Atrial fibrillation rhythm management: a matter of timing.

Rhythm control in patients with atrial fibrillation (AF) has evolved dramatically in the last decades. Several studies have informed us of the benefits of an early rhythm control strategy and primary rhythm control by catheter ablation (CA). Similarly, several studies have investigated the effects of CA in patients with longer AF duration and more comorbidities, especially heart failure. In the current review, we summarize the current evidence on rhythm control at different time points during the disease course of AF [Table 1 and Central illustration].

Real-world evidence of early rhythm control in patients with atrial fibrillation: A systematic review and meta-analysis.

BACKGROUND: The favorable benefits of early rhythm control (ERC) therapy in newly diagnosed patients with atrial fibrillation (AF) have been demonstrated in the EAST-AFNET 4 trial. However, the generalizability and applicability of ERC in real-world clinical settings remain inconclusive. METHODS: We conducted a systematic search of the PubMed and Embase databases to identify observational studies published between January 2020 and February 2024 that focused on real-world evidence pertaining to ERC. The effectiveness and safety outcomes in our study were analogous to those evaluated in the EAST-AFNET 4 trial. RESULTS: A total of 4 observational studies that fulfilled the inclusion criteria of EAST-AFNET 4 were included, involving 130,970 patients with AF, 30.7% of whom received ERC therapy. In our pooled analysis using the fixed-effects model, compared with rate control, ERC significantly decreased the occurrence risk of the primary composite outcome (hazard ratio [HR] 0.86, 95% confidence interval[CI] 0.82-0.91), cardiovascular death (HR 0.87, 95% CI 0.78-0.98), stroke (HR 0.80, 95% CI 0.73-0.87), and hospitalization with worsening heart failure (HR 0.91, 95% CI 0.84-0.99) or acute coronary syndrome (HR 0.72, 95% CI 0.59-0.87). In terms of safety outcomes, there were no differences in the composite safety outcome (HR 1.00, 95% CI 0.95-1.05) and all-cause death (HR 0.93, 95% CI 0.82-1.06) between the two studied groups. CONCLUSIONS: ERC therapy showed favorable effectiveness outcomes compared with rate control, whereas the safety outcomes between the two therapeutic strategies did not differ significantly, supporting the benefits of ERC therapy over rate control in selected real-world patients with AF. REGISTRATION: The study protocol was registered to PROSPERO (CRD42023443569).

Safety and efficacy of long-term sodium channel blocker therapy for early rhythm control: the EAST-AFNET 4 trial.

AIMS: Clinical concerns exist about the potential proarrhythmic effects of the sodium channel blockers (SCBs) flecainide and propafenone in patients with cardiovascular disease. Sodium channel blockers were used to deliver early rhythm control (ERC) therapy in EAST-AFNET 4. METHODS AND RESULTS: 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 (HF) or acute coronary syndrome) during SCB intake for patients with ERC (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. Flecainide or propafenone was given to 689 patients [age 69 (8) years; CHA2DS2-VASc 3.2 (1); 177 with HF; 41 with prior myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention; 26 with left ventricular hypertrophy >15 mm; median therapy duration 1153 [237, 1828] days]. The primary efficacy outcome occurred less often in patients treated with SCB [3/100 (99/3316) patient-years] than in patients who never received SCB [SCBnever 4.9/100 (150/3083) patient-years, P < 0.001]. There were numerically fewer primary safety outcomes in patients receiving SCB [2.9/100 (96/3359) patient-years] than in SCBnever patients [4.2/100 (135/3220) 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 HF. Clinical Trial Registration ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

Cardiocerebrovascular benefits of early rhythm control in patients with atrial fibrillation detected after stroke: a systematic review and meta-analysis.

Objective: This study aimed to evaluate the impact of early rhythm control (ERC) on the occurrence of cardiocerebrovascular events in patients diagnosed with atrial fibrillation detected after stroke (AFDAS). Methods: A systematic search was conducted across nine databases from inception to October 15, 2023 to identify clinical trials comparing ERC with usual care interventions in AFDAS patients. The primary outcome assessed was recurrent stroke, with secondary outcomes including all-cause mortality, adverse events related to arrhythmias, and dementia. Results: Analysis of five studies, consisting of two randomized clinical trials (RCTs) involving 490 patients and three cohort studies involving 95,019 patients, revealed a reduced rate of recurrent stroke [odds ratio (OR) = 0.30, 95% confidence interval (CI) 0.11-0.80, P = 0.016 in RCTs; OR = 0.64, 95% CI 0.61-0.68, P < 0.00001 in cohort studies] and all-cause mortality (hazards ratio = 0.94, 95% CI 0.90-0.98, P = 0.005 in cohort studies) in the ERC group compared to the usual care group. In addition, ERC was associated with superior outcomes in terms of dementia. Conclusions: Patients with AFDAS who underwent ERC treatment exhibited a decreased risk of cardiocerebrovascular events compared to those receiving usual care. These results support the potential benefits of implementing an ERC strategy for this specific patient population. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, Identifier [CRD42023465994].

Early Rhythm Control and Incident Dementia in Patients With Atrial Fibrillation and Prior Stroke.

BACKGROUND: Although early rhythm control (ERC) in patients with atrial fibrillation (AF) reduces the risk of stroke, there is no evidence thus far on whether ERC reduces the risk of developing dementia in patients with AF and prior stroke. OBJECTIVES: This study sought to evaluate whether ERC reduces the risk of developing dementia in patients with new-onset AF and prior stroke. METHODS: Using the Korean nationwide claims database, we identified patients with new-onset AF and prior stroke between 2010 and 2016. Patients who received rhythm control therapy within 1 year after AF onset were defined as the ERC group, otherwise patients were categorized as the usual care group. A propensity score weighting method was used to balance the 2 groups. Incident dementia defined by relevant diagnostic codes was evaluated. RESULTS: A total of 41,370 patients were included (mean age 70 ± 11 years; mean CHA2DS2-VASc score 5.3 ± 1.6): 10,213 in the ERC group and 31,157 in the usual care group. Compared with usual care, ERC was associated with lower risks of all dementia, Alzheimer's dementia, and vascular dementia (weighted HR: 0.825 [95% CI: 0.776-0.876], 0.831 [95% CI: 0.774-0.893], and 0.800 [95% CI: 0.702-0.913], respectively, all P < 0.001). The benefit of ERC was slightly accentuated in the younger age group (<65 years). The beneficial effect of ERC in reducing the risk of dementia was consistent regardless of the characteristics of prior stroke. CONCLUSIONS: ERC might be beneficial in the prevention of dementia in patients with AF and prior stroke. To prevent the progression of cognitive dysfunction, ERC should be considered in this population.

Economic analyses in cardiac electrophysiology: from clinical efficacy to cost utility.

Cardiac electrophysiology is an evolving field that relies heavily on costly device- and catheter-based technologies. An increasing number of patients with heart rhythm disorders are becoming eligible for cardiac interventions, not least due to the rising prevalence of atrial fibrillation and increased longevity in the population. Meanwhile, the expansive costs of healthcare face finite societal resources, and a cost-conscious approach to new technologies is critical. Cost-effectiveness analyses support rational decision-making in healthcare by evaluating the ratio of healthcare costs to health benefits for competing therapies. They may, however, be subject to significant uncertainty and bias. This paper aims to introduce the basic concepts, framework, and limitations of cost-effectiveness analyses to clinicians including recent examples from clinical electrophysiology and device therapy.

Expert Consensus on Comprehensive Early Rhythm Control in Addition to Guideline-Based Care for Atrial Fibrillation: A Modified Delphi Survey.

Atrial fibrillation (AF) practice guidelines recommend a rhythm-control strategy to improve symptoms and quality of life, noting the side effects of antiarrhythmic drugs and catheter ablation. Emerging evidence indicates that comprehensive early rhythm control with antiarrhythmic drugs or catheter ablation is associated with a lower risk of adverse cardiovascular outcomes versus the usual care. Using an online modified Delphi survey approach, perspectives and expert consensus among electrophysiologists were examined through a series of ranking and likelihood questions around treatment decision-making on (1) the use of comprehensive early rhythm-control strategies in patients with AF based on guidelines and emerging research and (2) treatment selection factors. A panel of 17 electrophysiologists reached a consensus on using early rhythm control (median 90, interquartile range 14) based on the view that early intervention improved cardiovascular outcomes (mean rank 1.6 of 3, 82% within 1 SD) and symptoms (1.8 of 3, 41%). AF-related symptoms were identified as the most important in making a treatment initiation decision (1.1 of 7, 88%), followed by AF type (2.5 of 7, 82%). Participants were most likely to initiate treatment at AF symptom onset (median 80; interquartile range 6). In making treatment selection decisions, participants ranked short-term/long-term safety (1.9 of 7, 88%) and efficacy (1.8 of 7, 53%) as the top 2 considerations. In conclusion, experts were in favor of early rhythm control; however, additional research is needed to address the role that early rhythm-control strategies play in current AF treatment management algorithms.

Atrial fibrillation and coronary artery disease: An integrative review focusing on therapeutic implications of this relationship.

The incidence of both atrial fibrillation (AF) and coronary artery disease (CAD) increases with advancing age. They share common risk factors and very often coexist. Evidence points to an intricate relationship between atrial tissue excitability and neuronal remodeling with ischemia at the microcirculatory level. In this review, we delineated this complex relationship, identified a common theme between the two, and discussed how the knowledge of this relationship translates into a positive and meaningful impact in patient management. Recent research indicates a high prevalence of CAD among AF patients undergoing coronary angiography. Further, the incidence of AF is much higher in those suffering from CAD compared to age-matched adults without CAD underlying this reciprocal relationship. CAD adversely affects AF by promoting progression via re-entry and increasing excitability of atrial tissue as a result of ischemia and electrical inhomogeneity. AF in turn accelerates atherosclerosis via endothelial dysfunctional and inflammation and together with enhanced thrombogenicity and hypercoagulability contribute to micro and macrothrombi throughout cardiovascular system. In a nutshell, the two form a vicious cycle wherein one disease promotes the other. Most AF recommendations focuses on rate/rhythm control and prevention of thromboembolism. Very few studies have discussed the importance of unmasking coexistent CAD and how the treatment of underlying ischemia will impact the burden of AF in these patients. Inflammation and endothelial dysfunction remain central to both disease processes and form a handsome therapeutic target in the management of the two diseases. The relationship between AF and CAD is complex and much more than mere coincidence. The two diseases share common risk factor and pathophysiology. Hence, it is impractical to treat them in isolation. Accordingly, we share the implications of managing underlying ischemia and inflammation to positively impact and improve quality of life among AF patients.

Cost-effectiveness of early rhythm control vs. usual care in atrial fibrillation care: an analysis based on data from the EAST-AFNET 4 trial.

AIMS: The randomized, controlled EAST-AFNET 4 trial showed that early rhythm control (ERC) reduces the rate of a composite primary outcome (cardiovascular death, stroke, or hospitalization for worsening heart failure or acute coronary syndrome) by ∼20%. The current study examined the cost-effectiveness of ERC compared to usual care. METHODS AND RESULTS: This within-trial cost-effectiveness analysis was based on data from the German subsample of the EAST-AFNET 4 trial (n = 1664/2789 patients). Over a 6-year time horizon and from a healthcare payer's perspective, ERC was compared to usual care regarding costs (hospitalization and medication) and effects (time to primary outcome; years survived). Incremental cost-effectiveness ratios (ICERs) were calculated. Cost-effectiveness acceptability curves were constructed to visualize uncertainty. Early rhythm control was associated with higher costs [+€1924, 95% CI (-€399, €4246)], resulting in ICERs of €10 638 per additional year without a primary outcome and €22 536 per life year gained. The probability of ERC being cost-effective compared to usual care was ≥95% or ≥80% at a willingness-to-pay value of ≥€55 000 per additional year without a primary outcome or life year gained, respectively. CONCLUSION: From a German healthcare payer's perspective, health benefits of ERC may come at reasonable costs as indicated by the ICER point estimates. Taking statistical uncertainty into account, cost-effectiveness of ERC is highly probable at a willingness-to-pay value of ≥€55 000 per additional life year or year without a primary outcome. Future studies examining the cost-effectiveness of ERC in other countries, subgroups with higher benefit from rhythm control therapy, or cost-effectiveness of different modes of ERC are warranted.

Early rhythm control vs. rate control in atrial fibrillation: A systematic review and meta-analysis.

Objective: It has long been debated whether rhythm control vs. rate control strategies have differing effects on mortality and morbidity for atrial fibrillation (AF). Recently, several randomized controlled studies (RCTs) and observational trials described that an early rhythm management method was linked to a lower likelihood of negative clinical outcomes in individuals with AF. We wanted to see if an early rhythm management method may help patients with AF. Methods: We performed a systematic search to retrieve studies assessing the outcomes of early rhythm control vs. rate control in AF by using PubMed, Web of Science, Cochrane Library, and Embase published between 01/01/2000 and 15/04/2022. Results: Finally, two RCTs, one retrospective analysis of RCTs, and four observational studies were identified. Compared with rate control, early rhythm control has been linked to lower all-cause mortality. [risk ratio (RR), 0.76; 95% CI 0.69-0.83; P < 0.00001; I 2 = 77%]. The early rhythm control group was also associated with a lower risk of cardiovascular mortality (RR, 0.68; 95% CI 0.63-0.74; P < 0.00001; I 2 = 33), stroke (RR, 0.77; 95% CI 0.67-0.87; P < 0.001; I 2 = 64), and heart failure hospitalization (RR, 0.74; 95% CI 0.59-0.93; P = 0.0009; I 2 = 93%). We found no significant difference in nights spent in hospital per year, acute coronary syndrome, major bleeding, and cardiac arrest/ventricular arrhythmia between the groups. Conclusion: In this meta-analysis, early rhythm therapy was linked to a lower risk of all-cause mortality, cardiovascular mortality, stroke, and heart failure hospitalization compared with the rate control group. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022333592.

Improved prognosis with integrated care management including early rhythm control and healthy lifestyle modification in patients with concurrent atrial fibrillation and diabetes mellitus: a nationwide cohort study.

BACKGROUND: Patients with concurrent atrial fibrillation (AF) and diabetes mellitus (DM) [AF-DM] have a high risk of cardiovascular and diabetes-related complications, but are less engaged in a comprehensive treatment approach. We evaluated the association of early rhythm control (ERC), lifestyle modification (LSM), and a combination of ERC and LSM with cardiovascular or diabetes-related complication risk in patients with AF-DM (type 2). METHODS: From the National Health Information Database, 47,940 patients diagnosed with AF-DM in 2009-2016 were included. We defined ERC as rhythm control therapy within two years of AF diagnosis and LSM as adherence to ≥ 2 of the healthy behaviors among non-current smoking, non-drinking, and regular exercise. We compared the primary (ischemic stroke) and secondary (macro- and microvascular complications, glycemic emergency, and all-cause death) outcomes in four groups: non-ERC and non-LSM (group 1), LSM only (group 2), ERC only (group 3), and both ERC and LSM (group 4). RESULTS: Of total, 10,617 (22%), 26,730 (55.8%), 2,903 (6.1%), and 7,690 (16.0%) were classified into groups 1 to 4, in sequence. The mean duration from AF diagnosis to ERC was 25.6 ± 75.5 days. During 4.0 (interquartile range: 2.5-6.2) years' follow-up, groups 2 and 3 were associated with 23% and 33% lower risks of stroke than group 1, respectively. Group 4 was associated with the lowest risk of stroke: hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.51-0.67, p < 0.001. Regarding secondary outcomes, the lowest risks were also observed in group 4; macro- and microvascular complications, glycemic emergency, and all-cause death had HRs (95% CIs) of 0.63 (0.56-0.70), 0.88 (0.82-0.94), 0.72 (0.62-0.84), and 0.80 (0.73-0.87), respectively, all p < 0.001. CONCLUSIONS: For AF-DM patients, ERC and LSM exert a synergistic effect in preventing cardiovascular and diabetes-related complications with the greatest lowered risk of stroke. A comprehensive treatment approach should be pursued in AF-DM patients.

Effectiveness of early rhythm control in improving clinical outcomes in patients with atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: Current guidelines recommend rhythm control for improving symptoms and quality of life in symptomatic patients with atrial fibrillation (AF). However, the long-term prognostic outcomes of rhythm control compared with rate control are still inconclusive. In this meta-analysis, we aimed to assess the effects of early rhythm control compared with rate control on clinical outcomes in newly diagnosed AF patients. METHODS: We systematically searched the PubMed and Embase databases up to August 2022 for randomized and observational studies reporting the associations of early rhythm control (defined as within 12 months of AF diagnosis) with effectiveness outcomes. The primary outcome was a composite of death, stroke, admission to hospital for heart failure (HF), or acute coronary syndrome (ACS). Hazard ratios (HRs) and 95% confidence intervals (CIs) from each study were pooled using a random-effects model, complemented with an inverse variance heterogeneity or quality effects model. RESULTS: A total of 8 studies involving 447,202 AF patients were included, and 23.5% of participants underwent an early rhythm-control therapy. In the pooled analysis using the random-effects model, compared with rate control, the early rhythm-control strategy was significantly associated with reductions in the primary composite outcome (HR = 0.88, 95% CI: 0.86-0.89) and secondary outcomes, including stroke or systemic embolism (HR = 0.78, 95% CI: 0.71-0.85), ischemic stroke (HR = 0.81, 95% CI: 0.69-0.94), cardiovascular death (HR = 0.83, 95% CI: 0.70-0.99), HF hospitalization (HR = 0.90, 95% CI: 0.88-0.92), and ACS (HR = 0.86, 95% CI: 0.76-0.98). Reanalyses using the inverse variance heterogeneity or quality effects model yielded similar results. CONCLUSIONS: Our current meta-analysis suggested that early initiation of rhythm control treatment was associated with improved adverse effectiveness outcomes in patients who had been diagnosed with AF within 1 year. REGISTRATION: The study protocol was registered to PROSPERO (CRD42021295405).

Sex Difference in Effectiveness of Early Rhythm- over Rate-Control in Patients with Atrial Fibrillation.

Background: This study aimed to investigate the associations between sex and the relative effect of rhythm control over rate control in patients with atrial fibrillation. Methods: We used the National Health Insurance Service database to select patients treated for atrial fibrillation within one year after diagnosis. The primary composite outcome comprised cardiovascular death, ischemic stroke, heart failure hospitalization, or acute myocardial infarction. Results: During the mean follow-up (4.9 ± 3.2 years), the benefit of rhythm control over rate control on the primary composite outcome became statistically insignificant after 3 months from atrial fibrillation diagnosis in women while remained steadily until 12 months in men. The risk of primary composite outcome for rhythm control was lower than that for rate control in both sexes if it was initiated within 6 months (men: HR = 0.86, 95%CI = 0.79-0.94; women: HR = 0.85, 95%CI = 0.78-0.93; P for interaction = 0.844). However, there was significant interaction between sex and the relative effect of rhythm control if it was initiated after 6 months (men: HR = 0.72, 95%CI = 0.52-0.99; women: HR = 1.32, 95%CI = 0.92-1.88; P for interaction = 0.018). Conclusion: Rhythm control resulted in lower risk of primary composite outcome than rate control in both sexes; however, the treatment initiation at an earlier stage might be considered in women.

Cardiovascular Outcomes With an Early Rhythm Control Strategy in Atrial Fibrillation: A Systematic Review.

In practice, atrial fibrillation (AF) is typically managed by controlling ventricular rate given similar long-term outcomes and a more tolerable drug profile when compared to rhythm control. However, despite treatment via rate control, patients remain at increased risk for cardiovascular complications. This systematic review provides a summary of literature evaluating the effectiveness of early rhythm control (ERC, initiated within 2 years of diagnosis) in AF in reducing cardiovascular complications. A systematic review utilizing the MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews was performed to identify literature evaluating effectiveness of rhythm control strategies and cardiovascular complication reduction rates in ERC. A total of three literature articles meeting the inclusion and exclusion criteria were included for evaluating the benefit of ERC. One of these examined was a trial that directly compared antiarrhythmic drug (AAD) versus catheter ablation (CA) therapy in maintenance of sinus rhythm (SR). This systematic review shows that ERC is associated with a reduction of cardiovascular events in AF patients compared to other treatment strategies.