Atherosclerotic vascular diseases such as coronary heart disease (CHD), ischaemic stroke and peripheral arterial disease (PAD) are the leading cause of death and disability worldwide.1 Each year about 500 000 and 2 million people in China suffer a myocardial infarction and stroke respectively, and the population disease rates have been increasing as a result of adverse changes in smoking, dietary patterns and lifestyle.2 In addition, there are about a further 6 million prevalent cases of CHD3 and 5 million of ischaemic stroke in China,4 who are all at significantly elevated risk of recurrent vascular events. During the past decades, large randomized trials have demonstrated reliably that long-term use of certain widely practical treatments such as statins, antiplatelet agents, beta-blockers and angiotensin-converting enzyme inhibitors (ACEI) are beneficial in reducing the risk of major vascular events among patients with existing atherosclerotic vascular diseases. Consequently, these treatments, especially lipid-lowering therapy with statins and antiplatelet therapy have become the mainstays of secondary preventive therapy for patients with atherosclerotic vascular disease.4-7
Despite significant improvements in the management of atherosclerotic vascular disease and the existence of various national and international guidelines, there are still substantial under-, over- and inappropriate uses of treatments in many patients with such conditions, with large variations in short- and long-term management of patients between different countries, different hospitals in same country and different conditions for which similar secondary preventions are indicated. Studies in Western countries showed that long-term aspirin and statin therapy were used routinely in patients with CHD, but to a less extent in patients with ischaemic stroke.8,9 A few studies have also reported on the use of secondary preventive medications in patients with atherosclerotic vascular disease in China, but each has its limitation, such as small sample size, being confined to a single city or single condition, or involving only in-hospital treatment.10-13 Consequently, there is still limited information about the overall pattern of long-term secondary prevention among patients with different types of atherosclerotic vascular disease in China. We reported here a large survey of long-term treatment patterns among 16 860 patients with different types of atherosclerotic vascular disease who were recruited from 72 sites in 14 cities in China, with particular reference to the long-term statin therapy.
This is a cross-sectional survey that was conducted between June 2007 and October 2009 involving 72 study sites in 14 cities. Studied people were those who attended screening clinics for a large international multicenter clinical trial, Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE).14 Of the hospitals involved, 24 were university-affiliated hospitals, and 21 contributed more than one study site. Of the 72 study sites, 45 were based in cardiology, 21 in neurology, and 6 in endocrinology or general medicine departments.
Potentially eligible patients were identified from in-patient and out-patient medical records in each hospital, typically covering a 12 months period. The main selection criteria were age of 50–80 years, prior history of atherosclerotic disease, such as one or more myocardial infarction, atherosclerotic cerebrovascular disease (CVD) (presumed ischaemic stroke, transient ischaemic attack or carotid revascularization), PAD (intermittent claudication or peripheral arterial revascularization), or diabetes mellitus plus other evidence of symptomatic CHD (stable or unstable angina, coronary revascularization, or acute coronary syndrome), and having no history of cancer within last five years, previous significant adverse reaction to a statin, active peptic ulcer disease or evidence of active inflammatory muscle disease. For identified candidates, detailed information about their disease diagnosis and supporting evidence for it (e.g., CT report for stroke cases) were further checked and verified centrally at the national study coordinating center in Beijing. Ethics approval for the pre-screening and screening process was obtained from the central ethics committee at the national coordinating center as well as from institute review boards at each participating hospital. All those who attended the screening clinics provided written informed consent.
In line with the study protocol, detailed information was collected at the screening visit by trained doctors through a face-to-face interview using a laptop-based questionnaire, which had comprehensive built-in checks to avoid missing values and minimize logical errors. The questionnaire included personal and demographic details, medical history, use of other medication and smoking and drinking habits. Standard operating procedures (SOPs) were provided to local investigators, and where necessary, standard definitions were used for reporting disease history (e.g., hypertension and diabetes) and risk factors (e.g., smoking). For current medication, all patients were asked to bring their drug bottles/packages to the screening visit, and the name of each drug being taken was checked and then entered into laptop through a central drug list incorporated into the system. For any statin use, further information on type, duration and dose was also recorded. All the collected data represented the patients' condition before they consider entry to the trial, and so was not influenced by the trial.
For data collected, percentage, mean or median (interquartile range) were calculated, adjusting simultaneously for age, sex and comorbidities. Chi-square tests were performed to test significant differences in drug use between different types of patients. A Logistic-regression model was used to assess the possible predictors of statin use. Odds ratios (OR) and 95% confidence intervals (CI) were reported for various comparisons. Data analyses were performed using SPSS 13.0 software package (SPSS Inc., USA). A two-sided P <0.05 was used to denote statistical significance.
Total 16 860 patients with age of (63±8) years attended a screening clinic between June 2007 and October 2009. The mean age was slightly higher in women than in men (65 years vs. 63 years), and 26% patients were women (Table 1). Of these patients, 39% reported diabetes, 64% with hypertension and 58% were ever smokers (smoked daily for at least 1 year now or in the past), with the smoking prevalence being significantly higher in men than in women (73% vs. 15%). Everyone screened had some evidence of atherosclerotic disease, 78% with a prior history of CHD, 40% with CVD (mainly ischaemic stroke), and 5% had PAD, with 21% reported more than one of these three conditions. The median time between the interview and the first diagnosis of vascular disease was 18 months (range, 9–40 months), with no significant difference between different types of patients.
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Table 1. Characteristics of surveyed patients (n=16 860)
Medications for secondary prevention
Of various treatments being taken, antiplatelet therapy was most frequently used, with 83% of the patients reporting current use. The proportion was much higher in patients with prior history of only CHD (90%) than in patients with only CVD (66%) or PAD (46%). Of those who used antiplatelet therapy, about 20% (18% of all) involved dual antiplatelet therapy with aspirin and clopidogrel, and again, the proportion was much higher in CHD than in other two conditions (25% vs. 1% vs. 1%, P <0.01 respectively). Statins and beta-blockers were used by about half of the patients, again with the percentages for both drugs being significantly higher in CHD than in other conditions (61% vs. 10% vs. 22%, P <0.01; 64% vs. 9% vs. 13%, P <0.01). ACEI, calcium channel blocker (CCB) and angiotensin II receptor blocker (ARB) were less frequently used in this group of patients (28%, 28% and 13% respectively) with the proportion again significantly higher in CHD than in other conditions. By contrast, use of any Traditional Chinese Medicine (TCM) was much more common in patients with CVD than in CHD patients (59% vs. 26%, P <0.01) (the type of TCM was not recorded) (Figure 1).
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Figure 1. Use of different medications by prior disease category. Results are the proportion of patients in that category taking each kind of medicine. CHD: coronary heart disease; CVD: cerebrovascular disease; PAD: peripheral arterial disease ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker; CCB: calcium channel blocker; TCM: traditional Chinese medicine. Statisitical analysis for difference of usage between different types of disease showed P <0.01 for all kinds of medicine.
Use of statin and possible correlates
Table 2 shows the percentage of statin use among patients with different types of condition by age, sex, and various other baseline characteristics. Both overall, and for specific conditions, the proportion of patients reporting statin use tended to decrease with increasing age, to be somewhat higher in men, in former smokers, in patients without hypertension or with diabetes and in patients treated in teaching hospitals. It also decreased significantly with increasing year since disease diagnosis, being 52%, 47%, 40% and 38% respectively for those with condition diagnosed <1, 1–2, 3–5 and >5 years ago, and this trend was particularly pronounced in patients with CHD (Table 2). After adjustment for various covariates, history of CHD was the strongest predictor of statin use in this dataset (7.51 folds higher use of statin compared with other conditions (95% CI: 6.61–8.53) with the opposite seen for a history of CVD (OR 0.51, 95% CI: 0.47–0.55). After allowing for co-morbidity, history of PAD had little effect on statin use although the number of patients involved was small. The higher rate of statin use in patients with CHD compared with those with other conditions appeared to be more pronounced at younger age, in men, in smokers, in patients without hypertension or diabetes, and in those who were diagnosed more recently.
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Table 2. Statin use by disease and patient characteristics (n (%))
Atorvastatin and simvastatin were the most widely used statins, each accounting for about 40% of overall statin use. The most commonly used doses for them were 10 mg and 20 mg daily respectively, each accounting for about 60% of the total use for each drug (Table 3). Across different types of conditions there was little difference in the main types and doses of statin routinely used.
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Table 3. Type and dosage of statins
This is one of the largest surveys of the use of secondary preventive treatments among patients with atherosclerotic diseases in urban China. Although not necessarily a nationally representative sample, it involved a large number of relatively unselected patients with various types of atherosclerotic conditions and covered a defined period of time and diverse regions, so the findings should represent reasonably well the current status of secondary preventive treatments for cardiovascular diseases in urban China. It showed that among Chinese patients with established atherosclerotic vascular diseases, there was substantial underuse of various proven secondary prevention treatments even though they are easily accessible. In particular, patients with CVD were poorly managed with only 10% of them treated with a statin and only two thirds with any antiplatelet therapy, both of which were clearly indicated for the condition. On the other hand TCMs were used by about 60% of the patients with CVD despite a lack of reliable randomized evidence about their effects. In CHD patients, antiplatelet therapy was commonly used but the use of statins, beta-blockers and ACEIs was still not optimal.
Over the past few decades, there have been improvements in the long-term care of the patients with CHD in Western countries.9,15 A survey in 22 European countries during 2006–2007 found that most patients with CHD were still taking various cardioprotective medications 6 months after discharge from hospital (aspirin 91%, beta-blockers 80%, statins 78% and ACEI 71%).9 This probably reflected to a large extent the continuation of routine use of such treatments during hospitalization. Indeed, data from the Global Registry of Acute Coronary Events (GRACE) in 26 413 patients from 14 countries in North America, South America, Europe, Australia, and New Zealand showed that by 2005 there was widespread use of various cardioprotective medications during hospitalization such as aspirin (95%), beta-blockers (91%), statins (85%) and ACEI (77%).16 A large outpatient registry showed similar rate of statin use (78%) among CHD patients in the USA.17 However, a recent published study showed that use of secondary prevention medications is low worldwide, especially in low-income countries and rural areas.18 Significant geographical variation was documented in an international registry, with particularly low use of statins in Asia, Eastern Europe and Latin America. Since the study included only about 700 patients from China, the information about long-term treatment use for CHD was extremely limited.19 Where results were available, they appeared inconsistent with each other.10-12 In the China Cholesterol Education Program (CCEP) of 4478 outpatients with CHD in 6 cities in 2006, 82% of patients were taking statins.10 However, the other two studies conducted during 2005–2007 involving 2278 and 2901 patients showed statins were taken by only about 60% of stable patients with history of acute coronary syndrome.11,12 Our findings for statin use in CHD patients are lower than those seen in CCEP but similar to the other two studies in China. The CCEP survey included only patients who attended outpatient clinics. They may use statins and other treatments better than those who were not included for regular medical consulting. Moreover, 79% of participants in CCEP had been diagnosed dyslipidemia and this may be another reason for the higher use of statins. In China, although the prescription of secondary preventive medicine for CHD at discharge was similar to Western countries,12 the long-term use of various proven therapies tended to be lower.
To date, much of the previous evidence on the long-term management of cardiovascular disease has been focused primarily on CHD, with little direct data on stroke patients. In general, patients with ischaemic stroke tend to be less well treated compared with CHD patients in many developed countries. Data from the Swedish Stroke Register showed that aspirin was prescribed in 80% and statin in only 40% of patients with ischaemic stroke at time of hospital discharge during 2005–2006. Among patients who received aspirin and statins at discharge, only about 60% of them were still taking them two years later.8 A small study in Beijing of 708 patients with cerebral infarction/transient ischaemic attack in 2006–2007 showed that aspirin and statin were used by 97% and 58% patients respectively at hospital discharge. However, to 3 months after discharge, only 73% and 19% were still taking these treatments, with only about 12% having measured blood LDL-C at <2.6 mmol/L.20 Our study provided further large scale evidence about the significant underuse of aspirin and statin (as well as many other treatments) in patients with ischaemic stroke in China.
This study found large variation in the use of statin among different types of patients. Of particular concern is the low frequency of statin use among certain high risk CHD patients, especially the elderly, and those with hypertension or diabetes. It is not entirely clear why such high risk patients, for whom the absolute benefits of statin and other treatments may be particularly great, would have less frequent use of treatment compared with other patients. This could be partly due to undue concern about increased adverse effects of treatment. This phenomenon of the so-called “treatment-risk paradox” associated with statin therapy has also been reported previously in Western populations.21 Furthermore, continued use of statins in CHD patients dropped substantially over time, a phenomenon also seen in many other populations.22
In this study, no information was collected about reasons for not taking statins. However, several possible reasons could be speculated upon based on the discrepancies observed between different types of patients in the study. First, the striking difference in statin use between CHD and CVD patients suggests that different attitude between cardiologists and neurologists may play an important role since secondary prevention is usually dictated by specialists in China. The clear and substantial benefits of statin treatment for patients with CHD started to emerge in 1994,23 whereas for stroke reliable evidence about the benefits of statins did not emerge until the publication of Heart Protection Study in 2002, which was further confirmed by the meta-analysis in 2005 and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial in 2006.5,24-26 Moreover, persistent concerns about the safety of long-term statin therapy in stroke patients may also explain the much lower use of statins stroke compared with CHD patients, especially since there is epidemiological evidence of an inverse association between risk of intracerebral hemorrhage and cholesterol levels,27,28 and cerebral hemorrhage is a more common cause of stroke in China compared with Western countries (estimates vary between about 20% and 50% of all strokes in China).29 Secondly, the treatment-risk paradox may be explained by misconceptions about benefit-harm trade off.21 Physicians may have disproportionally greater concern about adverse effects of statin in those patients with higher risk despite their standing most to gain. The potential hazards of statin therapy are extremely small in comparison with the clear benefits in high-risk patients,5,30 which highlights the importance of continuing education for both doctors and patients. Thirdly, cost may limit long-term use of statin. In China, it typically costs at least RMB 2600 yuan (1 dollar=RMB 6.3 yuan) for one year of treatment with 40 mg simvastatin daily, which amounts to about one fifth of the average annual income among an urban population and more than half in a rural population.31 In 2006-7, although about three-quarters of the urban population in China were covered by health insurance schemes, statin was only covered for a short period of time after hospital discharge in many areas.32 Furthermore, in most cities, the use of statin treatment was still guided by “target” of LDL-cholesterol, with the lipid-lowering treatment no longer being covered by the health insurance if the LDL-cholesterol is within the “normal reference range”. The more frequent use of aspirin, a much cheaper drug (e.g., RMB 240 yuan for one year of treatment of 100 mg daily), provides supportive evidence that cost could be a major factor in determining the long-term use of statin. With the recent progress in health care reform in China, expanding insurance coverage and reducing out-of-pocket payments should help increasing patients' adherence to secondary preventive therapy in longer term.
Despite the large sample size of relatively unselected patients, good coverage of diverse areas and standardized procedures with high quality data, the study is not without its limitations. First, the study mainly covered large and middle cities in China, so the results may not be generalisable to small cities or rural China, where the health care resources are much more limited.32 In small cities, the usage of secondary preventive therapy may be even lower. Secondly, although the study covered a defined period of time, the patients attended voluntarily and it is likely that those who attended may differ importantly from those who did not in their attitude and willingness to take treatments long-term. Thirdly, we do not have blood lipid levels available for all these screened patients since eligibility was based mainly on their prior disease history rather than lipid level.5,30
In summary, this large survey of relatively unselected patients shows that in urban China there is still substantial underuse of various effective secondary preventive treatments for atherosclerotic vascular disease, in particular, extremely low use of statins in patients with ischaemic stroke. This will be putting large number of patients at significantly elevated risk for recurrent vascular events. Further improvement to reduce the “evidence-practice” gap will require not only better delivery of proven therapies in a cost-effective and timely manner but also substantial reform of the health care system in China to improve access to good quality care.
Study Investigators: YANG Yue-jin, ZHENG Zhe (Fu Wai Hospital), XU Zhang-rong (The 306 Hospital of P.L.A.), SUN Ning-ling (People's Hospital, Peking University), GAO Wei (The Third Hospital, Peking University), ZHANG Shu-yang (Peking Union Medical College Hospital), WAN Zheng, SUN Yue-min, CHENG Yan (Tianjin Medical University General Hospital), LI Xin (The Second Hospital of Tianjin Medical University), LIU Ke-qiang, ZHANG Chun-sheng (Tianjin Union Medicine Centre), WANG Huai-zhen, ZHANG Zhe-cheng (Tianjin Third Central Hospital), ZHANG Huan (Tianjin Fourth Central Hospital), GUO Xu-kun (Tianjin Chest Hospital), LI Zhan-quan, CHEN Xiao-hong (The People's Hospital of Liaoning Province), LI Yin-jun (The Fourth People's Hospital of Shenyang), QI Guo-xian, ZHANG Chao-dong (The First Affiliated Hospital of China Medical University), SUN Ying-xian, MA Shu-mei (Shengjing Hospital of China Medical University), FENG Feng, TIAN Guo-ping (The First People's Hospital of Shenyang), JIN Yuan-zhe (The Fourth Affiliated Hospital of China Medical University), CHE Hang (Sujiatun District Central Hospital), DIAO Qing (The Fifth People's Hospital of Shenyang), WANG Dong, GE Zhi-ping (Baogang Hospital), SUN Gang (The Second Affiliated Hospital of Baotou Medical College), WANG Cai-li (The First Affiliated Hospital of Baotou Medical College), HAN Ya-jun (Inner Mongolia Autonomous Region Hospital), LIU Juan (The Affiliated People's Hospital of Inner Mongolia), WANG Dao-wen, WANG Wei (Tongji Hospital, Huazhong University of Science and Technology), CHEN Guo-hua (The First Hospital of Wuhan), GU Ye, WANG Jian-ming (Wuhan Puai Hospital), ZHAO Shi (The Central Hospital of Wuhan), Su Xi (Wuhan Asia Heart Hospital), Huang Zhen-wen, ZHANG Bo-ai (The First Affiliated Hospital of Zhengzhou University), ZHAO Yu-lan, LOU Ji-yu (The Second Affiliated Hospital of Zhengzhou University), ZHANG Lin (The Central Hospital of Zhengzhou), LI Dong-ye, SHEN Xia (The Affiliated Hospital of Xuzhou Medical College), FU Qiang, YU Zhi-gang (The Central Hospital of Xuzhou), ZHANG Hong-ju, ZHOU Lian-sheng (The First People's Hospital of Xuzhou), WU Wei-heng, RONG Liang-qun, WEI Xiu-e (The General Hospital of Xuzhou Mining Group), WANG Lan-ying (The Third People's Hospital of Xuzhou), ZHOU Chang-yong, PEI Hai-tao (The Affiliated Hospital of Medical College Qingdao University), ZHANG Fang, WANG Xu (Qingdao Municipal Hospital), YANG Ying (Qingdao Fu Wai Hospital), LI Wei-min, ZHANG Li-ming (The First Clinical College of Harbin Medical University), YU Bo, WANG Wei-zhi (The Second Affiliated Hospital of Harbin Medical University). ZHENG Yang, LIU Qing (The First Hospital of Jilin University), YANG Ping (China-Japan Union Hospital of Jilin University), PAN Hong-tao (The General Hospital of FAW), LIU Feng (Suzhou Kowloon Hospital, Shanghai Jiaotong University Medical School), ZHANG Yan-zhen (People's Hospital of Weifang), ZHAO Wei-dong, LIU Xin (The General Hospital of AISCO), XIAO Rui (Shuangshan Hospital of Anshan), LIU Bin (Tiexi Hospital of Anshan).
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