Article Text

Protocol
Registry for Evaluating Healthy Life Expectancy and Long-Term Outcomes after Catheter Ablation of Atrial Fibrillation in the Very Elderly (REHEALTH AF) study: rationale and design of a prospective, multicentre, observational, comparative study
  1. Yasuo Okumura1,
  2. Koichi Nagashima1,
  3. Ryuta Watanabe1,
  4. Katsuaki Yokoyama2,
  5. Takeshi Kato3,
  6. Hidehira Fukaya4,
  7. Hidemori Hayashi5,
  8. Shiro Nakahara6,
  9. Wataru Shimizu7,
  10. Yu-ki Iwasaki7,
  11. Yuhi Fujimoto7,
  12. Yasushi Mukai8,
  13. Koichiro Ejima9,
  14. Takayuki Otsuka10,
  15. Shinya Suzuki10,
  16. Masato Murakami11,
  17. Masaomi Kimura12,
  18. Masahide Harada13,
  19. Junjiroh Koyama14,
  20. Hideharu Okamatsu14,
  21. Teiichi Yamane15,
  22. Seigo Yamashita15,
  23. Michifumi Tokuda16,
  24. Ryohsuke Narui17,
  25. Mitsuru Takami18,
  26. Morio Shoda19,
  27. Tomoo Harada20,
  28. Ikutaro Nakajima20,
  29. Katsuhito Fujiu21,
  30. Kenichi Hiroshima22,
  31. Kojiro Tanimoto23,
  32. Tadashi Fujino24,
  33. Keijiro Nakamura25,
  34. Koji Kumagai26,
  35. Ayako Okada27,
  36. Hideki Kobayashi27,
  37. Tatsuya Hayashi28,
  38. Yuji Watari29,
  39. Mina Hatsuno29,
  40. Eizo Tachibana30,
  41. Kazuki Iso30,
  42. Kazumasa Sonoda31,
  43. Yoshiyasu Aizawa32,
  44. Akio Chikata33,
  45. Satoru Sakagami34,
  46. Masaru Inoue34,
  47. Hitoshi Minamiguchi35,
  48. Nobuhiko Makino35,
  49. Kazuhiro Satomi36,
  50. Yoshinao Yazaki36,
  51. Hideshi Aoyagi37,
  52. Makoto Ichikawa38,
  53. Hironori Haruta39,
  54. Takafumi Hiro40,
  55. Kimie Okubo41,
  56. Ken Arima42,
  57. Taiki Tojo43,
  58. Hajime Kihara44,
  59. Satoru Miyanaga45,
  60. Yoshiaki Fukuda46,
  61. Koji Oiwa47,
  62. Tamami Fujiishi48,
  63. Masashi Akabane49,
  64. Norikazu Ishikawa50,
  65. Kengo Kusano51,
  66. Koji Miyamoto51,
  67. Haruna Tabuchi52,
  68. Tomoyuki Shiozawa53,
  69. Kenjiro Miyamoto54,
  70. Hiroshi Mase55,
  71. Kenta Murotani56
  72. For the REHEALTH AF study
  1. 1Department of Cardiology, Nihon University Itabashi Hospital, Itabashi-ku, Tokyo, Japan
  2. 2Department of Cardiology, Nihon University Hospital, Chiyoda-ku, Tokyo, Japan
  3. 3Department of Cardiovascular and Internal Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
  4. 4Department of Cardiovascular Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
  5. 5Department of Cardiovascular Biology and Medicine, Juntendo University Graduate Schoool of Medicine, Bunkyo-ku, Tokyo, Japan
  6. 6Department of Cardiology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, Japan
  7. 7Department of Cardiovascular Medicine, Nippon Medical School Hospital, Bunkyo-ku, Tokyo, Japan
  8. 8Department of Cardiovascular Medicine, Japanese Red Cross Fukuoka Hospital, Fukuoka City, Fukuoka, Japan
  9. 9Department of Cardiology, Minamino Cardiovascular Hospital, Hachioji, Tokyo, Japan
  10. 10Department of Cardiovascular Medicine, The Cardiovascular Institute, Minato-ku, Tokyo, Japan
  11. 11Division of Cardiology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
  12. 12Divison of Cardiology, Pulmonary Medicine and Nephrology, Hirosaki University School of Medicine, Hirosaki, Aomori, Japan
  13. 13Department of Cardiology, Fujita Health University, Toyoake, Aichi, Japan
  14. 14Cardiovascular Center, Saiseikai Kumamoto Hospital, Kumamoto City, Kumamoto, Japan
  15. 15Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Minato-ku, Tokyo, Japan
  16. 16Division of Cardiology, Department of Internal Medicine, The Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
  17. 17Division of Cardiology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan
  18. 18Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  19. 19Department of Cardiology, Tokyo Women's Medical University Hospital, Shinjuku-ku, Tokyo, Japan
  20. 20Department of Cardiology, St.Marianna University School of Medicine Hospital, Kawasaki, Kanagawa, Japan
  21. 21Department of Cardiovascular Medicine, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
  22. 22Department of Cardiology, Kokura Memorial Hospital, Kitakyushu, Fukuoka, Japan
  23. 23Deparatment of Cardiology, National Hospital Organisation Tokyo Medical Center, Meguro-ku, Tokyo, Japan
  24. 24Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Ota-ku, Tokyo, Japan
  25. 25Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, Meguro-ku, Tokyo, Japan
  26. 26Department of Cardiovascular Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
  27. 27Department of Cardiovascular Medicine, Shinshu University Hospital, Matsumoto, Nagano, Japan
  28. 28Division of Cardiovascular Medicine, Saitama Medical Center, Jichi Medical University, Omiya, Saitama, Japan
  29. 29Department of Cardiology, Teikyo University Hospital, Itabashi-ku, Tokyo, Japan
  30. 30Division of Cardiology, Kawaguchi Municipal Medical Center, Kawaguchi, Saitama, Japan
  31. 31Division of Cardiology, Department of Medicine, Tokyo Rinkai Hospital, Edogawa-ku, Tokyo, Japan
  32. 32Department of Cardiology, International University of Health and Welfare Narita Hospital, Narita, Chiba, Japan
  33. 33Department of Cardiology, Toyama Prefectural Central Hospital, Toyama City, Toyama, Japan
  34. 34Department of Cardiology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Ishikawa, Japan
  35. 35Department of Cardiology, Osaka Police Hospital, Osaka City, Osaka, Japan
  36. 36Department of Cardiology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan
  37. 37Department of Cardiovascular Medicine, St Luke's International University, Chuo-ku, Tokyo, Japan
  38. 38Department of Cardiology, Sekishin Clinic, Kawagoe, Saitama, Japan
  39. 39Department of Cardiology, TMG Asaka Medical Center, Asaka, Saitama, Japan
  40. 40Circulatory medicine, Akabane Central General Hospital, Kita-ku, Tokyo, Japan
  41. 41Department of Cardiology, Itabashi Medical Association Hospital, Itabashi-ku, Tokyo, Japan
  42. 42Department of Cardiology, Kasukabe Medical Center, Kasukabe, Saitama, Japan
  43. 43Department of Cardiovascular medicine, Kitasato University Kitasato Institute Hospital, Minato-ku, Tokyo, Japan
  44. 44Department of Internal Medicine, Kihara Cardiovascular Clinic, Asahikawa, Hokkaido, Japan
  45. 45Division of Cardiology, Department of Internal Medicine, The Jikei University Daisan Hospital, Komae, Tokyo, Japan
  46. 46Department of Cardiology, Higashi Saitama General Hospital, Satte, Saitama, Japan
  47. 47Cardiology, Japan Community Health are Organization, Yokohama Chuo Hospital, Yokohama, Kanagawa, Japan
  48. 48Department of Cardiology, JCHO Sagamino Hospital, Sagamihara, Kanagawa, Japan
  49. 49Department of Cardiology, Akabane Clinic, Outawara, Tochigi, Japan
  50. 50Department of Cardiology, Zengyodanchi Ishikawa Clinic, Fujisawa, Kanagawa, Japan
  51. 51Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
  52. 52Department of Cardiology, Juntendo University Nerima Hospital, Nerima-ku, Tokyo, Japan
  53. 53Department of Cardiology, Juntendo University Shizuoka Hospital, Izunokuni, Shizuoka, Japan
  54. 54Department of Cardiology, Sapporo Shiroishi Memorial Hospital, Hokkaido, Sapporo, Japan
  55. 55Department of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
  56. 56Biostatistics Center, Kurume University School of Medicine, Kurume, Fukuoka, Japan
  1. Correspondence to Dr Yasuo Okumura; okumura.yasuo{at}nihon-u.ac.jp

Abstract

Introduction Data are lacking on the extent to which patients with non-valvular atrial fibrillation (AF) who are aged ≥80 years benefit from ablation treatment. The question pertains especially to patients’ postablation quality of life (QoL) and long-term clinical outcomes.

Methods and analysis We are initiating a prospective, registry-based, multicentre observational study that will include patients aged ≥80 years with non-valvular AF who choose to undergo treatment by catheter ablation and, for comparison, such patients who do not choose to undergo ablation (either according to their physician’s advice or their own preference). Study subjects are to be enrolled from 52 participant hospitals and three clinics located throughout Japan from 1 June 2022 to 31 December 2023, and each will be followed up for 1 year. The planned sample size is 660, comprising 220 ablation group patients and 440 non-ablation group patients. The primary endpoint will be the composite incidence of stroke/transient ischaemic attack (TIA) or systemic embolism (SE), another cardiovascular event, major bleeding and/or death from any cause. Other clinical events such as postablation AF recurrence, a fall or bone fracture will be recorded. We will collect standard clinical background information plus each patient’s Clinical Frailty Scale score, AF-related symptoms, QoL (Five-Level Version of EQ-5D) scores, Mini-Mental State Examination (optional) score and laboratory test results, including measures of nutritional status, on entry into the study and 1 year later, and serial changes in symptoms and QoL will also be secondary endpoints. Propensity score matching will be performed to account for covariates that could affect study results.

Ethics and dissemination The study conforms to the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies issued by the Ministry of Health, Labour and Welfare, Japan. Results of the study will be published in one or more peer-reviewed journals.

Trial registration number UMIN000047023.

  • cardiology
  • adult cardiology
  • thromboembolism
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Strengths and limitations of this study

  • This registry-based study is a multicentre observational study designed to compare the quality of life, physical status and long-term clinical outcomes between patients aged 80 years or more who elect to undergo ablation for atrial fibrillation (AF) (ablation group) and those who do not (non-ablation group).

  • Propensity score matching will substantially alleviate any selection bias within the two groups of patients whose characteristics will be similar because the investigators will include only relatively healthy patients in the non-ablation group.

  • Selection bias and potential confounding factors cannot be completely eliminated.

  • Because patients’ AF-related symptoms and quality of life will be assessed by means of simple self-report questionnaires, and physical status will be judged simply according to the Clinical Frailty Scale, patients’ status may not be fully reflected.

  • Patients to be included in the study are of a single race/ethnicity.

Introduction

Atrial fibrillation (AF) increases the risk of stroke, heart failure and mortality.1 2 Early intervention such as catheter ablation for maintenance of sinus rhythm has been reported to yield favourable clinical outcomes.3–5 With new developments in ablation technology over the past two decades, indications for AF ablation have gradually been expanded to include not only young patients but also middle-aged and elderly patients. Because of Japan’s now ‘super-aged’ society, AF ablation is being applied increasingly in patients aged 80 years or more. In 2009, researchers estimated the overall prevalence of AF among persons in Japan aged 40 years or more to be approximately 0.56% (716 000 persons) and projected that the overall prevalence will increase by decade, starting at 0.65% in 2010 and reaching 1.09% by 2050.6 Among persons aged 80 years or more (ie, very elderly persons), in particular, they documented a prevalence of 4.4% for men but 2.2% for women. In light of these trends, electrophysiologists ask a simple question: what can be improved by catheter ablation in very elderly patients with AF? Numerous studies related to catheter ablation in elderly patients have defined this patient population as being of age ≥75 years, and, although each was carried out as a retrospective single-centre or multicentre observational study, all have focused on recurrence of AF and ablation-related complications.7–9 These studies showed a similar AF recurrence rate between elderly patients and those who are younger but a modestly increased risk of complications in the elderly.7–9 The database analysis7 included over 100 000 patients, but there were several critical limitations; for example, heart failure was not clearly defined, details regarding patients’ status such as symptoms, quality of life (QoL), frailty or falls, and type of AF were unavailable, and serial changes in biomarkers and physical or mental functioning were not assessed. Only a few studies have investigated both the effects of catheter ablation on QoL and long-term clinical outcomes in patients aged ≥65 or ≥75 years.10–14 Thus far, no study has focused on patients aged ≥80 years because adequate data collection is challenging, with only a small number of such patients undergoing AF ablation worldwide. Because Japan has become a ‘super-aged society’, we consider it urgent to determine the clinical significance of catheter ablation for AF in patients aged ≥80 years. To resolve clinical questions that cannot be addressed by database and retrospective studies, we aim to explore the multiple effects of catheter ablation on clinical outcomes, focusing especially on long-term AF-related events and healthy life expectancy, by collecting real-world data regarding patients aged ≥80 years with AF who undergo catheter ablation and those who do not.

Methods

Study design and setting

The study will be based on Registry for Evaluating Healthy life Expectancy And Long-Term outcomes after CatHeter ablation of Atrial Fibrillation in the very elderly (REHEALTH AF), a large-scale, multicentre prospective registry of patients with AF in Japan. Enrolment began on 1 June 2022; the inclusion is scheduled to end on 31 December 2023, and all patients enrolled will be followed up for at least 1 year (with final follow-up occurring on or before 31 December 2024). Fifty-five institutions in Japan are registry participants (as shown in online supplemental figure 1), and these include 42 hospitals where ablation is performed and 10 hospitals and three private clinics where ablation is not performed. A flow diagram of the REHEALTH AF study, showing the overall patient pool, criteria for inclusion in and exclusion from the study, follow-up time and data analysis is shown in figure 1.

Figure 1

Flow diagram of the REHEALTH AF study. AF, atrial fibrillation; REHEALTH AF, Registry for Evaluating Healthy life Expectancy And Long-Term outcomes after catHeter ablation of Atrial Fibrillation in the very elderly.

Eligibility and non-eligibility

All patients included the study will be aged ≥80 years and diagnosed with non-valvular AF. All will have been visiting an outpatient clinic and have elected either to undergo or not undergo ablation for treatment of the AF. A patient’s decision to undergo ablation will have been based on their physician’s recommendation, whereas a patient’s decision to not undergo ablation will have been based on their physician’s recommendation or on their own personal preference. Therefore, the patients who have decided not to undergo ablation will be of two types, that is, those advised by their physician not to undergo ablation and those who simply choose not to undergo ablation. The study will include patients with any type of AF, that is, paroxysmal AF (recovery of sinus rhythm within 7 days of onset), persistent AF (AF lasting more than 7 days after onset), long-lasting persistent AF (persistent AF lasting for more than 1 year after onset) or persistent AF of unknown duration. All those included in the study will provide written informed consent for their inclusion. None of the patients considered for inclusion in the study will have undergone ablation within the previous 12 months, will have a Clinical Frailty Scale score of ≥7,15 will have severe dementia, will have severe valvular disease or an active tumour, will be on haemodialysis, or will have been judged by the research director or research coordinator not to be suitable for the study.

Study schedule

A website was created for the REHEALTH AF study and will be used to store all pseudonymised patient data, collected through a web-based registration system. Each patient’s name and hospital ID number will be replaced with a code but linked to the original record through the use of a key code. The coded data and key code will be stored separately. All participating investigators and/or research coordinators have been trained in how to use the study website, and for security purposes, each received his or her own ID for access to it. The study schedule is summarised in table 1.

Table 1

Study schedule (including items recorded) for ablation group and non-ablation group patients

In brief, after being screened for eligibility and providing written informed consent, study patients will undergo assessment of their physical status according to the Clinical Frailty Scale,15 of their QoL by means of the Five-Level Version of EQ-5D (EQ-5D-5L) questionnaire16 a two-part generic measure of health status, and of their AF-related symptoms by means of a patient-reported outcome measure (PROM). AF-related symptoms assessed by means of the PROM include palpitations, dizziness/lightheadedness, rapid heartbeat, dyspnoea/shortness of breath, general fatigue and/or fainting/syncope.17 18 The PROM, including the response alternatives, is shown in online supplemental figure 2. The first part of the EQ-5D-5L questionnaire is designed to assess health in five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression), each of which has five response levels. A summary index score based on the five dimensions ranges from 0 (meaning worst health) to 1 (meaning full health). The second part of the EQ-5D-5L questionnaire consists of a Visual Analogue Scale by which the patient rates his or her perceived health from 0 (‘worst health you can imagine’) to 100 (‘best health you can imagine’).16 If a patient desires assessment of dementia, that patient will be given the Mini-Mental State Examination (MMSE) at Nihon University Itabashi Hospital, Nihon University Hospital, or another participating facility.19 All patients’ clinical characteristics, laboratory values (haemoglobin concentration, creatinine concentration, N-terminal probrain natriuretic peptide (NT-proBNP) or brain natriuretic peptide, and nutritional status (Controlling Nutritional Status score,20 Glasgow Prognostic Score,21 Prognostic Nutritional Index22 and Geriatric Nutritional Risk Index23), electrocardiographic findings (sinus rhythm, AF/atrial tachycardia or other), transthoracic echocardiographic measures (left atrial diameter and left ventricular ejection fraction) and current medications will be determined at the time of registry enrolment but before ablation for patients who choose to undergo ablation (ablation group) or at the time of registry enrolment for patients who choose not to undergo ablation (non-ablation group). Because of the effect of changes in a patient’s medical status, the time between registration and ablation will be no longer than 4 weeks. Ablation details will be obtained for patients in the ablation group. One year after entry into the study, each patient’s symptoms, Clinical Frailty Scale score, QoL, MMSE score (if applicable), ECG, echocardiogram result and summary follow-up data will be obtained. If patients are followed up for more than 1.5 years, their symptoms, Clinical Frailty Scale score, QoL and ECG will be assessed and recorded 1.5 years after entry into the study if possible (table 1). Items obtained from each patient’s record at the time of enrolment and those obtained at the 1-year follow-up are shown in online supplemental table 1). Each patient’s pseudonymised baseline clinical information and follow-up data will be entered into an Excel spreadsheet at the participating hospital/clinic and saved to the website. For all study patients, the continuation, termination or initiation of oral anticoagulants, antiplatelet drugs and antiarrhythmic drugs will be investigated routinely and recorded. Onset and details of the occurrence of the primary and secondary study endpoints (see further) and invasive treatments (eg, catheter ablation and left atrial appendage closure) during the follow-up period will be also recorded. Any episode of AF occurring after ablation, lasting >30 s and documented on a standard ECG, event recorder or 24-hour Holter monitor, will be considered recurrent AF. If a patient is transferred to another hospital and discontinues or remains on the prescribed medication(s) during the follow-up period, this information will be collected, if possible, at least until the end of the 1-year follow-up period. All patient data including follow-up data will generally be updated every 3–6 months from each patient’s respective hospital/clinic. The general registry office will monitor and review the updated data in an independent manner every 6 months, and a patient’s hospital/clinic will be queried if some information entered into the database is unclear. Clinical events/endpoints will be judged by a clinical event committee.

Primary and secondary endpoints

The primary study endpoint will be the composite incidence of stroke/TIA, SE, another cardiovascular event (other than stroke/TIA, SE or cardiovascular death), major bleeding24 and/or all-cause death. Secondary endpoints are listed in box 1. In particular, we will focus on AF recurrence and changes in patients’ symptoms, Clinical Frailty Scale score and QoL from the time of enrolment to 1 year after ablation.

Box 1

Primary and secondary endpoints

  • Primary endpoint: composite incidence of stroke/TIA or SE, another cardiovascular event (a cardiovascular event other than stroke/TIA, SE or cardiovascular death), major bleeding and/or all-cause death.

  • Secondary endpoints.

  • Occurrence of any of the following:

  • Stroke/TIA or SE.

  • Cardiovascular event (stroke/TIA or SE, myocardial infarction/unstable angina, cardiovascular death, sudden death or hospitalisation for heart failure).

  • Major bleeding (ISTH criteria*).

  • Death from any cause.

  • Clinically significant bleeding.

  • Myocardial infarction, unstable angina.

  • Heart failure requiring hospitalisation or other cardiovascular event requiring hospitalisation.

  • Cardiovascular death.

  • Recurrence of atrial fibrillation after ablation.

  • Pacemaker implantation.

  • Fall.

  • Bone fracture.

  • Change in the following from the time of enrolment to 1 year:

  • Body weight.

  • Symptoms.

  • Blood pressure and pulse.

  • Clinical Frailty Scale score.

  • QoL (EQ-5D-5L: summary index score and visual analogue scale score).

  • MMSE score (optional item).

  • Electrocardiographic findings.

  • Echocardiographic measures.

  • Haemoglobin and creatinine.

  • NT-proBNP or BNP.

  • Nutritional status markers.

  • Use of antiarrhythmic drugs, anticoagulants or antiplatelet drugs.

  • *The ISTH defines major bleeding as follows: fatal bleeding, bleeding into a major organ or critical area (eg, intracranial, retroperitoneal, pericardial, intraspinal, intra-articular and intraocular bleeding), a decrease in the haemoglobin concentration of 20 g/L or more, or transfusion of at least 2 units of blood.24

  • BNP, brain natriuretic peptide; EQ-5D-5L, Five-Level Version of EQ-5D; ISTH, International Society for Thrombosis and Haemostasis; MMSE, Mini-Mental State Examination; NT-proBNP, N-terminal probrain natriuretic peptide; SE, systemic embolism; TIA, transient ischaemic attack.

Sample size and calculation data

A previous study (published in 2019), derived from a multicentre AF registry in Japan and covering mostly non-ablation patients, revealed a 17.8% incidence of the composite endpoint (stroke, all-cause mortality, major bleeding and cardiovascular events) among patients aged ≥75 years,25 and the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial (published in 2020) revealed a 22.4% incidence of cardiovascular hospitalisation of frail patients aged ≥80 years.26 Accordingly, we set the 1-year incidence of the primary endpoint in non-ablation group at 20%. Furthermore, to estimate the therapeutic effect in the ablation group with respect to that in the non-ablation group, we set the HR as follows: in a multivariate analysis of Japan’s ANAFIE registry consisting of 30 000 patients aged ≥75 years, most of whom have been treated by anticoagulants,27 the HR when ablation was performed was 0.58 (95% CI 0.42 to 0.79) for stroke, 0.66 (95% CI 0.47 to 0.94) for major bleeding and 0.55 (95% CI 0.44 to 0.69) for death from any cause. On the basis of these data, we set an HR of 0.6 as the expected therapeutic effect of ablation. Thus, the 1-year primary event rate in our non-ablation group will be 20%; the therapeutic effect of ablation will be an HR of 0.6, as necessary to detect a difference at α=0.05 (two-sided) and 1−β of ≥0.8. In calculating the number of patients needed by means of the Lakatos method, we found a need for 183 per group. We used PROC POWER (SAS V.9.4) to calculate the required number of cases and set the required number at 200 for each group. We realise that clinical characteristics of the non-ablation group patients are likely to differ from those of the ablation group patients. However, when 1:1 nearest neighbour matching was performed at a calliper width of 0.5 for the 2930 patients from SAKURA AF who did not undergo ablation and the 3451 AF Frontier Ablation Registry patients who underwent ablation, 48% (n=1414) of patients who did not undergo ablation were matched to patients in the ablation group.11 Thus, it appears that about twice as many patients who do not undergo ablation are needed for analysis, so we set that number to 400. The target numbers are 220 and 440, respectively, totalling 660, under the expectation that about 10% of patients will drop out or be censored.

Statistical analysis

Continuous variables will be presented as mean±SD or median (25th, 75th percentile) values and categorical variables as the number (%) of patients. Between-group differences in continuous variables will be analysed by t-test or Mann-Whitney U test; and between-group differences in categorical variables will be analysed by χ2 or Fisher’s exact test. Groups will be balanced by means of 1:1 nearest neighbour propensity score matching at a calliper width of 0.5 or by the inverse probability of treatment weighting method. Variables in the propensity score model will be selected in a data-driven manner, with the number of events taken into account. Variables that are unrelated to the exposure but related to the outcome will be preferentially included in the model.28 If overlap in the propensity scores is small, weighting estimation will be performed. Results obtained for all cohorts (including patients who were excluded by propensity score matching) will be shown as supplemental material. Cumulative event rates will be calculated by the Kaplan-Meier method and compared between the two main study groups and between the propensity score-matched groups by log-rank test. Event rates will be calculated as the total number (%) of events and the number per 100 person-years. The same method will be used for occurrence of each secondary endpoint. For serial changes in haemoglobin, creatinine, NT-proBNP, EQ-5D-5L and all other clinical variables from the time of enrolment to 1 year thereafter, difference in the change (%) between the ablation group and non-ablation group will be analysed. Factors related to occurrence of the primary endpoint will be subjected to multivariate Cox proportional hazards analysis, and HRs (with 95% CIs) for the ablation group in relation to the non-ablation group will be calculated, allowing for identification of any risk-lowering effect of ablation. The Cox proportional hazards model will also be adjusted for factors such as age, sex, weight and comorbidities to test for any interactions.

Ethics and dissemination

The study is registered with the UMIN Clinical Trials Registry. It conforms to the Declaration of Helsinki29 and the Ethical Guidelines for Clinical Studies issued by the Ministry of Health, Labour and Welfare, Japan. All study participants will provide written informed consent and may withdraw their consent at any time. This study protocol has been approved by the institutional review board (IRB) of Nihon University Itabashi Hospital, Clinical Research Judging Committee, and the participating hospitals’ IRBs. Results of the study will be published in one or more peer-reviewed journals.

Patient and public involvement statement

Neither patients nor members of the public have been or will be involved in the design of the study, its planning or the data collection or data analysis.

Discussion

This registry-based study is a prospective multicentre cohort study designed to examine the differences in symptoms, QoL, physical status and long-term clinical outcomes in patients aged 80 years or older who choose to undergo ablation therapy (ablation group) and those who do not (non-ablation group). The benefits of ablation may not be fully realised among elderly patients. A subanalysis of our previously reported registry data showed no beneficial effect on the composite mid-term clinical outcome—stroke, death, cardiovascular events and major bleeding—among patients aged ≥75 years,11 in keeping with results reported for patients aged ≥65 years from a subanalysis of the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA)12 and Catheter Ablation for Atrial Fibrillation with Heart Failure (CHASTLE-AF) trials.13 However, subanalysis of the CABANA data revealed QoL in the ablation group to be significantly improved even in patients aged ≥75 years,14 as reported out of a prospective multicentre Japanese registry of patients aged ≥70 years.30 In particular, whether the benefit of AF ablation, with respect to symptoms, QoL and clinical outcomes, holds true for patients aged ≥80 years has not been determined.

The REHEALTH AF study has several strengths in terms of its design. Being conducted as a multicentre observational study, it overcomes the obstacles that would be posed by a randomised controlled trial. Such a trial aimed at comparing outcomes among patients who do and do not undergo AF ablation can be ethically challenging in Japan. In addition, there are few patients aged ≥80 years who undergo ablation at any one hospital, so the study was designed in such a way that enrolling the necessary number of patients would be clinically feasible. Second, we chose a simple symptom questionnaire, a general QoL questionnaire (EQ-5D-5L) and the Clinical Frailty Scale (for assessment of patients’ physical status) because these instruments are not complex and thus are easy to administer in the context of the large number of busy hospitals/clinics that treat outpatients in Japan. Although the Atrial Fibrillation Effect on Quality-of-Life is a well-established instrument,14 30 it may be challenging for patients aged ≥80 years to complete; it has been used in only a few Japan-based registry-enrolled patients aged ≥80 years so far.30 Third, patients who undergo ablation are generally healthier than those who do not, so we plan to use propensity score matching to balance our two study groups. Propensity score matching is generally performed in retrospective studies, but unmeasured variables and potential selection bias remain problematic. To avoid these problems as much as possible, we plan to document important variables specific to elderly patients (body weight, frailty, history of falls, nutrition status, etc), and we asked the participating investigators to enrol healthy (Clinical Frailty Scale score of 1–4 and absence of dementia) patients who choose not to undergo AF ablation according either to their physician’s advice or their own preference. Prospectively collecting data on well-matched patients who do and do not undergo AF ablation will allow comparison of the multiple effects of ablation on symptoms, QoL and clinical outcomes between the two patient groups.

Regardless of its strengths, the study has its limitations. First, although it is an observational study that incorporates patient matching, selection bias and confounding factors cannot be completely controlled for. Second, because of the use of a simple PROM for AF-related symptoms, the EQ-5D-5L and the Clinical Frailty Scale, patient status specific to AF may not be fully captured. In particular, the PROM we are using for AF-related symptoms has not been methodically validated. However, two published registry-based studies addressing outcomes ablation for AF, one of the Japanese patients with AF18 and the other of patients with AF from 26 countries17 assessed, at 1 year after ablation, change in the same AF-related symptoms covered by our PROM, and significant improvement in these AF-related symptoms was documented in both studies. Third, the study’s patient population is of a single racial/ethnic background.

The REHEALTH AF study will stand as a prospective multicentre registry-based study designed specifically to investigate the effects of ablation as treatment for non-valvular AF in patients aged ≥80 years.

Ethics statements

Patient consent for publication

Acknowledgments

We express our gratitude to all study participants and all supporting staff. We thank the clinical event committee members (Atsushi Hirayama, MD, Department of Cardiology, Osaka Police Hospital, Osaka, Japan; Daisuke Fukamachi, Department of Cardiology, Nihon University Hospital, Tokyo, Japan) for their contributions. We also thank Ms Wendy Alexander-Adams and Mr Martin John for the English language editing.

References

Supplementary materials

Footnotes

  • Twitter @Tatsuya Hayashi3

  • Contributors YO wrote the first draft of the protocol manuscript and carried the overall responsibility for the full study and the study protocol. YO, KNas, TK, HF, HHay, SN, YI, YM and KE contributed substantially to the study concept and design, critically reviewed the manuscript and contributed to the acquisition, analysis and interpretation of data. KNas obtained the finding. YO, KNas, RW, KY, TK, HF, HHay, SN, WS, YI, YFujim, YM, KE, TO, SSu, MM, MK, MHar, JK, HO, TY, SY, MTo, RN, MTa, MS, THar, IN, KF, KH, KT, TFujin, KNak, KKum, AO, HKo, THay, YW, MHat, ET, KI, KSo, YA, AC, SSa, MIn, NM, HMi, KSa, YY, HA, MIc, HHar, THi, KOu, KA, TT, HKi, SM, YFuk, KOi, TFujii, MA, NI, KKus, KoM, HT, TS, KeM and HMa collectd the data and conducted the study, and approved the final version of this manuscript. KMu provided critical comments on statistical methods and contributed to the analysis and interpretation of the data.

  • Funding This work was funded in part by a Johnson & Johnson medical research grant (AS2022A000025196).

  • Competing interests The following authors have potential conflicts of interest: YO received research funding from Bayer Healthcare, Daiichi-Sankyo, Bristol-Meyers Squibb, Nippon Boehringer Ingelheim, Pfizer and Boston Scientific Japan, and accepted remuneration from Bayer Healthcare, Daiichi-Sankyo and Bristol-Meyers Squibb. KNas accepted remuneration from Johnson & Johnson K.K. TK received lecture fees from Daiichi-Sankyo, Bristol-Myers Squibb, Bayer Healthcare, Boston Scientific and Medtronic Japan. HF accepted remuneration from Daiichi-Sankyo, Bayer Yakuhin, Nippon Boehringer Ingelheim, Johnson & Johnson K.K., Abbott Medical Japan, Medtronic Japan and Japan Lifeline. SN received speaker honoraria from Bayer Healthcare, Daiichi-Sankyo, Bristol-Meyers Squibb and Medtronic Japan. WS received grants from Daiichi Sankyo Co., Ltd, and Nippon Boehringer Ingelheim; and remuneration for lectures, presentations, speakers bureaus, manuscript writing or educational events from Daiichi Sankyo, Nippon Boehringer Ingelheim, Bristol-Meyers Squibb, K.K., Bayer Yakuhin, Pfizer, Ono Pharmaceutical and Medtronic Japan. YM received lecture fees from Bayer Healthcare, Daiichi-Sankyo, Bristol-Meyers Squibb, Nippon Boehringer Ingelheim, Johnson & Johnson K.K., Japan Lifeline K.K, Medtronic Japan, Pfizer and Boston Scientific Japan. SSu received research funding from Daiichi Sankyo and remuneration from Bristol-Myers Squibb and Daiichi Sankyo. MHar received research funding from BIOTRONIK Japan, Medtronic Japan, Abbott Japan, Japan Lifeline, Nihon Kohden and Boston Scientific Japan, and accepted remuneration from Nippon Boehringer Ingelheim, Daiichi-Sankyo, Bristol-Meyers Squibb, Medtronic Japan, Japan Life Line and Abbott Japan. TY received speaker honoraria from Medtronic Japan and Abbott Medical Japan. MTo received research funding from Japan Lifeline and consulting fee from Medtronic Japan. MTa belongs to the Section of Arrhythmia, Division of Cardiovascular Medicine, Department of Internal Medicine. This section supported by an endowment from Abbott Japan, Medtronic Japan and Boston Scientific Japan. MS is affiliated with an endowed division supported by BIOTRONIK Japan, Boston Scientific Japan K.K., Medtronic Japan and Abbott Medical Japan. AO taught courses endowed by BIOTRONIK, Abbott, Medtronic, Boston Scientific Japan and Japan Lifeline. KSa accepted remuneration from Abbott Japan, Medtronic Japan and Japan Lifeline. HKi accepted remuneration from Otsuka Pharmaceutical., AstraZeneca, Bristol-Meyers Squibb, Ono Pharmaceutical, Pfizer and Novo Nordisk. KMu received honoraria for Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, MSD, Kyowa Kirin, Yakult Pharmaceutical and Boehringer Ingelheim. KKus received speaker honoraria from Daiichi-Sankyo, Nippon Boehringer Ingelheim, Bayer Yakuhin, Pfizer and Medtronic Japan, and research grants from Medtronic Japan and JSR. KoM received speaker honoraria from Medtronic Japan and Abbott Japan, and research funding from Bristol-Meyers Squibb, Pfizer, Medtronic Japan, Japan Lifeline and Boston Scientific Japan.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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