Coronary heart disease (CHD) is the second leading cause of cardiovascular death in the Chinese population. It accounts for 22% of cardiovascular deaths in urban areas and 13% in rural areas. Although mortality from CHD in China is relatively low compared with Western levels, the burden of CHD has been increasing. This is partly because of a worsening profile of risk factors, such as an increased prevalence of hypertension, hyperlipidaemia, overweight/obesity, diabetes, etc and partly because of an increase in the aged population. Large-scale, randomised controlled trials on thrombolytic, blood-pressure-lowering, antiplatelet and blood-cholesterol-lowering treatment as well as cardiac intervention have been conducted for Chinese patients with myocardial infarction. The studies provide important information for the prevention and management of chronic CHD and acute myocardial infarction in the Chinese population.
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Unlike in most Western populations, stroke is more common than coronary heart disease (CHD) in the Chinese population, especially in rural areas; CHD is the second leading cause of death from cardiovascular diseases. CHD mortality in the Chinese population is relatively low compared with Western levels but the burden of CHD has been increasing.1 During the past two decades, many projects on epidemiology and intervention strategies in cardiovascular diseases have been conducted in the Chinese population in collaboration with institutes and organisations nationally and internationally.1 These projects monitored the level and changing trends of cardiovascular diseases, explored the effects of related factors on the risk of CHD in different areas and evaluated the effectiveness of the intervention strategies in community and clinical settings. This report summarises the findings from a few major projects on epidemiology, and the prevention and the treatment of CHD in China.
EPIDEMIOLOGY OF CHD IN THE CHINESE POPULATION
Owing to the lack of a nationwide standard disease registration and classification system in China, there is no precise information about the number of events or deaths from CHD available for the whole country. The largest ever death registration and classification system using international standards in China covered more than 100 million residents from the selected urban and rural areas in 25 provinces and municipal cities since the mid-1980s. According to data from the system, in 2004 CHD accounted for 22% of deaths from cardiovascular diseases and 9% of total deaths in urban populations, while in rural populations the proportions were 13% and 4%, respectively.2 About 400 000 patients died from CHD, and 652 000 cases of CHD were diagnosed in 2004. Among the population aged ⩾35 years in 2004, the age-adjusted CHD mortality per 100 000 per year was 128.0 for urban men, 97.8 for urban women and 79.7 for rural men, 57.3 for rural women, using the new world standard population.3 Apart from the urban–rural differences, there were also remarkable differences in CHD morbidity and mortality between geographic regions. Generally speaking, CHD morbidity was high in the north, especially in the north east, but low in southeast coastal areas and in less economically developed areas.4–7
A steady increase in CHD mortality for the Chinese population has been observed in both urban and rural areas since the 1980s, when the standard death registration and classification system was established (fig 1). The same trend was observed from the Sino-MONICA project, Beijing Centre. It reported that the age-adjusted CHD mortality increased by 41% in men and 39% in women for the age group 35–74 years, from 1984 to 1999.1 Since 2000, CHD mortality has started to decrease in the population covered by the death registration and classification system.8 The age-adjusted CHD mortality (per 100 000 population per year) for men aged ⩾35 years in urban areas from 2000 to 2004 was 205.5, 192.7, 174.6, 156.5, 128.0, respectively. The trends were similar for urban women and rural men and women during the same period. The change in coding system from ICD-9 to ICD-10 that has been in place since 2001 may have contributed partly to the decline.
According to the incomplete hospital registration data reported to the Ministry of Health in 2004, acute myocardial infarction and other ischaemic heart diseases accounted for 4.1% of all patients discharged in hospitals located in large or medium-sized cities, and 2.1% in the hospitals located in counties. Patients with CHD used up to 5.0% of total bed days in city hospitals and 2.7% in county hospitals.2
The third national survey on healthcare service in China in 2003 showed that the prevalence of CHD was 4.6 per 1000 residences of all ages. It was six times higher in urban than in rural populations (12.4 per 1000 vs 2.0 per 1000).2
The incidence of coronary events increased by 2.7% annually in men, and 1.2% in women during the period of 1984 to 1997 in the Beijing centre (fig 2), according to the Sino-MONICA project.1 No published incidence data are available for CHD in China from large cohort studies from 2000 onwards.
MAJOR RISK FACTORS AND THEIR IMPACT ON CHD IN THE CHINESE POPULATION
There have been many dozens of large-scale prospective cohort studies conducted in various populations in China. The studies explored the association between major cardiovascular diseases and related factors in urban or rural populations, among those with different occupations and in different minorities. Table 1 summarises the relative risk of CHD for major risk factors estimated from combined prospective cohort studies in the Chinese population, the prevalence of these risk factors from the recent national survey and the estimated population-attributable risk fraction by urban and rural populations.
Among the major modifiable risk factors, hypertension, smoking and overweight are the most important contributors to the development of CHD in the Chinese population. This is not only because of the strong association of CHD with these risk factors but also because of the high prevalence of hypertension, smoking and overweight in the Chinese population.
Hypertension accounts for nearly 30% of the incidence of CHD in the Chinese adult population. This proportion can be translated into about 200 000 CHD events in 2004 in China due to hypertension. It also indicates that adequate prevention and control of hypertension would have a great effect on prevention of CHD at the population level.
Smoking contributed to about half of the incidence of CHD events for men and about 7% for urban women and 9% for rural women. The true impact may be much greater than the current estimates, which does not take into account the high prevalence of passive or environmental smoking in the Chinese population, especially for women. Although the prevalence of smoking in men has been decreasing slightly but continuously, over 60% of Chinese men are current smokers.1 Smoking is the only risk factor whose prevalence is higher in the rural than in the urban population (69% vs 63% for men, 6.3% vs 4.5% for women). This is also true for the population-attributable risk of smoking for CHD.
The high prevalence of overweight (25.7% in urban vs 19.3% in rural areas)1 and still increasing trends in the Chinese population make it the third most important contributor to the incidence of CHD in the Chinese adult population. Overweight accounts for 25.7% of CHD incidence in urban and 20.5% in rural areas for adults aged ⩾18 years.
Compared with Western populations, the average level of serum total cholesterol and the prevalence of dyslipidaemia are relatively low in the Chinese population. However, the level of cholesterol in the Chinese population has been increasing. The prevalence of hypercholesterolaemia (defined here as total cholesterol ⩾5.20 mmol/l) increased from 18% in 1982–4 to 33% in 1998 for men, and from 19% to 31% for women aged 35–59 years old.1 Hypercholesterolaemia accounts for 12.6% of the incidence of CHD in urban and 8.2% in rural populations using the cut-off point of 5.2 mmol/l. However, those with cholesterol level >3.5 mmol/l are also at an increased risk of developing CHD compared with those with lower level of cholesterol. With economic development in China, most people have changed their living conditions or lifestyles from heavy labouring work and traditional dietary habits to less physical activity and more energy-dense food. Overweight and hyperlipidaemia have become more prevalent in the Chinese population. The national survey on nutrition and health status in 2002 showed that combined dyslipidaemia (raised total cholesterol, triglycerides, low-density lipoprotein and low high-density lipoprotein) was 21% in urban and 18% in rural populations aged ⩾18 years.1 The real impact of dyslipidaemia on the development of CHD in the Chinese population is certainly more severe than that estimated above by considering only hypercholesterolaemia.
Diabetes or impaired glucose tolerance is a strong predictor of CHD.9 10 The population-attributable risk fraction for diabetes was about 6% in urban and 5% in rural people aged 18 years and older. The prevalence of diabetes and impaired glucose tolerance has been increasing in the Chinese population, although the exact rate of change is not known owing to the different age ranges and sampling frame in each survey as well as the changed diagnostic criteria over time.1
CHD and the above-mentioned major risk factors in the Chinese population are more common in urban than in rural populations, except for smoking, but the gap between urban and rural areas is getting narrower.1
The above five major preventable or controllable risk factors contributed most to the incidence of CHD. We would expect that the incidence of CHD should decrease remarkably in the Chinese population if the continuing national programmes on anti-smoking, prevention and control of hypertension and diabetes and health promotion can be implemented successfully.
The impact of smoking, hypertension and hyperlipidaemia on myocardial infarction in China is similar to that found in more developed Western countries according to findings from the INTERHEART study, a case–control study of 15 000 pairs of cases and controls from 52 countries (3000 pairs from China) which investigated the association of myocardial infarction with lifestyle-related and psychological risk factors.11
Clinical research on CHD in the Chinese population
Since the 1980s, several randomised controlled clinical trials (RCTs) have been conducted to test the efficacy of treatment and prevention of CHD among Chinese patients. Here we briefly summarise the study design and major results. Detailed information is given in the original papers.
This RCT compared the effectiveness of urokinase and defibrinogenase. Allocation of the patients was known to the investigators and end points were chest pain, ECG results and results of a serum enzyme test. Within 6 hours of onset of AMI 528 patients were randomly allocated to the urokinase treatment (n = 272) group and given 1.0×106–1.5×106 U/30 min, and 256 patients to the defibrinogenase treatment group and given 0.05–0.75 U/kg/30–60 min, by continuous intravenous drip infusion; 0.05 U/kg was again given on the third and fifth day. Opening of the occlusive artery within 2 h was seen among 58.1% of the patients in the urokinase group, and 40.6% of the patients in the defibrinogenase group (p<0.005 for the difference). The 4-week mortality rate was 8.1% in the urokinase group and 17.6% in the defibrinogenase group (p<0.005). Minor bleeding occurred among 4.8% of patients in the urokinase group and 16.8% in the defibrinogenase group (p<0.001). The study suggested that urokinase was more effective and safer than defibrinogenase in the treatment of AMI. The effects of low dose versus high dose, and early versus later starting urokinase, on AMI were compared in a larger sample size (n = 1138) later and the results indicated that low-dose urokinase was as effective as high doses, and that the earlier treatment was started the better the outcome. As the study was randomised using even or odd numbers to allocate the patients and the treatment was known to the doctors and the outcome assessors, the study was possibly biased and the size of the effects might be overestimated.
Effects of captopril on the early mortality and complications in 14 962 patients with AMI: Chinese Cardiac Study 1 (CCS-1)14–16
The multicentre, randomised, double-blind and placebo-controlled clinical trial recruited 14 962 patients with suspected AMI within 36 hours (median 16 h) of onset from 650 hospitals in 30 provinces or metropolitan cities. Subjects without clear contraindications were randomised into the captopril group (n = 7468, 6.25 mg as initial dose, 12.5 mg 2 hours later, then 12.5 mg three times daily if tolerated) and the placebo group (n = 7494). The 4-week mortality in the captopril group was slightly lower than in the control group, though the difference was not significant (9.1% vs 9.7%, p = 0.19); but the incidence of heart failure was lower in the treatment group than in the placebo group (17.0% vs 18.7%, p = 0.01). The study demonstrated that captopril was safe and effective in preventing patients with AMI from heart failure at an early stage. After 2 years of follow-up of 7079 patients with AMI (3554 in the captopril group and 3525 in the placebo group) in the CCS-1 study, the death rate was reduced by 10.6% (16.0% vs 17.9%, p = 0.03). It further demonstrated that early administration of captopril to patients with AMI could reduce cumulative mortality in the long term. This result was consistent with other international trials such as ISIS4. CCS-1 has contributed significantly to the meta-analysis of ACE inhibitors in AMI.
Effects of aspirin with clopidogrel or with metoprolol on AMI: Chinese Cardiac Study 2 (CCS-2/COMMIT)1718
This was a multicentre, randomised and placebo-controlled, clinical trial using the 2×2 factorial design to evaluate the effects of the antiplatelet agent clopidogrel plus aspirin and the effects of early β blocker metoprolol on the emergency treatment of myocardial infarction. The trial recruited 45 852 patients with AMI within 24 h of onset from 1250 hospitals in China who were randomly allocated to treatment or matching placebo. Ninety three per cent of the patients had ST-segment elevation or bundle branch block, and 7% had ST-segment depression. Treatment was to continue until discharge or up to 4 weeks in hospital.
A total of 22 961 patients were allocated to clopidogrel 75 mg daily, and 22 891 patients were allocated to matching placebo, in addition to aspirin 162 mg daily; 93% of patients completed the treatment. Results indicated that allocation to clopidogrel produced a highly significant 9% (95% CI 3% to 14%) proportional reduction in death, reinfarction or stroke, corresponding to nine fewer events per 1000 patients treated for about 2 weeks. There was also a significant 7% (95% CI 1% to 13%) proportional reduction in any death. Considering all fatal, transfused or cerebral bleeds together, no significant excess risk was noted with clopidogrel, either overall or in patients aged >70 years or in those given fibrinolytic treatment.
A total of 22 929 patients were allocated to metoprolol (up to 15 mg intravenously then 200 mg by mouth daily), 22 923 to placebo; 89% patients completed the treatment. The trial found that either composite of death, reinfarction or cardiac arrest, or death from any cause during the scheduled treatment period was significantly reduced by allocation to metoprolol. Allocation to metoprolol was associated with five fewer people having reinfarction and five fewer having ventricular fibrillation per 1000 treated. Overall, these reductions were counterbalanced by 11 more per 1000 developing cardiogenic shock. There was a substantial net hazard in haemodynamically unstable patients, and moderate net benefit in those who were relatively stable (particularly after days 0–1).
CCS-2/COMMIT demonstrated that clopidogrel 75 mg daily plus aspirin and other standard treatment safely reduced mortality and major vascular events in hospital for patients with AMI, while using metoprolol up to 15 mg intravenously then 200 mg by mouth daily at an early stage for patients with AMI may not be appropriate for Chinese patients.
Cardiac intervention in China started in 1984 with percutaneous transluminal coronary angioplasty. A total of 8000 patients underwent percutaneous transluminal coronary angioplasty in 1999, 11 753 in 2000, 16 345 in 2001 and about 90 000 in 2005. Percutaneous coronary intervention (PCI) has also been performed more frequently in China in recent years. The success rate (97% in 2001) was similar to that reported from other countries. Emergency PCI was performed for 2820 patients in 2001. The Chinese registry of unprotected left main coronary artery stenting (CHANCE study) recruited 224 patients who underwent elective unprotected left main coronary artery stenting with bare metal stents. After 2–73 months (mean (SD) 15.6 (12.3) months) of follow-up, the survival rate was 96.1% at 12 months, 92.9% at 24 months and 92.9% at 48 months; the event-free rate was 85.4%, 79.5% and 69.4%, respectively. The result suggested that unprotected left main coronary artery stenosis for selected patients was safe for long-term prognosis.
Cholesterol-lowering treatment with Xuezhikang for secondary prevention of CHD: China Coronary Secondary Prevention Study (CCSPS)21–23
Xuezhikang is a prepared Chinese medicine made of red-yeast rice fermentation products. It contains a family of monacolin-related substances, one of which is a naturally occurring lovastatin, in addition to unsaturated fatty acids and other substances. The CCSPS study is a multicentre, randomised, double-blind, placebo-controlled clinical trial which involved 66 centres around China to test the effectiveness of Xuezhikang on cholesterol lowering and secondary prevention of CHD. It recruited 4870 patients aged 18–75 years with a history of AMI from 28 days to 5 years; serum cholesterol ranged from 4.40 to 6.47 mmol/l (170–250 mg/dl). The eligible patients were randomised by coordinating centre and all lipids were tested in the central laboratory. The quality control of the laboratory for lipid measurement was constantly under the monitoring of the CDC of the USA. The outcomes were assessed independently by the end-point committee which was blinded to the treatment assignment. Among 4870 patients, 2429 were randomised to the group receiving treatment with Xuezhikang (0.6 g twice daily) and 2441 patients to the control group receiving placebo, in addition to their conventional treatment. The study subjects were followed up for an average of 4 years. Less than 2% of participants were lost to follow up but their survival status was known. Blood cholesterol and indices for safety were tested at weeks 6–8, and at the sixth month from randomisation. Baseline lipids and other comorbidities were comparable between treatment and control groups. Primary end points were non-fatal MI, fatal MI, sudden deaths and other coronary deaths. Secondary end points were other cardiovascular events, non-cardiovascular events, performance of cardiac intervention procedures (PCI or coronary artery bypass grafting, or both), and admission to hospital for any reason as well as any causes of death. Table 2 shows the change in lipid levels and the risk reduction of end points. A similar benefit was demonstrated in the subgroup analysis for elderly patients or patients with diabetes at baseline.
There was no significant difference in side effects or abnormal laboratory results between the treatment and placebo groups.
Varieties of red-yeast rice products are available and widely used as a traditional Chinese medicine or healthy supplement agents for treatment or prevention of cardiovascular disease. The CCSPS evaluated its efficacy in prevention of recurrence of CHD with a large-scale RCT. The results suggested that the product was effective in preventing the recurrence of coronary events and total deaths for patients with CHD without severe complications or a very high lipid profile. The use of Xuezhikang and similar products in the Chinese population and its impact on the prevention of CHD is worth investigating further.
MANAGEMENT OF CHD: PATTERN OF PRESCRIPTIONS
There is no systematic registration of prescriptions for the management of CHD in China. Data from the baseline information or the background treatment obtained from large clinical trials on AMI suggest that patients are more likely to be given nitrate in China. Patient management has changed (table 3) over the time following the available valid evidence from large RCTs. Over the past decade, more patients have been prescribed aspirin, ACE inhibitors and β blockers, but fewer patients have been given calcium antagonists.
Fast economic development in China has improved most people’s living conditions, but it has also resulted in some unhealthy, energy-dense food and tobacco products becoming affordable, especially in rural and in younger populations, those who lack sufficient knowledge about preventing cardiovascular disease and do not have adequate healthcare service. The burden of CHD in the Chinese population has been increasing; this is partly owing to the increasing incidence of CHD caused by more hypertension, hyperlipidaemia, overweight, diabetes, etc, and partly owing to the increase in the number and proportion of the aged population. Although we have made some progress in the research, management and prevention of CHD in the Chinese population, which have provided important evidence and built up the ability to control the disease, combating the epidemic of CHD is still a huge challenge for the health policy makers and healthcare system in China.
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