In 2019, the Guidelines for non-pharmacotherapy of cardiac arrhythmias (JCS/JHRS 2019) were published, covering areas such as treatment using cardiac electrical implantable devices (CIEDs), catheter ablation, surgical treatments, and therapies using left atrial appendage occlusion devices.1 According to the recent dramatic development of non-pharmacotherapy in the field of cardiac arrhythmias, major revisions had been made to the JCS/JHRS 2019 guidelines, owing to critical evaluation by many clinicians. Following the publication of the guidelines, however, more, important clinical evidence had been established in both Japan and abroad, and new concepts of treatment have been created. As updating and disseminating new information directly affects daily clinical practice, we decided to publish “The focused updated guidelines on non-pharmacotherapy of cardiac arrhythmias (JCS/JHRS 2021)” focusing on fields with significant progression, instead of waiting for the next revision of the entire guidelines. Our standards for selecting the issues in the focused update guidelines were as follows: (1) therapy with a previously undetermined recommendation level that has become specified because of new evidence from both Japan and abroad, (2) newly established therapeutic concepts, and (3) important issues in which omission in the previous guidelines was inevitable because of word limits. Accordingly, the main features of these focused updated guidelines are as follows. Although a large international clinical trial to test the utility of leadless pacemakers had been published when the previous guidelines were announced, we did not address the recommendation because it had been suggested that the incidence of complications owing to the small body size of Japanese patients might be higher than in Western patients. However, a subanalysis of a large clinical trial based on Japanese data,2 and our subsequent clinical experience, allowed us to describe the recommendation level. The novel anti-heart failure pacing therapy (ie, conduction system pacing [His bundle pacing]) has appeared as a novel but different concept to cardiac resynchronization therapy (CRT). When the previous guidelines were announced, there were no guidelines or expert consensus that clarified the recommended therapeutic level; however, the new ACC/AHA/HRS guidelines in 2019 stated a recommended level,3 and the initial concept of His bundle pacing was extended to conduction system pacing including both His bundle and left bundle pacing. Therefore, based on the present consideration, we describe recommended levels of conduction system pacing. The recently established concept of advance care planning (ACP) has facilitated the process of discussing and making decisions with healthcare patients for their preferred goals of care if they lose their communication ability in the future. When facing the end of life, ICD therapy (especially shock therapy) is not always desired by patients or their families; therefore, the decision to deactivate the ICD therapy can be acceptable. With the overlap in the timing of publishing JCS/JHFS 2021 Statement on Palliative Care in Cardiovascular Diseases,4 we decided to describe the class recommendations based on the evidence level and decision-making process in this focused update. In association with ACP, we also mention the indications for ICDs in elderly patients. The description of several important aspects of transcutaneous lead extraction (ie, bacteremia without lead infection, superficial infection around the subcutaneous pocket, antibiotic therapy, and CIED re-implantations after lead extraction) were excluded in the previous guidelines but are addressed in the focused update. Although large, international clinical trials demonstrating the efficacy of ATP (capabilities to terminate atrial fibrillation [AF] and prevent the aggravation of AF into a persistent type) had been published in other countries when the previous guidelines were announced, we did not address this therapy because of the absence of clinical evidence from Japan and because of word limits. Taking the novel Japanese evidence of ATP for AF with CIEDs5 into account, however, we decided to include ATP in the focused update. The JCS/JHRS 2020 guidelines on pharmacotherapy of cardiac arrhythmias addressed the clinical significance of asymptomatic (silent) AF and advanced methods of documenting AF.6 In response to the guidelines, we prescribe appropriate management of AF detected by CIED monitoring (focusing on anticoagulant therapy especially) in the focused update. The development of 3D mapping systems has largely contributed to identifying the precise position of catheters in the cardiac chambers without fluoroscopic guidance, thereby reducing the exposure to radiation during catheter ablation procedures. Problems due to radiation injury had been mentioned in previous guidelines; however, to promote awareness and knowledge of reducing the radiation exposure of clinicians, we focused on the use of advanced 3D mapping systems to reduce exposure dose. Besides intraoperative radiation exposure, we described unignorable radiation exposure by preprocedural computed tomography (CT) imaging. According to the CABANA study,7 a new large randomized clinical trial that tested the prognostic efficacy of catheter ablation in patients with AF, we reconsidered the class recommendations for catheter ablation of asymptomatic AF. Further, we were able to establish the class recommendations for catheter ablation in AF patients with heart failure based on even higher levels of evidence (ie, a large randomized clinical trial and meta-analysis including several important clinical studies8). Furthermore, the efficacy of early rhythm-control therapy for AF, either with antiarrhythmic drugs or catheter ablation (pulmonary vein isolation using the cryoballoon technique), has been reported by several large randomized clinical trials.9-11 Taking these results into account, we describe the significance of early rhythm-control to prevent deterioration of AF. As for the new technologies of catheter ablation, high-power radiofrequency delivery with a short duration and the expanded use of the cryoballoon technique for persistent AF are addressed. The management of anticoagulation therapy during the peri-catheter ablation period has been rewritten because various important clinical evidence has been documented in both Japan and abroad,12-18 and because a supplemental description was needed according to the contents of the Guidelines on non-pharmacotherapy of cardiac arrhythmias (JCS/JHRS 2019).6 Because percutaneous transcatheter therapies for left atrial appendage occlusion were not reimbursed in Japan when the previous guideline was announced, detailed description of this technology was postponed. However, sufficient clinical experience has since accumulated in both Japan and abroad, to understand the appropriate indications, safety, postoperative management, and long-term efficacy of this therapy.19 Therefore, we describe the class recommendations for this novel technology in the present focused update. This set of guidelines recommends indications for non-pharmacotherapy of arrhythmia based on the latest findings and evidence. We first surveyed materials based on evidence from the USA and Europe, then further critically examined the levels of evidence, collected information available in Japan, and examined all material based on the experiences and opinions of members and collaborators in the Joint Working Group. This revision adds new knowledge acquired from advances in diagnostic techniques and treatment methods, or recently reported important evidence, while considering consistency with each of the previously reported guidelines published by the JCS/JHRS Joint Working Group. The recommendation of classes and evidence levels used in this set of guidelines conform to those of the American Heart Association (AHA), American College of Cardiology (ACC), and Heart Rhythm Society (HRS) guidelines.20 The recommended class of indications for each diagnosis and treatment method is classified as I, IIa, IIb, or III, and the level of evidence is classified as level A, B, or C (Tables 1, 2). The guidelines also state the grade of recommendation and level of evidence based on the “Medical Information Network Distribution Service (MINDS) Handbook for Clinical Practice Guideline Development 2007”,21 published by the MINDS Evidence-based Medicine dissemination promotion project as a guideline preparation method (Tables 3, 4). However, the MINDS Grade of Recommendation and Level of Evidence should be used only as a reference, as this system regards the evidence level in a fundamentally different manner. The MINDS level of evidence (levels of evidence in literature on treatment) is a classification based on research design, and the highest level was adopted when multiple papers were considered. This set of guidelines is designed to be used as a reference by doctors diagnosing and treating diseases in clinical practice, but the final decision should be made by the attending physicians after ascertaining the patient's condition. Even when selecting a diagnosis or treatment that does not follow the guidelines, the decision of the attending physicians should be prioritized in consideration of the individual patient's situation. In actual clinical settings, it is more important for the attending physicians to make the judgment after considering the clinical background and social situation of each patient fully while complying with the guidelines. Although the leadless pacemaker is an emerging pacing technology, the clinically available mode of a leadless pacemaker in Japan, as of January 2021, is VVI; therefore, an appropriate indication should be considered. Symptomatic bradycardic atrial fibrillation (AF) is a Class I indication. Patients with atrioventricular (AV) block without AF or sinus node dysfunction might benefit from the leadless VVI pacemaker only when the risk of implantation of the atrial lead is higher than its benefit, the patient has severe frailty, is bed-ridden, or has less than 1-year survival (Table 5). An investigational device exemption (IDE) study included 36 patients from Japan.2 Albeit a smaller body status, the safety and efficacy endpoints in Japanese patients were comparable to those in patients from the rest of the world. Cardiac perforation occurred in approximately 1%, and 15% of them required surgical repair.2 Given that the risk factors for cardiac perforation include female sex, old age (≥85 years), chronic respiratory disease, body mass index <20 kg/m2, congestive heart failure, and steroid use, a typical candidate for a leadless pacemaker may be high-risk.22, 23 Hence, a careful risk evaluation is important. The leadless pacemaker is MRI conditional (1.5 and 3 T).24 There are no established data on radiation therapy, but a case study reported that up to 30 Gy radiation therapy in a patient with mediastinal malignancy with a leadless pacemaker inside the radiation field yielded no remarkable damage to the pacemaker.25 Nevertheless, it is recommended that electrical parameters should be checked prior to and after radiation therapy or MRI.24, 25 In hemodialysis patients, the leadless pacemaker is often chosen due to the venous occlusion caused by previous hemodialysis catheters, to improve the patency of an arteriovenous fistula, or to minimize the infection rate. In 3 studies of the Micra transcatheter pacing system (IDE, Micra Transcatheter Pacing System Continued Access Study, and Post-Approval Registry), 201 out of 2,819 patients (7%) were under hemodialysis.26 A majority of the patients (72%) had conditions that precluded transvenous pacing, including the need to preserve venous access (79%), prior infection (20%), and venous occlusion (17%). A successful implant was achieved in 98%, and safety and electrical parameters were similar to non-hemodialysis patients. Although an infection rate of 8% has been reported with conventional pacemakers,27 no infection was reported in these patients. Worldwide experience with successful retrieval of the leadless pacemaker has been reported.28 Data from the manufacturer recorded 40 successful retrievals, and operators for 29 successful retrievals provided information. Of the 29 retrievals, 11 were during the index procedure; 18 retrievals were performed after a median of 46 days (1-95 days). Reasons included threshold increment after tether removal (n = 5), loss of capture (n = 3), dislodgement (n = 3) for immediate retrieval, and elevated threshold at follow-up (n = 11), endovascular infection (n = 1), need for transvenous device (n = 2), and CRT upgrade (n = 1) for delayed retrieval. Average time of the retrieval and fluoroscopy was 63.11 min and 16.7 min, respectively, and no adverse events were observed. Of the 1820 patients in the Micra post approval registry, 105 had re-implantation of leadless pacemaker within 30 days after CIED extraction.29 The extracted CIEDs were pacemakers (70.5%), CRT-P (9.5%), and ICD/CRT-D (12.4%), and 93% were complete explants. Pacing-dependent patients underwent a same-day implant more frequently, and non-dependent patients underwent the implant after a median of 7 days; 91% had IV antibiotics pre-implantation, and 42% had them post-implantation as well. During an average of 8.5 months, 2 patients died of sepsis, and 4 patients required a system upgrade, but no leadless pacemaker was explanted due to re-infection. This finding might suggest that a leadless pacemaker is reasonably safe with no recurrent device infection, which may be due to the absence of a subcutaneous pocket, a smaller surface area as compared with the transvenous lead, a greater tendency of encapsulation, and a high-flow environment in the heart cavity. A total of 16 out of 720 patients (2.2%) in the IDE study developed 21 serious cases of bacteremia or endocarditis during follow-up.30 Infection occurred at a mean of 4.8 months after implantation; 13 events were caused by Gram-positive organisms and 3 by Gram-negative bacteria. Two of the three cases of endocarditis resulted in death; one patient with prosthetic aortic valve endocarditis died immediately postoperatively, the other with aortic valve endocarditis 108 days post leadless pacemaker implantation refused surgical intervention. All but 2 patients responded well to antibiotics, and no persistent bacteremia was observed after antibiotic cessation. MicraTM, the clinically available leadless pacemaker in Japan as of January 2021, provides accelerometer-based rate-adaptive pacing. Accelerometer signals identify 4 distinct segments of cardiac activity: isovolumic contraction and mitral/tricuspid valve closure (A1), aortic/pulmonic valve closure (A2), passive ventricular filling (A3), and atrial contraction (A4). Using the downloadable algorithm with accelerometer-based atrial sensing, the MARVEL study showed that AV synchrony improved in patients with complete AV block from 37.5% to 80% compared with VVI mode.31 An improved automated algorithm was evaluated in patients with sinus rhythm with complete AV block in the MARVEL 2 study.32 Median AV synchrony significantly improved in VDD mode compared with VVI mode (27% vs. 94%). AV synchrony ranged from 89.2% during the resting period to 69.8% while standing. The decline in AV synchrony could be due to orthostatic tachycardia or a decrease in the A4 signal because of reduced venous return. Long-lasting right ventricular (RV) pacing produces an iatrogenic desynchronized contraction of the left ventricle (LV), and possibly induces reduced contraction and mechanical remodeling of the LV.33, 34 To resolve this issue of RV pacing, several animal and clinical studies have demonstrated that artificial pacing of the His bundle instead of the RV can provide long-term physiological ventricular conduction.35-37 However, when this concept was initially proposed, permanent and stable His bundle pacing was technically difficult at that time, and therefore, this method was not widely used (Table 6). Recently, however, a newly designed pacing lead and delivery system aimed at pacing the His bundle has emerged and provided >80% success rate,38-43 and the method has been taken up very rapidly since. More recently, this concept has been further developed to enable transseptal left bundle pacing,44 and His bundle and left bundle pacing have become collectively known as “conduction system pacing”. Several clinical studies have demonstrated the efficacy of His bundle pacing for patients with bradycardia (mainly atrio-ventricular block) who have an indication for permanent pacing with a normal or moderately reduced LV ejection fraction (LVEF) (Table 7).38-43 Two randomized clinical trials compared the efficacy of RV pacing to that of His bundle pacing using a crossover design (switching from one pacing method to the other within a fixed period),38, 41 and demonstrated that His bundle pacing improved LVEF. However, the results from the 2 studies were not consistent regarding the improvement in NYHA functional class and 6-min walk distance. Two clinical observational trials, in which the patients were separately assigned to His bundle pacing at a certain hospital and RV pacing at a second hospital, showed an improvement in LVEF39 and reduction in heart failure hospitalizations.42 Furthermore, a meta-analysis accumulating data from many trials revealed LVEF improvement in patients with a preoperative LVEF <50%.43 To date, however, the efficacy of His bundle pacing has not been confirmed by large randomized clinical trials; previous clinical studies were small-scale, and did not show an improvement in the mortality rate as a single primary endpoint. At present, we recommend that it is reasonable to perform His bundle pacing instead of RV pacing in patients with atrioventricular block who have an indication for permanent pacing with 36%>LVEF>50% and who are expected to require ventricular pacing over time. However, for patients with normal cardiac function, the adverse effects of RV pacing on LV performance can be expected to be insignificant; therefore, an indication for His bundle pacing should be carefully considered. Additionally, upgrading to His bundle pacing in patients with preexisting standard RV pacing and moderately reduced LVEF (36%–50%) may impose an additional risk of lead extraction or lead implantation, and the clinical evidence of this challenge is not adequate. Implantation of His bundle pacing lead in patients with sick sinus syndrome but without a conduction system disturbance may cause iatrogenic injury to the conduction system; therefore, the indication for His bundle pacing should be very carefully considered. The efficacy of His bundle pacing in patients who had been proven to be non-responders to CRT was evaluated in 2 small-scale studies45-48 (Barba-Pichardo et al [n = 16]45 and Sharma et al [n = 8],48 which demonstrated a significant improvement in LVEF after His bundle pacing (LVEF increased from 29% to 36% and from 30% to 38%, respectively). Sharma et al evaluated His bundle pacing in 25 patients in whom CRT was impossible due to trans-venous LV pacing failure, and found an improvement in NHYA class and reduction in heart failure admissions (Table 8).48 Comparison between pre- and post-HBP. LVEF, NYHA class, and reduction in LAD, LVESD, and LVEDD significantly improved Comparison of the two groups. LVEF, NYHA class and distance of 6-min walk in both groups significantly and equally improved Comparison between pre- and post-HBP. LVEF, NYHA class, and reduction in LVEDD significantly improved Comparison between pre- and post-HBP. LVEF and NYHA class significantly improved, but the reduction in LVEDD did not. As for cases with a previous LVEF ≤35% (n = 72), LVEF improved from 25% to 40% Group 1: LVP failure (n = 25), CRT non-responder (n = 8) Three different clinical studies attempted to perform His bundle pacing antecedently in candidates for CRT (Table 8).45-48 One randomized study compared the efficacy of HBP to that of CRT using a crossover study design in 29 patients, and showed a significant improvement in LVEF and NYHA functional class for whichever method that was used.46 Furthermore, 2 other single-arm observational studies demonstrated a significant improvement in LVEF and NYHA functional class.47, 48 As there are no data showing the long-term superior efficacy of His bundle pacing over CRT, and because a pacing impulse delivered at the His bundle may fail to capture the left bundle in patients with left bundle branch block, antecedent His bundle pacing without a CRT attempt is difficult to recommend. Therefore, His bundle pacing in candidates for CRT can be considered as an alternative option when (1) heart failure is deteriorating even after CRT, when there is (2) no optimal cardiac vein for LV pacing, (3) an unacceptable increase in the LV pacing threshold, (4) unavoidable phrenic nerve stimulation, (5) repeated dislodgement of the trans-venous LV lead, (6) technical limitations, or when (7) CRT is impossible due to complications or the clinical situation. To resolve several problems of His bundle pacing, such as an increase in the pacing threshold and inability of left bundle capture in patients with complete left bundle branch block, a novel technique has emerged, aimed at pacing the left bundle directly by implanting a pacing lead at a distal site on the ventricular septum toward the LV.49-61 Although this method has been shown to be superior to His bundle pacing in reducing the pacing threshold,59 several concerns have been reported49, 61: perforation of the ventricular septum, injury to the conduction system, dislodgement of the lead, injury to the coronary artery (septal branch) and thromboembolism.51, 59-61 Furthermore, because the follow-up intervals of the studies49, 50, 56 were ≤3 months, the long-term efficacy of left bundle pacing has not been clarified. Some investigators have assumed that left bundle branch pacing can be an alternative method to CRT; however, the significance of this method is still unknown owing to the lack of evidence from a randomized clinical trial including a large number of heart failure patients.58 Whether to deactivate an implantable cardioverter defibrillator (ICD) that was implanted and has been maintained before the patient had reached the end of life remains controversial. Shock therapy not only causes pain to the patient but also distresses the family members who provide care for the patient, thereby contradicting the purpose of palliative care in terminally ill patients. A retrospective observational study of 49 ICD patients who were considered to be near the end of life notwithstanding any cardiovascular disease reported that 42.9% experienced ICD activation within the year before death. Moreover, ICDs were not deactivated in 24.5% of patients, even after an end-of-life diagnosis was made, and only one-third of ICDs were deactivated.62 A subanalysis of data from the MADIT-II study, which reported the ICD therapy status in 98 terminally ill patients, revealed that of 47 patients without ICD deactivation who did not establish Do Not Attempt Resuscitation (DNAR) orders, 6 (13%) experienced ICD shock therapy within 1 week before death, and 9 (19%) experienced ICD shock therapy within 24 hours of death.63 A Swedish observational study reported that 32 of 65 ICD patients with DNAR orders had deactivated ICDs, and 10 of 33 patients without deactivation experienced ICD shock therapy within 24 hours of death.64 Among 51 ICD patients who were diagnosed with end stage heart failure at the Tokyo Women's Medical University Hospital between 2010 and 2018, 12 of 39 patients with DNAR orders had deactivated ICDs. In addition, 21 patients (41%) experienced shock therapy within 3 months before death, 14 patients (27%) experienced shock therapy within 1 month before death, and 12 patients (24%) experienced electrical storms (including antitachycardia pacing) within 1 month before death.65 Thus, the worsening condition of terminally ill patients might contribute to the development of ventricular arrhythmias requiring ICD therapy. To avoid painful shock from the viewpoint of palliative care, cardiologists and healthcare professionals should discuss deactivation of ICDs in patients with end stage disease with the patients/family members (Table 9). Regarding the deactivation of ICDs, discussion is required before confirming the will of patients and families during the planning of end-of-life care based on advance care planning (ACP). This process needs to consider the ethics, cognitive ability of patient, etc, and judgment should be made not only by cardiologists and nurses but also based on consultation with palliative care and medical teams (including psychiatrists and psychologists); sufficient informed consent, depending on the individual situation, should be provided (Figure 1).4 The preparation of ACP directives at the end of life plays an important role with respect to the patient's will. Of course, the content of such directives can be subsequently changed. The HRS Expert Consensus Statement states that communication on ICD deactivation is essential; communication is an ongoing process that starts when informed consent is obtained prior to ICD implantation and continues as the patient's condition and treatment goals change with disease progression.66 However, a previous report found that only 4% of patients discussed ICD deactivation with their physician in the clinical setting.67 According to the survey results of ICD patients with malignancies whose prognoses were relatively easy to predict, 35.3% of patients with stage IV cancer underwent ICD deactivation.68 Thus, there are several possible reasons for disconnecting between the recommendations and actual clinical situations. Medical staff do not actively discuss end-of-life topics and tend to postpone certain issues, such as the deactivation of ICDs, until just before death.69 A survey in the USA reported that some clinicians thought that a DNAR order did not mean that ICD should be deactivated, and one-quarter of clinicians thought that ICD deactivation was ethically considered suicide assistance.67 Besides deactivation, not replacing the device is another option for treatment withdrawal. In addition, ICD can be deactivated while maintaining bradycardia pacing or biventricular pacing to prevent the worsening of heart failure symptoms and impairment of quality of life. These decisions should be determined following the steps described above. In ICD patients who are at the end of life notwithstanding any cardiovascular disease, the deactivation decision should be made closely with clinical psychologists, psychiatrists, and palliative care teams based on full evaluations of the psychological and physical stresses caused by ICD shock therapy while maintaining good communication with the patient's family. Early removal of the total device system (the device and all leads) is a Class I indication for a definite CIED infection, such as device pocket infection or lead infection with vegetation, regardless of whether there are any systemic infection symptoms or bacteremia. Early removal of the total device system is not always a Class I indication for bacteremia without a definite device-related infection. First-line management should be investigation of the infection focus, removal of all easily extracted lines, such as a central venous catheter and temporary pacing wire, and administration of antibiotics based on susceptibility testing results for identified bacteria. If the infection focus is unclear and the clinical course is poor, an indication for lead extraction should be considered based on the pathogenic bacteria, the patient's status, and the risk related to lead extraction.70 The following recommendations for lead extraction are based on specific pathogenic bacteria. Early removal of the total device system is recommended for patients with an implanted CIED device and an occult blood stream infection caused by Staphylococcus aureus, coagulase-negative staphylococci (CNS), Propionibacterium spp., or Candida spp. Staphylococcus aureus is an especially virulent bacterium that can cause tissue-destructive effects and severe clinical symptoms.71 CNS, such as S epidermidis, are weakly pathogenic bacteria; however, the incidence of device pocket infections due to CNS is high.72 Propionibacterium spp. are Gram-positive anaerobic rod bacteria that produce a biofilm similar to S aureus and CNS, resulting in antibiotic refractoriness in cases where the device remains in the patient.73 Candida spp. may cause a refractory blood stream infection, especially in compromised hosts, due to biofilm production.74 Early lead extraction is recommended for bacteremia caused by alpha-/beta-hemolytic Streptococcus spp. and Enterococcus spp. Lead extraction should also be attempted if the bacteremia is recurrent or refractory to antibiotic therapy. The risk of a concomitant infection with the device is considered low.75 Lead extraction is recommended if the bacteremia from Gram-negative bacteria or S pneumoniae is recurrent or refractory to antibiotic therapy. The risk of a concomitant infection with the device is considered low, and antibiotic therapy only may be curative.75 A superficial pocket infection does not reach the device, is caused by surface skin closure sutures, and occurs within 30 days of device implantation. Oral antibiotics effective against Staphylococcus aureus should be administered and local lesion care to the superficial infection site is mandatory for at least 7-10 days until pocket redness and systemic symptoms, such as fever and inflammatory reactions, disappear. Superficial lesions should be treated in the same way as device infections if the le
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