Sudden cardiac death in China: current status and future perspectives

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1 Europace (2015) 17, ii14 ii18 doi: /europace/euv143 SUPPLEMENT: REVIEW Sudden cardiac death in China: current status and future perspectives Shu Zhang* State Key Laboratory of Cardiovascular Disease, Arrhythmia Center, Clinical EP Lab and Arrhythmic Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishilu, Beijing , PR China Received 27 February 2015; accepted after revision 24 April 2015 Sudden cardiac death (SCD) is a major cause of mortality worldwide. Similar to the number of SCDs in western countries including the USA, the number of SCDs in China is annually. However, there are significant differences in patient characteristics between Chinese primary prevention population and U.S. primary prevention population. In contrast to western countries where implantable cardioverter-defibrillator (ICD) devices have been well adopted as a major effective method for both primary and secondary prevention of SCD, China has a low prevalence of ICD utilization ( 1.5 device per 1 million people). Socioeconomic and political factors, awareness and knowledge of SCD, and the difference in disease patterns have led to the underutilization of ICD in China. China, as the most populated and the second largest economic country in the world, has now taken variable approaches to address this pressing health problem and enhances the delivery of lifesaving therapies, including arrhythmia ablation and medical treatment besides ICD, to patients who are at risk of SCD Keywords Sudden cardiac death Implantable cardioverter-defibrillator Ventricular tachycardia Ventricular fibrillation Primary prevention The global health problem of sudden cardiac death Sudden cardiac death (SCD) is a sudden, unexpected death caused by loss of heart function (also called sudden cardiac arrest). It is the largest cause of natural death in the USA, causing an estimated adult deaths in the USA each year. 1 Sudden cardiac death is responsible for half of all heart disease deaths. In Europe that consists of 46 countries with a population of 730 million, the incidence of SCD is estimated between and people annually. 2 Thus, the number of SCD of Western Europeans is similar to that in the USA based on WHO database, 3 SCD has become a global health problem when comparing the mortality associated with SCD with those caused by all other non-communicable diseases. For example, in 2005, there were 58 million deaths in the world ( 1% of the population), of which 35 million are due to noncommunicable diseases (cardiovascular, cancer, etc.). This is twice the number of deaths from all communicable diseases, which include HIV/AIDS and tuberculosis. Sudden cardiac death still accounts for.50% of all coronary heart disease deaths and 15 20% of all deaths. 4,5 As a result, the reduction of SCD remains a major challenge to the management of global public health problems. China has the largest population in the world with 1.3 billion people, more than three times the U.S. population. With rapid development of the economy and improvements in standard of living, the disease spectrum in China has changed profoundly in the last few decades. The average life expectancy has increased dramatically from 35 years before 1949 to 71.8 years in According to the Chinese health statistical digest, the death rate from heart diseases in 2007 was / population for urban areas and 86.01/ for rural areas. Currently, cardiovascular and cerebrovascular diseases together constitute the leading cause of the mortality for both men and women in China. 6 The true incidence of SCD in China remained unclear until Led by Dr Hua Wei and Dr Shu Zhang, one of China s 10th national 5-year ( ) projects called the Clinical Applications of Implantable Cardioverter Defibrillators (ICDs) and the Prevention of Sudden Cardiac Death has provided valuable statistics regarding SCD in China. 7 This project enrolled a total population of from four different representative areas in China, including the populations of three major cities: Beijing in the North; Guangzhou in the South; and Kelamayi in the West; and one rural population in Shanxi province of central China. At 1-year follow-up, there were 2983 deaths, of which 284 were SCD. Thus, the prevalence of annual SCD rate was 41.8/ for the general population. The prevalence of SCD was significantly higher in males (44.6/ ) than in females (39.0/ ). Based on this project, SCD is estimated to account for over deaths in 1.3 billion citizens in China annually. * Corresponding author. Tel: ; fax: , address: zsfuwai@vip.163.com, zsfuwai@126.com Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 Sudden cardiac death in China ii15 Underlying pathophysiology of sudden cardiac death Most SCDs are caused by ventricular fibrillation (VF) or ventricular tachycardia (VT) degenerating into VF. Underlying pathophysiology of SCD is complex. Based on decades of investigations, mostly conducted in western countries, a variety of risk factors and relevant comorbidities have been proposed. Coronary heart disease is certainly the most common disease contributing to SCD, representing 75% of SCDs. 5,8 Then, cardiomyopathy (dilated, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy) and primary electric disorder related to channelopathies account for most of the remainder. 5 However, in 5% of SCDs or cardiac arrests, a significant cardiac abnormality is not found. Other risk factors that are associated with SCD include hypertension, smoking, high cholesterol, diabetes, obesity, etc. In comparison with the findings in western countries, systemic and large scale investigations into the causes of SCD in China are limited. A retrospective analysis of 553 cases of SCD out of a total of consecutive autopsies in eight regions in China was recently conducted by Wang et al. 9 This analysis found that the main cause of SCD was coronary atherosclerotic disease (coronary heart disease, 50.3%), which is similar to the finding in western countries ( 75% of SCD cases due to coronary heart disease). Other causes of SCD in this analysis included myocarditis (14.8%) and hypertrophic cardiomyopathy (4.5%), with unexplained sudden death accounting for 12.1% of the cases. Although the incidence of coronary heart disease in the Chinese population is lower than that in western countries, it has increased in recent years due to rapid social progress, changes in lifestyles, and urbanization. In China, there are 2 million patients who have myocardial infarction and new cases each year. The major risk factors of cardiovascular disease continue to increase with 350 million smokers, 200 million overweight and 60 million obese people, 160 million people with hypertension, 160 million people with dyslipidaemia, and 20 million people with diabetes mellitus. 10 For hypertrophic cardiomyopathy, a population-based echocardiographic analysis of 8080 adults showed that the age- and sex-adjusted prevalence of idiopathic hypertrophic cardiomyopathy was 80 per adults, which translates to at least 1 million cases in China. 11 Along with world leading investigators, Chinese physicians have also identified several gene mutations for hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome, Brugada syndrome, and other hereditary heart diseases specific to the population. 12,13 Comparison in patient characteristics of primary prevention population between Americans and Chinese There are many risk factors that can increase a person s risk of SCD, including heart diseases such as coronary heart disease, chronic heart failure, cardiomyopathy, channelopathy, and non-cardiac disease such as aging, high cholesterol, hypertension, diabetes, smoking, obesity, kidney disease, familial predisposition, and certain drugs. 14 It had been found in the U.S. database that 75% of SCD cases are linked to a previous heart attack, e.g. myocardial infarction. 5 A person s risk of SCD is higher during the first 6 months after a heart attack in patients with coronary artery disease. To see whether Chinese people follow the same patterns as found in the USA, we recently compared the major risks of SCD between Americans and Chinese. The analysis was performed using the US OMNI ICD registry and the China Society of Pacing and Electrophysiology (CSPE) ICD registry in which all patients received an ICD for primary prevention with left ventricular ejection fraction,35%. 15 The incidence of tachyarrhythmia (VT/VF) with appropriate ICD therapies and the mortality rate were determined at 12 months. Parameters of patient characteristics included age, gender, ischaemic heart disease, coronary artery disease, history of myocardial infarction, diabetes, and hypertension. Results found that the overall VT/ VF incidence at 12 months was 24.2% in CSPE database (n ¼ 199) and 16.3% in OMNI (ICD only patients: n ¼ 1894, P ¼ 0.02 vs. CSPE data), and the mortality rate was 7.1% in CSPE database and 6.2% in OMNI database (P ¼ 0.49). For the subset of patients who had left ventricular ejection fraction (LVEF),25% (16% of CSPE database and 38% of OMNI database), the VT/VF incidence was 26.0% in the CSPE database and 20.3% in OMNI database (P ¼ 0.61). Significant differences in patient characteristics between CSPE database vs. OMNI database included age, ischaemic heart disease, coronary artery disease, history of myocardial infarction, diabetes, and hypertension (Table 1). There was no significant difference in gender (77 vs. 73% male, P ¼ 0.24). 15 Thus, the overall VT/VF incidence at 12 months is higher in the Chinese primary population than in the U.S. primary population. Moreover, the patient characteristics in the Chinese primary prevention population seem different from those of the U.S. primary prevention population. The finding raises the question whether the strategies of identifying patients with risk of SCD and SCD prevention are different. Further investigation in patient characteristics and pathophysiology of SCD in Chinese population is warranted, which will ultimately improve SCD prevention in China. Prevention of sudden cardiac death: present and future There are two strategies to prevent SCD: primary prevention and secondary prevention. Primary prevention is aimed at preventing the first life-threatening arrhythmic event while secondary prevention is aimed at preventing the recurrence of a potentially fatal arrhythmic event in patients who once had an experience of SCD. The strategies to reduce the risks of SCD include treatment of primary diseases, life style changes, and the use of certain medications such as b-blocker. Yet, ICD is the only proven means for SCD prevention currently and can effectively terminate lethal ventricular tachyarrhythmia or initiate pacing for severe bradycardia. Several large clinical trials have demonstrated the prevention of SCD and improvement in mortality reduction including cardiac mortality. 13,16 18 There are over ICDs implanted each year for prevention of SCD in the USA. 19 However, the number of ICDs implanted in China is far smaller even though the guidelines for ICD implantations are mainly adopted from 2012 ACCF/AHA/HRS Guidelines for Implantable Defibrillator and Cardiac Resynchronization Therapy for

3 ii16 S. Zhang Table 1 Difference in patient characteristics of primary prevention population between Americans and Chinese CSPE (n 5 199) OMNI (n ) P-Value... Age (years), mean + SD , Gender, n (%) Male 157 (78.9) 1390 (73.4) 0.24 Female 46 (22.1) 504 (26.6) Ischaemic, n (%) 79 (39.7) 1230 (64.9), LVEF (%), mean + SD , LVEF,25%, n (%) 33 (16.6) 659 (37.5), Coronary artery disease, n (%) 53 (26.6) 1265 (66.8), Hypertension, n (%) 68 (34.2) 1325 (70.0), Diabetes, n (%) 38 (19.1) 622 (32.8), Myocardial infarction, n (%) 26 (13.1) 1042 (55.0), CSPE, China Society of Pacing and Electrophysiology (CSPE) ICD registry; OMNI, US OMNI ICD registry; LVEF, left ventricular ejection fraction. Figure 1 The growth of the number of annual ICD implants in China. The ordinate is the number of implanted ICDs and the abscissa is years from 2002 to Inserted numbers above bars indicate the number of implanted ICDs in the corresponding year. Cardiac Rhythm Abnormalities. 20 In China, the first ICD was surgically implanted in 1991 and the first transvenous ICD was implanted in As shown in Figure 1, the number of ICD implantation continues to grow yearly. In 2013, the total number of ICDs implanted in China is 1903 units (or 3235 including CRT-ICD, based on the CSPE database) with 45% for primary prevention and 55% for secondary prevention (in the USA, 75% of ICDs implanted for primary prevention). Sixty-nine per cent of implanted ICDs were singlechamber devices and 31% were dual-chamber devices in year When considering the incidence of SCD in China ( total annual cases), the current rate of ICD implantation is insufficient. The penetration of ICD utilization in 2009 was 434 per million people in the USA, 290 in Germany, 108 in France, 174 in Italy, 220 in Netherlands, and 97 in United Kingdom, but only 1 per million people received ICD therapy in China. 21 In the last 5 years, the penetration of ICD use has increased from 1 to 1.5 per million people (or 2.5 per million people when combining ICD and CRT-ICD, based on the CSPE database). Many reasons contribute to the low rate of ICD utilization despite China being recognized as the second largest economic country in the world. Implantable cardioverter-defibrillators are too expensive for most patients in China due to the relatively low per capita annual income (US$2000 in urban and US$700 in rural areas in year 2007) and low reimbursement for the cost of ICD therapy. 22 Furthermore, physician training programmes that are needed for ICD implantation and follow-ups are not sufficient. Finally, many physicians and patients have still not recognized the role of ICD in SCD prevention. Thus, the number of ICD implants has remained low in China. 23 The relationship between ICD use and economic factors in China can be seen in Figure 2. Beijing, Shanghai, Zhejiang, Jiangsu, Tianjin, and Guangdong are top six regions in per capita income in China and the higher number of ICD implantation per million inhabitants in these

4 Sudden cardiac death in China ii17 Figure 2 Distribution of the numbers of ICD implantation by provinces and cities in China in year Panel A gives the number of implanted ICDs per million inhabitants while panel B gives the actual number of implanted ICDs. The abscissa gives 26 provinces and 4 megacities in China. regions (far left bars in Figure 2) is likely related to the well-developed economy in these regions. The penetration of ICD utilization in less developed regions and/or provinces with less insurance reimbursement (bars on the right of Figure 2)islow. With regard to pharmacological prevention of SCD, the most widely used drugs for coronary artery disease in China are b-blockers. Another antiarrhythmic drug, amiodarone, is widely used for many arrhythmias. Clinical data involving Chinese patients are limited. The CCS-2 COMMIT (Chinese Cardiac Study-2 Clopidogrel and Metoprolol in Myocardial Infarction Trial) study enrolled patients with acute myocardial infarctions. The study demonstrated that the use of early b-blocker therapy reduced the risk of re-infarction and VF, but increased the risk of cardiogenic shock, especially early in hospital admission. Consequently, in-hospital b-blocker therapy is now used in China only when patient haemodynamic condition has stabilized. 24 Community-based resuscitation programmes are an effective means to deal with SCD. However, the knowledge of cardiopulmonary resuscitation (CPR) is limited in China. Currently, there are no local or national laws to mandate citizen training in CPR. Publicly accessible Automated External Defibrillators (AEDs) have been made available only recently in a few important sites such as international airports and hotels, large stadiums, and prominent tourist sites. Extensive public availability of AEDs in China will not occur for some time due to socioeconomic constraints. Because of high cost of ICDs in China and uncertainty of medication to prevent SCD, arrhythmia ablation has been used to improve clinical symptoms and quality of life in patients with frequent reoccurrence of ventricular tachyarrhythmia. Yao et al. 25 found that patients who underwent radiofrequency ablation of VT and did not receive ICD had no SCD or tachyarrhythmia during the 12-month follow-up. In 2012, there were arrhythmia ablation cases in China, of which 2330 cases were for VT and were for atrial flutter and atrial fibrillation (based on the CSPE database). It is obvious that much progress remains to be made in China in appropriately identifying patients at risk of SCD and instituting effective yet affordable measures in primary and secondary prevention of SCD. In order to identify specific risk factors and optimize risk stratification, the Chinese government recently funded the 12th 5-year project ( ) that will prospectively follow malignant arrhythmias and SCD events in high-risk patients and establish a national registry system for patients at a high risk of SCD. The study recently performed by Hua et al., 26 as one of research initiatives, uses T-wave alternans to stratify patients at a high risk of ventricular tachyarrhythmia. Currently, along with other emerging countries, the CSPE takes the leadership role in the IMPROVE SCA Clinical Study (Improve the Prevention of Sudden Cardiac Arrest in Emerging Countries). 27 This study aims to demonstrate that primary prevention patients with one or more additional risk factors are at a similar risk of lifethreatening ventricular arrhythmias when compared with secondary prevention patients, and would receive similar benefit from an ICD, or CRT-ICD implant. The study evaluates the benefits of therapy for high-risk patients in countries where defibrillation therapy for primary prevention of SCA is underutilized. The results of this study may be beneficial in helping clinicians identify and refer the

5 ii18 S. Zhang highest-risk primary prevention patients for ICDs, help local societies expand guidelines to include primary prevention of SCA utilizing ICDs, convince regulators to provide coverage for ICD implants in these patients, and provide additional local evidence to allow patients to make an informed decision whether to receive an ICD. Moreover, many hospitals in China have enhanced EP physician training programmes. For example, the number of hospitals that are qualified for ICD implantation has increased from 210 in 2009 to 315 in 2013, and the number of new EP physicians will increased annually by via government training programmes. Additionally, with the government s sponsorship, many regional educational activities of SCD awareness are conducted frequently. 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