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1.
Heart ; 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-32114516

RESUMO

INTRODUCTION: There is conflicting evidence regarding the benefits of percutaneous coronary intervention (PCI) in patients with grey zone fractional flow reserve (GZFFR artery) values (0.75-0.80). The prevalence of ischaemia is unknown. We wished to define the prevalence of ischaemia in GZFFR artery and assess whether PCI is superior to optimal medical therapy (OMT) for angina control. METHODS: We enrolled 104 patients with angina with 1:1 randomisation to PCI or OMT. The artery was interrogated with a Doppler flow/pressure wire. Patients underwent Magnetic Resonance Imaging (MRI) with follow-up at 3 and 12 months. The primary outcome was angina status at 3 months using the Seattle Angina Questionnaire (SAQ). RESULTS: 104 patients (age 60±9 years), 79 (76%) males and 79 (76%) Left Anterior Descending (LAD) stenoses were randomised. Coronary physiology and SAQ were similar. Of 98 patients with stress perfusion MRI data, 17 (17%) had abnormal perfusion (≥2 segments with ≥25% ischaemia or ≥1 segment with ≥50% ischaemia) in the target GZFFR artery. Of 89 patients with invasive physiology data, 26 (28%) had coronary flow velocity reserve <2.0 in the target GZFFR artery. After 3 months of follow-up, compared with patients treated with OMT only, patients treated by PCI and OMT had greater improvements in SAQ angina frequency (21 (28) vs 10 (23); p=0.026) and quality of life (24 (26) vs 11 (24); p=0.008) though these differences were no longer significant at 12 months. CONCLUSIONS: Non-invasive evidence of major ischaemia is uncommon in patients with GZFFR artery. Compared with OMT alone, patients randomised to undergo PCI reported improved symptoms after 3 months but these differences were no longer significant after 12 months. TRIAL REGISTRATION NUMBER: NCT02425969.

2.
EuroIntervention ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32122822

RESUMO

AIMS: Novel parameters that detect failed microvascular reperfusion might better identify the patients likely to benefit from adjunctive treatments during primary percutaneous coronary intervention (PCI). We hypothesised that a novel invasive parameter, the thermodilution-derived temperature recovery time (TRT), would be associated with microvascular obstruction (MVO) and prognosis. METHODS AND RESULTS: TRT was derived and validated in two independent ST-elevation myocardial infarction populations and was measured immediately post-PCI. TRT was defined as the duration (seconds) from the nadir of the hyperaemic thermodilution curve to 20% from baseline body temperature. MVO extent (% left ventricular mass) was assessed by cardiovascular magnetic resonance imaging at 2-7 days. In the retrospective derivation cohort (n=271, mean age 60±12 years, 72% male), higher TRT was associated with more MVO (coefficient: 4.24 [95% CI: 2.26-6.22) p<0.001), independently of IMR>32, CFR≤2, hyperaemic Tmn>median, thermodilution waveform, age and ischaemic time. At 5-years, higher TRT was multivariably associated with all-cause death/ heart failure hospitalisation (OR: 4.14 [95% CI: 2.08-8.25] p<0.001) and major adverse cardiac events (OR: 4.05 [95% CI: 2.00-8.21] p<0.001). In the validation population (n=144, mean age 60±11 years, 80% male), the findings were confirmed prospectively. CONCLUSIONS: TRT represents a novel diagnostic advance for predicting MVO and prognosis.

4.
JAMA Cardiol ; 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31995119

RESUMO

Importance: Accurate prediction of risk of death or hospitalizations in patients with heart failure (HF) may allow physicians to explore how more accurate decisions regarding appropriateness and timing of disease-modifying treatments, advanced therapies, or the need for end-of-life care can be made. Objective: To develop and validate a prognostic model for patients with HF. Design, Setting, and Participants: Multivariable analyses were performed in a stepwise fashion. Harrell C statistic was used to assess the discriminative ability. The derivation cohort was Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) participants. The models were validated using the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF). A total of 8399 participants enrolled in PARADIGM-HF. Data were analyzed between June 2016 and June 2018. Main Outcomes and Measures: Cardiovascular death, all-cause mortality, and the composite of cardiovascular death or HF hospitalization at both 1 and 2 years. Results: Complete baseline clinical data were available for 8011 patients in PARADIGM-HF. The mean (SD) age of participants was 64 (11.4) years, 78.2% were men (n = 6567 of 8011), and 70.6% were New York Heart Association class II (n = 5919 of 8011). During a mean follow-up of 27 months, 1546 patients died, and 2031 had a cardiovascular death or HF hospitalization. The common variables were: male sex, race/ethnicity (black or Asian), region (Central Europe or Latin America), HF duration of more than 5 years, New York Heart Association class III/ IV, left ventricular ejection fraction, diabetes mellitus, ß-blocker use at baseline, and allocation to sacubitril/valsartan. Ranked by χ2, N-terminal pro brain natriuretic peptide was the single most powerful independent predictor of each outcome. The C statistic at 1 and 2 years was 0.74 (95% CI, 0.71-0.76) and 0.71 (95% CI, 0.70-0.73) for the primary composite end point, 0.73 (95% CI, 0.71-0.75) and 0.71 (95% CI, 0.69-0.73) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.67-0.74) for all-cause death, respectively. When validated in ATMOSPHERE, the C statistic at 1 and 2 years was 0.71 (95% CI, 0.69-0.72) and 0.70 (95% CI, 0.68-0.71) for the primary composite end point, 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.69-0.72) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.68-0.72) for all-cause death, respectively. An online calculator was created to allow calculation of an individual's risk (http://www.predict-hf.com). Conclusions and Relevance: Predictive models performed well and were developed and externally validated in large cohorts of geographically representative patients, comprehensively characterized with clinical and laboratory data including natriuretic peptides, who were receiving contemporary evidence-based treatment.

5.
Eur J Heart Fail ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944496

RESUMO

AIMS: To develop a risk model for sudden cardiac death (SCD) in high-risk acute myocardial infarction (AMI) survivors. METHODS AND RESULTS: Data from the Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left Ventricular Dysfunction trial (CAPRICORN) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT) were used to create a SCD risk model (with non-SCD as a competing risk) in 13 202 patients. The risk model was validated in the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS). The rate of SCD was 3.3 (95% confidence interval 3.0-3.5) per 100 person-years over a median follow-up of 2.0 years. Independent predictors of SCD included age > 70 years; heart rate ≥ 70 bpm; smoking; Killip class III/IV; left ventricular ejection fraction ≤30%; atrial fibrillation; history of prior myocardial infarction, heart failure or diabetes; estimated glomerular filtration rate < 60 mL/min/1.73 m2 ; and no coronary reperfusion or revascularisation therapy for index AMI. The model was well calibrated and showed good discrimination (C-statistic = 0.72), including in the early period after AMI. The observed 2-year event rates increased steeply with each quintile of risk score (1.9%, 3.6%, 6.2%, 9.0%, 13.4%, respectively). CONCLUSION: An easy to use SCD risk score developed from routinely collected clinical variables in patients with heart failure, left ventricular systolic dysfunction or both, early after AMI was superior to left ventricular ejection fraction. This score might be useful in identifying patients for future trials testing treatments to prevent SCD early after AMI.

6.
JACC Heart Fail ; 8(3): 188-198, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31926854

RESUMO

OBJECTIVES: The purpose of this study was to investigate the effects of mineralocorticoid receptor antagonists (MRAs) on systolic blood pressure (SBP) and outcomes according to baseline SBP in patients with heart failure with reduced ejection fraction (HFrEF). BACKGROUND: MRAs are greatly underused in patients with HFrEF, often because of fear of adverse events. Concern about hypotension has been raised by the demonstration that MRAs are particularly effective treatment for resistant hypertension. METHODS: The effect of MRA therapy was studied in 4,396 patients with HFrEF randomized in the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. RESULTS: Mean SBP change from baseline to 6 months was +1.4 ± 18.1 mm Hg in the placebo group and -1.2 ± 17.9 mm Hg in the MRA group. The between-treatment difference was 2.6 mm Hg (95% confidence interval [CI]: 1.5 to 3.6; p < 0.001). All outcomes were reduced by MRA therapy overall, with consistent effects across SBP categories (e.g., all-cause mortality, overall hazard ratio [HR] of 0.72; 95% CI: 0.64 to 0.82; p < 0.001; SBP ≤105 mm Hg; HR: 0.72; 95% CI: 0.56 to 0.94; SBP >105 to ≤115 mm Hg; HR: 0.78; 95% CI: 0.60 to 1.02; SBP >115 to ≤125 mm Hg; HR: 0.71; 95% CI: 0.53 to 0.94; SBP >125 to ≤135 mm Hg; HR: 0.79; 95% CI: 0.57 to 1.10; and SBP > 135 mm Hg; HR: 0.67; 95% CI: 0.50 to 0.90; p for interaction = 0.95). Hypotension was infrequent and not more common with MRA therapy than with placebo, overall (4.6% vs. 3.9%; p = 0.25) or in any SBP category. CONCLUSIONS: MRA treatment had little effect on SBP in patients with HFrEF, and the clinical benefits were not modified by baseline SBP. MRA treatment infrequently caused hypotension, even when the baseline SBP was low. The treatment discontinuation rates between MRA and placebo therapy were similar. Low SBP is not a reason to withhold MRA therapy in patients with HFrEF.

7.
Arterioscler Thromb Vasc Biol ; 40(3): 506-522, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31996025

RESUMO

OBJECTIVE: There is substantial interest in how GLP-1RA (glucagon-like peptide-1 receptor agonists) and SGLT2 (sodium-glucose cotransporter 2) inhibitors reduce cardiovascular and renal events; yet, robust mechanistic data in humans remain sparse. We conducted a narrative review of published and ongoing mechanistic clinical trials investigating the actions of SGLT2 inhibitors and GLP-1RAs to help the community appreciate the extent of ongoing work and the variety and design of such trials. Approach and Results: To date, trials investigating the mechanisms of action of SGLT2 inhibitors have focused on pathways linked to glucose metabolism and toxicity, hemodynamic/volume, vascular and renal actions, and cardiac effects, including those on myocardial energetics. The participants studied have included those with established cardiovascular disease (including coronary artery disease and heart failure), liver disease, renal impairment, obesity, and hypertension; some of these trials have enrolled patients both with and without type 2 diabetes mellitus. GLP-1RA mechanistic trials have focused on glucose-lowering, insulin-sparing, weight reduction, and blood pressure-lowering effects, as well as possible direct vascular, cardiac, and renal effects of these agents. Very few mechanisms of action of SGLT2 inhibitors or GLP-1RAs have so far been convincingly demonstrated. One small trial (n=97) of SGLT2 inhibitors has investigated the cardiac effects of these drugs, where a small reduction in left ventricular mass was found. Data on vascular effects are limited to one trial in type 1 diabetes mellitus, which suggests some beneficial actions. SGLT2 inhibitors have been shown to reduce liver fat. We highlight the near absence of mechanistic data to explain the beneficial effects of SGLT2 inhibitors in patients without diabetes mellitus. GLP-1RAs have not been found to have major cardiovascular mechanisms of action in the limited, completed trials. Conflicting data around the impact on infarct size have been reported. No effect on left ventricular ejection fraction has been demonstrated. CONCLUSIONS: We have tabulated the extensive ongoing mechanistic trials that will report over the coming years. We report 2 exemplar ongoing mechanistic trials in detail to give examples of the designs and techniques employed. The results of these many ongoing trials should help us understand how SGLT2 inhibitors and GLP-1RAs improve cardiovascular and renal outcomes and may also identify unexpected mechanisms suggesting novel therapeutic applications.

8.
Circulation ; 141(2): 100-111, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31736328

RESUMO

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. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

9.
Circulation ; 141(2): 90-99, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31736335

RESUMO

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. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

10.
Eur J Heart Fail ; 22(2): 196-213, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31816162

RESUMO

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose-lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors]. Regarding safety of DPP-4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP-4 inhibitors. GLP-1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT-2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT-2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT-2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose-lowering therapies in patients with HF.

11.
Circ Heart Fail ; 12(12): e006539, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31813280

RESUMO

BACKGROUND: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction. METHODS: Baseline characteristics (including biomarkers and quality of life) and outcomes (primary outcome: composite of first heart failure hospitalization or cardiovascular death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (EF≥45%), I-Preserve (Irbesartan in heart failure with Preserved ejection fraction), and TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial). RESULTS: Women were older and more often obese and hypertensive but less likely to have coronary artery disease or atrial fibrillation. Women had more symptoms and signs of congestion and worse quality of life. Despite this, the risk of the primary outcome was lower in women (hazard ratio, 0.80 [95% CI, 0.73-0.88]), as was the risk of cardiovascular death (hazard ratio, 0.70 [95% CI, 0.62-0.80]), but there was no difference in the rate for first hospitalization for heart failure (hazard ratio, 0.92 [95% CI, 0.82-1.02]). The lower risk of cardiovascular death in women, compared with men, was in part explained by a substantially lower risk of sudden death (hazard ratio, 0.53 [0.43-0.65]; P<0.001). E/A ratio was lower in women (1.1 versus 1.2). CONCLUSIONS: There are significant differences between women and men with heart failure with preserved ejection fraction. Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00853658, NCT01035255.

12.
Eur J Heart Fail ; 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31849164

RESUMO

AIMS: To investigate the relationship between heart rate and outcomes in heart failure and reduced ejection fraction (HFrEF) patients in sinus rhythm (SR) and atrial fibrillation (AF) adjusting for natriuretic peptide concentration, a powerful prognosticator. METHODS AND RESULTS: Of 13 562 patients from two large HFrEF trials, 10 113 (74.6%) were in SR and 3449 (25.4%) in AF. The primary endpoint was the composite of cardiovascular death or heart failure hospitalization. Heart rate was analysed as a categorical (tertiles, T1-3) and continuous variable (per 10 bpm), separately in patients in SR and AF. Outcomes were adjusted for prognostic variables, including N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and also examined using change from baseline heart rate to 1 year (≤ -10 bpm, ≥ +10 bpm, < ±10 bpm). SR patients with a higher heart rate had worse symptoms and quality of life, more often had diabetes and higher NT-proBNP concentrations. They had higher risk of the primary endpoint [T3 vs. T1 adjusted hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.35-1.66; P < 0.001; per 10 bpm: 1.12, 95% CI 1.09-1.16; P < 0.001]. In SR, heart rate was associated with a relatively higher risk of pump failure than sudden death (adjusted HR per 10 bpm 1.17, 95% CI 1.09-1.26; P < 0.001 vs. 1.07, 95% CI 1.02-1.13; P = 0.011). Heart rate was not predictive of any outcome in AF. CONCLUSIONS: In HFrEF, an elevated heart rate was an independent predictor of adverse cardiovascular outcomes in patients in SR, even after adjustment for NT-proBNP. There was no relationship between heart rate and outcomes in AF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT01035255 and NCT00853658.

13.
Open Heart ; 6(2): e001115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31673393

RESUMO

Objectives: Ultra-small superparamagnetic particles of iron oxide (USPIO)-enhanced MRI can detect cellular inflammation within tissues and may help non-invasively identify cardiac transplant rejection. Here, we aimed to determine the normal reference values for USPIO-enhanced MRI in patients with a prior cardiac transplant and examine whether USPIO-enhanced MRI could detect myocardial inflammation in patients with transplant rejection. Methods: Ten volunteers and 11 patients with cardiac transplant underwent T2, T2* and late gadolinium enhancement 1.5T MRI, with further T2* imaging at 24 hours after USPIO (ferumoxytol, 4 mg/kg) infusion, at baseline and 3 months. Results: Ten patients with clinically stable cardiac transplantation were retained for analysis. Myocardial T2 values were higher in patients with cardiac transplant versus healthy volunteers (53.8±5.2 vs 48.6±1.9 ms, respectively; p=0.003). There were no differences in the magnitude of USPIO-induced change in R2* in patients with transplantation (change in R2*, 26.6±7.3 vs 22.0±10.4 s-1 in healthy volunteers; p=0.28). After 3 months, patients with transplantation (n=5) had unaltered T2 values (52.7±2.8 vs 52.12±3.4 ms; p=0.80) and changes in R2* following USPIO (29.42±8.14 vs 25.8±7.8 s-1; p=0.43). Conclusion: Stable patients with cardiac transplantation have increased myocardial T2 values, consistent with resting myocardial oedema or fibrosis. In contrast, USPIO-enhanced MRI is normal and stable over time suggesting the absence of chronic macrophage-driven cellular inflammation. It remains to be determined whether USPIO-enhanced MRI may be able to identify acute cardiac transplant rejection. Trial registration number: NCT02319278349 (https://clinicaltrials.gov/ct2/show/NCT02319278) Registered 03.12.2014 EUDraCT 2013-002336-24.

15.
Cardiovasc Endocrinol Metab ; 8(1): 35-38, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31646296

RESUMO

Over the last three decades, trials of coronary revascularization have taken into account whether populations did or did not have diabetes. What has not been considered is whether or not patients with diabetes in these studies have type 1 or type 2 diabetes. 'Diabetes' appears to be largely used as a synonym for type 2 diabetes. The number of patients with type 1 diabetes has not been reported in most trials. Many questions remain unanswered. Do patients with type 1 diabetes have the same response to various modes of revascularization as those with type 2 diabetes? We know type 2 diabetes affects coronary endothelial function and the coronary artery wall but to what extent does type 1 diabetes affect these? Any response to revascularization does not just depend on the coronary artery but also on the myocardium. How does type 1 diabetes affect the myocardium? To what extent do patients with type 1 diabetes have viable or ischaemic myocardium or scar? What does 'diabetic cardiomyopathy' refer to in the context of type 1 diabetes? This manuscript reviews the evidence for revascularization in type 1 diabetes. We conclude that there has been a near absence of investigation of the pros and cons of revascularization in this population. Investigations to establish both the nature and extent of coronary and myocardial disease in these populations are necessary. Clinical trials of the pros and cons of revascularization in type 1 diabetes are necessary; many will declare that these will be too challenging to perform.

16.
N Engl J Med ; 381(21): 1995-2008, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31535829

RESUMO

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.).


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Compostos Benzidrílicos/efeitos adversos , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/mortalidade , Terapia Combinada , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Feminino , Glucosídeos/efeitos adversos , Hemoglobina A Glicada/análise , Insuficiência Cardíaca/complicações , Hospitalização , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/tratamento farmacológico
17.
JACC Heart Fail ; 7(10): 878-887, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31521682

RESUMO

OBJECTIVES: The authors investigated the impact of coronary artery bypass grafting (CABG) on first and recurrent hospitalization in this population. BACKGROUND: In the STICH (Surgical Treatment for Ischemic Heart Failure) trial, CABG reduced all-cause death and hospitalization in patients with and ischemic cardiomyopathy and left ventricular ejection fraction <35%. METHODS: A total of 1,212 patients were randomized (610 to CABG + optimal medical therapy [CABG] and 602 to optimal medical therapy alone [MED] alone) and followed for a median of 9.8 years. All-cause and cause-specific hospitalizations were analyzed as time-to-first-event and as recurrent event analysis. RESULTS: Of the 1,212 patients, 757 died (62.4%) and 732 (60.4%) were hospitalized at least once, for a total of 2,549 total all-cause hospitalizations. Most hospitalizations (66.2%) were for cardiovascular causes, of which approximately one-half (907 or 52.9%) were for heart failure. More than 70% of all hospitalizations (1,817 or 71.3%) were recurrent events. The CABG group experienced fewer all-cause hospitalizations in the time-to-first-event (349 CABG vs. 383 MED, adjusted hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.74 to 0.98; p = 0.03) and in recurrent event analyses (1,199 CABG vs. 1,350 MED, HR: 0.78, 95% CI: 0.65 to 0.94; p < 0.001). This was driven by fewer total cardiovascular (CV) hospitalizations (744 vs. 968; p < 0.001, adjusted HR: 0.66, 95% CI: 0.55 to 0.81; p = 0.001), the majority of which were due to HF (395 vs. 512; p < 0.001, adjusted HR: 0.68, 95% CI: 0.52-0.89; p = 0.005). We did not observe a difference in non-CV events. CONCLUSIONS: CABG reduces all-cause, CV, and HF hospitalizations in time-to-first-event and recurrent event analyses. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595).

18.
Circ Cardiovasc Interv ; 12(8): e007830, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31362541

RESUMO

BACKGROUND: The benefits of routine invasive management in patients with prior coronary artery bypass grafts presenting with non-ST elevation acute coronary syndromes are uncertain because these patients were excluded from pivotal trials. METHODS: In a multicenter trial, non-ST elevation acute coronary syndromes patients with prior coronary artery bypass graft were prospectively screened in 4 acute hospitals. Medically stabilized patients were randomized to invasive management (invasive group) or noninvasive management (medical group). The primary outcome was adherence with the randomized strategy by 30 days. A blinded, independent Clinical Event Committee adjudicated predefined composite outcomes for efficacy (all-cause mortality, rehospitalization for refractory ischemia/angina, myocardial infarction, hospitalization because of heart failure) and safety (major bleeding, stroke, procedure-related myocardial infarction, and worsening renal function). RESULTS: Two hundred seventeen patients were screened and 60 (mean±SD age, 71±9 years, 72% male) were randomized (invasive group, n=31; medical group, n=29). One-third (n=10) of the participants in the invasive group initially received percutaneous coronary intervention. In the medical group, 1 participant crossed over to invasive management on day 30 but percutaneous coronary intervention was not performed. During 2-years' follow-up (median [interquartile range], 744 [570-853] days), the composite outcome for efficacy occurred in 13 (42%) subjects in the invasive group and 13 (45%) subjects in the medical group. The composite safety outcome occurred in 8 (26%) subjects in the invasive group and 9 (31%) subjects in the medical group. An efficacy or safety outcome occurred in 17 (55%) subjects in the invasive group and 16 (55%) subjects in the medical group. Health status (EuroQol 5 Dimensions) and angina class in each group were similar at 12 months. CONCLUSIONS: More than half of the population experienced a serious adverse event. An initial noninvasive management strategy is feasible. A substantive health outcomes trial of invasive versus noninvasive management in non-ST elevation acute coronary syndromes patients with prior coronary artery bypass grafts appears warranted. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01895751.

19.
Lancet Diabetes Endocrinol ; 7(10): 776-785, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31422062

RESUMO

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: Treatment with GLP-1 receptor agonists has beneficial effects on cardiovascular, mortality, and kidney outcomes in patients with type 2 diabetes. FUNDING: None.

20.
Eur J Heart Fail ; 21(8): 974-984, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31271255

RESUMO

AIMS: Insulin causes sodium retention and hypoglycaemia and its use is associated with worse outcomes in heart failure (HF) with reduced ejection fraction. We have investigated whether this is also the case in HF with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We examined the association between diabetes/diabetes treatments and the risk of the primary composite of cardiovascular death or HF hospitalization, as well as other outcomes in adjusted analyses in CHARM-Preserved (left ventricular ejection fraction ≥ 45%), I-Preserve and TOPCAT (Americas) pooled. Of 8466 patients, 2653 (31%) had diabetes, including 979 (37%) receiving insulin. Patients receiving insulin were younger, had a higher body mass index, prevalence of ischaemic aetiology, N-terminal pro-B-type natriuretic peptide and use of diuretics, worse New York Heart Association class and signs and symptoms, and worse quality of life and renal function, compared to patients with diabetes not on insulin. Among the 1398 patients with echocardiographic data, insulin use was associated with higher left ventricular end-diastolic pressure and more diastolic dysfunction than in other participants. The primary outcome occurred at a rate of 6.3 per 100 patient-years in patients without diabetes, and 10.2 and 17.1 per 100 patient-years in diabetes patients without and with insulin use, respectively [fully adjusted hazard ratio (aHR) insulin-treated diabetes vs. other diabetes: 1.41, 95% confidence interval (CI) 1.23-1.63, P < 0.001]. The adjusted HR is 1.67 (95% CI 1.20-2.32, p = 0.002) for sudden death (insulin-treated diabetes vs. other diabetes). CONCLUSIONS: Insulin use is associated with poor outcomes in HFpEF. Although we cannot conclude a causal association, the safety of insulin and alternative glucose-lowering treatments in HF needs to be evaluated in clinical trials.

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