BACKGROUND: Expectations that reestablishing and maintaining sinus rhythm in patients with atrial fibrillation might improve survival were disproved in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. This report describes the cause-specific modes of death in the AFFIRM treatment groups. METHODS AND RESULTS: All deaths in patients enrolled in AFFIRM underwent blinded review by the AFFIRM Events Committee, and a mode of death was assigned. In AFFIRM, 2033 patients were randomized to a rhythm-control strategy and 2027 patients to a rate-control strategy. During a mean follow-up of 3.5 years, there were 356 deaths in the rhythm-control patients and 310 deaths in the rate-control patients (P=0.07). In the rhythm-control group, 129 patients (9%) died of a cardiac cause, and in the rate-control group, 130 patients (10%) died (P=0.95). Both groups had similar rates of arrhythmic and nonarrhythmic cardiac deaths. The numbers of vascular deaths were similar in the 2 groups: 35 (3%) in the rhythm-control group and 37 (3%) in the rate-control group (P=0.82). There were no differences in the rates of ischemic stroke and central nervous system hemorrhage. In the rhythm-control group, there were 169 noncardiovascular deaths (47.5% of the total number of deaths), whereas in the rate-control arm, there were 113 noncardiovascular deaths (36.5% of the total number of deaths) (P=0.0008). Differences in noncardiovascular death rates were due to pulmonary and cancer-related deaths. CONCLUSIONS: Management of atrial fibrillation with a rhythm-control strategy conferred no advantage over a rate-control strategy in cardiac or vascular mortality and may be associated with an increased noncardiovascular death rate.
To examine the risk of death associated with antiarrhythmic drug (AAD) therapy in a nationwide unselected cohort of patients with atrial fibrillation (AF).
All patients admitted with AF in Denmark from 1995 to 2004 and their subsequent use of AADs were identified by individual-level linkage of nationwide registries. Multivariable Cox proportional-hazard models with time-dependent covariates were used to analyse the risk of death associated with AAD therapy. A total of 141,500 patients were included in the study; of these 3356 (2.4%) patients received treatment with flecainide, 3745 (2.6%) propafenone, 23,346 (16.5%) sotalol, and 10,376 (7.3%) amiodarone. Annualized mortality rates were 2.54, 4.25, 5.29, and 7.42 per year per 100 person years for flecainide, propafenone, sotalol, and amiodarone, respectively. Multivariable Cox proportional-hazard models did not show increased risk of death associated with any of the AADs. Hazard ratio (95% confidence interval) for flecainide 0.38 (0.32-0.44), propafenone 0.65 (0.58-0.71), sotalol 0.65 (0.63-0.67), and amiodarone 0.94 (0.89-1.00).
In an unselected cohort of patients with AF, antiarrhythmic treatment with flecainide, propafenone, sotalol, or amiodarone was not associated with increased risk of death. From a safety perspective, this indicates appropriate selection of patients for AAD therapy.
Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study.
Uncertainty remains over optimal antithrombotic treatment of patients with atrial fibrillation presenting with myocardial infarction and/or undergoing percutaneous coronary intervention. We investigated the risk and time frame for bleeding following myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation according to antithrombotic treatment.
Patients with atrial fibrillation and admitted with myocardial infarction or for percutaneous coronary intervention between 2000 and 2009 (11 480 subjects, mean age 75.6 years [SD ±10.3], males 60.9%) were identified by individual level linkage of nationwide registries in Denmark. Fatal or nonfatal (requiring hospitalization) bleeding was determined according to antithrombotic treatment regimen: triple therapy (TT) with vitamin K antagonist (VKA)+aspirin+clopidogrel, VKA+antiplatelet, and dual antiplatelet therapy with aspirin+clopidogrel. We calculated crude incidence rates and adjusted hazard ratios by Cox regression models. Within 1 year, 728 bleeding events were recorded (6.3%); 79 were fatal (0.7%). Within 30 days, rates were 22.6, 20.3, and 14.3 bleeding events per 100 person-years for TT, VKA+antiplatelet, and dual antiplatelet therapy, respectively. Both early (within 90 days) and delayed (90-360 days) bleeding risk with TT exposure in relation to VKA+antiplatelet was increased; hazard ratio 1.47 (1.04;2.08) and 1.36 (0.95;1.95), respectively. No significant difference in thromboembolic risk was observed for TT versus VKA+antiplatelet; hazard ratio, 1.15 (0.95;1.40).
High risk of bleeding is immediately evident with TT after myocardial infarction/percutaneous coronary intervention in patients with atrial fibrillation. A continually elevated risk associated with TT indicates no safe therapeutic window, and TT should only be prescribed after thorough bleeding risk assessment of patients.
Controversy continues concerning the choice of rhythm control vs rate control treatment strategies for atrial fibrillation (AF). A recent clinical trial showed no difference in 5-year mortality between the 2 treatments. We aimed to determine whether the 2 strategies have similar effectiveness when applied to a general population of patients with AF with longer follow-up.
We used population-based administrative databases from Quebec, Canada, from 1999 to 2007 to select patients 66 years or older hospitalized with an AF diagnosis who did not have AF-related drug prescriptions in the year before the admission but received a prescription within 7 days of discharge. Patients were followed until death or administrative censoring. Mortality was analyzed by multivariable Cox regression.
Among 26,130 patients followed for a mean (SD) period of 3.1 years (2.3 years), there were 13,237 deaths (49.5%). After adjusting for covariates, we found that the effect of rhythm vs rate control drugs changed over time: after a small increase in mortality for patients treated with rhythm control in the 6 months following treatment initiation (hazard ratio [HR], 1.07; 95% CI, 1.01-1.14), the mortality was similar between the 2 groups until year 4 but decreased steadily in the rhythm control group after year 5 (HR, 0.89; 95% CI, 0.81-0.96; and HR, 0.77; 95% CI, 0.62-0.95, after 5 and 8 years, respectively).
In this population-based sample of patients with AF, we found little difference in mortality within 4 years of treatment initiation between patients with AF initiating rhythm control therapy vs those initiating rate control therapy. However, rhythm control therapy seems to be superior in the long-term.
Comparison of management patterns and clinical outcomes in patients with atrial fibrillation in Canada and the United States (from the analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management [AFFIRM] database).
Little is known about differences in practice patterns or outcomes in the management of patients who have atrial fibrillation in Canada compared with those in the United States (US). We evaluated the effect that the country of enrollment may have on the management patterns and clinical outcomes in patients who participated in the AFFIRM study. Three thousand four hundred patients came from the US and 660 from Canada. In the US, patients were more likely to have a history of coronary artery disease (39% vs 35%, p = 0.03), hypertension (72% vs 67%, p = 0.01), or congestive heart failure (24% vs 18%, p = 0.0002). More US participants were
Epidemiological studies of exposures that vary with time require an additional level of methodological complexity to account for the time-dependence of exposure. This study compares a nested case-control approach for the study of time-dependent exposure with cohort analysis using Cox regression including time-dependent covariates.
A cohort of 1340 subjects with four fixed and seven time-dependent covariates was used for this study. Nested case-control analyses were repeated 100 times for each of 4, 8, 16, 32, and 64 controls per case, and point estimates were compared to those obtained using Cox regression on the full cohort. Computational efficiencies were evaluated by comparing central processing unit times required for analysis of the cohort at sizes 1, 2, 4, 8, 16, and 32 times its initial size.
Nested case-control analyses yielded results that were similar to results of Cox regression on the full cohort. Cox regression was found to be 125 times slower than the nested case-control approach (using four controls per case).
The nested case-control approach is a useful alternative for cohort analysis when studying time-dependent exposures. Its superior computational efficiency may be particularly useful when studying rare outcomes in databases, where the ability to analyze larger sample sizes can improve the power of the study.
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Concerns have been expressed about the reliability of clinical practice guidelines. We analyzed 3 guidelines from medical specialty societies about dronedarone hydrochloride, an antiarrhythmic drug related to amiodarone hydrochloride, for treatment of patients with atrial fibrillation. We compared the recommendations in these guidelines with the conclusions about dronedarone that we reached by applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Method to the same evidence base. In our analysis, as a rate control drug, dronedarone was better than placebo only for a surrogate outcome (heart rate). As a rhythm control drug, dronedarone was associated with 13 (95% CI, -15 to 61) excess deaths per 1000 patients treated as compared with placebo. Compared with amiodarone, dronedarone was less effective (214 [95% CI, 130 to 294] more recurrences of atrial fibrillation per 1000 patients treated) and similarly tolerated (-28 [95% CI, -69 to 33] more serious adverse events requiring drug suspension per 1000 patients treated). Despite the limits of the evidence, all 3 guidelines recommended dronedarone for prevention of recurrences of atrial fibrillation; 2 of the guidelines recommended it as a rate control agent. Our findings raise questions about the reliability of these clinical practice guidelines, as well as the financial associations between many of the panel members and the manufacturer of dronedarone.
Risk factors for stroke are well known in atrial fibrillation (AF) patients, while less is known on the effect of these factors on total mortality.
Our aim was to study the impact of cardiovascular drug classes on mortality in AF patients treated in primary care.
The study population was chosen based on patient data from 75 primary care centres in Sweden compiled in a database. Individuals diagnosed with AF who were older than 45 years were enrolled (n?=?12,302, of whom 6,660 were men). Cox regression analysis with mortality (years to death) as outcome was conducted in the men and women separately, as well in the age categories
To study mortality rates among men and women with atrial fibrillation (AF) and concomitant chronic heart failure (CHF) prescribed different classes of cardiovascular drugs in primary health care.
A cohort of men (n = 1159) and women (n = 1155) aged 45 years or above and diagnosed with both AF and CHF from patient records from 75 primary care centers in Sweden were included in the study. Regression models with mortality as the outcome were used, with adjustment for a propensity score comprising age, cardiovascular co-morbidities, education, marital status, and pharmacotherapy. We analysed using Cox regression with hazard ratio (HR), and Laplace regression with years until 10% of the patients had died, with 95% confidence intervals (95% CI). Independent variables were prescribed cardiovascular drugs.
Individuals prescribed anticoagulants versus no treatment gained 1.95 years (95% CI 0.47-3.43), anticoagulants versus antiplatelets 1.26 years (95% CI 0.42-2.10), calcium channel blockers 1.17 years (95% CI 0.21-2.14), and statins 1.49 years (95% CI 0.39-2.59). Among patients 80 years or above no significant effect by anticoagulants was seen, HR 0.73 (95% CI 0.43-1.23).
Our findings suggest that life may be prolonged in patients with AF and concomitant CHF in primary care prescribed anticoagulants, calcium channel blockers, and statins.
Comment In: Scand Cardiovasc J. 2014 Oct;48(5):259-6125228263