Impact of dronedarone in atrial fibrillation and flutter on stroke reduction

Christine Benn Christiansen1, Christian Torp-Pedersen1, Lars Køber21Department of Cardiology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; 2Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkBackground: Dronedarone has been developed for treatment of atrial fibrillation (AF) or atrial flutter (AFL). It is an amiodarone analogue but noniodinized and without the same adverse effects as amiodarone.Objective and methods: This is a review of 7 studies (DAFNE, ADONIS, EURIDIS, ATHENA, ANDROMEDA, ERATO and DIONYSOS) on dronedarone focusing on efficacy, safety and prevention of stroke. There was a dose-finding study (DAFNE), 3 studies focusing on maintenance of sinus rhythm (ADONIS, EURIDIS and DIONYSOS), 1 study focusing on rate control (ERATO) and 2 studies investigating mortality and morbidity (ANDROMEDA and ATHENA).Results: The target dose for dronedarone was established in the DAFNE study to be 400 mg twice daily. Both EURIDIS and ADONIS studies demonstrated that dronedarone was superior to placebo for maintaining sinus rhythm. However, DIONYSOS found that dronedarone is less efficient at maintaining sinus rhythm than amiodarone. ERATO concluded that dronedarone reduces ventricular rate in patients with chronic AF. The ANDROMEDA study in patients with severe heart failure was discontinued because of increased mortality in dronedarone group. Dronedarone reduced cardiovascular hospitalizations and mortality in patients with AF or AFL in the ATHENA trial. Secondly, according to a post hoc analysis a significant reduction in stroke was observed (annual rate 1.2% on dronedarone vs 1.8% on placebo, respectively [hazard ratio 0.66, confidence interval 0.46 to 0.96, P = 0.027]). In total, 54 cases of stroke occurred in 3439 patients (crude rate 1.6%) receiving dronedarone compared to 76 strokes in 3048 patients on placebo (crude rate 2.5%), respectively.Conclusion: Dronedarone can be used for maintenance of sinus rhythm and can reduce stroke in patients with AF who receive usual care, which includes antithrombotic therapy and heart rate control.Keywords: atrial fibrillation, stroke, dronedaron

A re-examination of the BEST Trial using composite outcomes, including emergency department visits

Objectives: The influence of choice of endpoint on trial size, duration, and interpretation of results was examined in patients with heart failure who were enrolled in BEST (Beta-blocker Evaluation of Survival Trial). Background: The choice of endpoints in heart failure trials has evolved over the past 3 decades. Methods: In the BEST trial, we used Cox regression analysis to examine the effect of bucindolol on the current standard composite of cardiovascular death or heart failure hospitalization (CVD/HFH) compared with the original primary mortality endpoint and the expanded composite that included emergency department (ED) visits. We also undertook an analysis of recurrent events primarily using the Lin, Wei, Ying, and Yang model. Results: Overall, 448 (33%) patients on placebo and 411 (30%) patients on bucindolol died (hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78 to 1.02; p = 0.11). A total of 730 (54%) patients experienced CVD/HFH on placebo and 624 (46%) on bucindolol (HR: 0.80; 95% CI: 0.72 to 0.89; p < 0.001). Adding ED visits increased these numbers to 768 (57%) and 668 (49%), respectively (HR: 0.81; 95% CI: 0.73 to 0.90; p < 0.001). A total of 568 (42%) patients on placebo experienced HFH compared with 476 (35%) patients on bucindolol (HR: 0.78; 95% CI: 0.69 to 0.89; p < 0.001), with a total of 1,333 and 1,124 admissions, respectively. With the same statistical assumptions, using the composite endpoint instead of all-cause mortality would have reduced the trial size by 40% and follow-up duration by 69%. The rate ratio for recurrent events (CVD/HFH) was 0.83 (95% CI: 0.73 to 0.94; p = 0.003). Conclusions: Choice of endpoint has major implications for trial size and duration, as well as interpretation of results. The value of broader composite endpoints and inclusion of recurrent events needs further investigation. (Beta Blocker Evaluation in Survival Trial [BEST]; NCT00000560

Consequences of overutilization and underutilization of thrombolytic therapy in clinical practice

AbstractOBJECTIVESThe aim of this study was to evaluate the consequences, measured as mortality and in-hospital stroke, of the use of thrombolytic therapy among patients with acute myocardial infarction (AMI), who do not fulfill accepted criteria or who have contraindications to thrombolytic therapy (i.e., overutilization) and among patients who are withheld thrombolytic treatment despite fulfilling indications and having no contraindications (i.e., underutilization).BACKGROUNDThe implementation of treatment with thrombolysis in clinical practice is not in accordance with the accepted criteria from randomized studies. The consequence has been over- and underutilization of thrombolytic therapy among patients with AMI in clinical practice. The outcome of overutilization of thrombolytic therapy has not been described previously.METHODSWe examined 6,676 consecutive patients admitted to the hospital with an AMI and recorded characteristics, in-hospital complications and long-term mortality.RESULTSOverall, 41% of the patients received thrombolytic therapy. Thrombolytic therapy was underutilized in 14.3% and overutilized in 12.9% of the patients. The use of thrombolytic therapy was associated with reduced mortality in every subgroup examined, including patients without an accepted indication, with an accepted indication and in patients with prior stroke. The risk ratio of in-hospital stroke was not increased in connection with thrombolytic therapy, not even in patients with prior stroke (relative risk = 0.237, 95% confidence interval: 0.031 to 1.810, p = 0.17).CONCLUSIONSWith the large benefit known to be associated with thrombolytic therapy and the favorable result of thrombolytic therapy in patients with contraindications observed in this study, we conclude that a formal evaluation of thrombolytic therapy in wider patient categories is warranted

Diabetes is an independent predictor of survival 17 years after myocardial infarction: follow-up of the TRACE registry

<p>Abstract</p> <p>Background</p> <p>In patients hospitalized for myocardial infarction, there are limited data examining the long-term prognostic effect of diabetes.</p> <p>The aim of this study was to systematically evaluate the development of diabetes as an independent long-term prognostic factor after myocardial infarction.</p> <p>Methods</p> <p>Prospective follow-up of 6676 consecutive MI patients screened for entry in the Trandolapril Cardiac Evaluation (TRACE) study. The patients were analysed by Kaplan-Meier survival analysis, landmark analysis and Cox proportional hazard models and outcome measure was all-cause mortality.</p> <p>Results</p> <p>The mortality in patients with diabetes was 82,7% at 10 years of follow-up and 91,1% at 15 years of follow-up, while patients without diabetes had a mortality of 60,2% at 10 years of follow-up and 72,9% at 15 years of follow-up (p < 0.0001). Landmark analysis continued to show prognostic significance of diabetes throughout the duration of follow-up. Multivariable Cox proportional-hazards model showed that the hazard ratio for death in patients with diabetes overall was 1.47 (95% confidence intervals (CI) 1.35-1.61) and varied between 1.19 (CI 1.04-1.37) and 2.13 (CI 1.33-3.42) in the 2-year periods of follow-up.</p> <p>Conclusions</p> <p>Diabetes is an important independent long-term prognostic factor after MI and continues to predict mortality even 17 years after index MI.</p> <p>This underscores the importance of aggressive diagnostic and therapeutic approach in diabetes patients with MI.</p

Flow measurement at the aortic root:impact of location of through-plane phase contrast velocity mapping

BACKGROUND: Cardiovascular magnetic resonance (CMR) is considered the gold standard of cardiac volumetric measurements. Flow in the aortic root is often measured at the sinotubular junction, even though placing the slice just above valve level may be more precise. It is unknown how much flow measurements vary at different levels in the aortic root and which level corresponds best to left ventricle volumetry. METHODS: All patients were older than 70 years presenting with at least one of the following diagnoses: diabetes, hypertension, prior stroke and/or heart failure. Patients with arrhythmias during CMR and aortic stenosis were excluded from the analyses. Stroke volumes were measured volumetrically (SV(ref)) from steady-state free precision short axis images covering the entire left ventricle, excluding the papillary muscles and including the left ventricular outflow tract. Flow sequences (through-plane phase contrast velocity mapping) were obtained at valve level (SV(V)) and at the sinotubular junction (SV(ST)). Firstly, SV(V) and SV(ST) were compared to each other and secondly, after excluding patients with mitral regurgitations to ensure that stroke volumes measured volumetrically would theoretically be equal to flow measurements, SV(V) and SV(ST) were compared to SV(ref). RESULTS: Initially, 152 patients were included. 22 were excluded because of arrhythmias during scans and 9 were excluded for aortic stenosis. Accordingly, data from 121 patients were analysed and of these 63 had visually evident mitral regurgitation on cine images. On average, stroke volumes measured with flow at the sinotubular junction was 13–16 % lower than when measured at valve level (70.0 mL ±13.8 vs. 81.8 mL ±15.5). This was in excess of the expected difference caused by the outflow to the coronary arteries. In the 58 patients with no valvulopathy, stroke volumes measured at valve level (79.0 mL ±12.4) was closest to the volumetric measurement (85.4 mL ±12.0) but still significantly lower (p < 0.001). Flow measured at the ST-junction (68.1 mL ±11.6) was significantly lower than at valve level and the volumetric measurements. The mean difference between SV(ref)–SV(V) (6.4 mL) and SV(ref)-SV(ST) (18.2 mL) showed similar variances (SD 7.4 vs. 8.1 respectively) and hence equal accuracy. CONCLUSIONS: Aortic flow measured at valve level corresponded best with volumetric measurements and on average flow measured at the sinotubular junction underestimated flow approximately 15 % compared to valve level. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02036450. Registered 08/01/2014

Prevalence of prediabetes and undiagnosed diabetes in patients with HFpEF and HFrEF and associated clinical outcomes

Purpose: The prevalence and consequences of prediabetic dysglycemia and undiagnosed diabetes is unknown in patients with heart failure (HF) and preserved ejection fraction (HFpEF) and has not been compared to heart failure and reduced ejection fraction (HFrEF). Methods: We examined the prevalence and outcomes associated with normoglycemia, prediabetic dysglycemia and diabetes (diagnosed and undiagnosed) among individuals with a baseline glycated hemoglobin (hemoglobin A1c, HbA1c) measurement stratified by HFrEF or HFpEF in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity programme (CHARM). We studied the primary outcome of HF hospitalization or cardiovascular (CV) death, and all-cause death, and estimated hazard ratios (HR) by use of multivariable Cox regression models. Results: HbA1c was measured at baseline in CHARM patients enrolled in the USA and Canada and was available in 1072/3023 (35%) of patients with HFpEF and 1578/4576 (34%) patients with HFrEF. 18 and 16% had normoglycemia (HbA1c &lt; 6.0), 20 and 22% had prediabetes (HbA1c 6.0–6.4), respectively. Finally among patients with HFpEF 22% had undiagnosed diabetes (HbA1c &gt; 6.4), and 40% had known diabetes (any HbA1c), with corresponding prevalence among HFrEF patients being 26 and 35%. The rates of both clinical outcomes of interest were higher in patients with undiagnosed diabetes and prediabetes, compared to normoglycemic patients, irrespective of HF subtype, and in general higher among HFrEF patients. For the primary composite outcome among HFpEF patients, the HRs were 1.02 (95% CI 0.63–1.65) for prediabetes, HR 1.18 (0.75–1.86) for undiagnosed diabetes and 2.75 (1.83–4.11) for known diabetes, respectively, p value for trend across groups &lt; 0.001. Dysglycemia was also associated with worse outcomes in HFrEF. Conclusions: These findings confirm the remarkably high prevalence of dysglycemia in heart failure irrespective of ejection fraction phenotype, and demonstrate that dysglycemia is associated with a higher risk of adverse clinical outcomes, even before the diagnosis of diabetes and institution of glucose lowering therapy in patients with HFpEF as well as HFrEF