Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: the EAST - AFNET 4 trial.

BACKGROUND: A strategy of systematic, early rhythm control (ERC) improves cardiovascular outcomes in patients with atrial fibrillation (AF). It is not known which aspects of ERC contribute to outcome reduction. METHODS: Using the EAST - AFNET 4 trial data set, potential mediators of the effect of early rhythm control were identified in the total study population at 12-month follow-up and further interrogated by use of a 4-way decomposition of the treatment effect in an exponential model predicting future primary outcome events. RESULTS: Fourteen potential mediators of ERC were identified at the 12-month visit. Of these, sinus rhythm at 12 months explained 81% of the treatment effect of ERC compared to usual care during the remainder of follow-up (4.1 years). In patients not in sinus rhythm at 12 months, ERC did not reduce future cardiovascular outcomes (hazard ratio 0.94, 95% confidence interval 0.65-1.67). Inclusion of AF recurrence in the model only explained 31% of the treatment effect, and inclusion of systolic blood pressure at 12 months only 10%, respectively. There was no difference in outcomes in patients who underwent AF ablation compared to those who did not undergo AF ablation. CONCLUSIONS: The effectiveness of early rhythm control therapy is mediated by the presence of sinus rhythm at 12 months in the EAST - AFNET 4 trial. Clinicians implementing early rhythm control should aim for rapid and sustained restoration of sinus rhythm in patients with recently diagnosed AF and cardiovascular comorbidities.Funded by AFNET, DZHK, EHRA, Deutsche Herzstiftung (DHS), Abbott Laboratories, Sanofi. EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010 -021258-20

Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial.

AIMS: Clinical practice guidelines restrict rhythm control therapy to patients with symptomatic atrial fibrillation (AF). The EAST-AFNET 4 trial demonstrated that early, systematic rhythm control improves clinical outcomes compared to symptom-directed rhythm control. METHODS AND RESULTS: This prespecified EAST-AFNET 4 analysis compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) to symptomatic patients. Primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis. At baseline, 801/2633 (30.4%) patients were asymptomatic [mean age 71.3 years, 37.5% women, mean CHA2DS2-VASc score 3.4, 169/801 (21.1%) heart failure]. Asymptomatic patients randomized to early rhythm control (395/801) received similar rhythm control therapies compared to symptomatic patients [e.g. AF ablation at 24 months: 75/395 (19.0%) in asymptomatic; 176/910 (19.3%) symptomatic patients, P = 0.672]. Anticoagulation and treatment of concomitant cardiovascular conditions was not different between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomized to early rhythm control and in 97/406 patients randomized to usual care (hazard ratio 0.76, 95% confidence interval [0.6; 1.03]), almost identical to symptomatic patients. At 24 months follow-up, change in symptom status was not different between randomized groups (P = 0.19). CONCLUSION: The clinical benefit of early, systematic rhythm control was not different between asymptomatic and symptomatic patients in EAST-AFNET 4. These results call for a shared decision discussing the benefits of rhythm control therapy in all patients with recently diagnosed AF and concomitant cardiovascular conditions (EAST-AFNET 4; ISRCTN04708680; NCT01288352; EudraCT2010-021258-20)

Safety and efficacy of long-term Sodium Channel Blocker therapy for Early Rhythm Control: The EAST-AFNET 4 trial.

BACKGROUND AND AIMS: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers flecainide and propafenone (SCB) in patients with cardiovascular disease. SCB were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4. METHODS: We analysed the primary safety outcome (death, stroke, or serious adverse events related to rhythm-control therapy) and primary efficacy outcome (cardiovascular death, stroke and hospitalization for worsening of heart failure or acute coronary syndrome) during SCB-intake for ERC patients (n = 1395) in EAST-AFNET 4. The protocol discouraged flecainide and propafenone in patients with reduced left ventricular ejection fraction and suggested stopping therapy upon QRS prolongation >25% on therapy. RESULTS: Flecainide or propafenone was given to 689 patients (age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with heart failure; 41 with prior myocardial infarction, CABG or PCI; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1,153 [237, 1,828] days). The primary efficacy outcome occurred less often in patients treated with SCB (3/100 (99/3,316) patient-years) than in patients who never received SCB (SCBnever 4.9/100 (150/3,083) patient-years, p < 0.001). There were numerically fewer primary safety outcomes in patients receiving SCB (2.9/100 (96/3,359) patient-years) than in SCBnever patients (4.2/100 (135/3,220) patient-years, adjusted p = 0.015). Sinus rhythm at 2 years was similar between groups (SCB 537/610 (88); SCBnever 472/579 (82)). CONCLUSION: Long-term therapy with flecainide or propafenone appeared to be safe in the EAST-AFNET 4 trial to deliver effective ERC therapy, including in selected patients with stable cardiovascular disease such as coronary artery disease and stable heart failure. CLINICAL TRIAL REGISTRATION: ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org

Blood-based cardiometabolic phenotypes in atrial fibrillation and their associated risk: EAST-AFNET 4 biomolecule study.

BACKGROUND: Atrial fibrillation (AF) and concomitant cardiometabolic disease processes interact and combine to lead to adverse events such as stroke, heart failure, myocardial infarction, and cardiovascular death. Circulating biomolecules provide quantifiable proxies for cardiometabolic disease processes. Their role in defining subphenotypes of AF is not known. METHODS AND RESULTS: This prespecified analysis of the EAST-AFNET4 biomolecule study assigned patients to clusters using polytomous variable latent class analysis (poLCA) based on baseline concentrations of thirteen precisely-quantified biomolecules potentially reflecting ageing, cardiac fibrosis, metabolic dysfunction, oxidative stress, cardiac load, endothelial dysfunction, and inflammation. In each cluster, rates of cardiovascular death, stroke, or hospitalization for heart failure or acute coronary syndrome, the primary outcome of EAST-AFNET 4, were calculated and compared between clusters over median 5.1 years follow-up. Findings were independently validated in a prospective cohort of 748 patients with AF (BBC-AF; median follow up 2.9 years).Unsupervised biomolecule analysis assigned 1586 patients (71 years old, 46% women) into four clusters. The highest-risk cluster was dominated by elevated BMP10, IGFBP7, NT-proBNP, ANGPT2 and GDF15. Patients in the lowest-risk cluster showed low concentrations of these biomolecules. Two intermediate-risk clusters differed by high or low concentrations of hsCRP, IL-6, and D-dimer. Patients in the highest-risk cluster had a 5-fold higher cardiovascular event rate than patients in the low-risk cluster. Early rhythm control was effective across clusters (pinteraction = 0.63). Sensitivity analyses and external validation in BBC-AF replicated clusters and risk gradients. CONCLUSIONS: Biomolecule concentrations identify cardiometabolic subphenotypes in patients with atrial fibrillation at high and low cardiovascular risk

Presenting Pattern of Atrial Fibrillation and Outcomes of Early Rhythm Control Therapy.

BACKGROUND: Whether atrial fibrillation (AF) pattern or timing of AF therapy modifies the effectiveness of early rhythm control (ERC) is not known. OBJECTIVES: This study sought to compare clinical characteristics and outcomes in patients presenting with different AF patterns on ERC vs usual care. METHODS: The effects of ERC were compared in first-diagnosed AF (FDAF), paroxysmal AF (paroxAF), and persistent AF (persAF) in this prespecified analysis of the EAST-AFNET 4 (Early treatment of atrial fibrillation for stroke prevention) trial. Associations between AF pattern and primary outcomes (first primary outcome: cardiovascular death, stroke, and hospitalization for heart failure and acute coronary syndrome; second primary outcome: nights spent in hospital per year) were compared over a mean follow-up of 5.1 years. Changes in health-related quality of life were assessed by the EQ-5D. RESULTS: FDAF patients (n = 1,048, enrolled 7 days after diagnosing AF) were slightly older (71 years of age, 48.0% female) than patients with paroxAF (n = 994, 70 years of age, 50.0% female) and persAF (n = 743, 70 years of age, 38.0% female). ERC reduced the primary outcome in all 3 AF patterns. Hospitalizations for acute coronary syndrome were highest in FDAF (incidence rate ratio [IRR]: 1.50; 95% CI: 0.83-2.69; P for interaction = 0.032) compared with paroxAF (IRR: 0.64; 95% CI: 0.32-1.25) and persAF (IRR: 0.50; 95% CI: 0.25-1.00). FDAF patients spent more nights in hospital (IRR: 1.38; 95% CI: 1.12-1.70; P for interaction = 0.004) than paroxAF (IRR: 0.84; 95% CI: 0.67-1.03), and persAF (IRR: 1.02; 95% CI: 0.80-1.30) patients. ERC improved health-related quality of life (EQ-5D score) in patients with paroxAF and persAF but not in patients with FDAF (P = 0.019). CONCLUSIONS: ERC reduces the first primary composite outcome in all AF patterns. Patients with FDAF are at high risk for hospitalization and acute coronary syndrome, particularly on ERC. (Early treatment of atrial fibrillation for stroke prevention trial; ISRCTN04708680; Early Treatment of Atrial Fibrillation for Stroke Prevention Trial [EAST]; NCT01288352; Early treatment of Atrial fibrillation for Stroke prevention Trial [EAST]; EudraCT2010-021258-20)

Early Rhythm Control in Patients With Atrial Fibrillation and High Comorbidity Burden.

BACKGROUND: The randomized EAST-AFNET4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial-Atrial Fibrillation Network) demonstrated that early rhythm control (ERC) reduces adverse cardiovascular outcomes in patients with recently diagnosed atrial fibrillation and stroke risk factors. The effectiveness and safety of ERC in patients with multiple cardiovascular comorbidities is not known. METHODS: These prespecified subanalyses of EAST-AFNET4 compared the effectiveness and safety of ERC with usual care (UC) stratified into patients with higher (CHA2DS2-VASc score ≥4) and lower comorbidity burden. Sensitivity analyses ignored sex (CHA2DS2-VA score). RESULTS: EAST-AFNET4 randomized 1093 patients with CHA2DS2-VASc score ≥4 (74.8±6.8 years, 61% female) and 1696 with CHA2DS2-VASc score <4 (67.4±8.0 years, 37% female). ERC reduced the composite primary efficacy outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome in patients with CHA2DS2-VASc score ≥4 (ERC, 127/549 patients with events; UC, 183/544 patients with events; hazard ratio [HR], 0.64 [0.51-0.81]; P < 0.001) but not in patients with CHA2DS2-VASc score <4 (ERC, 122/846 patients with events; UC, 133/850 patients with events; HR, 0.93 [0.73-1.19]; P=0.56, Pinteraction=0.037). The primary safety outcome (death, stroke, or serious adverse events of rhythm control therapy) was not different between study groups in patients with CHA2DS2-VASc score ≥4 (ERC, 112/549 patients with events; UC, 132/544 patients with events; HR, 0.84 [0.65, 1.08]; P=0.175), but occurred more often in patients with CHA2DS2-VASc scores <4 randomized to ERC (ERC, 119/846 patients with events; UC, 91/850 patients with events; HR, 1.39 [1.05-1.82]; P=0.019, Pinteraction=0.008). Life-threatening events or death were not different between groups (CHA2DS2-VASc score ≥4, ERC, 84/549 patients with event, UC, 96/544 patients with event; CHA2DS2-VASc scores <4, ERC, 75/846 patients with event, UC, 73/850 patients with event). When female sex was ignored for the creation of higher and lower risk groups (CHA2DS2-VA score), the Pinteraction was not significant for the primary efficacy outcome (P=0.25), but remained significant (P=0.044) for the primary safety outcome. CONCLUSIONS: Patients with recently diagnosed atrial fibrillation and CHA2DS2-VASc score ≥4 should be considered for ERC to reduce cardiovascular outcomes, whereas those with fewer comorbidities may have less favorable outcomes with ERC. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01288352; URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20; URL: https://www.isrctn.com/; Unique identifier: ISRCTN04708680