Identification of High-risk Patients for Implantable Cardioverter-Defibrillator Therapy in Asia

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Abstract

Sudden cardiac death (SCD) is a serious medical problem worldwide. Multiple landmark studies have demonstrated the benefit of implantable cardioverter-defibrillator (ICD) therapy in preventing SCD in at-risk patients. Although the data available in Asia are limited, the disease pattern seems to be different from that in the western world. The Asian population seems to have a lower incidence of SCD. Coronary heart disease, which is the major underlying cause of SCD in the west, may play a less important role in Asian countries. In addition, non-structural heart disease seems to be a more prevalent cause of SCD in Asia. It is thus questionable whether the results of ICD trials can be applied directly to Asian countries, as most of these trials seldom recruited Asian patients. This article will review SCD in Asia, focusing on the epidemiology and risk factors for SCD in Asia and highlighting some unique features that may be different from those seen in the western world.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Jeffrey WH Fung, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, China. E: jwhfung@cuhk.edu.hk
Received date
29 September 2010
Accepted date
01 December 2010
Citation
Asia-Pacific Cardiology 2011;3(1):77-9
DOI
https://doi.org/10.15420/apc.2011:3:1:77

Sudden cardiac death (SCD) is a major global health problem. It can be defined as either an unexpected death within one hour of symptom onset or a non-witnessed death discovered within 24 hours in someone without prior symptoms or any prior condition that would appear fatal. A large majority of SCD events occur in out-of-hospital settings. There is a very high mortality rate if patients are not treated within minutes. The most common mechanisms leading to SCD are ventricular tachycardia (VT) and ventricular fibrillation (VF). Data from multiple large clinical trials have consistently shown that implantable cardioverter-defibrillator (ICD) therapy carries a significant survival benefit for high-risk patients. Nowadays, ICD use has become the mainstay therapy in the prevention of SCD. However, ICD is an expensive therapy that is not without risk and adverse effects for patients. It is thus important to identify patients who are truly at risk of developing SCD in order to optimise the benefit of ICD therapy.

SCD is a challenging condition in Asian countries as well as in the west. There has been an increasing trend for ICD implantation in Asian countries, as shown in the 2005 World Survey of Cardiac Pacing and Cardioverter-Defibrillators.1 In Asia, the indications for ICD implantation mainly follow the guidelines from the US and Europe;2,3 however, most of the landmark ICD studies seldom recruited Asian patients. Therefore, it is questionable whether direct extrapolation of these guidelines to people in Asia is feasible.

This article will address the epidemiology and risk factors for SCD in Asia and highlight some unique features in this area that may be different from those seen in the western world.

Epidemiology of Sudden Cardiac Death in Asia

The incidence of SCD in the US is around one per 1,000 population per year.4 The incidence in Europe seems to be similar.5 In Asia, data from Japan show a similar incidence to that seen in the US and Europe, with the annual rate estimated to be one to two per 1,000 population per year.6 In China, from a project involving four major cities the annual incidence of SCD was estimated to be 0.42 per 1,000 population.7

In Hong Kong, the SCD incidence rate was found to be only 0.018 per 1,000 population.8 In another epidemiological study for SCD among adults 35 years of age and older in the US,9 it was found that Asian people living in the US had a lower SCD incidence (212.6 per 100,000) compared with Caucasians (407.1 per 100,000) and blacks (502.7 per 100,000). Data are not available for other Asian countries. Although only limited data are available, there seems to be a lower incidence of SCD in some Asian populations compared with the West. The underlying reason for this difference is unclear.

Sudden Cardiac Death in Patients with Structural Heart Disease

Most cases of SCD occur in patients with structural heart disease, including both ischaemic and non-ischaemic aetiologies. Coronary artery disease (CAD) is the single most important heart disease related to SCD in western countries, accounting for approximately 80% of SCD in the US.10 Patients with CAD can develop SCD owing to acute myocardial ischaemia or remodelling of the heart post-myocardial infarction resulting in scarring and fibrosis.

Although CAD is also a major disease in Asian countries, it seems to play a less important role in SCD than in the west. In a report of autopsy findings over 51 years in South Korea, CAD was the underlying cause of SCD in only 49.7% of cases.11 In a large registry of 4,122 post-myocardial infarction patients in Japan, the incidence of SCD was only 1.2% during an average follow-up of 4.1 years.12

The benefit of ICD over antiarrhythmic agents in reducing mortality has been well demonstrated in patients with prior ventricular tachyarrhythmia (secondary prevention)13-15 and in patients without arrhythmic events but at risk (primary prevention).16-19 The guidelines for ICD implantation were based on the results of these trials. However, as mentioned above, Asian patients were rarely recruited in these studies. As a result, it is uncertain whether ICD can offer a similar degree of benefit to the Asian population, especially in patients without a prior ventricular arrhythmic event but at risk (primary prevention). The applicability of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II), a primary ICD prevention trial, was tested in two Asian studies.

Prospective observational studies were conducted by Tanno et al.20 and Siu et al.21 by recruiting patients who fulfilled the inclusion criteria of MADIT II17 (patients with Q-wave myocardial infarction for over one month, left ventricular systolic function <30% and age over 21 years) but who had not undergone ICD implantation. They compared the incidence of SCD in their cohorts with the original study. The Japan cohort showed a significantly lower incidence of SCD compared with the conventional group in MADIT II (2 versus 12.1%), whereas the Hong Kong cohort found no significance difference (10.0 versus 12.1%). The difference in the result may be explained by the different patient characteristics. Most of the patients in the Japan group underwent coronary revascularisation (87%, including 60% who underwent primary percutaneous intervention), whereas fewer than 60% of the patients in the MADIT II group and Hong Kong cohort underwent a revascularisation procedure. The higher percentage of patients in New York Heart Association (NYHA) functional class I in the Japan cohort (79%) might also reflect the fact that these subjects had less severe disease.

Efforts have been made to look for risk factors for SCD. Left ventricular ejection fraction (LVEF) is the single most important predictor of SCD in patients with both ischaemic and non-ischaemic cardiomyopathy. Patients with lower LVEF have a higher risk of developing VT and SCD. The landmark ICD primary prevention studies identified that patients with severely reduced LVEF (defined as LVEF Ôëñ35 or Ôëñ30%) experienced a survival benefit from prophylactic ICD implantation (prevention of SCD) compared with antiarrhythmic agents. LVEF was also found to be a prognostic indicator in Asian studies. In a Japanese post-myocardial infarction registry (HIJAM-II),12 patients with lower LVEF had a significantly higher incidence of SCD; however, the incidence was increased to a lesser degree than in those with a similarly low LVEF in previous studies in the west. In the HIJAM-II registry, the incidence of SCD in patients with LVEF ≤30% was 5.1% at five years compared with 12.1% at two years in MADIT-II,17 15.5% at three years in the Trandolapril Cardiac Evaluation (TRACE) study22 and 10% at two years in the Valsartan in Acute Myocardial Infarction (VALLIANT) study.23 Besides the difference in the ethnicity of the subjects, the discrepancy can be explained by the higher rate of revascularisation in HIJAM-II subjects (about 80%). In other studies recruiting post-myocardial infarction patients with a high rate of revascularisation, a similarly low risk of SCD was also noted.20,24 These results highlight the importance of coronary revascularisation in CAD for reducing SCD.

Sudden Cardiac Death in Patients without Structural Heart Disease

Less commonly, SCD occurs in patients without structural heart disease, mainly in young, active and previously healthy individuals. A number of distinct channelopathies are recognised as causes of sudden death in these patients, including Brugada syndrome, congenital long QT syndrome, catecholaminergic polymorphic VT, short QT syndrome, Wolf-Parkinson-White syndrome and idiopathic ventricular fibrillation.

SCD in patients without structural heart disease seems to be more prevalent in Asian countries. In a single-centre review of 186 SCD patients in Korea, 44.1% of the patients had no evidence of structural heart disease.25 An ICD registry in Taiwan reviewed patients receiving ICD implantation for secondary prevention of SCD.26 By comparing the characteristics of these patients with patients in the three landmark ICD secondary prevention trials - the Canadian Implantable Defibrillator Study (CIDS), Antiarrythmics Versus Implantable Defibrillators (AVID) and the Cardiac Arrest Study Hamburg (CASH) - a higher proportion of the Asian patients had a structurally normal heart (23%), whereas non-structural causes contributed to a much lower proportion of SCD cases in the western trials (AVID 3%, CASH 9% and CIDS 4%). This may suggest the importance of non-structural heart disease as a cause of SCD in Asia.

Of all the non-structural cardiac diseases related to SCD, Brugada syndrome is probably the most important in Asian countries. It was first reported by Brugada in 199227 and is characterised electrocardiographically by typical ST segment elevation in the right precordial leads in patients without demonstrable heart disease. These patients are prone to developing ventricular tachyarrhythmia resulting in syncope or sudden death. The only effective treatment to prevent SCD in these patients is ICD implantation.28,29

Brugada syndrome is more prevalent in Asia than in western countries.30 In Thailand, it is one of the leading causes of death in young men, second only to road traffic accidents.31 Before this condition was named as Brugada syndrome, the term sudden unexplained nocturnal death syndrome (SUNDS) was given to the condition of sudden unexplained death in apparently healthy young South-East Asian men, which usually occurred at night and during sleep. Other names describing similar conditions included 'bangungut' in the Philippines,32 'lai tai' in Thailand,33 'pokkuri' in Japan34 and 'dab tsog' in Laos.35 SUNDS was later found to be phenotypically, genetically and functionally the same disorder as Brugada syndrome.36

Although patients with Brugada syndrome can develop SCD, most of them remain asymptomatic. ICD implantation is warranted only for those at high risk of developing lethal arrhythmia. Identifying high-risk factors for Brugada syndrome is crucial for prognosis and treatment. Brugada et al.37 reported that survivors of sudden cardiac arrest had the highest recurrence rate (up to 69%) during a mean follow-up of 54 months, whereas syncope patients with a spontaneous type I electrocardiogram (ECG) pattern had a recurrence rate of 19% over a mean of 26 months. Studies in the Asian population produced similar findings. In a Brugada registry in Japan, Atarashi et al.38 found that symptomatic patients with prior VF or syncope had a high rate of developing arrhythmic events (25.7%). In another registry of Chinese Brugada syndrome patients in Hong Kong,39 50% of the survivors of previous SCD had an arrhythmic event within 30 months, while 17% of patients with a history of syncope developed such an event within 25 months. Thus, it is recommended that an ICD should be implanted in symptomatic patients with Brugada syndrome.

However, there are controversies concerning the risk stratification and treatment of asymptomatic patients. Brugada et al.37 found that among asymptomatic patients the inducibility of ventricular arrhythmia by electrophysiological study may indicate poor prognosis, and thus they advise more aggressive treatment for these patients. However, this result was not reproduced by Priori et al.40 The Hong Kong Brugada syndrome registry also found a low predictive value of programmed electrical stimulation in predicting future events.39

Need for Other Risk Factors - Not Only in Asia

Currently, low LVEF of any cause is considered to be the strongest predictor of SCD. As a result, it is the single most important selection criterion for ICD implantation. However, most ICD recipients do not experience any ventricular arrhythmia (MADIT II). On the other hand, when the absolute number of SCD events was measured, it was found that the majority of events occurred in the general population group rather than the high-risk subgroups,41 because they emerged from a larger population base. SCD is usually the first presentation in people without a prior history of cardiac disease who have not undergone any cardiac assessment before. So, unfortunately, the current primary ICD guidelines protect only a minority of SCD victims.

This reality is reflected by the results of community study in the US, the Oregon Sudden Unexpected Death Study.42 The data from the study showed that 714 SCD cases were recorded over a two-year period. Of these cases, only 121 (17%) had their LV function assessed, and severe LV dysfunction (defined as LVEF ≤35%) was found in only 36 patients (5%). Other available risk stratification methods (including ambulatory ECG monitoring, heart rate variability, signal-averaged ECG, QT dispersion and T-wave alternans) have poor positive predictive value for identifying patients at risk of SCD. Moreover, the current challenge is not only to search for additional risk factors for the already known highest-risk clinical subgroups, but also to identify the high-risk subgroup within the larger general population at lower risk. More work is needed in both the western and the eastern world.

Conclusion

SCD is a serious medical problem worldwide. Although ICD is an effective treatment, it is costly and currently benefits only a small proportion of those at risk. Although the data available are limited in Asia, the cardiac disease pattern seems to be different from that seen in the west. The Asian population seems to have a lower incidence of SCD, less SCD related to CAD and more SCD related to non-structural heart disease. In concordance with the large studies in the west, LV systolic function is also a significant risk factor for SCD. However, LVEF as the sole predictor may not be sufficient for riskstratifying the general population. More work is needed to develop methods that allow early and accurate identification of individuals who are at risk of SCD.

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