|Year : 2016 | Volume
| Issue : 4 | Page : 1-5
The “Chinese Dose” of statin
Department of Geriatric, Chinese PLA General Hospital, Beijing, China
|Date of Web Publication||26-Dec-2018|
Prof. Ping Ye
Department of Geriatric, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, 100853 Beijing
Source of Support: None, Conflict of Interest: None
The benefits of atherosclerotic cardiovascular disease prevention/treatment and lipid-lowering therapy come from the reduction of cholesterol itself. However, based on safety considerations, all guidelines note that high-intensity statin therapy is not suitable for the Asian/Chinese population. Therefore, moderate-intensity statin therapy is more beneficial for the Chinese population. However, for some very high-risk patients when moderate-intensity statin cannot satisfy the lipid-lowering needs, statin combination with ezetimibe is an ideal choice.
Keywords: Cardiovascular disease, coronary heart disease, dyslipidemia, statin
|How to cite this article:|
Ye P. The “Chinese Dose” of statin. Cardiol Plus 2016;1:1-5
| Introduction|| |
With the development of a social economy, the Chinese national lifestyle has undergone profound changes. Given the accelerated aging of the population and the urbanization process, the prevalence of risk factors for cardiovascular diseases is obvious; therefore, the number of patients with cardiovascular diseases continues to increase.
In the last decade, mortality from atherosclerotic cardiovascular disease (ASCVD) has increased rapidly, and ASCVD has become the leading cause of mortality in China and throughout the world. According to the “Report on Cardiovascular Diseases in China 2015”, mortality from cardiovascular diseases is the leading cause of death among urban and rural residents; it accounts for 44.6% of deaths in rural areas and 42.51% in urban areas. In other words, for every five deaths, two are the result of cardiovascular diseases. The social burden of cardiovascular diseases is increasing gradually, and the prevention and treatment of cardiovascular diseases has become a significant public health issue. Survey data show that hypercholesterolemia is the greatest contributor to the rising cardiovascular mortality rate in the Chinese population over the last 20 years.
After more than 100 years of study, the correlation between cholesterol and human ASCVD has become increasingly clear. A large number of epidemiological survey studies and clinical trials in different fields have further confirmed that hypercholesterolemia is the cause of atherosclerosis and that reducing cholesterol can prevent ASCVD. The results of the Framingham Heart Study in 1984 indicated that high blood cholesterol levels increase the risk of developing cardiovascular and cerebrovascular events; when the total cholesterol level was reduced by 1%, the risk of coronary heart disease decreased by 2%–3%. The results of the Multiple Risk Factor Intervention Trial published in 1990 showed that cholesterol level and cardiovascular mortality had a clear correlation; when the total cholesterol level was reduced by 1%, the risk of coronary heart disease decreased by 2%.
The meta-analysis of the Cholesterol Treatment Trialists' (CTT) Collaboration in 2010 covered 26 randomized studies on statins and included a total of 170,000 patients. The results showed that the active reduction of low-density lipoprotein-cholesterol (LDL-C) led to increased clinical benefits. The results of 5 randomized trials comparing intensive and regular statin therapies (Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial, the Aggrastat to Zocor trial, the Treating to New Targets trial, the Incremental Decrease in Endpoints through aggressive lipid lowering (IDEAL) trial, and the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine trial) showed that compared with conventional statin therapy, intensive statin therapy could further reduce coronary mortality and the incidence of nonfatal myocardial infarction by 13% (P < 0.0001), the incidence of coronary revascularization by 19% (P < 0.0001), and ischemic stroke by 16% (P = 0.005). These results suggest that the intensive reduction of LDL-C levels can result in increased cardiovascular and cerebrovascular benefits, thus, supporting the concept of intensive statin therapy.
Based on this concept, the “2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults” (abbreviated hereafter as “2013 ACC/AHA Guideline”) discarded the previous target value for LDL-C, described four populations that could benefit from statins, and emphasized the clinical use of intensive statin therapy. At the same time, the 2013 ACC/AHA Guideline noted that intensive statin therapy is not suitable for the Asian population 7, which prompted us to determine which statin dose is suitable for the Chinese population.
| Consideration of the “Chinese Dose” of Statins|| |
What is “Chinese dose” of statins?
The newly released “Chinese Guidelines on the Prevention and Treatment of Dyslipidemia in Adults (2016 edition)” (abbreviated hereafter as “the New Guideline”) proposes that the clinical benefits in the reduction of ASCVD events resulting from statins use show a positive linear correlation with the resulting decrease LDL-C levels and that the clinical benefits of statin therapy result from the effects of LDL-C reduction. Although recent guidelines in other countries recommend the clinical use of high-intensity statin therapy (equal to the maximum allowable dose) at the beginning of treatment, the enhanced benefits and safety of using the maximum allowable dose of statins have not been confirmed for the Chinese population. Therefore, the New Guideline recommends the routine use of moderate-intensity statin therapy for the Chinese population with dyslipidemia (this daily dose can reduce LDL-C by 25%–50%). This can be considered as “Chinese dose of statin.”
The moderate-intensity statin therapy recommended in the New Guideline is based on the consideration of risk-stratified management, efficacy, safety, and health economics. The New Guideline suggests that in clinical practice, the basic target cholesterol level of lipid-lowering therapy should be based on the different ASCVD risk levels. According to the New Guideline, reducing the LDL-C level to below 1.8 mmol/L is only required for patients at very high risk of ASCVD, while the target LDL-C values for high-risk and low- to moderate-risk patients are set at <2.6 mmol/L and <3.4 mmol/L, respectively. Therefore, in terms of stratified management, not everybody requires intensive lipid-lowering therapy. Although further reductions in LDL-C levels could result in increased clinical cardiovascular benefits, the drug-related adverse reactions would increase significantly. When the dose of statins doubles, the cost of treatment increases; furthermore, the increase in the LDL-lowering efficacy is smaller (6% of the overall statin efficacy). Therefore, even from a health economics standpoint, moderate-intensity statin therapy should be selected as the initial statin therapy regimen.
Why is it called the “Chinese dose”?
Moderate-intensity statin therapy is called the “Chinese dose' based on the blood lipid characteristics of Chinese people and validation in clinical studies.
First, the Chinese population has a lower average cholesterol level compared with other populations. National studies on diabetes mellitus and metabolic disorders in China indicate that the average LDL-C level of Chinese residents is 103 mg/dL (2.68 mmol/L) and that the LDL-C level in nearly 80% of Chinese patients is below 130 mg/dL (3.37 mmol/L). Even in very high-risk populations, such as patients with coronary heart disease, data from a number of studies in China show that their LDL-C level is approximately 112 mg/dl (2.9 mmol/l), which is not very high.,, Therefore, moderate-intensity statin therapy (i.e., that which reduces the LDL-C level by 25%–50%) can achieve the LDL-C target value in the majority of moderate-and high-risk Chinese patients with hyperlipidemia and even in some of very high-risk patients.
Next, the statin dose required by Chinese patients differs from the requirements for the European population. The Heart Protection Study 2 – Treatment of high-density lipoprotein to reduce the incidence of vascular events (HPS2-THRIVE) is a multicenter, randomized, double-blind, and placebo-controlled collaboration between China and Europe. The study included a total of 25,673 ASCVD patients. In this study, LDL-C was reduced to 1.51 mmol/L (58 mg/dl) in 74% of Chinese patients after the administration of 40 mg simvastatin (moderate-intensity statin therapy, as defined by Chinese guideline); conversely, only 1/3 of the European patients achieved the 1.74 mmol/L level after the administration of 40 mg simvastatin. Gene polymorphism results in different baseline levels for different patients. These results further confirm that the statin dose required by Chinese ASCVD patients differs from that required by the European population.
Clinical advantages of the “China dose”
In recent years, the return of the “cholesterol hypothesis” has powerfully proven that reducing LDL-C and not intensive statin therapy is the goal of treatment. The PROVE IT-Thrombolysis in Myocardial Infarction 22 study showed that the endpoint benefit of high-intensity statin therapy did not differ from that of moderate-intensity statin therapy in subjects with a baseline blood lipid LDL-C level below 132 mg/dL (3.4 mmol/l).
In recent years, many clinical studies in China have compared high-intensity and moderate-intensity statin therapy (e.g., the China Intensive Lipid Lowering with Statins in Acute Coronary Syndrome (ACS) (CHILLAS) study, the Intensive Statin Therapy for Chinese Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention (ISCAP) study, and the Asian Lipitor Pretreatment in ACS (ALPACS) study). The CHILLAS study was the first multicenter study to compare the efficacy and safety of intensive statin therapy and moderate-dose statin therapy in Chinese ASC patients 15. The study results showed that intensive statin therapy did not produce greater cardiovascular benefits than moderate-dose statin therapy (heart rate: 1.39, P = 0.261). An analysis of the results showed that with 3 months of therapy, the LDL-C reduction in the intensive statin therapy group was only 6.4% higher than that in the moderate-dose statin therapy group. The meta-analysis of the CTT collaboration previously confirmed 6 that the major endpoint benefits directly depend on the level of LDL-C reduction; when the difference in LDL-C levels between the statin group and the placebo group reached 30%–40% and the differences in LDL-C levels between the moderate-dose group and the high-dose statin group reached ≥20%, significant cardiovascular benefits were obtained. The difference in LDL-C levels between the two groups in the CHILLAS study was almost negligible, with corresponding cardiovascular benefits.
The ISCAP and ALPACS studies obtained results similar to those of the CHILLAS study. The ISCAP study included Chinese patients undergoing elective percutaneous coronary intervention (PCI). The results showed that the use of intensive atorvastatin before PCI could not reduce the incidence of 30-day and 6-month major adverse cardiovascular events. The ALPACS study was a collaboration between China and South Korea. The results of that study also indicated that high-dose atorvastatin loading before PCI in Asian (Chinese and Korean) populations could not obtain increased cardiovascular benefits within 30 days.
The publication of the negative results of intensive statin use in these three clinical studies further confirms that in Chinese patients, the benefits of statin therapy arise from the reduction of cholesterol levels rather than “the pleiotropic effect.” The fundamental benefit of statins requires long-term adherence.
A previous pharmacokinetics study confirmed that after the administration of the same dose of statins, the area under the plasma drug concentration-time curve and the maximum peak concentration of plasma drug for Asians were approximately two times those of Caucasians, suggesting that Asians are more sensitive to statins. Clinical studies have also confirmed that the safety of statins has racial differences. The HPS2-THRIVE study results showed that with the same statin dose, the incidence rate of ALT >3×ULN in European patients was 0.02%/year, while that in Chinese patients was 0.24%/year. The incidence rate of any muscle disease was 0.07%/year in European patients and 0.66% in Chinese patients. The incidence rate of muscle diseases and increased liver enzymes in the Chinese population was approximately 10 times higher than that in the Western population. Even in Europe, the rate of high-intensity statin use is not high. Data show that the rate of high-intensity statin use among European ACS patients is below 27%. The European Atherosclerosis Society (EAS) noted that poor tolerance is the major reason for dropping out of intensive statin therapy. Therefore, Chinese patients, who have lower statin tolerance, should undergo Chinese dose of statin therapy.
In terms of cost, Professor Hu noted that 80 and 10 mg tablets of atorvastatin cost the same in the USA, and after patent protection expired, the price of 80 mg generic atorvastatin was approximately 0.34 US dollars (approximately 2 RMB yuan). However, in China, the administration of 80 mg atorvastatin costs approximately 40 RMB yuan every day, resulting in an unsatisfactory cost/benefit.
How to use the “Chinese dose” well
The clinical advantage of the “Chinese dose” is obvious and imperative; how, then, can clinicians use the ‘Chinese dose” well? In this era of personalized treatment, clinical decision-making should be patient-centered and should comprehensively consider the treatment goals, ASCVD risk reduction, drug costs, patient preference, drug interactions, and possible side effects.
In 2003, a meta-analysis of the effect of LDL-C reduction through statins on ischemic heart disease and stroke showed that the incidence of ischemic heart disease events (ischemic heart disease-caused mortality and nonfatal myocardial infarction) decreased by 11% in the 1st year of statin therapy, by 24% in the 2nd year, by 33% in years 3–5, and by 33% in years 6 and after. These results confirmed that with increased duration of statin treatment, the risk of developing myocardial infarction and sudden death is lower.
Overall, statin therapy, especially adherence to long-term statin therapy, can result in increased cardiovascular benefits. Nonetheless, the statin use rate for Chinese ASCVD patients is still very low. In the HPS2-THRIV study, the rate of statin use among Chinese ASCVD patients was only 48.5%, which was considerably lower than that of the European population (60.3%); furthermore, the percentage of patients who used statins for more than 3 years was only 8.9%. Another study examining the use of secondary preventive medications in Chinese patients with coronary heart disease showed that the rate of statin treatment among Chinese patients also decreased annually, only 46% of patients were taking statins for more than 5 years.
Based on the benefits of long-term statin treatment, Professor Hu in his published article clearly noted that the current major focus of statin use in China should not follow the trend of encouraging large doses of statins; instead, the focus should be on encouraging patients who require statins to start early and remain on them and not to reduce their dosage or withdraw from treatment. With early statin use, patients can obtain benefits earlier, and adherence to statin use can result in long-term benefits.
| Advancing to the Era of Combined Lipid-Lowering Therapy|| |
What is the current treatment status of Chinese patients with dyslipidemia? The DYSlipidemia International Survey-China (DYSIS-China) study is a nationwide survey of 25,697 patients receiving lipid-lowering treatment for at least 3 months in 122 hospitals in 22 provinces and cities in China that aims to understand the use of lipid-lowering drugs and the achievement of target blood lipid levels. The results showed that 71.1% of patients belonged to the high-risk/very high-risk population and that 88.9% of patients used a single statin agent for treatment, which mainly comprised moderate-intensity statin treatment (e.g., a lipid-lowering effect equivalent to 20 mg or 40 mg simvastatin/day). However, the percentages of high-risk and very-high-risk patients who did reach the goal were 39.7%, the DYSIS-China study results are thought-provoking. The current condition in China that the high-risk/very high-risk patients with dyslipidemia were mainly treated with a single statin agent at moderate intensity is not ideal. How can we change this status to increase the target lipid reaching rate in these very high-risk patients?
Current guidelines/expert consensuses are usually based on the use of risk factors and ASVCD to perform risk stratification on patients with dyslipidemia, thus resulting in the stratified management of blood lipids, including the formulation of personalized blood lipid treatment goals and the selection of appropriate lipid-lowering treatment regimens.
For very high-risk patients, moderate-intensity statin therapy cannot satisfy their intensive lipid-lowering requirements (LDL-C <1.8 mmol), but high-intensity statin therapy carries safety concerns. In addition, Asian/Chinese patients have worse tolerance of statins. Therefore, the demand for clinically effective and safe intensive lipid-lowering treatment regimens in China is greater than that in Western countries.
The return of the “cholesterol hypothesis” questions the unique status of statins-dominated treatment regimes. Regardless of the types and doses of lipid-lowering drugs or whether a combination of compounds is used, lowering LDL-C levels are the key to treatment. Thus, nonstatin drugs are gradually entering into consideration. Ezetimibe is currently the only cholesterol absorption inhibitor on the market worldwide; when combined with statins, the agents complement each other to further enhance their cholesterol-lowering efficacy, making this combined treatment equivalent to the maximum effect produced by 8 times the statin dose. When ezetimibe is combined with moderate-intensity statin therapy, LDL-C is reduced by more than 50%,, making the combination of ezetimibe and statins the preferred intensive lipid-lowering treatment regimen in Chinese.
The release of the improved reduction of outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study results in 2015 further established the status of the ezetimibe/simvastatin combination regimen as the preferred intensive lipid-lowering treatment. The IMPROVE-IT study suggested that for very high-risk patients, such as ACS patients, reducing LDL-C to 50 mg/dl could further decrease the risk of cardiovascular events; in addition, the long-term intensive reduction of LDL-C (in the study, 2/3 had initial combination therapy) could reduce the total risk of both first-time and recurrent overall cardiovascular events by 9%. In terms of safety, there was no significant difference between the combination therapy group and the single-statin treatment group. Further subgroup analysis based on LDL-C levels showed that the safety of the intensive LDL-C reduction regimen was still excellent and even in the LDL-C <30 mg/Dl group.
The release of the IMPROVE-IT study results had an enormous impact on the current concept of cholesterol-lowering therapy. The commentary article published in the New England Journal of Medicine suggested that the LDL hypothesis should now be considered the “LDL principle,” meaning that regardless of the types and doses of lipid-lowering drug, lowering LDL-C levels is the key to treatment.
| Conclusion|| |
The benefits of ASCVD prevention/treatment and lipid-lowering therapy come from the reduction of cholesterol itself. However, based on safety considerations, all guidelines note that high-intensity statin therapy is not suitable for the Asian/Chinese population. Therefore, moderate-intensity statin therapy is more beneficial for the Chinese population. However, for some very high-risk patients when moderate-intensity statin cannot satisfy the lipid-lowering needs, statin combination with ezetimibe is an ideal choice.
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Conflicts of interest
There are no conflicts of interest.
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