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.

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.

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.

Risk Factor Management in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with increased morbidity and mortality. There is growing evidence that numerous cardiovascular diseases and risk factors are associated with incident AF and that lone AF is rare. Beyond oral anticoagulant therapy, rate and rhythm control, therapy targeting risk factors and underlying conditions is an emerging AF management strategy that warrants better implementation in clinical practice. This review describes current evidence regarding the association between known modifiable risk factors and underlying conditions and the development and progression of AF. It discusses evidence for the early management of underlying conditions to improve AF outcomes. It also provides perspective on the implementation of tailored AF management in daily clinical practice.

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.

The importance of whether atrial fibrillation or heart failure develops first.

AIMS: Atrial fibrillation (AF) and heart failure often co-exist. It is unknown whether the sequence in which AF and heart failure develop is of significance regarding prognosis. We assessed the prognosis of AF patients hospitalized for heart failure based on the timing of AF and heart failure development. METHODS AND RESULTS: Consecutive AF patients hospitalized for heart failure were included. Patients who had developed AF before or consecutively with heart failure ('AF first') were compared with patients who had developed heart failure before AF ('heart failure first'). The primary endpoint was a composite of cardiovascular hospitalization or all-cause mortality. The majority of patients hospitalized for AF and heart failure consisted of patients who had developed AF first (137 of 182 patients, 75%, vs. 45 of 182 patients, 25%). The two groups were similar regarding age and gender, but patients with AF first less often had coronary artery disease and had higher ejection fractions than patients with heart failure first (39 ± 14% vs. 32 ± 13%, P = 0.004). During 16 ± 11 months follow-up, the primary composite endpoint occurred less often in patients with AF first than in patients with heart failure first (49.6% vs. 77.7% of patients, P = 0.001). Development of AF first remained beneficial regarding the primary endpoint on multivariable analysis (adjusted hazard ratio 0.50, 95% confidence interval 0.29-0.86, P = 0.01). CONCLUSION: The majority of patients hospitalized for AF and heart failure consisted of patients who had developed AF first. Prognosis in these patients was relatively benign as compared with those who had developed heart failure first.

Role of inflammation in early atrial fibrillation recurrence.

AIMS: Outcome of rhythm control in atrial fibrillation (AF) is still poor due to various mechanisms involved in the initiation and perpetuation of AF. Differences in timing of AF recurrence may depend on different types of mechanisms. The aim of this study was to assess the mechanisms involved in early AF recurrence in patients with short-lasting AF. METHODS AND RESULTS: Patients with short-lasting persistent AF undergoing rhythm control (n= 100) were included. Markers of mechanisms involved in the initiation and perpetuation of AF were assessed, including clinical factors, echocardiographic parameters, and biomarkers. Primary endpoint was early AF recurrence (recurrence <1 month). Secondary endpoint was progression to permanent AF. Median total AF history was short: 4.2 months. Early AF recurrences occurred in 30 patients (30%) after a median of 6 (inter-quartile range 2-14) days. Baseline log(2) interleukin (IL)-6 [adjusted hazard ratio (HR) 1.3, 95% confidence interval (CI) 1.0-1.7, P= 0.02] and present or previous smoking (adjusted HR 3.6, 95% CI 1.2-10.9, P= 0.03) were independently associated with early AF recurrence, suggesting that inflammation played an important role in early recurrences. Atrial fibrillation became permanent in 29 patients (29%). Baseline transforming growth factor-ß1, left ventricular ejection fraction, and early AF recurrence were independently associated with progression to permanent AF. CONCLUSION: In patients with short-lasting AF, early AF recurrence seemed to be associated with inflammation as represented by IL-6. Treatment aimed against inflammation may therefore prevent early AF recurrences, which can improve rhythm control outcome.

Effect of lenient versus strict rate control on cardiac remodeling in patients with atrial fibrillation data of the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) study.

OBJECTIVES: The aim of this study was to evaluate echocardiographic remodeling in permanent atrial fibrillation (AF) patients treated with either lenient or strict rate control. BACKGROUND: It is unknown whether in permanent AF, lenient rate control is associated with more adverse cardiac remodeling than strict rate control. METHODS: Echocardiography was conducted at baseline and at follow-up in 517 patients included in the RACE II (RAte Control Efficacy in permanent atrial fibrillation II) trial. Echocardiographic parameters were compared between patients randomized to lenient rate control (n = 261) or strict rate control (n = 256). RESULTS: Baseline echocardiographic parameters were comparable between patients randomized to lenient and strict rate control. Between baseline and follow-up, significant adverse atrial or ventricular remodeling was not observed in either group. There were also no significant differences in atrial and ventricular remodeling between patients who continuously had heart rates between 80 and 110 beats/min and patients who continuously had heart rates <80 beats/min during follow-up. Lenient rate control was not independently associated with changes in echocardiographic parameters: mean adjusted effect on left atrial size was 1.6 mm (p = 0.09) and 1.1 mm on left ventricular end-diastolic diameter (p = 0.23). Instead, female sex was independently associated with adverse remodeling: mean adjusted effect on left atrial size was 2.4 mm (p = 0.02) and 6.5 mm on left ventricular end-diastolic diameter (p < 0.0001). CONCLUSIONS: Female sex, not lenient rate control, seemed to be associated with significant adverse cardiac remodeling in patients with permanent AF such as those enrolled in the RACE II study. (RAte Control Efficacy in Permanent Atrial Fibrillation [RACE II]; NCT00392613).

Rationale and current perspective for early rhythm control therapy in atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia and an important source for mortality and morbidity on a population level. Despite the clear association between AF and death, stroke, and other cardiovascular events, there is no evidence that rhythm control treatment improves outcome in AF patients. The poor outcome of rhythm control relates to the severity of the atrial substrate for AF not only due to the underlying atrial remodelling process but also due to the poor efficacy and adverse events of the currently available ion-channel antiarrhythmic drugs and ablation techniques. Data suggest, however, an association between sinus rhythm maintenance and improved survival. Hypothetically, sinus rhythm may also lead to a lower risk of stroke and heart failure. The presence of AF, thus, seems one of the modifiable factors associated with death and cardiovascular morbidity in AF patients. Patients with a short history of AF and the underlying heart disease have not been studied before. It is fair to assume that abolishment of AF in these patients is more successful and possibly also safer, which could translate into a prognostic benefit of early rhythm control therapy. Several trials are now investigating whether aggressive early rhythm control therapy can reduce cardiovascular morbidity and mortality and increase maintenance of sinus rhythm. In the present paper we describe the background of these studies and provide some information on their design.

Prognostic importance of natriuretic peptides and atrial fibrillation in patients receiving cardiac resynchronization therapy.

AIMS: The aim of this study was to investigate the prognostic value of natriuretic peptides and atrial fibrillation (AF) on response to cardiac resynchronization therapy (CRT) and mortality. METHODS AND RESULTS: This study included 338 consecutive CRT patients. Response to CRT was defined as a reduction in left ventricular end-systolic volume of ≥15% in the absence of death at 6-month follow-up. During follow-up (27 ± 19 months), 139 patients (41%) had AF, being new onset in 40 patients (21%). Forty-two patients (12%) had permanent AF. Response to CRT was observed in 168 of 302 patients (56%): 60 of 123 patients (43%) with AF vs. 108 of 179 patients (60%) without AF (P = 0.047). Low baseline atrial natriuretic peptide (ANP) [odds ratio for log(2) ANP 0.49, 95% confidence interval (CI) 0.35-0.68, P < 0.001] and large left ventricular end-systolic volume (odds ratio for every 50 mL 1.40, 95% CI 1.09-1.79, P = 0.009) were independent predictors of response. Neither the presence of AF nor the increase in AF burden independently predicted response. Ninety patients (27%) died; 50 patients (36%) with AF vs. 40 patients (20%) without AF (log rank P = 0.029). Important predictors of all-cause mortality were new-onset AF (hazard ratio 8.11, 95% CI 3.31-19.85, P < 0.001), permanent AF (hazard ratio 3.19, 95% CI 1.61-6.30, P = 0.001), and baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) (hazard ratio for log(2) NT-proBNP 0.77, 95% CI 0.66-0.90, P = 0.001). CONCLUSION: In patients treated with CRT, lower ANP and larger left ventricular end-systolic volume were independent predictors of response. New-onset AF, permanent AF, and NT-proBNP were independently associated with increased all-cause mortality.

Myocardial perfusion imaging does not adequately assess the risk of coronary artery disease in patients with atrial fibrillation.

AIMS: The role of coronary artery disease (CAD) in atrial fibrillation (AF) is poorly investigated. This study investigated the value of myocardial perfusion single-photon emission computed tomography (SPECT) in the assessment of risk of CAD in patients with a history of AF. METHODS AND RESULTS: Out of consecutive patients without previous coronary angiogram or history of CAD referred for SPECT, patients with a history of AF (n = 129) were compared with age- and gender-matched controls (n = 124). Primary endpoint was positive SPECT, i.e. unambiguous signs of ischaemia. There was no significant difference with regard to positive SPECT outcome between AF patients and controls (14 patients, 11% vs. 21 patients, 17%; P = 0.16). Coronary angiography (CAG) performed after SPECT demonstrated a higher yield of positive SPECT regarding significant CAD in control patients (10 out of 15 patients, 67%) than in AF patients (2 out of 13 patients, 15%; P = 0.006). CONCLUSION: Positive SPECT outcome was similar in patients with AF and in controls. Nevertheless, in AF patients a positive SPECT outcome was less often related to significant CAD in those patients who subsequently underwent CAG. These results emphasize the need for new non-invasive techniques to adequately assess the risk of significant CAD in AF patients.

Upstream therapy of atrial fibrillation.

Failure of current pharmacological therapy for atrial fibrillation in maintaining sinus rhythm may be due to structural atrial remodeling caused by inflammation and fibrosis. Upstream therapy that interferes in the structural remodeling process may be effective in maintaining sinus rhythm. This article reviews upstream therapy in atrial fibrillation. Various prospective and retrospective studies demonstrate that upstream therapy, consisting of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, fish oils, glucocorticoids, or moderate physical activity, is associated with a reduced incidence of new-onset atrial fibrillation (i.e., primary prevention) and with a reduced recurrence of atrial fibrillation (i.e., secondary prevention). Larger clinical trials are required to further elucidate the position of upstream therapy in the primary and secondary prevention of atrial fibrillation.