Efficacy and safety of Saireito (TJ-114) in patients with atrial fibrillation undergoing catheter ablation procedures: A randomized pilot study (2024)

Study design and protocol

The SAIreito Reduces Early recurrence after Intervention for aTrial fibrillation, Or not (SAIREITO) trial is a physician-initiated, non-company-sponsored, dual-center prospective randomized controlled pilot trial, comparing 30-day use of Saireito (N = 50) and a control (N = 50) in patients undergoing catheter ablation for symptomatic AF (Japan Registry of Clinical Trials: jRCTs05120037). The study protocol was approved by the institutional review board of Kyoto University Hospital and a participating institution (Mitsubishi Kyoto Hospital). Written informed consent was obtained from all the study patients. Patients with symptomatic AF undergoing first-time catheter ablation were recruited. Patients were eligible for the study if they were 20 to 85 years old, Exclusion criteria were contraindications or intolerance to Saireito including previous interstitial pneumonia, primary aldosteronism, an allergy to Saireito, and renal insufficiency (estimated glomerular filtration rate < 30 ml/min/1.73m² or on hemodialysis). Patients who had been treated with Saireito, Goreisan, and immunosuppressive drugs including steroids, those with a history of MAZE surgery or LA ablation, severe hepatic insufficiency, inability to be followed for one year, and unwillingness to sign the consent form for participation, and those whom the attending physician considered inappropriate to enroll in the study were also excluded. Between 5^th October 2020 and 25^th January 2022, 100 patients were enrolled in this trial.

The participants were randomly assigned to take Saireito or not in a 1:1 ratio before the ablation procedure. Randomization was performed via a computer-generated sequence using a permuted block design stratified by age (< 70 years or ≥ 70 years), gender, center, AF type, AF duration (< 3 years or ≥ 3 years), and type of the ablation procedure for pulmonary vein (PV) isolation (radiofrequency catheter ablation or cryoballoon ablation). In patients assigned to the 30-day use of Saireito, the drug was started on the day of the ablation procedure at a dose of 3 g for three times daily between meals. The operators were masked to the treatment assignment at the time of the ablation procedure, while the participants were not masked to the treatment assignment. For safety reasons, the participants were permitted to discontinue the intake of Saireito during the treatment period when side effects of Saireito were suspected.

Ablation procedure

The ablation procedure was performed under the guidance of a three-dimensional mapping system (CARTO, Biosense-Webster, Diamond Bar, CA, USA; Ensite NavX, Abbott, Chicago, IL, USA; Rhythmia, Boston Scientific, Natick, MA, USA). PV isolation with radiofrequency catheter ablation was an extensive encircling PV isolation with two circular-shaped catheters placed in the ipsilateral superior and inferior pulmonary veins. After successful PV isolation, we checked whether dormant conduction between LA and PVs was provoked by adenosine triphosphate under isoproterenol infusion. When dormant conduction was induced, additional radiofrequency energy applications were delivered until disappearance of dormant conduction. In PV isolation with cryoballoon, single-shot freezing was performed for each PV, and electro-anatomical mapping with a high-density mapping catheter was performed to confirm the completion of PV isolation. When there was a conduction gap between PV and LA, touch-up ablation was performed using radiofrequency ablation catheter. Whether to perform additional ablation, such as tricuspid valve isthmus ablation, left atrial roof line ablation, mitral isthmus ablation, and superior vena cava isolation, was left to the discretion of the operators.

All AADs were discontinued before the ablation procedure, and restarted only when recurrent atrial tachyarrhythmias were detected. A second catheter ablation procedure was usually recommended to patients with recurrent atrial tachyarrhythmias after the blanking period of 3 months.

Follow-up

Patients were scheduled to receive a periodical follow-up at the out-patient clinic of the centers where the index ablation was performed at 1-, 3-, 6-, and 12-month post ablation. A 12-lead electrocardiogram (ECG) was obtained at every visit. A one-channel ECG was recorded twice daily and at any time when the patient had symptoms with the use of an ambulatory electrogram recorder (HCG-801, OMRON HEALTHCARE Co., Ltd) for a duration of 1 month upon hospital discharge. Twenty-four-hour Holter-monitoring was performed at 3–6 months. The monitored ECGs during the index hospital admission were analyzed by the attending physicians. Ambulatory ECGs were read by cardiologists at the core laboratory. Holter-monitoring was read by clinicians at the local center. When patients became unable to visit the out-patient clinic of the local center, the follow-up data were obtained by contacting the physicians in charge or the patients. All data were evaluated and inputted by cardiologists or by the clinical research coordinators who were unaware of the treatment assignments.

Definitions and outcome measures

AF was defined as paroxysmal when it terminated spontaneously or under AADs within 7 days of onset, and was considered persistent when it lasted for more than 7 days. The European Heart Rhythm Association (EHRA) score was used to assess AF related symptoms: Grade 1 = none (excluded from the current study); Grade 2 = mild/moderate (normal daily activity not affected); Grade 3 = severe (normal daily activity affected); and Grade 4 = disabling (normal daily activity discontinued) [12].

The primary outcome measure was the total number of episodes of frequent atrial tachyarrhythmias defined as a composite of definite recurrent atrial tachyarrhythmias, frequent premature atrial contractions (PACs) (>5 per 30 beats), and short runs (>5 beats) of PACs, detected by the monitor or ambulatory ECG during the 30-day treatment period post ablation. The recurrent atrial tachyarrhythmias were defined as AF or atrial tachycardia (AT) lasting for >30 seconds or requiring repeat ablation, hospital admission, or usage of AADs. The secondary outcome measures were recurrent atrial tachyarrhythmias during the blanking period of 90-day, recurrent atrial tachyarrhythmias within 1-year after the blanking period of 90-day post-ablation, and Saireito-related adverse symptoms during the treatment period of 30 days. The Saireito-related adverse symptoms included a cough and digestive symptoms such as nausea, anorexia, and diarrhea. The serum cardiac enzymes such as the creatine kinase (CK), CK-MB and troponin I were measured before, and 6-hour, 1-day, 2-day, and 1-month after the procedure. The serum inflammatory biomarkers such as the white blood cells and C-reacting protein were measured before, and 1-day, 2-day, and 1-month after the procedure. The serum level of brain natriuretic peptides (BNP) and N-terminal pro BNP (NT-proBNP) were also measured before and 1-month after the procedure. Moreover, the extent of the body temperature elevation, body weight gain, and intravenous furosemide use during the index hospitalization were recorded. The quality of life was assessed by the Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) score [13] before and 1-month, 3-month, and 1-year after the procedure.

Statistical analysis

This was the first pilot study to evaluate the efficacy of Saireito in reducing early atrial tachyarrhythmias after AF ablation. Therefore, 50 patients in each group were set as the sample-size without calculation of the statistical power. The primary outcome measure, i.e., the total number of episodes of frequent atrial tachyarrhythmias during the treatment period of 1-month post ablation was presented as the mean value ± SD and compared using the Student t test. Other data were presented as values and percentages, and the mean value ± SD or median with the first quartile to third quartile. Categorical variables were compared with the χ² test or Fisher exact test. Continuous variables were compared using the Student t test or Wilcoxon rank sum test based on their distribution. The cumulative incidence and event-free survival was estimated by the Kaplan-Meier method and the differences were assessed by the log-rank test. All analyses regarding the primary and secondary endpoints were performed by the intention-to-treat manner. Statistical analyses were performed using JMP 14 pro (SAS Institute Inc, Cary, NC) software. All the analyses were two-tailed, and a P value of <0.05 was considered statistically significant.

Study patients

A total of 100 patients were enrolled between August 2020 and January 2022 in the study. Among the 50 patients assigned to the Saireito group, 3 (6.0%) prematurely discontinued the drug because of adverse symptoms (Fig 1). All study patients completed the 1-year follow-up, except for 1 patient in the control group who died due to colon cancer within a year.

The baseline characteristics of the study patients are shown in Table 1. The average age was about 70 years and 82.0% of patients had paroxysmal AF. PV isolation was performed using cryoballoon in two-thirds of patients. All baseline characteristics were well balanced between the 2 groups.

Clinical outcomes as an efficacy of Saireito-use

In the intention-to-treat analysis, the Saireito group was associated with a numerically smaller number of frequent atrial tachyarrhythmias as compared to the control group during the treatment period of 30 days (3.1±4.6 times versus 5.2±9.4 times, P = 0.17) (Fig 2A). Daily numbers of frequent atrial tachyarrhythmias during the 30 days after the procedure in the 2 groups are shown in Fig 3. Mean daily number of frequent atrial tachyarrhythmias during Day-6 to Day-10 and Day-11 to Day-15 post-procedure was significantly lower in the Saireito group than in the control group (0.12 times/day and 0.27 times/day, P = 0.03, 0.08 times/day and 0.24 times/day, P = 0.001, respectively). Meanwhile, the cumulative incidence of the first episode of frequent atrial tachyarrhythmias did not differ between the 2 groups (68.0% versus 64.0%, P = 0.99) (Fig 2B). Furthermore, there was no difference between the groups in the event-free rates from definite recurrent atrial tachyarrhythmia within 90 days and after the blanking period of 90 days following the procedure (S1 Fig). The numerically lower number of the atrial tachyarrhythmias in the Saireito group during the treatment period was consistent in the patient subgroups (S1 Table).

The serum cardiac enzymes, such as CK, CK-MB, and Troponin I, peaked out at 6-hour after the procedure, and the levels did not significantly differ between the Saireito and control groups (Fig 4A). The inflammatory biomarkers, i.e., the serum white blood cells and C-reacting protein peaked out at Day-1 and Day-2, respectively, and the levels were comparable between the 2 groups (Fig 4B). The NT-proBNP level in the control group numerically increased immediately after the procedure but significantly decreased at 30-day, while that in the Saireito group was stable during the 30-day treatment period (Fig 4C). The BNP level was comparable between the 2 groups during the treatment period. AFEQT score at 1-month post-procedure was significantly improved from baseline in both group (61.3 [51.7–76.0] versus 81.7 [69.6–89.0], P<0.001 in Saireito group; 62.1 [49.8–75.2] versus 80.4 [71.9–90.6], P<0.001 in control group), with no significant difference between the 2 groups (Fig 4D). The elevation in the body temperature during the index admission was significantly larger in the Saireito group than in the control group (Fig 4E). There was no significant difference in the extent of body weight gain and intravenous furosemide use between the 2 groups.

Adverse outcomes as a measure of the safety of Saireito-use

The prevalence of adverse symptoms including a cough and digestive symptoms during the treatment period of 30 days was significantly higher in the Saireito group than in the control groups (18.0% versus 2.0%, P = 0.005) (Table 2). Three patients (6.0%) prematurely discontinued Saireito: 78-year-old patient at Day-12 for a fever and a cough, a 67-year-old female at Day-13 for nausea, and an 84-year-old male at Day-17 for a cough. The increase in the adverse symptoms during the treatment period was more pronounced in the elderly patients (≥70 years old), males, or early (<3 years) AF patients with no heart failure, chronic kidney disease, or with high BNP levels (S1 Table).

Interstitial pneumonia occurred in 2 patients (4.0%) who had had no obvious lung disease and had completed the 30-day use of Saireito: an 83-year-old male with an onset at Day-31 and a 74-year-old male with an onset at Day-40 post procedure (S2 Fig). Both patients received short-term steroid therapy and fully recovered from the pneumonia. No pseudoaldosteronism or new-onset severe liver failure as a side effect of Saireito did not occur during the study period.

Limitations

There were several important limitations in this study. First, the current study did not have a statistical power for the primary outcome because of the small sample size, which precluded any definitive conclusions. However, we for the first time evaluated the efficacy and safety of the 30-day use of Saireito after catheter ablation for symptomatic AF in this pilot trial. Second, the assigned treatment was blinded only to the operators during the ablation procedure, but not to the participants, because of unavailability of the placebo of Saireito. Patients’ wariness toward newly started Saireito after ablation might have affected the adverse symptoms. Third, implantable loop recorder was not used in this study. Although the patients received intensive monitoring with an ambulatory electrogram recorder during 30-day treatment period after the procedure, there may have been substantial undetected episodes of frequent atrial tachyarrhythmias during follow-up.

S1 Table

Clinical outcomes in the subgroups.

(DOCX)

S1 Fig

Event-free survival from definite recurrent atrial tachyarrhythmias within and after 90-days.

(TIF)

S2 Fig

Two cases of interstitial pneumonia in the Saireito group.

(TIF)

1. Oral H, Knight BP, Özaydın M, Tada H, Chugh A, Hassan S, et al. Clinical significance of early recurrences of atrial fibrillation after pulmonary vein isolation. J Am Coll Cardiol. 2002;40:100–104doi: 10.1016/s0735-1097(02)01939-3 [PubMed] [CrossRef] [Google Scholar]

2. O’Donnell D, Furniss SS, Dunuwille A, Bourke JP. Delayed cure despite early recurrence after pulmonary vein isolation for atrial fibrillation. Am J Cardiol. 2003;91:83–85doi: 10.1016/s0002-9149(02)03005-9 [PubMed] [CrossRef] [Google Scholar]

3. Richter B, Gwechenberger M, Socas A, Marx M, Gössinger HD. Frequency of recurrence of atrial fibrillation within 48 hours after ablation and its impact on long-term outcome. Am J Cardiol. 2008;101:843–847doi: 10.1016/j.amjcard.2007.11.021 [PubMed] [CrossRef] [Google Scholar]

4. Ding Y, Pan Y, Wang M, Cao L, Xu H, Wei L, et al. Factors influencing kinesiophobia during the “blanking period” after radiofrequency catheter ablation in patients with atrial fibrillation by the fear-avoidance model. Int J Cardiol. 2022;363:49–55doi: 10.1016/j.ijcard.2022.06.021 [PubMed] [CrossRef] [Google Scholar]

5. Roux J-Fo, Zado E, Callans DJ, Garcia F, Lin D, Marchlinski FE, et al. Antiarrhythmics after ablation of atrial fibrillation (5A study). Circulation. 2009;120:1036–1040doi: 10.1161/CIRCULATIONAHA.108.839639 [PubMed] [CrossRef] [Google Scholar]

6. Leong-Sit P, Roux J-F, Zado E, Callans DJ, Garcia F, Lin D, et al. Antiarrhythmics after ablation of atrial fibrillation (5a study). Circ Arrhythm Electrophysiol. 2011;4:11–14 [PubMed] [Google Scholar]

7. Darkner S, Chen X, Hansen J, Pehrson S, Johannessen A, Nielsen JB, et al. Recurrence of arrhythmia following short-term oral amiodarone after catheter ablation for atrial fibrillation: A double-blind, randomized, placebo-controlled study (AMIO-CAT trial). Eur Heart J. 2014;35:3356–3364doi: 10.1093/eurheartj/ehu354 [PubMed] [CrossRef] [Google Scholar]

8. Kaitani K, Inoue K, Kobori A, Nakazawa Y, Ozawa T, Kurotobi T, et al. Efficacy of antiarrhythmic drugs short-term use after catheter ablation for atrial fibrillation (EAST-AF) trial. Eur Heart J. 2016;37:610–618doi: 10.1093/eurheartj/ehv501 [PubMed] [CrossRef] [Google Scholar]

9. Hattori T, Maruyama H, Nishimura H, Nakai Y, Sakakibara I, Kase Y, et al. Effects of saireito, a japanese herbal medicine, on edema via antagonistic actions against aldosterone in anti-gbm nephritic rats. Clin Exp Nephrol. 2006;10:13–18doi: 10.1007/s10157-005-0402-7 [PubMed] [CrossRef] [Google Scholar]

10. f*ckunishi S, Nishida S, Nakamura K, Yokohama K, Ohama H, Asai A, et al. Co-administration of saireito enabled the withdrawal of corticosteroids in an elderly woman with autoimmune hepatitis. Intern Med. 2016;55:43–47doi: 10.2169/internalmedicine.55.5128 [PubMed] [CrossRef] [Google Scholar]

11. Heimesaat MM, Kato S, Hayashi S, Kitahara Y, Nagasawa K, Aono H, et al. Saireito (TJ-114), a japanese traditional herbal medicine, reduces 5-fluorouracil-induced intestinal mucositis in mice by inhibiting cytokine-mediated apoptosis in intestinal crypt cells. Plos One. 2015;10:e0116213doi: 10.1371/journal.pone.0116213 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

12. Wynn GJ, Todd DM, Webber M, Bonnett L, McShane J, Kirchhof P, et al. The european heart rhythm association symptom classification for atrial fibrillation: Validation and improvement through a simple modification. Europace. 2014;16:965–972doi: 10.1093/europace/eut395 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

13. Spertus J, Dorian P, Bubien R, Lewis S, Godejohn D, Reynolds MR, et al. Development and validation of the atrial fibrillation effect on quality-of-life (AFEQT) questionnaire in patients with atrial fibrillation. Circ Arrhyth and Electrophysiol. 2011;4:15–25doi: 10.1161/CIRCEP.110.958033 [PubMed] [CrossRef] [Google Scholar]

14. Kaneko T, Chiba H, Horie N, Hashimoto K, Satoh K, Kusama K, et al. Effect of two different groups of chinese medicines on nitric oxide production by mouse macrophage-like cells. In Vivo. 2004;18:771–778 [PubMed] [Google Scholar]

15. Ono T, Liu N, Makino T, Nogaki F, Muso E, Honda G, et al. Suppressive mechanisms of sairei-to on mesangial matrix expansion in rat mesangioproliferative glomerulonephritis. Nephron Exp Nephrol. 2005;100:e132–142doi: 10.1159/000085059 [PubMed] [CrossRef] [Google Scholar]

16. Nagai A, Shibamoto Y, Ogawa K. Therapeutic effects of saireito (Chai-ling-tang), a traditional japanese herbal medicine, on lymphedema caused by radiotherapy: A case series study. Evid Based Complement Alternat Med. 2013;2013:241629doi: 10.1155/2013/241629 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

17. Kishida Y, Miki H, Nishii T, Inoue T, Nishida S, Yoshikawa H, et al. Therapeutic effects of saireito (TJ-114), a traditional japanese herbal medicine, on postoperative edema and inflammation after total hip arthroplasty. Phytomedicine. 2007;14:581–586doi: 10.1016/j.phymed.2006.12.024 [PubMed] [CrossRef] [Google Scholar]

18. Morimoto N, Kakudo N, Mitsui T, Kuro A, Ueda Y, Hihara M, et al. The effectiveness of saireito, a traditional japanese herbal medicine, in reducing postoperative edema after acquired ptosis surgery: A prospective controlled trial. Evidence-Based Complementary and Alternative Medicine. 2018;2018:1–8doi: 10.1155/2018/4742305 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

19. Saad EB, Marrouche NF, Saad CP, Ha E, Bash D, White RD, et al. Pulmonary vein stenosis after catheter ablation of atrial fibrillation: Emergence of a new clinical syndrome. Ann Intern Med. 2003;138:634–638doi: 10.7326/0003-4819-138-8-200304150-00010 [PubMed] [CrossRef] [Google Scholar]

20. Fong HK, Abdullah O, Gautam S. Cough as the sole manifestation of pericardial effusion. BMJ Case Rep. 2018;2018doi: 10.1136/bcr-2017-222327 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

21. Pisani CF, Hachul D, Sosa E, Scanavacca M. Gastric hypomotility following epicardial vagal denervation ablation to treat atrial fibrillation. J Cardiovasc Electrophysiol. 2008;19:211–213doi: 10.1111/j.1540-8167.2007.00937.x [PubMed] [CrossRef] [Google Scholar]

29 May 2024

PONE-D-23-41672Efficacy and safety of Saireito (TJ-114) in patients with atrial fibrillation undergoing catheter ablation procedures: a randomized pilot studyPLOS ONE

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Reviewer #1:I have read with interest the manuscript titled " Efficacy and safety of Saireito (TJ-114) in patients with atrial fibrillation undergoing catheter ablation procedures: a randomized pilot study”. The authors conducted a randomized placebo-controlled prospective single-blinded clinical trial analyzing the anti-inflammatory and anti-edema effects of the Japanese herbal medicine Saireito post-catheter ablation of atrial fibrillation. In particular, in this pilot study they analyzed whether the intake of this traditional herbal medicine reduced the burden of frequent atrial arrhythmias in the 30 days after the procedure (primary endpoint). This period is within the so-called blanking period, in which the burden of atrial arrhythmias might paradoxically increase due to the fact that ablation lesions have not yet completely stabilized and usually is not taken into account in clinical trials, however patients still might experience discomfort due to symptoms with quality-of-life reduction and might necessitate ER visits and/or hospitalization. All anti-arrhythmic drugs were discontinued before ablation procedure in order to avoid bias and analyze Saireito true effect. The authors demonstrated that at the end of the follow up Saireito did not reduce atrial arrhythmias in a statistically significant fashion, however there was a tendency in this reduction, more pronounced in the first two weeks, and trials with bigger sample sizes might provide better insights on the topic. Moreover the use of Saireito was associated with adverse events, in particular with a non-negligible rate of interstitial pneumonia (4%, i.e. two patients).

I think this manuscript is well written and does not have any major issue in form or design of the study. The study design and the endpoints are clear, as well as inclusion and exclusion criteria. The topic is debated among experts and the use of this Herbal Medicine might be a novelty. I therefore wholeheartedly congratulate the Authors for their work.

I would like to highlight the following aspects:

1. The study is single-blinded for the operators, participants were not masked to the treatment assignment. The reason of this choice should be clearly stated.

2. Ablation procedures, both using RF and cryoballoon, have a plethora a possible variables to be considered to define ablation success. However, maybe due to word limit, it was not clearly defined how ablation success was evaluated. Please elaborate on this and provide the exact variables used to define clinical success. Furthermore were mapping systems used? Was remapping after energy delivery evaluated?

3. In the “Methods – Follow up” section I would suggest to change the sentence “The monitored ECGs during the index admission were read by the attending physicians”, In particular I would suggest to use the word “analyze” in lieu of read, to better convey the message I think the Author intended to pass on.

4. A 30-day period was chosen. Why did the Author chose such period? I think it would be interesting to analyze the effect of Saireito on the whole blanking period, which is conventionally defined as 90 days for most trials, or at least 45 days, as some authors advocates for shorter blanking periods.

5. Was the use of Implantable Loop Recorders (ILRs) to detect atrial arrhythmias taken into consideration? I think the use of ILRs could have provided invaluable data on this matter, virtually eliminating the possibility of undetected episodes of atrial arrhythmias (a limit clearly stated by the Authors on the manuscript)

6. I think the abstract conclusion section should be changed to avoid misleading the readers, in particular I would change the part “but the favorable effect was remarkable in the first 2 weeks” with “there was a tendency in their reduction, more pronounced in the first two weeks”.

7. Last but not least, the use of Saireito was associated with adverse events, in particular with a non-negligible rate of interstitial pneumonia (4%, i.e. two patients) which could theoretically lead to further morbidity and mortality and have long lasting effects on the patients. Did the two patients had any long-lasting effects due to pneumonia? Furthemore, could you elaborate more on this aspect and in particular on its pathogenesis? Moreover, considering that, as you cited, interstitial pneumonia is a side effects of Ogon, a component of Saireito, is it possible and/or plausible to avoid its use in the Saireito compound? Considering this non-negligible rate of this complication, are further studies using Saireito ethically viable in your opinion?

I congratulate again the Authors for their invaluable work.

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Reviewer #1:Yes:Domenico Pecora

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10 Jul 2024

Response to Reviewers

We deeply appreciate the editor and the reviewer for the critically important comments and suggestions on our paper. We have revised our manuscript according to those comments.

All essential changes in the revised manuscript were highlighted in red font.

Our replies to the comments and suggestions of the editor and the reviewer are written below.

Reviewer #1: I have read with interest the manuscript titled " Efficacy and safety of Saireito (TJ-114) in patients with atrial fibrillation undergoing catheter ablation procedures: a randomized pilot study”. The authors conducted a randomized placebo-controlled prospective single-blinded clinical trial analyzing the anti-inflammatory and anti-edema effects of the Japanese herbal medicine Saireito post-catheter ablation of atrial fibrillation. In particular, in this pilot study they analyzed whether the intake of this traditional herbal medicine reduced the burden of frequent atrial arrhythmias in the 30 days after the procedure (primary endpoint). This period is within the so-called blanking period, in which the burden of atrial arrhythmias might paradoxically increase due to the fact that ablation lesions have not yet completely stabilized and usually is not taken into account in clinical trials, however patients still might experience discomfort due to symptoms with quality-of-life reduction and might necessitate ER visits and/or hospitalization. All anti-arrhythmic drugs were discontinued before ablation procedure in order to avoid bias and analyze Saireito true effect. The authors demonstrated that at the end of the follow up Saireito did not reduce atrial arrhythmias in a statistically significant fashion, however there was a tendency in this reduction, more pronounced in the first two weeks, and trials with bigger sample sizes might provide better insights on the topic. Moreover the use of Saireito was associated with adverse events, in particular with a non-negligible rate of interstitial pneumonia (4%, i.e. two patients).

I think this manuscript is well written and does not have any major issue in form or design of the study. The study design and the endpoints are clear, as well as inclusion and exclusion criteria. The topic is debated among experts and the use of this Herbal Medicine might be a novelty. I therefore wholeheartedly congratulate the Authors for their work.

I would like to highlight the following aspects:

1. The study is single-blinded for the operators, participants were not masked to the treatment assignment. The reason of this choice should be clearly stated.

Thank you for your important comments. As you indicated, the assigned treatment was blinded only to the operators during the ablation procedure, but not to the patients. This is an important limitation of the study. We added the following sentences in the Limitation section.

<Limitations>

Second, the assigned treatment was blinded only to the operators during the ablation procedure, but not to the participants, because of unavailability of the placebo of Saireito. Patients’ wariness toward newly started Saireito after ablation might have affected the adverse symptoms. (Page 11, Line 4- Page 11, Line 7)

2. Ablation procedures, both using RF and cryoballoon, have a plethora a possible variables to be considered to define ablation success. However, maybe due to word limit, it was not clearly defined how ablation success was evaluated. Please elaborate on this and provide the exact variables used to define clinical success. Furthermore were mapping systems used? Was remapping after energy delivery evaluated?

Thank you for your comment. Our main strategy in AF ablation was pulmonary vein (PV) isolation. Whether to perform additional ablations were left to the discretion of the operators. When PV isolation was performed by radiofrequency catheter ablation, adenosine-triphosphate test was performed to check dormant conduction. When cryoballoon was used for PV isolation, 3D-electrioanatomical mapping was performed to confirm the completion of PV isolation. We added the following sentences in the Methods section.

<Methods>

The ablation procedure was performed under the guidance of a three-dimensional mapping system (CARTO, Biosense-Webster, Diamond Bar, CA, USA; Ensite NavX, Abbott, Chicago, IL, USA; Rhythmia, Boston Scientific, Natick, MA, USA). PV isolation with radiofrequency catheter ablation was an extensive encircling PV isolation with two circular-shaped catheters placed in the ipsilateral superior and inferior pulmonary veins. After successful PV isolation, we checked whether dormant conduction between LA and PVs was provoked by adenosine triphosphate under isoproterenol infusion. When dormant conduction was induced, additional radiofrequency energy applications were delivered until disappearance of dormant conduction. In PV isolation with cryoballoon, single-shot freezing was performed for each PV, and electro-anatomical mapping with a high-density mapping catheter was performed to confirm the completion of PV isolation. When there was a conduction gap between PV and LA, touch-up ablation was performed using radiofrequency ablation catheter. Whether to perform additional ablation, such as tricuspid valve isthmus ablation, left atrial roof line ablation, mitral isthmus ablation, and superior vena cava isolation, was left to the discretion of the operators. (Page 4, Line 21 – Page 21, Line 7)

3. In the “Methods – Follow up” section I would suggest to change the sentence “The monitored ECGs during the index admission were read by the attending physicians”, In particular I would suggest to use the word “analyze” in lieu of read, to better convey the message I think the Author intended to pass on.

Thank you very much for your kind comment. As you suggested, we revised the following sentences in the Methods section.

<Methods>

Twenty-four-hour Holter-monitoring was performed at 3-6 months. The monitored ECGs during the index hospital admission were analyzed by the attending physicians. (Page 5, Line 17 – Page 5, Line 18)

4. A 30-day period was chosen. Why did the Author chose such period? I think it would be interesting to analyze the effect of Saireito on the whole blanking period, which is conventionally defined as 90 days for most trials, or at least 45 days, as some authors advocates for shorter blanking periods.

Thank you for your important comment. We agree that the 90-day period is a gold standard for the blanking-period after catheter ablation for AF. Recently, however, a shorter blanking period of 2-month has been also proposed (Heart Rhythm 2024;21:521–529, J Cardiovasc Electrophysiol. 2020;31:2363–2370). Furthermore, in the recent report by Onishi et al (Int J Cardiol. 2021 Oct 15:341:39-45), patients with early arrhythmia recurrences between 1- and 3-month post ablation was associated with much higher rate of late arrhythmia recurrence beyond the blanking period of 90 days, as compared to those with early arrhythmia recurrences within 1 month.

Also considering the risk of potential side effects of Saireito, we chose relatively short treatment period of 30 days in this pilot study.

5. Was the use of Implantable Loop Recorders (ILRs) to detect atrial arrhythmias taken into consideration? I think the use of ILRs could have provided invaluable data on this matter, virtually eliminating the possibility of undetected episodes of atrial arrhythmias (a limit clearly stated by the Authors on the manuscript)

We totally agree with your opinion. We wanted to use ILRs to precisely assess the burden of early atrial tachyarrhythmias after procedure in this study. However, in Japan, ILRs were officially covered by medical insurance only for syncope and embolic stroke of unknown sources (ESUS). Also, the present study was non-company-sponsored physician-initiated study. Therefore, we used the ambulatory ECG monitors instead of ILRs, which is a limitation of the study. We added descriptions regarding this point in the limitation section, as pasted below.

<Limitations>

Third, implantable loop recorder was not used in this study. Although the patients received intensive monitoring with an ambulatory electrogram recorder during 30-day treatment period after the procedure, there may have been substantial undetected episodes of frequent atrial tachyarrhythmias during follow-up. (Page 11, Line 7 – Page 11, Line 10)

6. I think the abstract conclusion section should be changed to avoid misleading the readers, in particular I would change the part “but the favorable effect was remarkable in the first 2 weeks” with “there was a tendency in their reduction, more pronounced in the first two weeks”.

Thank you for your kind comment. We revised the conclusion section of the abstract according to your suggestion, as pasted below.

<Abstract>

Conclusions Thirty-day use of Saireito following AF ablation was associated with a tendency toward reduced number of episodes of frequent atrial tachyarrhythmias during the treatment period, with more pronounced effect in the first two weeks. (Page 2, Line 16 - Page 2, Line 18)

7. Last but not least, the use of Saireito was associated with adverse events, in particular with a non-negligible rate of interstitial pneumonia (4%, i.e. two patients) which could theoretically lead to further morbidity and mortality and have long lasting effects on the patients. Did the two patients had any long-lasting effects due to pneumonia? Furthemore, could you elaborate more on this aspect and in particular on its pathogenesis? Moreover, considering that, as you cited, interstitial pneumonia is a side effects of Ogon, a component of Saireito, is it possible and/or plausible to avoid its use in the Saireito compound? Considering this non-negligible rate of this complication, are further studies using Saireito ethically viable in your opinion?

I congratulate again the Authors for their invaluable work.

Thank you for your comment. Interstitial pneumoniae (IP) is a main safety concern for the use of Saireito. It is considered a side effect of Ogon, a component of Saireito. Unfortunately, it is difficult to remove Ogon from Sareito. The two patients with IP received short-term steroid therapy and fully recovered from IP without any long-lasting effects.

We added the following sentences in the Results and Discussion sections.

<Results>

Interstitial pneumonia occurred in 2 patients (4.0%) who had had no obvious lung disease and had completed the 30-day use of Saireito: an 83-year-old male with an onset at Day-31 and a 74-year-old male an onset at Day-40 post procedure (Figure S2). Both patients received short-term steroid therapy, and fully recovered from the pneumonia. No pseudoaldosteronism or new-onset severe liver failure as a side effect of Saireito did not occur during the study period. (Page 8, Line 24 – Page 8, Line 28)

<Discussion>

Regarding the safety of Saireito-use, interstitial pneumonia, which is one of the side effects of Ogon (a component of Saireito), occurred in 2 elderly patients (4.0%) in the Saireito group. Given the very low prevalence of spontaneous interstitial pneumonia (<0.1%) and the timing of the onset of the pneumonia in those 2 cases (within 10 days after the treatment period), causal relationships between Saireito use and interstitial pneumonia were strongly suspected. The physicians should be cautious of interstitial pneumonia with Saireito use especially in elderly patients. Considering the pronounced effect of Saireito in reducing atrial tachyarrhythmias in the first 2 weeks after ablation and the risk of side effects of Saireito, especially interstitial pneumonitis, 2 weeks rather than 30 days may be better to maximize the benefit and minimize the risk of Saireito use after AF ablation. The prevalence of adverse symptoms, i.e., coughs and digestive symptoms were more frequent in the Saireito group (18.0%) than in the control group (2.0%), leading to discontinuation of the drug in 3 patients (6.0%) in the present study. However, in the acute phase after AF ablation, such symptoms are commonly observed and may be a sign of iatrogenic pulmonary stenosis, pericardial effusion, or acute gastric hypomotility.19-21 Therefore, newly added medications after AF ablation are likely to be discontinued for those adverse symptoms. (Page 10, Line 14 – Page 10, Line 25)

12 Jul 2024

Efficacy and safety of Saireito (TJ-114) in patients with atrial fibrillation undergoing catheter ablation procedures: a randomized pilot study

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