1 INTRODUCTION

Atrial fibrillation (AF) is the most common form of arrhythmia. The prevalence of AF increases with age,¹ ranging from <1% in people aged <50 years to 10%–17% in people aged ≥80 years.² The presence of AF can reduce quality of life and exercise tolerance,^{3, 4} and is associated with a 1.5- to 2-fold increase in the risk of death and heart failure and a 5-fold increase in the risk of stroke and systemic thromboembolic events (SEE).^{3, 4}

Japan has the highest proportion of elderly people in the world,^{5, 6} so population aging is particularly relevant. Increased age is associated with an increased prevalence of frailty, with a recent study reporting that frailty affected 10% of adults aged 50–64 years and 43.7% of adults aged ≥65 years.⁷

Recent studies have demonstrated an association between frailty and AF.^{8, 9} Although the incidence of cardiovascular events, such as stroke and SEE, is high in patients with AF,^{3, 4} patients with AF complicated with frailty are at an even higher risk of stroke/SEE, major bleeding, and all-cause death.^{10, 11}

Catheter ablation (CA) is a well-established treatment for AF,^12-14 demonstrating superiority over antiarrhythmic drug therapy in patients with persistent or paroxysmal AF.^{15, 16} Previous studies have examined frailty and the effects of CA in patients with non-valvular AF (NVAF).^17-19 However, the prevalence of frailty and whether CA for NVAF improves frailty have not been fully examined in elderly Japanese patients with CA in the real-world clinical setting.

This subgroup analysis of the Real-world ablation therapY with anti-cOagUlants in Management of Atrial fibrillation (RYOUMA) registry aimed to clarify the rate of frailty in patients undergoing CA for NVAF, assess whether CA for NVAF improves frailty in Japanese patients aged ≥65 years based on the 5-item frailty screening index,^{20, 21} and describe CA outcomes and complications in patients with and without frailty. We also aimed to examine the rates of AF recurrence in the frailty, pre-frailty, and robust groups.

2 METHODS

3 RESULTS

3.2 Frailty assessment

Table 3 shows the number of patients who were classified as frail, pre-frail, or robust preoperatively and at 3 and 6 months postoperatively. Of the 26 patients who were classed as frail preoperatively, 21 responded to the questionnaire at 6 months after CA. Of these, 2 (9.5%) were classed as robust and 10 (47.6%) were classed as pre-frail, with only 9 (42.9%) still being classed as frail at 6 months after CA. Moreover, of the 109 patients who were classed as pre-frail preoperatively, 86 responded to the questionnaire at 6 months after CA. Of these, 26 (30.2%) were classed as robust at 6 months after CA, and only 52 (60.5%) were still classed as pre-frail. However, 8 patients (9.3%) who were initially classed as pre-frail progressed to frailty at 6 months after CA.

TABLE 3. Number of patients in the frailty, pre-frailty, and robust groups before catheter ablation (preoperative) and at 3 and 6 months after CA.

	Preoperative
	Frailty n = 26	Pre-frailty n = 109	Robust n = 68
3 months
Frailty	8 (36.4)	13 (14.9)	2 (3.2)
Pre-frailty	9 (40.9)	54 (62.1)	15 (24.2)
Robust	5 (22.7)	20 (23.0)	45 (72.6)
6 months
Frailty	9 (42.9)	8 (9.3)	3 (5.4)
Pre-frailty	10 (47.6)	52 (60.5)	13 (23.2)
Robust	2 (9.5)	26 (30.2)	40 (71.4)

• Note: The percentage of patients in each group at 3 and 6 months was calculated based on the number of patients from the original preoperative population who responded to the questionnaires at 3 and 6 months (i.e., not all patients who were classified preoperatively responded to the questionnaires at 3 and 6 months).

The changes over time in the five frailty screening index items after CA in the robust, pre-frailty, and frailty groups are shown in Figure 1. The frailty and pre-frailty groups showed a trend toward an improvement in weight loss, walking speed, and fatigue after CA.

3.4 AF recurrence and cardiac function after CA

At 3 months after CA, the percentage of patients without AF recurrence was 96.2% in the frailty group, 96.3% in the pre-frailty group, and 88.2% in the robust group. At 6 months after CA, the percentage of patients without AF recurrence was 88.5% in the frailty group, 91.7% in the pre-frailty group, and 86.8% in the robust group (Figure 2). The rates of antiarrhythmic drug use at 1, 3, and 6 months after CA were 2 (2.7%), 0%, and 1 (3.8%) in the frailty group, 10 (10.1%), 2 (1.8%), and 3 (2.8%) in the pre-frailty group, and 1 (1.5%), 2 (2.9%), and 3 (4.4%) in the robust group, respectively.

Numerically, left ventricular diastolic dimension, left ventricular systolic dimension, left ventricular ejection fraction, and left atrial diameter did not markedly change at 3 months after CA versus before CA in any of the three groups, but there was a trend toward an improvement in left atrial volume index at 3 months in all three groups (Table S2).

4 DISCUSSION

This is the first report to evaluate the improvement in the degree of frailty after CA for NVAF, assessed using the 5-item frailty screening index.^{20, 21} The first finding was that CA showed a tendency to improve some components of the frailty screening index, such as weight loss, walking speed, and fatigue, in patients with frailty and pre-frailty. The second finding was that the incidence of major bleeding, cardiovascular events, and cardiac events in patients with frailty was 0.3%/person-year, 0.5%/person-year, and 0.5%/person-year, respectively, but no cardiovascular deaths were noted. Moreover, no cases of stroke/SEE or intracerebral hemorrhage were observed in any of the three groups. The third finding was that after CA, all three groups had low rates of AF recurrence.

Among the patients who underwent CA for NVAF, 12.8% were classified as frail, 53.7% as pre-frail, and 33.5% as robust. In a recent report of elderly patients with NVAF in Japan, 19.5% were classified as frail, 62.6% were classified as pre-frail, and 17.9% were classified as robust.¹¹ In that study, the proportions of patients with frailty and pre-frailty were higher than in this study, possibly because the previous study included subjects aged ≥75 years, whereas the present study included patients aged ≥65 years. This difference in the age distribution may have led to a difference in the proportion of patients with frailty or pre-frailty. Moreover, the need for CA was determined at the attending physician's discretion; therefore, selection bias may have existed in patient enrollment, leading to the inclusion of more robust patients. This tendency to select more robust patients for CA has been noted previously in the consensus statement on CA for AF.¹²

This study showed that CA improved some components of the frailty screening index, including weight loss, walking speed, and fatigue. It is possible that an improvement in sinus rhythm restoration or a decrease in the AF burden after CA may have led to increased physical activity, in turn increasing appetite and limiting weight loss. It is also possible that discontinuation of antiarrhythmic drugs reduced weight loss, as antiarrhythmic drugs have been reported to produce gastrointestinal symptoms, reducing appetite. Moreover, the possibility of anorexia because of symptoms of right heart failure in patients with AF has been reported.²⁴ Therefore, improving AF symptoms with CA may have led to the reduction in weight loss.

It is important to note that there is some overlap between AF symptoms and the features used to determine frailty (e.g., weight loss and shortness of breath). CA improved the symptoms of AF, which may have been reflected as an improvement in frailty. Another consideration is that more robust patients were selected in this study. These patients may be more energetic, influencing the improvement in physical activity and/or walking speed after CA. Patients with more severe frailty or very elderly patients might not demonstrate such an improvement in frailty after undergoing CA to treat AF; therefore, the results should be interpreted with caution in these groups.

Patients undergoing CA also receive lifestyle guidance, which may help them to become more health conscious, contributing to more comprehensive AF management.²⁵ The improvement in walking speed in this study may be expected, as a previous study showed that CA for AF improves physical capability soon after the procedure.²⁶ Thus, a higher proportion of patients after CA versus before CA answered “no” to “Do you think your walking speed is slower than before?,” in turn reducing the frailty screening index score and suggesting an improvement in walking speed. Fatigue may have been largely due to AF, explaining the improvement in fatigue after CA. Moreover, patients may have become more aware of lifestyle changes after CA, as shown in the AF Better Care (ABC) pathway (“A,” avoid stroke with anticoagulation; “B,” better symptom management; “C,” cardiovascular and comorbidity management, including lifestyle factors).²⁵

Notably, a proportion of patients in the robust group were reclassified into the frailty and pre-frailty groups during the postoperative follow-up period. Although some items of the frailty screening index improved in the frailty and pre-frailty groups, certain items did not improve in the robust group despite the efficacy of CA being similarly high in this group. As shown in Figure 1, the percentage of patients in the robust group with weight loss and memory impairment increased during the follow-up period. One possible reason for weight loss is that as part of AF management, patients are instructed to exercise, eat healthy, and lose weight,²⁵ and this would be particularly promoted for robust patients, possibly leading to greater weight loss and a consequent increase in frailty score.

In this study, the proportion of patients experiencing cardiovascular events and cardiac events was considered high after CA for NVAF in patients with frailty. This is in line with previous studies showing that frailty is a risk factor for major adverse cardiac events and cardiovascular mortality.^{27, 28} In addition to the high proportion patients with cardiovascular and cardiac events, the number of major bleeding events was high in patients with frailty who underwent CA for NVAF. The results are similar to those of the ANAFIE registry study, which showed that the rate of major bleeding was significantly higher in Japanese patients with NVAF complicated with frailty than in those classed as pre-frail or robust,¹¹ although no statistical comparisons among the three groups were made in the present study.

Patients with AF are at a high risk of stroke/SEE.^{3, 4} Although the incidence of stroke/transient ischemic attack in patients with AF undergoing CA is reported to be 0%–2.0%,¹² this risk is thought to be further increased in those with frailty.¹¹ However, no cases of stroke/SEE were observed in this study.

This study also demonstrated that both the frailty and pre-frailty groups had low rates of AF recurrence after CA, as did the robust group. This may have been because of the large number of patients with paroxysmal AF in the pre-frailty and frailty groups (n = 86) compared with the lower number of patients with long-lasting (n = 34) or permanent (n = 15) AF in these groups. The low AF recurrence rates may also be attributable to the short follow-up period of 6 months. Given that the rates of postoperative antiarrhythmic drug use were low, this is not likely to be the main reason for the low AF recurrence rates. It is important to note that the first 3 months after CA for AF are referred to as the 3-month blanking period, during which time AF recurrence is thought to be quite common and does not necessarily indicate procedural failure.^{4, 29} For this reason, guidelines recommend that physicians judge the success of AF ablation no earlier than 6 months after the procedure.^{4, 29, 30} Thus, although a certain proportion of patients in all three groups demonstrated recurrence within 6 months, this was expected. Further follow-up of these patients beyond the 6-month period would be useful to determine whether the incidence of AF recurrence differs between the frailty/pre-frailty groups and the robust group or whether the AF recurrence rates simply result from natural variation during the 6-month post-procedural period.

5 CONCLUSIONS

Among elderly patients with NVAF who underwent CA, approximately 10% were classified as frail and 50% as pre-frail. In this population, frailty screening index components, such as weight loss, walking speed, and fatigue, seemed to result from impaired physical activity, which suggests that elderly patients may benefit from CA for NVAF. However, large-scale studies are needed in the future to confirm our findings.

FUNDING INFORMATION

This work was supported by Daiichi Sankyo Co., Ltd. Daiichi Sankyo Co., Ltd. was involved in the study design, planning of the data analysis, data interpretation, and development of the manuscript, but was not involved in data management and statistical analysis.

CONFLICT OF INTEREST STATEMENT

KS has received honoraria from Boehringer Ingelheim, Daiichi Sankyo, Abbott, Medtronic, and Johnson & Johnson. KK has received honoraria from Daiichi Sankyo, Boehringer Ingelheim, Fukuda Denshi, Nihon Kohden, Toray, and Japan Lifeline. KU has received honoraria from Japan Lifeline. T Kurita has received honoraria from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, Abbott, Medtronic, and Johnson & Johnson. AN has received honoraria from Boehringer Ingelheim, Daiichi Sankyo, Bristol Myers Squibb, Abbott, and Johnson & Johnson, and endowments from Medtronic and DVX. IM has received honoraria from Daiichi Sankyo and Abbott. FM has received honoraria from Medtronic, Abbott, and Biotronik. RK has received grant support from Boston Scientific, Abbott, Bayer, and Japan Lifeline. T Kimura and AT are employees of Daiichi Sankyo. MG has received honoraria from Pfizer, Ferring Pharma, Daiichi Sankyo, Merck Biopharma, and Novartis. KA has received honoraria from Boston Scientific, Japan Lifeline, Nihon Kohden, Biotronik, Toray Industries, ASTEC, Abbott, Boehringer Ingelheim, and Century Medical.

ETHICS STATEMENT

Ethics approval was obtained from the institutional review boards of the participating institutions.

PATIENT CONSENT STATEMENT

All patients provided written informed consent.