Dyslipidemia and Management of Atherosclerotic Cardiovascular Diseases in China: New Evidence and New Guidelines

Dayi Hu

Introduction

The 2016 revision of the “Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults” is the outcome of the joint efforts of the members of an expert panel for more than 1 year,and is based on the 2007 guidelines. There is no doubt that the release of the 2007 guidelines greatly facilitated the management of dyslipidemia and the prevention and treatment of atherosclerotic cardiovascular diseases (ASCVDs) in China. However,an update of the guidelines for the management of dyslipidemia in Chinese adults is urgently needed since huge changes have occurred in the concepts of dyslipidemia research and control during the last decade.

During the past 2 decades, the expert panels have always complied with the following three principles throughout the formulation of the ”Suggestions for the Prevention and Treatment of Dyslipidemia”(1997), the 2007 “Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults,” and the 2016 revised guidelines:

1. During the formulation of Chinese guidelines,international guidelines for the management of dyslipidemia are used for reference; however,the data and evidence from Chinese studies should be fully emphasized. Foreign guidelines cannot be followed completely, and Chinesespecific ones should be formulated.

2. The formulation of guidelines is a pure public welfare and scientific activity, which cannot be affected by commercial benefits.

3. All guidelines are formulated by an expert panel consisting of well-known and very experienced professionals, and the final consensus is achieved by joint discussion based on the review and evaluation of all captured evidence.

In addition, the release of the guidelines is approved by the Bureau of Disease Prevention and Control,National Health and Family Planning Commission,People’s Republic of China.

New Situation and New Challenges for the 2016 Guidelines

The 2007 guidelines were formulated mainly on the basis of the findings of epidemiological studies in China, with a highlight of stratification of the risk of cardiovascular diseases, including stroke, based on Chinese national data. Notably, the weight of hypertension was increased in the risk stratification since ischemic stroke is highly prevalent in China.Until 2007, there had been only one randomized,double-blind clinical trial to test the efficacy of Xuezhikang capsules for the secondary prevention of myocardial infarction in China. Since 2007 there have been an increasing number of intervention studies regarding dyslipidemia in China. In the Sino-European Collaborative HPS-2 THRIVE study, 12,000 Chinese patients were recruited.

The 2013 cholesterol and ASCVD guidelines,which were released by the American College of Cardiology (ACC) and the American Heart Association (AHA) in 2014, completely subverted the conventional Adult Treatment Panel (ATP) systems that had been proposed for many years. The 2013 guidelines proposed removal of a dyslipidemia target, including low-density lipoprotein cholesterol (LDL-C), listed four kinds of populations requiring statin therapy, and recommended highdose and high-frequency statin interventions, which were simultaneously questioned and opposed by the National Lipid Association, the European Society of Cardiology, the European Atherosclerosis Society, the International Atherosclerosis Society,and Chinese lipid experts.

Recently, a series of wrong viewpoints regarding dyslipidemia intervention and ASCVD prevention and treatment have emerged in China because of commercial benefits. Most notably, the multiple efficacies of statins, in addition to their leading role of anti-in flammatory action, such as lowering cholesterol levels, were overstated, on the basis of foreign small and short-term follow-up exploratory studies observing surrogate end point. Then a sequential therapy with 80 mg atorvastatin for acute coronary syndrome (ACS) and during the perioperative period of percutaneous coronary intervention(PCI) was proposed. More importantly, this wrong concept has been extensively transferred to countylevel hospitals.

Major Highlights of the 2016 Guidelines

Inconsistent with the recommendations in the ACC/AHA guidelines, the “Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults” (2016 revision) defines an assigned value for LDL-C according to the stratification of the risk of developing ASCVD. After full discussion and a ballot, the 2016 guidelines recommend a decrease of LDL-C concentration from less than 2.0 mmol/L (80 mg/dL) in 2007 to less than 1.8 mmol/L (70 mg/dL)in 2016 for the secondary prevention of ASCVD.

The 2016 guidelines insist on the cholesterol theory, and exclude the overestimation of the multiple efficacies of statins.

On the basis of Chinese national data and evidence, the new guidelines emphasize that most Chinese patients do not require and cannot tolerate the high-frequency and high-dose statin therapy recommended in the ACC/AHA guidelines, and propose a moderate-frequency or low-frequency statin therapy and a combination regimen if required,adapted to actual Chinese conditions.

The sequential therapy with high-frequency and high-dose atorvastatin is not recommended for ACS and during the perioperative period of PCI in the 2016 guidelines.

Recommendations for Lowering LDL-C Concentrations in the 2016 Guidelines

How should we understand the LDL-C target? With the publication of the new guidelines, still some people suggest revising the lipid-lowering target,and they address that the new European guidelines propose a 50% reduction of LDL-C concentration as compared with the baseline and an LDL-C concentration reduction to less than 1.8 mmol/L in extremely high-risk patients. Actually, after the release of the ACC/AHA guidelines in November 2013, the Chinese marketing department of a foreign company that manufactures statins immediately prepared a presentation to advocate the statement of 50/18 which intentionally put the reduction of LDL-C concentration by 50% relative to the baseline first. Chinese lipid expert team found that such a statement did not accord with the regulations for safe and effective use of statins and was not supported by the evidence from clinical studies,and it was proposed on the basis of commercial benefits. It might misguide the use of statins, endanger patients’ safety and increase the burden of medical insurance. Therefore the new guidelines clearly recommend that the target should be 18/50 rather than 50/18. In fact, the recommendation in the European guidelines at that time was right, which was for a reduction of LDL-C concentration to less than 1.8 mmol/L in extremely high-risk patients, and if such a target was not achieved, the LDL-C level was recommended to be reduced to 50% of the baseline level. The target of lowering LDL-C concentration to less than 1.8 mmol/L can be achieved in most Chinese patients following statin therapy at moderate or low doses. In addition, such a treatment regimen is safe, saves medical expenses, and results in a high adherence among Chinese patients. Even in European and American patients, treatment with statins at the largest dose is not required to achieve this target.

The 2016 guidelines show that moderate and low doses are feasible for most Chinese patients requiring statin therapy, and there is no clinical evidence to support the use of high-dose and high-frequency statin therapy for ACS or during the perioperative period of PCI since all results from Chinese clinical trials are negative. In addition, the new guidelines recommend administration of statins with an increased dose or a combination with non-statin agents for patients who do not achieve the LDL-C target following moderate-dose or low-dose statin therapy. Currently, ezetimibe is the only agent with clear-cut clinical evidence. After the online publication of the new guidelines, an enterprise advocated that the statin dose should be increased first until patients cannot tolerate the treatment, and then combination therapy should be considered.This suggestion is not suitable for actual Chinese clinical practices, and attempts to mislead Chinese clinical practices in a wrong direction with foreign guidelines. Firstly, the mean baseline LDL-C concentration is much lower in Chinese patients than in European and American patients, and most Chinese patients may achieve the LDL-C target following moderate-dose or low-dose statin therapy. Secondly,the incidence of adverse reactions is 10 times greater in Chinese patients than in European patients following treatment with simvastatin at a daily dose of 40 mg, and severer adverse reactions are seen in Chinese patients than in European patients. The results of the IDEAL study, which aimed to compare the effects of 80 mg atorvastatin versus 40 mg simvastatin on the risk of cardiovascular disease among patients with a previous myocardial infarction, showed no significant difference in the clinical benefits from the two treatment strategies, and a significantly higher incidence of adverse events was seen with atorvastatin treatment than with simvastatin therapy. Thirdly, treatment with a double dose of a statin increases the effectiveness of LDL-C concentration lowering by 6%, whereas statin therapy in combination with 10 mg ezetimibe results in a 20% increase in the LDL-C-lowering efficacy,and such an increase is mainly attributed to 5 mg ezetimibe. It is therefore considered that the combination of statin therapy and ezetimibe therapy at low doses results in a high increase in the treatment efficacy and low occurrence of adverse reactions. In addition, 10 mg atorvastatin or other statins in combination with 10 mg ezetimibe has a comparative or higher efficacy of lowering LDL-C concentration than 80 mg atorvastatin alone. Fourthly, atorvastatin given at 10 or 80 mg is charged at the same price in Europe and America; however, the cost of 80 mg atorvastatin is eight times higher than that of 10 mg atorvastatin in China. The French experts who participated in the formulation of the European guidelines for lipid management, presented at the 2016 Great Wall International Congress of Cardiology,reported that atorvastatin is given to 80% of French patients at a dose of 10 mg. Chinese physicians studying at the Mayo Clinic have witnessed a dose of 20 mg atorvastatin in most of the prescriptions in the hospital. Experiences from French clinical practices showed that patients with familial hypercholesterolemia who required high-frequency and high-dose statin therapy were usually intolerant of 80 mg atorvastatin treatment, and then combination therapy was given.

In summary, the 2016 guidelines were formulated on the basis of public welfare, scientific and Chinese-specific evidence, which does not blindly follow the ACC/AHA guidelines and decisively rejects commercial benefits. The release of the new guidelines indicates the completion of the historical succession of the consensuses proposed by the China Cholesterol Education Program. Explaining and implementing the new guidelines is our job and duty, and is the responsibility of the China Cholesterol Education Program. Coincidentally,the new guidelines are released after the National Health Conference of China has been held, I hope they will facilitate the prevention and treatment of ASCVD in China.

Con flict of Interest

This article is based in part on an article first published in theChinese Journal of Cardiology(2016;44(10):826–27).