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.

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.

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.

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.

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.

Should aldosterone blockade be used beyond current indications in heart failure?

Aldosterone receptor antagonists (ARAs) are becoming important supplementary options in the pharmacologic treatment of congestive heart failure (CHF), and the indication for ARAs continues to grow. Aldosterone is a stimulator of myocardial fibrosis, causing progression of CHF and serving as an important factor in the pathogenesis of diastolic heart failure (ie, heart failure with normal ejection fraction). The beneficial effects of ARAs have already been demonstrated in patients with severe CHF and patients with symptoms of CHF and left ventricular dysfunction early after myocardial infarction. ARAs may also be important in mild to moderate CHF, but current evidence has not been convincing. More is to be expected from the potential role of ARAs in heart failure with normal ejection fraction and perhaps in atrial fibrillation. It is hoped that the results of large randomized clinical trials further elucidate the indications of ARAs beyond current guidelines.

New risk factors for atrial fibrillation: causes of 'not-so-lone atrial fibrillation'.

Atrial fibrillation (AF) is a prevalent arrhythmia in patients with cardiovascular disease. The classical risk factors for developing AF include hypertension, valvular disease, (ischaemic) cardiomyopathy, diabetes mellitus, and thyroid disease. In some patients with AF, no underlying (cardiovascular) pathology is present and the aetiology remains unknown. This condition is known as lone AF. However, in recent years, other factors playing a role in the genesis of AF have gained attention, including obesity, sleep apnoea, alcohol abuse and other intoxications, excessive sports practice, latent hypertension, genetic factors, and inflammation. In this review, we address these 'new risk factors' (i.e. as opposed to the classical risk factors) and the mechanisms by which they lead to AF.

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.

Persistent atrial fibrillation is associated with appropriate shocks and heart failure in patients with left ventricular dysfunction treated with an implantable cardioverter defibrillator.

AIM: The objective of this study was to investigate whether persistent atrial fibrillation (AF) and new-onset AF are associated with appropriate shocks, cardiovascular mortality, chronic heart failure (CHF), and inappropriate shocks in implantable cardioverter defibrillator (ICD) patients with left ventricular dysfunction. METHODS: We included 290 consecutive ICD patients with a documented left ventricular ejection fraction < or = 0.35 and compared outcomes between patients without AF (n = 207), those with persistent AF (n = 64), and those with new-onset AF (n = 19). RESULTS: The patients with persistent AF were older, more frequently had valve disease and cardiac surgery, and less frequently had coronary artery disease as compared with the patients without AF. Patients with persistent AF had a higher New York Heart Association class, however, left ventricular ejection fraction rates between these 2 groups were comparable (0.28 +/- 0.07 vs 0.29 +/- 0.08, P = not significant). No difference was found between patients with new-onset AF and those without AF. During follow-up (2.6 +/- 1.9 years), more patients with persistent AF received appropriate ICD shocks as compared with those without AF (24 [38%] vs 49 [24%], P = .04). Deterioration of CHF occurred more often in patients with persistent AF (19 [30%], P = .001) and those with new-onset AF (9 [47%], P < .001) as compared with patients without AF (31 [14%]). Multivariate analysis revealed that patients with persistent AF had an increased risk for appropriate ICD shocks (adjusted hazard ratio [HR] 1.9, 95% CI 1.2-3.2, P = .009). Persistent AF (adjusted HR 2.1, 95% CI 1.1-3.9, P = .03) and new-onset AF (adjusted HR 2.5, 95% CI 1.1-5.7, P = .02) were found to be independent risk indicators of CHF deterioration. CONCLUSIONS: In ICD patients with left ventricular dysfunction, persistent AF is associated with appropriate ICD shocks and deterioration of CHF. New-onset AF is related to deterioration of CHF.

Right ventricular pacing and the risk of heart failure in implantable cardioverter-defibrillator patients.

BACKGROUND: Right ventricular (RV) pacing in implantable cardioverter-defibrillator (ICD) patients may have detrimental effects on morbidity and mortality, in particular by inducing heart failure (HF). OBJECTIVE: We investigated whether RV pacing increases the risk of HF in an asymptomatic ICD population. METHODS: We evaluated all patients without symptomatic HF who received an ICD. The primary endpoint was the occurrence of HF, which was defined as new HF, hospitalization for HF, or death due to HF. The secondary endpoint was appropriate shocks. RESULTS: The study population consisted of 456 patients with mean left ventricular ejection fraction (LVEF) 40% +/- 13%. Mean follow-up was 31 +/- 22 months. Because of the bimodal distribution of pacing, patients were divided into two groups: paced 50% (median 96%; n = 143). HF occurred more often in the paced >50% group (20% versus 9%; P <.001). Multivariate analysis identified RV pacing >50% (adjusted hazard ratio [HR] 1.85; 95% confidence interval [CI] 1.08-3.15; P = .03), baseline LVEF <26% (adjusted HR 3.15; 95% CI 1.77-5.59; P <.001), angina pectoris, history of atrial fibrillation, and baseline diuretic use as independent predictors of HF. RV pacing caused more HF events in patients with LVEF <26% (n = 64; 55% of paced >50% patients versus 20% of paced 50% also independently predicted appropriate shocks (adjusted HR 1.50; 95% CI 1.02-2.20; P = .04). CONCLUSION: RV pacing was associated with an increased risk of HF in asymptomatic ICD patients, particularly in those with preexistent left ventricular dysfunction.