Japan Implantable Devices in Coronary Artery Disease (JID-CAD) study design

Abstract

Background

There is little information regarding appropriate therapies for coronary artery disease (CAD) patients with implantable devices – such as implantable cardioverter-defibrillators (ICDs), cardiac resynchronization therapy devices (CRT-Ds) and cardiac resynchronization therapy pacemaker (CRT-P) devices – in Japan. To address this lack of information, we have launched the Japan Implantable Devices in Coronary Artery Disease (JID-CAD) study.

Methods

This study has been designed as a prospective, multicenter, non-randomized and observational investigation. All patients will be followed up every six months over a two-year period. The primary endpoint will be the administration of appropriate device therapy. Secondary endpoints include administration of inappropriate therapy, death, hospitalization, or cardiovascular events.

Conclusion

In this report, we discuss the current clinical situation of appropriate therapy, and how it is influenced by catheter ablation and revascularization therapy in patients with CAD.

1. Introduction

Implantable cardiac defibrillator devices, such as implantable cardiac cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy with ICD (CRT-D), comprise the therapy of choice for prevention of sudden cardiac death, and are used widely for both primary and secondary prophylaxis [1–3]. ICDs were first approved by the Japanese government more than 20 years ago; they are widely used, and are considered the most effective therapy for lethal ventricular tachyarrhythmia, both in Japan and globally. The Japan Cardiac Device Treatment Registry (JCDTR), run by the Japanese Heart Rhythm Society (JHRS), founded in 2006, records the current clinical situation of cardiac implantable defibrillator devices [4,5].

Mortality rates from coronary artery disease (CAD) are between 10% and 12.5% lower in Japanese patients than in Eastern and Northern European cohorts, and are approximately 20% lower than in Western Europeans and North Americans [6]. The estimated incidence of acute myocardial infarction in Japan was reported as 30−60 per 100,000 males and 10−20 per 100,000 females, between 1990 and 2000 [7]. Mortality rates are expected to rise in Japan owing to changes in diet and lifestyle [8]. In fact, the incidence CAD was relatively stable until 2000 [9], though recent research suggests that rates have been increasing since then [10].

The rate of CAD in Japanese patients implanted with ICDs is lower than in Western countries; the percentage of devices implanted for primary prevention is also markedly lower [4,11,12]. The prognosis of Japanese patients with CAD was hypothesized to improve following application of MADIT-II criteria [1,13–15]; however, some investigators have suggested that application of MADIT-II criteria to Japanese patients may be inappropriate [13]. Nonetheless, patients with CAD and implanted devices for primary prevention in Japan had more frequent appropriate therapy and worse prognosis than expected [16]. One possible factor in these unexpected results may be the implantation of cardiac implantable devices in patients with relatively severe prognoses, or late-stage congestive heart failure [16].

The indications for cardiac implantable devices have been adapted in line with the advancement of therapy for CAD and lethal ventricular arrhythmia. However, the relationship between indications and expected prognosis has not been well established in Japanese CAD patients, and use of cardiac implantable devices is currently influenced by the availability of intervention therapy for CAD and lethal arrhythmia.

The purpose of this study is to clarify the current status of cardiac implantable defibrillation therapy and prognosis in Japanese patients with CAD, and to evaluate the influence of CAD-specific therapies – including intervention and stenting – and lethal ventricular tachyarrhythmias on the choice of defibrillation therapy. The study will be prospective, multicenter, observational and non-randomized in nature. We anticipate that the data collected will facilitate more effective decision-making in the treatment of ventricular arrhythmias and CAD therapy, and the institution of more appropriate guidelines for the implantation of defibrillation devices in Japan.

2. Material and methods

2.1. Participating centers

Approximately 60 centers across Japan will participate in this study. After obtaining written informed consent, patients over the age of 20, with CAD and cardiac implantable devices (ICD, CRT-D), or cardiac resynchronization therapy with pacing (CRT-P), will be enrolled. Other doctors or centers may also participate in this study with the permission of the Central Committee of JID-CAD.

2.2. Patients

Criteria for enrollment were as follows: (1) ICD/CRT-D/CR-P newly implanted in accordance with the guideline on non-pharmacological therapy for cardiac arrhythmias, published by the Japanese Circulation Society in 2011 [17]; (2) CAD including myocardial infarction, effort angina and vasospastic angina; and (3) age ≥20 years, regardless of gender.

2.3. Data collection

Parameters to be recorded at the time of enrollment are shown in Table 1; those to be recorded during follow-up, in Table 2.

Table 1.

Parameters to be recorded at time of enrollment.

Information on implantation

1. Name of institute and date of registration

2. Age and gender of the patient

3. Date of implantation

4. Names of operators

5. Purpose of implantation (primary or secondary prevention)

6. Implantation indications based on Japanese guidelines from 2011a

7. Name and manufacturer of the implanted device

8. Mode of implanted device [single chamber with lead placed only at the ventricle(s) or dual chamber with lead placed at the atrium and ventricle(s)]

9. Mode on setting at the implantation (e.g. zone settings, VF sensing criteria, VT sensing criteria, monitor only setting)

10. Implanted leads (atrium, ventricle 1, ventricle 2)

11. Defibrillation threshold and minimum energy for defibrillation

12. Complications

Patient characteristics

1. Height and body weight at time implantation

2. Aspects related to coronary artery disease (interval since last myocardial infarction, data relating to first and latest myocardial infarction, if known)

Type of angina pectoris (effort, vasospastic, both)

Location of the diseased coronary vessel in patients with prior myocardial infarction

3. Cardiac disease other than coronary artery disease

4. History of atrial fibrillation/flutter

5. Disease other than cardiac disease

6. New York Heart Association (NYHA) classification

7. Left ventricular ejection fraction (LVEF), method of assessment

8. Coronary angiography (CAG) findings at time of registration, and ischemic area if coronary artery bypass graft (CABG) has been performed

9. History of coronary artery reconstruction [percutaneous coronary intervention (PCI), CABG]

10. ECG (rhythm, QRS duration before and after implantation, and chest radiograph findings)

11. History of non-sustained ventricular tachycardia (NSVT)

12. Therapy and related data (most recent, if performed more than once) for NSVT/VT (catheter ablation, cardiac surgery)

13. Dyssynchrony (degree, method)

14. Signal-averaged ECG

15. Microvolt T wave alternans

16. Electrophysiologic study

17. Holter ECG

18. Blood and laboratory data

Medication given at implantation

1. Antiarrhythmic drugs

2. Diuretics (ACE inhibitors or ARBs)

3. Antiplatelet or anticoagulant therapy

At implantation

1. Wearable cardioverter-defibrillator (WCD)

2. Hemodialysis

^aRefer to [17].

Table 2.

Parameters to be recorded during follow-up observation periods.

1.Date of follow-up 2.Documentation of primary and secondary endpoints 3. Primary endpoint information (1) Events of VT/VF (nature of therapy and first data recording during observation periods, if events occurred more than once) (2) Clinical background at the occurrence of a primary endpoint (ECG, chest radiograph, blood and laboratory data) and presumed cause of induced VT/VF (3) Therapy for primary endpoint [admission, vascular reconstruction (PCI, CABG), and therapy for VT/VF (ablation, surgery, change of programming, reoperation of device, antiarrhythmic agents)] 4.Secondary endpoint Appropriate therapy (first date of administration if events occurred more than once during observation periods) (1) Death (2) Admission (3) Complications related to device implantation (no relation to primary endpoint) (4) Cardiovascular events not related to device 5. Clinical background not related to primary endpoint (1) NSVT (base on device memory) (2) Vascular reconstruction (PCI, surgery)

The data collection methods will follow the principles outlined by the Nippon Storm Registry [18]. Registration for this study will be administered by the medical staff of each center, who will be required to complete a hard copy data sheet immediately after implantation of the cardiac implantable device, to be sent to the secretary of the JHRS office. Cardiac Device Representatives (CDR) [18] may assist medical staff in record keeping related to cardiac devices. The JHRS office will have access to the JID-CAD website, and will input patient data according to the prescribed documents. The JHRS secretary will assign patient-specific identities (JID-CAD IDs), which will be shared electronically with the medical staff in each center. Medical staff may input information on their own patients into the website via their personal computers. If errors or inconsistent data are found on a data sheet, the JHRS secretary will immediately contact the center׳s medical staff for clarification.

The follow-up data will be collected by each participating center every six months for two years after implantation. At the outpatient clinic, follow-up data will be retrieved from the cardiac device. Medical staff will input information on their own patients into the JID-CAD website. To protect patient confidentiality, the patients׳ name will not be included in reports, and the JID-CAD ID only will be used for further analysis. The above method facilitates data sharing with an independent committee for data management.

Data collection will commence in October 2014 following Ethics Committee approval in each center. Patients will be followed up for at least two years. Registration of new patients will be terminated in September 2016. If the target 800 patients are not recruited by that date, the registration term may be extended, subject to agreement of central members.

2.4. Data analysis

The primary endpoints of this study are the occurrence of appropriate therapy, defined as the occurrence of shock therapy or anti-tachyarrhythmia pacing (ATP) therapy, in patients with ICD and CRT-D; or the occurrence of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) in patients with CRT-P. The Kaplan–Meier method will be used to estimate the cumulative probability of death or appropriate therapy at each time point. We will conduct multivariate analysis using the logistic regression or Cox proportional hazard model to elucidate factors influencing the primary endpoint, such as baseline characteristics or clinical therapy, including antiarrhythmic and revascularization therapy for the coronary artery.

Secondary endpoints include time to the occurrence of inappropriate therapy, prognosis (death and cause of death, hospitalization due to heart failure or other cause) and cardiovascular events. The Kaplan–Meier method will be also used to estimate the cumulative probability at each time point. Furthermore, we will perform multivariate analysis using the logistic regression or Cox proportional hazard model to elucidate factors influencing the time to the occurrence of a secondary endpoint, such as baseline characteristics or clinical therapy, including antiarrhythmic therapy and revascularization therapy for the coronary artery.

2.5. Definition of terms

• Secondary prevention: A case in which the cardiac implantable device is implanted for the prevention of sudden cardiac death from spontaneous sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), not including VT/VF induced during electrophysiological testing.

• Primary prevention: A case in which the cardiac implantable device is implanted for the prevention of sudden cardiac death in a case excluding the abovementioned secondary prevention.

• Sustained VT: VT lasting ≥30 s, irrespective of ventricular rate or hemodynamic state; or loss of consciousness during VT, even where VT lasts <30 s.

• Non-sustained VT: Ventricular premature beats lasting ≥6 beats.

In cases with CRT-P, secondary prevention is defined as having a history of spontaneous VT/VF, and primary prevention as having no history of spontaneous VT/VF.

2.6. Role of the funding source

The JID-CAD study was organized and supported by the JHRS. There is no specific sponsor. The authors have full access to all data and take full responsibility for study׳s data integrity, and for the decision to submit this manuscript for publication.

3. Discussion

In patients with a history of myocardial infarction and VT, an ICD can prevent sudden cardiac death and reduce total mortality [19]. A known history of myocardial infarction can help to establish the substrate for fatal ventricular tachyarrhythmias, either acutely or during short-term or long-term follow-up [20]. Regarding the risk of sudden cardiac death after acute myocardial infarction, typical survival curves demonstrate an initial sharp decline that plateaus between six and 12 months. In the VALIANT (Valsartan in Acute Myocardial Infarction) study, for example, the risk of sudden death was highest in the first month after myocardial infarction (1.4% per month) and subsequently declined over two years to 0.14% per month [21]. Nevertheless, several randomized clinical trials have failed to show a survival benefit for ICDs when implanted early after myocardial infarction in high-risk patients [22]. Although ICD therapy has been associated with a reduction in the rate of death due to arrhythmias, this was offset by an increase in the rate of death from non-arrhythmic causes [22]. The etiology of the acute myocardial infarction – sudden cardiac death paradox is unclear, but may be related to the changing nature of the substrate over a period of several months after acute myocardial infarction [22]. Further investigation is needed to explain the actual causes of death in the early post-myocardial infarction period, and to find which interventions can be applied to reduce the increased rate of sudden death [20].

Limited data exist concerning the long-term incidence and prognosis of heart failure after myocardial infarction, particularly in the era of coronary revascularization. New-onset heart failure significantly increases the mortality risk among these patients [23]. Current ICD trials have shown that the time from shock to a heart failure event ranges from 160 to 204 days, depending on the number of appropriate or inappropriate shocks and the etiology of heart failure [24]. Patients with chronic CAD who are treated with ICDs have improved survival rates but an increased risk of heart failure [25]. Thus, heart failure patients with an ICD shock are at increased risk of heart failure-related hospitalization and heart failure events [26,27].

In addition to triggering heart failure, ICD shocks are painful, and furthermore do not provide complete protection against sudden cardiac death [28]. Prophylactic and therapeutic VT ablation appear to prolong the time to recurrence of VT or a rapid rate of non-sustained VT in patients with stable VT, previous myocardial infarction, and reduced left ventricular ejection fraction (LVEF) [19,29]. In the Surgical Treatment for Ischemic Heart Failure (STICH) trial, patients with CAD and an EF≥35% were randomized to receive either a coronary artery bypass graft (CABG) or medical therapy. There was no interaction between ischemia and treatment for any clinical endpoint [30]. In CAD with severe LV dysfunction, inducible myocardial ischemia does not identify patients with worse prognosis, or those that could benefit from CABG over optimal medical therapy [30]. Thus, it is largely unknown whether revascularization therapy attenuates infrequent VT, or influences appropriate ICD shock in Japanese patients.

The previous multinational study [31] showed variation across countries in readmission rates, mortality, and outcome after myocardial infarction. This may have resulted from differences in health-care policy, quality of health systems and clinical practice. These factors could account for differences in appropriate device therapy, and hospitalization and mortality rates in Japan, which have not yet been determined. Therefore, in this study, we will elucidate the current status of appropriate device therapy in CAD patients implanted with a cardiac device, and evaluate how appropriate therapy is influenced by catheter ablation and revascularization.

Conflict of interest

All authors declare no conflict of interest related to this study.