Long-term outcome of targeted therapy of underlying conditions in patients with early persistent atrial fibrillation and heart failure: data of the RACE 3 trial.

AIMS: The Routine vs. Aggressive risk factor driven upstream rhythm Control for prevention of Early persistent atrial fibrillation (AF) in heart failure (HF) (RACE 3) trial demonstrated that targeted therapy of underlying conditions improved sinus rhythm maintenance at 1 year. We now explored the effects of targeted therapy on the additional co-primary endpoints; sinus rhythm maintenance and cardiovascular outcome at 5 years. METHODS AND RESULTS: Patients with early persistent AF and mild-to-moderate stable HF were randomized to targeted or conventional therapy. Both groups received rhythm control therapy according to guidelines. The targeted group additionally received four therapies: angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers (ARBs), statins, mineralocorticoid receptor antagonists (MRAs), and cardiac rehabilitation. The presence of sinus rhythm and cardiovascular morbidity and mortality at 5-year follow-up were assessed. Two hundred and sixteen patients consented for long-term follow-up, 107 were randomized to targeted and 109 to conventional therapy. At 5 years, MRAs [76 (74%) vs. 10 (9%) patients, P < 0.001] and statins [81 (79%) vs. 59 (55%), P < 0.001] were used more in the targeted than conventional group. Angiotensin-converting enzyme inhibitors/ARBs and physical activity were not different between groups. Sinus rhythm was present in 49 (46%) targeted vs. 43 (39%) conventional group patients at 5 years (odds ratio 1.297, lower limit of 95% confidence interval 0.756, P = 0.346). Cardiovascular mortality and morbidity occurred in 20 (19%) in the targeted and 15 (14%) conventional group patients, P = 0.353. CONCLUSION: In patients with early persistent AF and HF superiority of targeted therapy in sinus rhythm maintenance could not be preserved at 5-year follow-up. Cardiovascular outcome was not different between groups. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00877643.

Antiarrhythmic drugs in patients with early persistent atrial fibrillation and heart failure: results of the RACE 3 study.

AIMS: Maintaining sinus rhythm in patients with persistent atrial fibrillation (AF) is challenging. We explored the efficacy of class I and III antiarrhythmic drugs (AADs) in patients with persistent AF and mild to moderate heart failure (HF). METHODS AND RESULTS: In the RACE 3 trial, patients with early persistent symptomatic AF and short history of mild to moderate HF with preserved or reduced left ventricular ejection fraction (LVEF) were randomized to targeted or conventional therapy. Both groups received AF and HF guideline-driven treatment. Additionally, the targeted-group received mineralocorticoid receptor antagonists, statins, angiotensin-converting enzyme inhibitors and/or receptor blockers, and cardiac rehabilitation. Class I and III AADs could be instituted in case of symptomatic recurrent AF. Eventually, pulmonary vein isolation could be performed. Primary endpoint was sinus rhythm on 7-day Holter after 1-year. Included were 245 patients, age 65 ± 9 years, 193 (79%) men, AF history was 3 (2-6) months, HF history 2 (1-4) months, 72 (29.4%) had HF with reduced LVEF. After baseline electrical cardioversion (ECV), 190 (77.6%) had AF recurrences; 108 (56.8%) received class I/III AADs; 19 (17.6%) flecainide, 36 (33.3%) sotalol, 3 (2.8%) dronedarone, 50 (46.3%) amiodarone. At 1-year 73 of 108 (68.0%) patients were in sinus rhythm, 44 (40.7%) without new AF recurrences. Maintenance of sinus rhythm was significantly better with amiodarone [n = 29/50 (58%)] compared with flecainide [n = 6/19 (32%)] and sotalol/dronedarone [n = 9/39 (23%)], P = 0.0064. Adverse events occurred in 27 (25.0%) patients, were all minor and reversible. CONCLUSION: In stable HF patients with early persistent AF, AAD treatment was effective in nearly half of patients, with no serious adverse effects reported.

Targeted therapy of underlying conditions improves quality of life in patients with persistent atrial fibrillation: results of the RACE 3 study.

AIMS: Atrial fibrillation (AF) reduces quality of life (QoL). We aim to evaluate effects of targeted therapy of underlying conditions on QoL in patients with AF and heart failure (HF). METHODS AND RESULTS: The Routine versus Aggressive risk factor driven upstream rhythm Control for prevention of Early atrial fibrillation in heart failure (RACE 3) study randomized patients with early persistent AF and HF to targeted or conventional therapy. Both groups received guideline-driven treatment. The targeted group received four additional therapies: mineralocorticoid receptor antagonists; statins; angiotensin converting enzyme inhibitors and/or receptor blockers; and cardiac rehabilitation including physical activity, dietary restrictions, and counselling. Quality of life was analysed in 230 patients at baseline and 1 year with available Medical Outcomes Study Short-Form Health Survey (SF-36), University of Toronto AF Severity Scale (AFSS) questionnaires, and European Heart Rhythm Association (EHRA) class. Improvements in SF-36 subscales were larger in the targeted group for physical functioning (Δ12 ± 19 vs. Δ6 ± 22, P = 0.007), physical role limitations (Δ32 ± 41 vs. Δ17 ± 45, P = 0.018), and general health (Δ8 ± 16 vs. Δ0 ± 17, P < 0.001). Dyspnoea at rest improved more (Δ-0.8 ± 1.3 vs. Δ-0.4 ± 1.2, P = 0.018) and EHRA class was lower at 1-year follow-up in the targeted group. Patients with AF at 1 year, improvement in physical functioning (Δ9 ± 9 vs. Δ-3 ± 16, P = 0.001), general health (Δ7 ± 16 vs. Δ-7 ± 19, P = 0.004), and social functioning (Δ6 ± 23 vs. Δ-4 ± 16, P = 0.041) were larger in the targeted group. CONCLUSION: A strategy aiming to treat underlying conditions improved QoL more compared with conventional therapy in patients with early persistent AF and HF. Its benefit was even observed in patients in AF at 1 year. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00877643.

Targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: results of the RACE 3 trial.

Aims: Atrial fibrillation (AF) is a progressive disease. Targeted therapy of underlying conditions refers to interventions aiming to modify risk factors in order to prevent AF. We hypothesised that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF. Methods and results: We randomized patients with early persistent AF and mild-to-moderate heart failure (HF) to targeted therapy of underlying conditions or conventional therapy. Both groups received causal treatment of AF and HF, and rhythm control therapy. In the intervention group, on top of that, four therapies were started: (i) mineralocorticoid receptor antagonists (MRAs), (ii) statins, (iii) angiotensin converting enzyme inhibitors and/or receptor blockers, and (iv) cardiac rehabilitation including physical activity, dietary restrictions, and counselling. The primary endpoint was sinus rhythm at 1 year during 7 days of Holter monitoring. Of 245 patients, 119 were randomized to targeted and 126 to conventional therapy. The intervention led to a contrast in MRA (101 [85%] vs. 5 [4%] patients, P < 0.001) and statin use (111 [93%] vs. 61 [48%], P < 0.001). Angiotensin converting enzyme inhibitors/angiotensin receptor blockers were not different. Cardiac rehabilitation was completed in 109 (92%) patients. Underlying conditions were more successfully treated in the intervention group. At 1 year, sinus rhythm was present in 89 (75%) patients in the intervention vs. 79 (63%) in the conventional group (odds ratio 1.765, lower limit of 95% confidence interval 1.021, P = 0.042). Conclusions: RACE 3 confirms that targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent AF. Trial Registration number: Clinicaltrials.gov NCT00877643.

Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT.

BACKGROUND: ASSERT demonstrated that subclinical atrial fibrillation (SCAF) is common in pacemaker patients without prior AF and is associated with increased risk of ischemic stroke or systemic embolism. SCAF episodes vary in duration and little is known about the incidence of different durations of SCAF, or their prognosis. METHODS AND RESULTS: ASSERT followed 2580 patients receiving a pacemaker or ICD, aged >65 years with hypertension, without prior AF. The effect of SCAF duration on subsequent risk of ischemic stroke or embolism was evaluated with time-dependent covariate Cox models. Patients in whom the longest SCAF was ≤6 min were excluded from the analysis (n=125). Among 2455 patients during mean follow-up of 2.5 years, the longest single episode of SCAF lasted >6 min to 6 h in 462 patients (18.8%), >6-24 h in 169 (6.9%), and >24 h in 262 (10.7%). SCAF duration >24 h was associated with a significant increased risk of subsequent stroke or systemic embolism (adjusted hazard ratio [HR] 3.24, 95% confidence interval [CI] 1.51-6.95, P=0.003). The risk of ischemic stroke or systemic embolism in patients with SCAF between 6 min and 24 h was not significantly different from patients without SCAF. CONCLUSIONS: SCAF >24 h is associated with an increased risk of ischemic stroke or systemic embolism.

Clinical, biomarker, and genetic predictors of specific types of atrial fibrillation in a community-based cohort: data of the PREVEND study.

Aims: Atrial fibrillation (AF) may present variously in time, and AF may progress from self-terminating to non-self-terminating AF, and is associated with impaired prognosis. However, predictors of AF types are largely unexplored. We investigate the clinical, biomarker, and genetic predictors of development of specific types of AF in a community-based cohort. Methods: We included 8042 individuals (319 with incident AF) of the PREVEND study. Types of AF were compared, and multivariate multinomial regression analysis determined associations with specific types of AF. Results: Mean age was 48.5 ± 12.4 years and 50% were men. The types of incident AF were ascertained based on electrocardiograms; 103(32%) were classified as AF without 2-year recurrence, 158(50%) as self-terminating AF, and 58(18%) as non-self-terminating AF. With multivariate multinomial logistic regression analysis, advancing age (P< 0.001 for all three types) was associated with all AF types, male sex was associated with AF without 2-year recurrence and self-terminating AF (P= 0.031 and P= 0.008, respectively). Increasing body mass index and MR-proANP were associated with both self-terminating (P= 0.009 and P< 0.001) and non-self-terminating AF (P= 0.003 and P< 0.001). The only predictor associated with solely self-terminating AF is prescribed anti-hypertensive treatment (P= 0.019). The following predictors were associated with non-self-terminating AF; lower heart rate (P= 0.018), lipid-lowering treatment prescribed (P= 0.009), and eGFR <60 mL/min/1.73 m2 (P= 0.006). Three known AF-genetic variants (rs6666258, rs6817105, and rs10821415) were associated with self-terminating AF. Conclusions: We found clinical, biomarker and genetic predictors of specific types of incident AF in a community-based cohort. The genetic background seems to play a more important role than modifiable risk factors in self-terminating AF.

Effects of a simple cardiac rehabilitation program on improvement of self-reported physical activity in atrial fibrillation - Data from the RACE 3 study.

BACKGROUND AND AIM: Physical inactivity is associated with an increased prevalence of atrial fibrillation (AF). We aim to evaluate whether cardiac rehabilitation (CR) motivates patients to become and stay physical active, and whether CR affects sinus rhythm maintenance and quality of life (QoL) in patients with persistent AF and moderate heart failure. METHODS: In the Routine versus Aggressive risk factor driven upstream rhythm Control for prevention of Early atrial fibrillation in heart failure study patients were randomized to conventional or targeted therapy. Targeted therapy contained next to optimal risk factor management a 3-month CR program, including self-reported physical activity and counseling. Successful physical activity was assessed in the targeted group, defined as activity of moderate intensity ≥ 150 min/week, or ≥ 75 min/week of vigorous intensity. AF was assessed at 1 year on 7-days Holter monitoring, QoL using general health, fatigue and AF symptom questionnaires. RESULTS: All 119 patients within the targeted group participated in the CR program, 106 (89%) completed it. At baseline 80 (67%) patients were successfully physical active, 39 (33%) were not. NTproBNP was lower in active patients. During 1-year follow-up physical active patients stayed active: 72 (90%) at 12 weeks, 72 (90%) at 1 year. Inactive patients became active: at 12 weeks 25 (64%) patients and 30 (77%) at 1 year. No benefits were seen on sinus rhythm maintenance and QoL for successful physical active patients. CONCLUSION: In patients with persistent AF and moderate heart failure participation in CR contributes to improve and to maintain physical activity.