JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

Several randomized controlled trials (RCTs) have investigated the role of ICDs for primary prevention in patients with reduced left ventricular ejection fraction (LVEF), and have shown efficacy in preventing sudden cardiac death (SCD) in heart failure patients with LVEF ≤35%.^{8, 9} On the other hand, the DANISH trial, a prospective comparative study of ICDs in 1,116 patients with nonischemic cardiomyopathy, showed no clear mortality benefit of ICDs for primary prevention in patients with nonischemic cardiomyopathy.¹⁰ A meta-analysis of 6 trials for nonischemic cardiomyopathy, including DANISH,¹¹ showed that ICDs significantly reduced relative mortality; however; it was unclear whether the ICD was more useful in selected patients. It is necessary to identify the patient population in which ICDs are most useful.

In the subanalysis of the Nippon Storm study, Sasaki et al. reported that the incidence of appropriate ICD therapy in nonischemic cardiomyopathy patients for primary prevention was 21%, during a mean follow-up of 775 days.¹² The HINODE study¹³ showed that the mortality and appropriate ICD therapy rates were similar to those in MADIT-RIT for Japanese heart failure patients. In that study, 171 propensity-matched patients for primary prevention from among 354 enrolled patients were compared to 985 patients in the MADIT-RITstudy,¹⁴ which revealed no significant differences in annual survival rates (96.3% in the HINODE group vs. 96.9% in the MADIT-RIT group, P=0.29) or annual appropriate ICD therapy-free rates (94.7% vs. 96.8%, P=0.61) between the 2 groups. The incidence of fatal arrhythmias in patients with heart failure in Japan in recent years is comparable to that in Europe and the USA, but higher than previously thought.

Sarcoidosis is a systemic inflammatory disease characterized by non-caseating granulomas of unknown cause.⁴⁷ Among the affected organs, pulmonary involvement is the most common, but cardiac involvement (cardiac sarcoidosis) is observed in ≈5% of patients, and cardiac involvement is responsible for about half of all deaths due to sarcoidosis.^{48, 49} In recent years, isolated cardiac sarcoidosis with lesions only in the heart⁵⁰ and a poor prognosis⁵¹ as been reported, which has increased the importance of differential diagnosis.

The indications for leadless pacemakers (Figures 2,3) were discussed in the 2021 JCS/JHRS Guideline Focus Update for Non-pharmacologic Treatment of Arrhythmias⁶ regarding venous obstruction and stenosis, and the need for preservation of venous access. Since then, the indications for leadless pacemakers have continued to expand, and various evidences have emerged. This Focus Update describes the new models and modes that have become available, as well as new findings on efficacy and safety. Recommendations for leadless pacemaker implantation are listed in Table 5.

Pacemaker therapy for reflex syncope is recommended in Japan for patients aged ≥40 years with documented long cardiac arrest (>3 s symptomatic, >6 s asymptomatic) and when other therapies such as counterpressure maneuver and orthostatic training are ineffective.⁵.

Recently, the efficacy of a dual-chamber pacemaker with a closed loop stimulation sensor (DDD-CLS) in preventing recurrent syncope in patients with recurrent cardioinhibitory reflex syncope has been reported. The DDD-CLS works with an algorithm that estimates myocardial contractility from changes in intracardiac impedance caused by right ventricular leads and adjusts the pacing rate.

A small, randomized open trial confirmed the efficacy of DDD-CLS in reducing recurrent syncope,^{108, 109} and a double-blind study reported that DDD-CLS reduced recurrent syncope and prolonged the time to first syncope^{110, 111} and improved quality of life (QOL).¹¹² In a retrospective study with 5-year follow-up, DDD-CLS significantly reduced the risk of syncope compared with physiotherapy.¹¹³ A multicenter study of the head-up tilt test after DDD pacemaker implantation showed that DDD-CLS reduced syncope and hypotension caused by the head-up tilt test compared with DDD.¹¹⁴ It is thought that the CLS sensor increases heart rate and maintains cardiac output from the early phase of reflex syncope, preventing syncope.

Based on the current evidence, this Focus Update recommends DDD-CLS pacemaker therapy as recommended Class IIa in patients aged ≥40 years with recurrent cardioinhibitory syncope who have undergone a head-up tilt test and demonstrated cardiac cardioinhibitory syncope. The long-term results are unknown, and a large-scale study is desirable in the future. Because the Head Up Tilt Study did not demonstrate the efficacy of conventional pacemakers in preventing reflex syncope with hypotensive reactions,¹¹⁵ we continue to recommend Class III as before (Table 6).

Although a secondary analysis of PRAETORIAN showed that subcutaneous ICDs (S-ICDs) reduce lead-related complications by 30% compared with transvenous ICDs,¹¹⁶ the inability of S-ICDs to provide pacing for bradycardia and antitachycardia pacing for VT has led some patients to abandon S-ICD implantation. Recently, a solution was developed by combining an S-ICD with a dedicated leadless pacemaker. With this system, when antitachycardia pacing is ineffective, defibrillation is performed by the S-ICD. Animal studies have reported good communication between the S-ICD and the leadless pacemaker, as well as the success rates of antitachycardia pacing.^117-119.

A multicenter, prospective, single-arm study in humans is ongoing as of February 2024, and results on the safety and efficacy of treatment with a combined S-ICD and leadless pacemaker are expected to be evaluated.

The S-ICD is recommended Class I in Japan for patients who are eligible for transvenous ICD implantation, have difficult venous access or are at high risk for infection and do not require bradycardia pacing, antitachycardia pacing for VT or CRT.⁵ In addition to the S-ICD, an extravascular ICD (EV-ICD) with a substernal lead has been developed and is undergoing clinical trials in Japan as of May 2023. However, it is not suitable for patients who require continuous pacing because the pacing threshold is higher than that of transvenous ICDs. When placing a lead under the sternum, its position should be confirmed by multidirectional fluoroscopic imaging to avoid myocardial injury and pneumothorax. Because the lead has 2 coils and 2 ring electrodes, multiple sensing and pacing vectors can be selected.

In a multicenter prospective single-arm study (316 patients),¹²⁰ the success rate of defibrillation during EV-ICD implantation was 98.7% (median energy 15 J) with no intraoperative complications. The success rate of antitachycardia pacing was 50.8%. Complications at 6 months after implantation were hematoma, infection, pain, wound dehiscence, lead migration, and inappropriate therapy in 7.3% of patients. Inappropriate therapy occurred in 29 patients, with P-wave oversensing being the most common.¹²¹ In unsuccessful defibrillation cases, studies analyzing CT images have suggested anatomic factors such as a large rib cage width, myocardium extending very posteriorly, and a caudal heart position in the chest, but multivariate analysis showed no significant differences.¹²² Further studies on EV-ICDs are needed to accumulate evidence.

When bradycardia is the primary pathology, hemodynamic improvement is delivered predominantly by heart rate maintenance; thus, dyssynchronous contraction (the “harmful effect”) by right ventricular apical pacing (RVP) is unlikely to be a major concern. In contrast, when left ventricular systolic dysfunction coexists, dyssynchronous contractions induced by RVP greatly outweigh the benefit of heart rate maintenance, resulting in a worsening of the condition (Figure 4). Substantial RVP (pacing burden >20–40%) has been reported to increase cardiovascular events such as deterioration of LVEF and heart failure hospitalization.^122-124 Right ventricular high septal pacing, which captures the myocardium closer to the conduction system, has been attempted as an alternative to RVP, but did not protect left ventricular function.¹²⁵.

Pacing-induced cardiomyopathy, a condition in which LVEF decreases over time under RVP, occurs in 12–20% of patients after pacemaker implantation.¹²⁶ Previous studies demonstrated that a higher pacing burden, paced QRS duration >160 ms, and low preoperative LVEF were risk factors for pacing-induced cardiomyopathy, especially in patients with mild-to-moderate LV dysfunction.^{127, 128}.

His bundle pacing (HBP), which directly captures the conduction system rather than the local myocardium, was expected to retain the physiological activation pattern in animal models¹²⁹ and clinical cases.¹³⁰ However, the low procedural success rate of HBP remains a major issue.¹³¹ In recent years, a delivery catheter system for implantation of a lead has become available, resulting in an increase in the procedural success rate. The clinical efficacy of CSP has gradually become evident, and not only HBP but also left bundle branch area pacing (LBBAP) is again attracting attention^{97, 100, 128, 131-140} (Figures 4,5 and Table 7).

CRT has been shown in multiple RCTs to be effective in patients with moderate to severe heart failure with reduced LVEF despite optimal medical therapy and a QRS duration ≥120 ms.^204-209 In these RCTs and meta-analyses, complete left bundle branch block (CLBBB) waveform, and wide QRS (>150 ms) predicted the benefit of CRT,^204-211 and mid-range QRS duration between 120 and 150 ms (120 ms≤QRS duration<150 ms) showed insufficient benefit of CRT, so-called “nonresponders”.^{210, 211} On the other hand, clinical characteristics for higher CRT efficacy have been proposed, such as sex, body size (including racial differences), and heart size, and if these are taken into account, CRT may be effectively used for mid-range QRS cases.^{133, 194, 212-216}.

However, there is no consensus on the interpretation of these clinical characteristics, and there are currently differences in the definitions of mid-range QRS and recommended classes of CRT in various societies’ guidelines.^{92, 145, 217, 218} (Table 8). In preparing this Focus Update, we reviewed the recommended classifications based on the results of studies reported since the JCS/JHRS 2019 Guidelines on the Nonpharmacotherapy of Cardiac Arrhythmias.

In catheter ablation of atrial fibrillation (AF), pulmonary vein isolation (PVI) alone is not effective in maintaining sinus rhythm in some cases, especially in patients with persistent AF. In addition to PVI, various techniques for ablation of non-pulmonary veins substrates (beyond PVI) have been proposed, and many randomized controlled trials (RCTs) have investigated the efficacy of beyond PVI in maintaining sinus rhythm. This Focus Update offers a comprehensive review of these updates.

All physicians, regardless of specialty, should be aware that andexanet alfa, a neutralizing agent for factor Xa (FXa) inhibitors (i.e., apixaban, edoxaban, and rivaroxaban), is now available (Figure 10).³ Although the use of neutralizers for non-major bleeding should be discouraged, all patients on oral anticoagulants should be appropriately given a neutralizing agent when life-threatening bleeding or bleeding that is difficult to control occurs.

Andexanet alfa is a genetically engineered FXa decoy protein that has been modified to inactivate the prothrombin-to-thrombin catalytic activity of FXa. When andexanet alfa is administered, the FXa inhibitor binds to andexanet alfa rather than to its original target, FXa, which preserves FXa function and neutralizes the FXa inhibitory effect.

Andexanet alfa can act as a neutralizer of the 3 FXa inhibitors in a single drug when administered at high or low doses (Figure 11). According to a final report⁴³⁸ of the international phase III ANNEXA-4⁴³⁷ trial in patients with acute major bleeding within 18 h of taking an FXa inhibitor (479 patients including 19 Japanese), 93% of the apixaban group (n=172), 71% of the edoxaban group (n=28), and 94% of the rivaroxaban group (n=132) showed anti-Xa inhibitory activity after rapid intravenous injection of andexanet alfa. The neutralizing effect was maintained until the end of 2-h continuous intravenous infusion. Because the half-life of andexanet alfa in blood is approximately 4 h, the neutralizing effect gradually diminished after the end of intravenous infusion, and 80% of patients achieved good hemostasis. Although 10% of patients had a post-dose embolic event, all events occurred before the resumption of oral anticoagulant. This Focus Update recommends the use of andexanet alfa in patients with AF in the setting of life-threatening or difficult-to-control bleeding that requires immediate correction of the FXa inhibitor effect (Table 24).

Figure 11 shows the administration method of andexanet alfa, as well as that of idarucizumab, a neutralizing agent for dabigatran that became available earlier for clinical use. In contrast to idarucizumab, which maintains its neutralizing effect for 24 h after rapid intravenous infusion, the neutralizing effect of andexanet alfa is achieved by rapid intravenous infusion followed by a 2-h continuous infusion (Figure 11). Specifically, when it is <8 h after the last dose, a higher dose is given to neutralize rivaroxaban or edoxaban, but a lower dose is given for apixaban. A lower dose is given for all FXa inhibitors if >8 h have elapsed since the last dose. Because andexanet alfa dose-dependently inactivates the anti-IIa and anti-Xa activities of heparin, monitoring, such as activated clotting time (ACT), is required when using andexanet alfa under heparin administration.

Considering the circumstances in which andexanet alfa is used, any delay in administering it should be avoided. Start with a loading dose of 2 V (400 mg) at 30 mg/min, and check the appropriate dose (high or low) by the end of the loading dose administration. If the dose is high, repeat the same loading dose after completion of the initial loading dose. If the dose is low, continuous infusion is started just after completion of the initial loading dose.

A meta-analysis of studies using idarucizumab, andexanet alfa, or a prothrombin complex concentrate at the onset of life-threatening or difficult-to-control bleeding under DOAC treatment⁴³⁹ showed that 76.7% of patients in the idarucizumab group and 80.7% of patients in the andexanet alfa group achieved good hemostasis. The mortality rate was 17.4% in the idarucizumab group and 18.9% in the andexanet alfa group. The embolization rate was significantly lower in the idarucizumab group (3.8%) than in the andexanet alfa group (10.7%). In addition to neutralizers, the patient's individual risk of embolism, bleeding-induced hypercoagulability, and withdrawal of anticoagulants can affect the incidence of embolism after major bleeding. For example, the rate of intracranial bleeding with a high risk of subsequent embolism was 69% in ANNEXA-4⁴³⁷ with andexanet alfa, but 33% in RE-VERSE AD,⁴⁴⁰ which tested the neutralizing effect of idarucizumab on dabigatran.

It is unclear whether andexanet alfa itself carries a risk of hypercoagulation and embolism in patients on FXa inhibitors who have a major bleeding event.⁴⁴¹ The final results of the RCT comparing andexanet alfa to conventional therapy for intracranial bleeding in patients on Xa inhibitors (ANNEXA-1 trial) will answer this question.

Physicians who may be involved in emergency treatment for major bleeding should confirm in advance the storage location of neutralizers for each anticoagulant and the shortest delivery route to the administration site. They should also simulate the administration method and be prepared to respond quickly and accurately when a neutralizing agent is needed. In the event of major bleeding under FXa inhibitor therapy, some institutions may not have ready access to andexanet alfa. In such cases, the use of a prothrombin complex concentrate may be considered, although it is not covered by insurance as of February 2024. In a meta-analysis of patients with major bleeding under DOAC treatment, the prothrombin complex concentrate achieved hemostasis in 80.1%, death in 17.4%, and embolization in 4.3%, which were acceptable results compared with specific neutralizers. The study showed a 3.63-fold increased risk of death in patients who did not achieve good hemostasis.⁴³⁹.

In Japan, where the use of DOACs is more prevalent than of warfarin, major bleeding is expected to increase in patients taking DOACs. When patients on anticoagulants develop life-threatening bleeding or bleeding that is difficult to stop, we collect as much accurate information as possible about which anticoagulant was last taken, and use an appropriate neutralizing agent. It is important to keep in mind that anticoagulation therapy should be resumed to prevent subsequent embolisms when the patient enters a stable phase.

Digitalis has long been widely used as a heart rate regulator in AF patients. A meta-analysis of 19 trials published between 1993 and 2014 reported that digitalis use was associated with increased mortality rates,⁴⁴² especially in AF without heart failure (HF). Therefore, recent guidelines do not recommend the use of digitalis in patients with AF and preserved cardiac function.

Digitalis is often used clinically to control the heart rate in AF patients with reduced cardiac function, because its inotropic effects can be expected to improve cardiac function. However, previous clinical studies have reported that long-term use of digitalis increases the mortality rate,^443-445 and an additional analysis of the AF-CHF trial also showed that digitalis use was related to all-cause death, cardiac death, and arrhythmia-related death.⁴⁴³ Based on these results, in the 2021 JCS/JHFS Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure,⁴⁴⁶ long-term use of digitalis is listed as Class III (harm). Additionally, because digitalis has an inferior effect on improving the prognosis as compared with β-blockers,⁴⁴⁵ the JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias states that β-blockers are the first choice for controlling heart rate in AF with reduced cardiac function, and digitalis is positioned as the second choice.³.

However, the RATE-AF trial⁴⁴⁷ published in 2020 reported different outcomes.⁴⁴⁸ This randomized open-label trial included 160 patients with persistent AF (mean heart rate 100±18 beats/min) with HF symptoms (NYHA class II or higher). The patients were divided into a digoxin group (mean 161 μg/day) and a bisoprolol group (mean 3.2 mg/day). Doses were adjusted to achieve a heart rate of 100 beats/min or less (concomitant use of other drugs was allowed if the effect was poor), and the effects on improving quality of life (QOL) were compared. There was no significant difference in the resting heart rate (76.9±12.1 beats/min in the digoxin group vs. 74.8±11.6 beats/min in the bisoprolol group, P=0.40) at 6 months, and QOL was similar in both groups. At 12 months, the median NT-proBNP was 960 pg/mL in the digoxin group and 1,250 pg/mL in the bisoprolol group (P=0.005), and the digoxin group exhibited better outcomes in various aspects, including NT-proBNP level and sub-items such as daily activity, treatment satisfaction, and NYHA class. Adverse events were also lower in the digoxin group (25% vs. 64%, P<0.001). Until now, there have been no reports showing the superiority of digitalis over β-blockers in heart rate control in AF complicated by HF, but a meta-analysis has cast doubt on the effectiveness of β-blockers in improving the prognosis for AF patients complicated with HF.⁴⁴⁹ In view of this, they reported that the use of other drugs should be considered in a well-balanced manner, rather than preferentially using β-blockers.⁴⁴⁸ However, because this trial enrolled a small number of patients with only persistent AF, and evaluated the improvement of QOL and symptoms but not the long-term prognostic efficacy, digitalis should not be simply regarded as a superior drug.

On the other hand, many of the reports that digitalis is associated with a poor prognosis have been observational studies or post-hoc analysis of RCTs, and it has been pointed out that they may be looking at confounding between digitalis and the patients’ backgrounds.⁴⁴⁹ Furthermore, meta-analyses in RCTs have shown that the digitalis has no effect on prognosis.⁴⁵⁰.

Considering all findings, despite the unexplored long-term prognostic efficacy of digitalis, its recommendation level has been upgraded from Class III (harm) to Class IIb (usable) when digoxin blood levels are regularly checked (Table 25³).