Harrell C index) and calibration (Nam-D Agostino calibration statistic) of TRS-HFDM for time to HF hospitalization or death due to HF. RESULTS: The mean age of participants was 62.8±6.6 years, and 38% were female. The prevalence of TRS-HFDM for 0, 1, 2, 3 and 4+ were 42.1%, 34.9%, 14.6%, 6.0%, and 2.5% respectively. Increasing TRS-HFDM corresponded to an increasing HF risk: 1.3/1000 person years (PY) (TRS-HFDM : 0) to 64.7/1000 PY (TRS-HFDM : 4+). TRS-HFDM demonstrated robust discrimination for HF outcomes (C-index 0.78). Furthermore, the score was well calibrated for HF outcomes (calibration statistic p=0.13). Similar results were seen in participants without baseline HF (C-index 0.75). CONCLUSION: The TRS-HFDM discriminates for HF specific risk among people with T2DM. Using the TRS-HFDM to identify those who maximally benefit from therapies that reduce HF risk warrants evaluation. This article is protected by copyright. All rights reserved.

14.
Eur J Heart Fail ; 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33368858

RESUMO

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.

15.
Diabetes Obes Metab ; 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33319454

RESUMO

AIMS: Coronavirus disease 2019 (COVID-19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, has shown significant cardio- and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high-risk patients with COVID-19. MATERIALS AND METHODS: DARE-19 (NCT04350593) is an investigator-initiated, collaborative, international, multicentre, randomized, double-blind, placebo-controlled study testing the dual hypotheses that dapagliflozin can reduce the incidence of cardiovascular, kidney and/or respiratory complications or all-cause mortality, or improve clinical recovery, in adult patients hospitalized with COVID-19 but not critically ill on admission. Eligible patients will have ≥1 cardiometabolic risk factor for COVID-19 complications. Patients will be randomized 1:1 to dapagliflozin 10 mg or placebo. Primary efficacy endpoints are time to development of new or worsened organ dysfunction during index hospitalization, or all-cause mortality, and the hierarchical composite endpoint of change in clinical status through day 30 of treatment. Safety of dapagliflozin in individuals with COVID-19 will be assessed. CONCLUSIONS: DARE-19 will evaluate whether dapagliflozin can prevent COVID-19-related complications and all-cause mortality, or improve clinical recovery, and assess the safety profile of dapagliflozin in this patient population. Currently, DARE-19 is the first large randomized controlled trial investigating use of sodium-glucose cotransporter 2 inhibitors in patients with COVID-19.

17.
Can J Diabetes ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-33189580

RESUMO

Glucagon-like peptide-1 receptor agonists and sodium-dependent glucose cotransporter-2 inhibitors have demonstrated clinically significant benefits on glycated hemoglobin, weight, blood pressure and cardiorenal outcomes. The emerging evidence from clinical trials and meta-analyses that assessed the combination of these 2 classes of drugs has been promising. An expert forum that included individuals with expertise in endocrine, cardiology and nephrology issues was held in May 2020 to review the literature on the metabolic and cardiorenal benefits of these 2 classes, independently and in combination, in adults with type 2 diabetes mellitus. Although hard outcome data are not available, the group concluded that the combination of glucagon-like peptide-1 receptor agonists with sodium-dependent glucose cotransporter-2 inhibitors is an emerging option for managing adults with type 2 diabetes as long as cost is not a barrier. Ongoing research may offer further insights on hard cardiorenal outcomes for this therapeutic combination as well as provide direction on the potential of this approach in obesity, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and populations without diabetes.

18.
Can J Cardiol ; 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33191198

RESUMO

The Canadian Cardiovascular Society (CCS) atrial fibrillation (AF) guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health care systems regarding related issues. The most recent comprehensive CCS AF guidelines update was published in 2010. Since then, periodic updates were published dealing with rapidly changing areas. However, by 2020 a large number of developments had accumulated in a wide range of areas, motivating the committee to create a complete guideline review. The 2020 iteration of the CCS AF guidelines represents a comprehensive renewal that integrates, updates, and replaces the past decade of guidelines, recommendations, and practical tips. It is intended to be used by practicing clinicians across all disciplines who care for patients with AF. The Grading of Recommendations, Assessment, Development and Evaluations system was used to grade recommendation strength and the quality of evidence. Areas of focus include: AF classification and definitions, epidemiology, pathophysiology, clinical evaluation, screening and opportunistic AF detection, detection and management of modifiable risk factors, integrated approach to AF management, stroke prevention, arrhythmia management, sex differences, and AF in special populations. Extensive use is made of tables and figures to synthesize important material and present key concepts. This document should be an important aid for knowledge translation and a tool to help improve clinical management of this important and challenging arrhythmia.

20.
Annu Rev Physiol ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33197224

RESUMO

SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose-dependent and -independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone. Expected final online publication date for the Annual Review of Physiology, Volume 83 is February 10, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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