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Consensus and Guideline

Chinese Guideline on the Primary Prevention of Cardiovascular Diseases

Author Information
doi: 10.1097/CD9.0000000000000025

Abstract

Introduction

With an aging population and change in lifestyle, cardiovascular disease has become a major public health issue in China, threatening the health and wellbeing of Chinese population.[1,2] In response to the growing concern of cardiovascular disease, guidelines have been developed for the prevention and treatment of risk factors for cardiovascular diseases such as hypertension, dyslipidemia, and diabetes.[3–5] In 2011, the Chinese Society of Cardiology (CSC) of Chinese Medical Association issued the first “Chinese Guidelines for Prevention of Cardiovascular Diseases”,[6] which was updated in 2017.[7] The development and implementation of these guidelines have played a positive role in the prevention and treatment of cardiovascular disease in China. However, a primary prevention guideline focusing on comprehensive prevention and control of cardiovascular risk factors in China has not yet been developed. In 2016, the European Society of Cardiology (ESC) issued the “2016 European Guidelines on Cardiovascular Disease Prevention in Clinical Practice”,[8] while in 2019, the American College of Cardiology (ACC)/American Heart Association (AHA) issued the “2019 ACC/AHA Guidelines on the Primary Prevention of Cardiovascular Disease”.[9] However, given the significant differences in characteristics of cardiovascular disease and risk factors between Chinese and Western populations,[10] some aspects of the European and the United States guidelines are not fully applicable in the Chinese population. To improve the national capacity to prevent cardiovascular disease as a whole and to strive to achieve the strategic goals of the “Healthy China 2030” Planning Outline of reducing premature mortality of the 4 major chronic non-communicable diseases (cardiovascular disease, cancer, diabetes, and chronic respiratory disease) by 30% from 2015 to 2030 and implement the prevention-oriented strategy for chronic disease control, the “Chinese Guideline on the Primary Prevention of Cardiovascular Diseases” (hereinafter referred to as the Guideline) was developed under the leadership of the CSC in a joint collaboration of the Cardiovascular Disease Prevention and Rehabilitation Committee of Chinese Association of Rehabilitation Medicine, the Cardiovascular Disease Committee of Chinese Association of Gerontology and Geriatrics, and the Thrombosis Prevention and Treatment Committee of Chinese Medical Doctor Association. The Guideline was written with reference to the latest research evidence and related national and international guidelines, following the “Chinese Society of Cardiology of Chinese Medical Association's Recommendations on the Development of Guideline or Expert Consensus on Cardiovascular Disease and Document Writing Standards”. The Guideline adheres to the principles of science and justice to form a recommendation document based on the latest clinical research evidence to guide the practice of cardiovascular disease prevention in China. Comparisons between the current guideline and the 2011 and 2017 Cardiovascular Disease Prevention Guideline in China are shown in Supplementary Table 1 [https://links.lww.com/CD9/A8].

Methodology for developing the guideline

Organization structure

The development of the Guideline adheres to the “Chinese Society of Cardiology of Chinese Medical Association's Recommendations on the Development of Guideline or Expert Consensus on Cardiovascular Disease and Document Writing Standards”. Under the organization of the CSC guideline development working group, a joint guideline development committee and a guideline development working group were established, and corresponding authors, writing group members, and expert committee members were nominated. The expert committee includes healthcare professionals engaged in both clinical medicine (cardiology and endocrinology) and public health/preventive medicine (eg, epidemiology, nutrition, and sports medicine) to ensure broad representation.

Content and target population

The guideline working group unanimously agreed that the target population of this guideline is Chinese adults aged 18 years and older without an established clinical diagnosis of cardiovascular disease.

The guideline focuses on the primary prevention of atherosclerotic cardiovascular disease (ASCVD). ASCVD refers to the clinically diagnosed atherosclerotic diseases, including acute coronary syndrome, stable coronary artery disease, postoperative revascularization, ischemic cardiomyopathy, ischemic stroke, transient ischemic attack, and peripheral atherosclerotic disease. In view of the epidemiological characteristics of the high incidence of hemorrhagic stroke in China, the assessment and control of the total cardiovascular risk, including hemorrhagic stroke, is also emphasized with respect to blood pressure management. Other types of cardiovascular disease, such as heart failure, atrial fibrillation, and valvular heart disease, are not within the main scope of the Guideline.

Systematic literature review

Following extensive consultation and multiple rounds of discussion, the expert committee identified 6 key issues: risk assessment, lifestyle intervention, blood lipid management, blood pressure management, type 2 diabetes management, and aspirin use. The writing group members subsequently performed a systematic search of the literature for relevant publications on these core issues. Recently published systematic reviews were used as direct references, while domestic research evidence was added; where no recent systematic review was identified, a search strategy was formulated for systematic literature review. The quality of observational studies and randomized controlled trials (RCTs) was evaluated using the Newcastle Ottawa scale and Cochrane risk of bias tool, respectively. Where observational evidence lacked a core question, the writing group directly analyzed data from long-term cohort studies in China to extract first-hand evidence. Following the literature review and data analysis stages, the writing group provided recommendations on the core questions with reference to the relevant recommendations of recent international guidelines. Finally, the writing group and core expert committee discussed the core questions and reached a consensus on the class of recommendation (COR) [Table 1] and level of evidence (LOE) [Table 2] of the guideline.

Table 1 - Class of recommendation
Class of recommendation Definition Suggested wording to use
I Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, or effective Is recommended or is indicated
II Conflicting evidence and/or a divergence of opinion exists regarding the usefulness/efficacy of the treatment or procedure
 IIa Weight of evidence and/or opinion is in favor of the usefulness/efficacy of the treatment or procedure Should be considered
 IIb Usefulness/efficacy is less well established by evidence and/or opinion May be considered
III Evidence and/or general agreement that a given treatment or procedure is not useful/effective; and may be harmful in some cases Is not recommended

Table 2 - Level of evidence
Level of evidence Definition
A Evidence derived from multiple randomized clinical trials or meta-analyses
B Evidence derived from a single randomized clinical trial or multiple large non-randomized studies
C Consensus of the experts and/or small studies, retrospective studies, or registries

Writing and reviewing

The writing group designated by the guideline development working group was responsible for the 6 sections of the guideline: risk assessment, lifestyle intervention, blood lipid management, blood pressure management, type 2 diabetes management, and aspirin use. Each section was reviewed by core members of the expert committee. The manuscript was revised by the writing group members and was reviewed and approved by all the members of the expert committee. The Guideline was finalized following subsequent review and approval by the corresponding authors.

Further information

The full text and simplified versions of the guideline will be published in the form of books, journal articles, and multimedia materials for the use of clinicians, public health practitioners, and researchers. Despite the efforts of the authors, deficiencies in the guideline may remain, such as the lack of high-level evidence for some recommendations and the fact that the majority of clinical trial evidence is derived from Western populations.

Epidemiology of cardiovascular disease in China and challenges in primary prevention

Epidemiology of cardiovascular disease in China

Cardiovascular disease, a major public health concern threatening the health and wellbeing of Chinese adults, leads to 4 million deaths per year and accounts for over 40% of total mortality in China. It is also a major cause of disability and impaired quality of life. Stroke and ischemic heart disease are the main manifestations of cardiovascular disease, ranking first and second as causes of death in China.[2] With the aging of the population and adverse trends in cardiovascular disease risk factors, the morbidity and mortality of cardiovascular disease are increasing year on year. Mortality associated with ASCVD, which is dominated by ischemic heart disease and ischemic stroke, has increased significantly in recent decades. The prevention and treatment of these conditions have become progressively more challenging. From 1990 to 2016, the proportion of ASCVD deaths out of the total cardiovascular disease deaths increased from 40% to 61%, and the annual number of deaths increased from 1 million to 2.4 million.[10] In contrast, the previous worsening trend in the incidence of hemorrhagic stroke in China has improved, and associated mortality has declined significantly, with the proportion out of total cardiovascular deaths decreasing from 39% in 1990 to 27% in 2016. However, the incidence of hemorrhagic stroke in China remains significant when viewed globally; hemorrhagic stroke accounts for 15%–20% of total cardiovascular events and 30% of all stroke events,[11,12] 2–3 times higher than the incidence observed among Caucasian populations.[13,14] It is, therefore, evident that the epidemiological characteristics of cardiovascular disease in the Chinese population are different from those in the European and the United States populations. Therefore, it is necessary to develop cardiovascular disease prevention and treatment strategies applicable to the Chinese population and based on evidence from studies conducted in China.

Current status and challenges of primary prevention of cardiovascular disease in China

Primary prevention of cardiovascular disease

Primary prevention of cardiovascular disease is defined as preventive measures to reduce the risk of developing clinical cardiovascular events by controlling the major risk factors of cardiovascular disease such as smoking, hypertension, dyslipidemia, and diabetes, prior to the occurrence of cardiovascular events.[15] Primary prevention measures have been shown to effectively delay or prevent the occurrence of cardiovascular events, thereby reducing the morbidity and mortality of cardiovascular disease. Studies have shown that 40%–70% of decreases in mortality from cardiovascular disease in Western countries can be attributed to risk factor control.[16]

Lifestyle

Maintaining a healthy lifestyle is an early measure to prevent the occurrence and development of cardiovascular disease risk factors and clinical events and is the cornerstone of cardiovascular disease prevention. According to the “2019 Annual Report on Cardiovascular Health and Diseases in China”,[1] the lifestyle behaviors of Chinese people have in general improved since the 1990s. However, salt intake remains at an average of 14.5 g/day, more than twice the recommended level in relevant Chinese guidelines; only 14.7% of people aged 20 years and above partake in regular exercise, falling to 12.4% for people aged 30–39; and the smoking rate among men is as high as 50.5%, one of the highest rates globally. Furthermore, national survey data have shown that 52.7% of smokers aged 20–34 years smoked daily before the age of 20. These data indicate that unhealthy lifestyles remain prevalent in China, particularly among young and middle-aged people. It is therefore imperative to strengthen lifestyle intervention measures to prevent cardiovascular disease.

Risk factors of cardiovascular disease

With population aging and the prevalence of unhealthy lifestyles, the number of patients with hypertension, dyslipidemia, and diabetes mellitus is increasing rapidly. In addition to lifestyle intervention, most patients with these conditions required pharmacological intervention. Increasing the rate of awareness, treatment, and control of cardiovascular risk factors is key to the primary prevention of cardiovascular disease.

Hypertension is the most important modifiable risk factor affecting the incidence and mortality of cardiovascular disease in China. Approximately 50% of the morbidity and 20% of the mortality of cardiovascular disease can be attributed to hypertension.[17]

Although significant progress has been made in the prevention and treatment of hypertension in China, 2012–2015 survey data showed that the weighted prevalence of hypertension in adults ≥18 years was 23.2%. The estimated number of people with hypertension was 245 million. However, only 46.9% of people from this group were aware that they had hypertension, while 40.7% were receiving antihypertensive medication, and only 15.3% had their blood pressure under control. In particular, the prevalence of hypertension in the population aged 35–44 years was 15.0%, but the rate of awareness, treatment, and control was only 31.7%, 24.5%, and 9.9%, respectively.[18] Furthermore, 23.2% of young and middle-aged Chinese people had blood pressure levels of 130–139/80–89 mmHg, and two-thirds of them progressed to a diagnosis of hypertension within 15 years. The risk of cardiovascular disease among Chinese adults with a blood pressure level of 130–139/80–89 mmHg was 3.01 times higher than that for people with blood pressure <130/80 mmHg.[19] These findings indicate that there is significant scope for improvement in the prevention and control of hypertension in China. Early diagnosis and treatment of young and middle-aged people with hypertension are essential to reduce the long-term risk of cardiovascular disease.

The prevalence and number of patients with dyslipidemia have increased significantly in China since 2000. The 2010–2013 Chronic Disease and Nutrition Status Surveillance in China showed that the prevalence of dyslipidemia was as high as 40.4%.[20] Studies have shown that the level of low-density lipoprotein cholesterol (LDL-C), a causal risk factor of ASCVD, is significantly increased in the Chinese population, with 8.1% of Chinese adults having a level ≥4.14 mmol/L and 26.3% at ≥3.4 mmol/L. Only 39% of the population has an ideal LDL-C level (≤2.6 mmol/L).[21] However, the current awareness, treatment, and control rates of dyslipidemia among people aged ≥18 years were only 31%, 19.5%, and 8.9%, respectively.[22]

Diabetes is an independent risk factor for cardiovascular disease. Moreover, when ASCVD develops in patients with diabetes, the pathological changes are diffuse and complex and lead to a poor prognosis. Therefore, recent national and international guidelines have considered patients with diabetes as a high-risk group for cardiovascular disease.[3,5–9] In 2013, the prevalence of diabetes in adults aged over 18 years in China was 10.9%, with an estimated 103 million patients, 5 times that reported in 1980. However, the awareness and treatment rates of diabetes were only 36.5% and 32.2%, respectively, and the control rate among patients receiving treatment was only 49.2%.[23]

Even among people at high risk of cardiovascular disease, the status of primary prevention is far from optimistic. A cross-sectional survey in 39 communities in 7 regions of China from 2014 to 2016 showed that among women aged ≥45 years with a 10-year cardiovascular disease risk ≥10%, the rates of antihypertensive and lipid-lowering treatment were 44.4% and 10.2%, respectively, while those in men were as low as 36.3% and 6.3%, respectively. Although the treatment rate for women was slightly higher than that for men, the control rate was lower than that for men.[24]

In summary, the incidence and mortality of cardiovascular disease in China are continuing to increase. Although some favorable trends have been observed in the prevalence of certain unhealthy lifestyle attributes and in the prevention and control of risk factors, a considerable gap to the goal of a healthy population exists. The primary prevention of cardiovascular disease presents a significant challenge. Advocating a healthy lifestyle for all individuals is the cornerstone for the prevention of cardiovascular disease. In parallel, it is necessary to further standardize the detection, diagnosis, and treatment of risk factors such as hypertension, dyslipidemia, and diabetes and to improve their rate of awareness, treatment, and control. Lifestyle intervention and risk factor control represent the core of primary prevention and are key to the control of the cardiovascular disease.

General recommendations for primary prevention of cardiovascular disease

 

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Recommendations COR LOE
Multidisciplinary cooperation is recommended for the control of cardiovascular disease risk factors[25,26] I A
Physician-patient communication is recommended for the selection of appropriate intervention strategies for the patient[27] I B
Social factors related to the patient's health should be assessed to ensure that strategies for prevention and intervention can be implemented[28–30] I B
COR: Class of recommendation; LOE: Level of evidence.

Overview

The Guideline emphasizes that the prevention and control of cardiovascular disease risk factors should be patient-centered and based on multidisciplinary teamwork and optimal physician-patient communication. Reasonable, effective, and feasible individualized intervention strategies should be selected after a full evaluation of the patient's social determinants and individual wishes.

Supporting evidence

Control cardiovascular risk factors through multidisciplinary cooperation

Team-based prevention and treatment practice refers to improving the quality of cardiovascular disease prevention through the efforts of multidisciplinary professionals and cooperation with patients and family members. Such a multi-party cooperative practice strategy can improve clinical decision-making. Previous studies have shown that, compared with conventional models, team-based multidisciplinary cooperation can further reduce the risk of cardiovascular disease in patients with hypertension, diabetes, and dyslipidemia.[25,26]

Determine appropriate intervention strategies through physician-patient communication

Adequate communication between the physician and patient can promote an intervention strategy optimal for the patient. Physicians should invite patients to participate in their own risk assessments and discuss treatment goals and the benefits and risks of various interventions with their patients. The direct participation of patients clinical decision-making can avoid obstacles that may be encountered in the treatment process.[27]

Assess the social factors related to the patient's health

Socio-economic status has a significant impact on the development of risk factors and treatment compliance and represents an important determinant of cardiovascular disease incidence and mortality.[28] Multiple observational studies have shown that low income,[28] low education level,[28] unemployment,[29] poor community environment,[30] and other social factors can significantly increase the incidence of cardiovascular disease. Therefore, clinicians should establish the optimal intervention measures for the individual patient through physician-patient communication according to the patient's economic status, education level, cultural background, work, and living environment, and other relevant factors.

Assessment of cardiovascular risk

 

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Recommendation COR LOE
Total risk assessment is the foundation of the primary prevention of cardiovascular disease[3,7–9,31–34] I B
For adults aged 18–75, it is recommended to follow the “risk assessment algorithm for primary prevention of cardiovascular disease in Chinese adults” for risk assessment and risk stratification: Diabetes (age ≥40 years), LDL-C ≥4.9 mmol/L (or TC ≥7.2 mmol/L), or CKD at stage 3/4 are considered as high risk.[35–47] Individuals not meeting these conditions should undergo an assessment for 10-year risk of ASCVD and total cardiovascular disease[3,7,9,48]; those aged <55 years with moderate 10-year risk should undergo a further assessment of lifetime cardiovascular risk[3,7,49–51] I B
For individuals with a moderate 10-year risk, intervention strategies should be determined by considering risk-enhancing factors[52–66] IIa B
ASCVD: Atherosclerotic cardiovascular disease; CKD: Chronic kidney disease; COR: Class of recommendation; LDL-C: Low-density lipoprotein cholesterol; LOE: Level of evidence; TC: Total cholesterol.

Overview

Total risk assessment is the foundation of decision-making in the primary prevention of cardiovascular disease. Risk assessment should be carried out prior to initiating an intervention. The intensity of any risk-factor intervention strategy should be determined according to the patient's absolute risk and risk stratification (I, B). The Guideline recommends that the risk of cardiovascular disease should be evaluated using the “risk assessment algorithm for primary prevention of cardiovascular disease in Chinese adults” [Figure 1], established based on data from long-term cohort studies in the Chinese population (I, B).

F1
Figure 1:
Risk assessment algorithm for primary prevention of cardiovascular disease in Chinese adults. Risk factors include smoking, low HDL-C and age ≥45/55 (male/female); the levels of risk factors are all pre-intervention levels. ASCVD: Atherosclerotic cardiovascular disease; BMI: Body mass index; CKD: Chronic kidney disease; CVD: Cardiovascular disease; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; TC: Total cholesterol.

The evaluation process is divided into 3 steps. The first step is to identify individuals at high risk. Patients with diabetes (aged ≥ 40 years), LDL-C ≥4.9 mmol/L (or total cholesterol (TC) ≥7.2 mmol/L), or chronic kidney disease (CKD) at stage 3/4 are directly classified as a high-risk group for cardiovascular disease, without the need for 10-year or lifetime risk assessment. The second step is to assess the 10-year risk. For individuals who do not meet the criteria mentioned above for high risk, the 10-year risk of ASCVD and total cardiovascular disease (I, B) should be assessed according to the algorithm. The 10-year ASCVD risk assessment algorithm is adopted from the “2016 Chinese guideline for the management of dyslipidemia in adults”.[3,48] In the algorithm, LDL-C or TC levels and hypertension are considered key parameters for risk stratification combined with 3 additional risk factors of ASCVD: smoking, low high-density lipoprotein cholesterol (HDL-C), and age ≥45/55 years (male/female). There are 21 combinations of risk factors, and the average 10-year risk of ASCVD of <5%, 5%–9%, and ≥10% for a given combination are defined as low risk, moderate risk, and high risk, respectively. Diabetes patients aged <40 years are considered to be relatively young with shorter disease duration, and their ASCVD risk directly associated with diabetes is unlikely to reach a high-risk level. Therefore, the 10-year ASCVD risk and lifetime risk for these individuals should be assessed in conjunction with other risk factors. The 10-year ASCVD risk stratification is primarily used to guide lipid-lowering and glucose-lowering therapies and aspirin use (aspirin use should also consider the risk-enhancing factors in Table 3; see the “Use of aspirin” section), while the risk of total cardiovascular disease, including ASCVD and hemorrhagic stroke, should be considered in decisions regarding antihypertensive treatment strategies (see the “Blood pressure control” section for further details).

Table 3 - Cardiovascular disease risk enhancement factors
Items Content
Target organ damage Coronary artery calcification score ≥ 100 AU[53,54,68]
B-mode ultrasound showed carotid intima-media thickness ≥0.9 mm or the presence of carotid atherosclerosis[65,66,68,69]
Ankle-brachial index < 0.9[54,68]
Left ventricular hypertrophy: ECG Sokolow-Lyon voltage > 3.8 mV or Cornell Product > 244 mV·ms, or echocardiography showed left ventricular mass index ≥ 115/95 g/m2 (male/female), or interventricular septal thickness ≥11 mm[70,71]
Serum biomarker Non HDL-C ≥4.9 mmol/L (190 mg/dL)[52,55,56]
Apolipoprotein B ≥ 130 mg/dL[55,56]
Lipoprotein a ≥ 125 nmol/L or 50 mg/dL[55,57]
Triglyceride ≥ 2.3 mmol/L (200 mg/dL)[72–74]
High sensitivity C-reactive protein ≥ 2.0 mg/L[54,68]
Other factors Family history of early onset cardiovascular disease (onset age < 55/65 years old (male/female))[54,68]
Cornell product: (RavL + SV3) × QRS interval; ECG: Electrocardiogram; HDL-C: High-density lipoprotein cholesterol; Sokolow-Lyon voltage: Sv1 + Rv5 or Rv6.

When high-normal blood pressure (130–139/85–89 mmHg) is combined with the risk factors of smoking, low HDL-C, and age ≥45/55 years (male/female), grade 1 hypertension is combined with two of the above risk factors, or grade 2 hypertension is combined with one of the above risk factors, the 10-year risk of cardiovascular disease is ≥10%, which is high risk. In other cases, the stratification of total cardiovascular risk is consistent with that of ASCVD. The third step is to assess the lifetime risk. To identify individuals with a high risk of cardiovascular disease among young and middle-aged populations, the risk of cardiovascular disease in the remaining life (lifetime) should be assessed for those aged <55 years whose 10-year cardiovascular disease risk is medium. Individuals with two or more of the following risk factors are at high lifetime risk of cardiovascular disease: (1) systolic blood pressure (SBP) ≥160 mmHg or diastolic blood pressure (DBP) ≥100 mmHg; (2) non-HDL-C ≥5.2 mmol/L (200 mg/dL); (3) HDL-C < 1.0 mmol/L (40 mg/dL); (4) body mass index (BMI) ≥28 kg/m2; and (5) smoking.

Of note, the above-mentioned risk stratification considers only the presence of main concomitant diseases and risk factors. In clinical practice, the situation for each patient may be more complicated, and doctors and patients will need to fully discuss the risks for a given individual. For example, it can be difficult to determine whether to initiate statin therapy for people with medium risk. Furthermore, with respect to the use of aspirin in primary prevention, it is challenging to weight benefits and harms based only on the 10-year ASCVD risk.[67] In the event of the above circumstances, whether to initiate intervention measures should be determined in combination with the cardiovascular disease risk enhancement factors (IIa, B) [Table 3].[52–57,65,66,68–74]

Supporting evidence

Overall risk assessment as the basis of decision-making in primary prevention of cardiovascular disease

Cardiovascular disease is the result of multiple risk factors. The risk of cardiovascular disease not only depends on the level of a certain risk factor but also on the interaction of multiple risk factors,[37] and the joint intervention of multiple risk factors may have a synergistic effect, which can further reduce the risk of cardiovascular disease.[75] Therefore, it is insufficient to control single risk factors in isolation. Attention should be paid to the comprehensive assessment of the overall risk of cardiovascular disease. Risk assessment of cardiovascular disease refers to predicting the probability or risk that an acute cardiovascular event will occur within a specific period in the future (5 years, 10 years, or the rest of life), based on the level and combination of multiple cardiovascular risk factors.[76]

Overall risk assessment is the basis of decision-making for the primary prevention of cardiovascular disease (I, B). National and international guidelines for the prevention and control of cardiovascular disease and risk factors recommend that the initiation and target level of intervention should be determined according to the individual's overall risk stratification for cardiovascular disease. The corresponding intensity of interventions should be administered to different risk levels to maximize the expected benefit and avoid potential risk caused by over-treatment while optimizing the allocation of medical resources and associated expenses.[3,7–9,31–34]

Risk assessment process

Cardiovascular risk assessment should be based on a mathematical model established using data from cohort studies with long-term follow-up. The widely used prediction models globally include the models from the Framingham Heart Study, the SCORE model in Europe, and Pooled Cohort Studies Equations in the United States.[76] However, previous studies have shown that prediction models based on European and American population data cannot be fully extrapolated to the Chinese population.[77–79] Therefore, Chinese researchers have established prediction models for 10-year incidence risk of coronary heart disease,[77] stroke,[80] ischemic cardiovascular disease,[11,78] ASCVD,[48] and total cardiovascular disease[79] using data from long-term follow-up of participants in Chinese cohort studies. To maintain continuity in the risk assessment tool, the current Guideline adopts the 10-year ASCVD risk assessment algorithm of the “2016 Chinese guideline for the management of dyslipidemia in adults”[3,48] as the decision-making basis for lipid-lowering, glucose-lowering, and aspirin use; furthermore, the total cardiovascular risk including ASCVD and hemorrhagic stroke is assessed to identify individuals at high risk of total cardiovascular disease, and to better guide decision-making regarding the use of antihypertensive treatment which is closely related to hemorrhagic stroke.

The first step of risk assessment is to identify individuals at high risk of cardiovascular disease, including patients with diabetes aged ≥40 years or those with extremely high levels of LDL-C (or TC), or those with CKD at stage 3/4. Multiple observational studies and meta-analyses have shown that the risk of cardiovascular disease in patients with diabetes is significantly increased.[35,36] Although some studies have shown that the risk of cardiovascular disease in patients with diabetes is not equal to that of patients with cardiovascular disease,[81] patients with diabetes frequently have multiple cardiovascular risk factors[37]; furthermore, their atherosclerotic lesions are more serious,[82] long-term cardiovascular risk is higher,[38] and once cardiovascular events occur, these patients have a worse prognosis.[39] In addition, data from RCTs and meta-analyses have indicated that statins can reduce the risk of ASCVD in patients with diabetes aged 40–75 years.[40] Patients with severe hypercholesterolemia (LDL-C ≥4.9 mmol/L or TC ≥7.2 mmol/L) also have a significantly higher risk of ASCVD. Genetic abnormalities such as familial hypercholesterolemia (FH) and long-term exposure to hypercholesterolemia may lead to an extremely high risk of early-onset ASCVD.[41–43] A growing body of evidence indicates that intensive cholesterol-lowering therapy can significantly reduce the risk of ASCVD in this patient population.[44,45] In addition, multiple cohort studies and meta-analyses have shown that the risk of cardiovascular disease is increased in patients with reduced estimated glomerular filtration rate (eGFR), more than 2-fold in patients with eGFR <15 ml·min−1·1.73 m−2, independent of conventional risk factors.[46,47] Therefore, with reference to relevant national and international guidelines,[3,7–9] patients with diabetes (aged ≥40 years) or LDL-C ≥ 4.9 mmol/L (or TC ≥7.2 mmol/L) or CKD at stage 3/4 should be considered at high risk of cardiovascular disease and should receive active intervention without the need for 10-year or lifetime risk assessment.

The second step of risk assessment is to assess the 10-year risk of ASCVD and total cardiovascular disease following the process recommended in this Guideline for individuals who do not meet the above-mentioned high-risk conditions.

In the 10-year risk assessment of ASCVD, the algorithm of “2016 Chinese guideline for the management of dyslipidemia in adults” should be followed.[3] This algorithm is based on the prediction model established by long-term follow-up data from the Multi-provincial Cohort Study in China. The model has been shown to have good discrimination and calibration capabilities.[48] In addition, despite ASCVD representing the main type of cardiovascular disease in the Chinese population, hemorrhagic stroke continues to account for almost 20% of cardiovascular disease incidence and almost 30% of deaths from cardiovascular disease.[10–12] Therefore, the risk of ASCVD and the total risk of cardiovascular disease, including hemorrhagic stroke, should be considered in the primary prevention of cardiovascular disease in the Chinese population.

The third step of risk assessment is to assess the lifetime risk in people under 55 years of age with a moderate 10-year risk of cardiovascular disease. Age is the most important risk factor in the predictive model of the 10-year risk of cardiovascular disease. Even for young and middle-aged people with 3 cardiovascular risk factors, the 10-year cardiovascular risk might not reach the high-risk level. However, the cumulative exposure of risk factors may increase the long-term risk of cardiovascular disease. The opportunity for early prevention may be missed based on 10-year risk assessment results alone, and the concept of lifetime risk of cardiovascular disease has therefore been proposed.[83] Lifetime risk refers to the absolute cumulative risk of the target event occurring over the average life expectancy of the given individual. Studies on the lifetime risk of cardiovascular disease in the United States, Japan, and other countries have been reported.[84,85] Cohort studies in China have also evaluated the lifetime risk of cardiovascular disease in the Chinese population.[49,50] These findings suggest that early intervention for individuals at high lifetime risk can avoid or delay the occurrence of cardiovascular disease, ensure a longer event-free life expectancy, and provide greater benefit throughout life.[51] In recent years, the lifetime risk assessment of cardiovascular disease has been introduced into the guidelines for cardiovascular disease prevention and control in Europe, the United States, and China to supplement the 10-year cardiovascular disease risk assessment. The present Guideline follows the lifetime risk assessment program of “2016 Chinese guideline for the management of dyslipidemia in adults”.[3] Lifetime risk assessment of cardiovascular disease provides a basis for risk management in young and middle-aged populations and is of particular importance for motivating individuals to improve their lifestyle and enhance treatment compliance.

Cardiovascular disease risk enhancement factors

High-risk individuals should receive active intervention, and drug therapy should be initiated in addition to lifestyle intervention. Low-risk individuals are recommended to maintain a healthy lifestyle and undergo regular risk factor screening. For individuals with a moderate 10-year risk, sometimes the advantages and disadvantages of preventive intervention are unclear, and it may be difficult to decide whether to initiate pharmacological treatment. For individuals with moderate risk, the average predicted risk with certain combinations of conventional risk factors is 5%–9%. However, in reality, the presence of various risk factors and other combined factors may lead to an individual risk higher or lower than the average predicted level.

In addition to conventional cardiovascular disease risk factors, multiple studies have reported that indicators such as target organ damage,[53,54,58–60,65,66] serum biomarkers,[52,54–57] and family history of cardiovascular disease, preeclampsia, and rheumatoid arthritis[9,61] are closely related to cardiovascular disease. However, studies have shown that after being added into the prediction model based on conventional risk factors, ankle-brachial index (ABI),[54] intima-media thickness of carotid artery (IMT),[62] FH,[54] high-sensitivity C-reactive protein (hsCRP),[54] non-HDL-C, triglycerides (TG), and apolipoprotein B (ApoB)[55] have failed to improve the predictive ability or risk stratification of the model. Indicators such as coronary artery calcification (CAC), carotid IMT and plaque, ABI, ApoB, lipoprotein a (Lp (a)), and hsCRP are not yet universally evaluated in primary medical settings, and that the cost-effectiveness of these assessments remains unclear. Therefore, factors currently included in national and international cardiovascular disease risk assessment models are primarily conventional cardiovascular disease risk factors.[76] Factors that are closely related to cardiovascular disease but are not currently suitable for inclusion in the prediction model may be used as cardiovascular disease risk enhancement factors. Where the risks and benefits of treatment are unclear for individuals with moderate 10-year risk, the above risk enhancement factors should be considered in combination to determine whether or not to initiate intervention measures (IIa, B). The greater the number of risk enhancement factors present, the more likely the individual will be at high risk, and vice versa. It is worth noting that when the CAC score is 0, the risk of ASCVD in most individuals is <5%,[63] and pharmacological intervention[64] will likely not yet be required.

Lifestyle intervention

Balanced diet

 

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Recommendations COR LOE
A diet emphasizing intake of fresh vegetables, fruits, legumes, nuts, whole grains, and fish is recommended to reduce the risk of cardiovascular disease[86–96] I B
Avoiding a high cholesterol intake can be beneficial to reduce the risk of ASCVD[94] IIa B
Replacement of saturated fat with dietary polyunsaturated fat can be beneficial to reduce the risk of ASCVD[97,98] IIa B
The intake of trans fat (trans fatty acids) should be avoided to reduce the risk of ASCVD[97,99–102] III B
Avoiding excessive sodium intake (≤5 g of salt per day) can be beneficial to reduce the risk of cardiovascular disease[103–105] IIa B
Carbohydrate intake should provide 50%–55% of daily energy to reduce the risk of ASCVD[99,106–112] IIa B
ASCVD: Atherosclerotic cardiovascular disease; COR: Class of recommendation; LOE: Level of evidence.

Overview

A balanced diet includes the consumption of fiber-rich foods such as fresh vegetables and whole grains; limited consumption of saturated fat, salt used in cooking and seasoning (including salt, soy sauce, and sauce products), and cholesterol; avoidance of trans fat intake; and other measures such as controlled carbohydrate intake, which together can help to reverse or reduce obesity, hypercholesterolemia, diabetes, and hypertension and prevent cardiovascular disease. However, previous RCTs focused on dietary patterns and cardiovascular outcomes are limited, and the majority of evidence comes from observational studies. A number of studies have focused on the relationship between dietary patterns and cardiovascular mortality, particularly with respect to the consumption of sugar or low-calorie sweeteners, high or low carbohydrate diets, refined grains, trans fat, saturated fat, sodium (salt), red meat (eg, pork, beef, or lamb) and processed red meat products (eg, bacon, sausage, or ham).[86–99,104,106–108,110–116]

The balanced diet for Chinese residents model proposed by the Chinese Nutrition Society emphasizes food diversification and energy balance. The recommended intake is 250–400 g of rice, wheat, corn, potato, and other cereal and potato foods (including 50–150 g of whole grains and beans and 50–100 g of potatoes), 300–500 g of vegetables, 200–350 g of fruits, 120–200 g of fish, poultry, eggs, and lean meat (including 40–50 g eggs, equivalent to 1 egg), and 300 g of milk. Consumption of a balanced diet can increase the intake of cellulose, vitamins, and potassium, reduce blood lipid levels, and improve cardiovascular health.[117] The diet structure and main food sources of this model are shown in Table 4.

Table 4 - Dietary components and main food sources
Component Examples of main food sources
Saturated fat Animal fats (eg, beef tallow, lard oil, and butter) and some vegetable fats (eg, coconut oil and palm oil)
Unsaturated fat Olive oil, rapeseed oil, sunflower seed oil, soybean oil, peanut oil, corn oil, camellia oil, safflower seed oil, and fish oil
Trans fat Hydrogenated vegetable oil (eg, oleomargarine, margarine, coffee mate, and refined vegetable oils)
Carbohydrate Sugar, rice, wheat, corn, oats, sorghum, and other grains; watermelon, banana, grape, and other fruits; dried fruits, dried beans, and root vegetables such as carrots and sweet potatoes
Protein Meat, eggs, milk, and beans

Supporting evidence

A balanced diet helps to reduce the risk of cardiovascular disease

Observational studies have shown that participants who consume a mainly plant-based diet including fruit, nuts, vegetables, beans, low-fat plant or animal protein (preferably fish), intrinsic soluble and insoluble plant fibers, or a Mediterranean diet (consisting mainly of whole grains, nuts, vegetables, and fruit supplemented with olive oil, fish, and red wine, including poultry and dairy products, red meat, or meat products) have a lower rate of all-cause mortality.[86–89,91,92,94,118,119] The results of the PREDIMED study showed that a Mediterranean diet combined with extra virgin olive oil or nuts reduced the incidence of composite end-point events (myocardial infarction, stroke, or death from cardiovascular disease) and primarily stroke in the study population.[86] Further analysis showed that an “ultra-vegetarian” diet with the highest proportion of plant-derived foods could significantly reduce the mortality rate.[96] The CARDIVEG study divided overweight subjects into a low-calorie vegetarian diet group and a Mediterranean diet group, with a cross-over study design. The results showed that both diet patterns could effectively reduce body weight, BMI, and fat mass. However, the vegetarian diet was more effective in reducing LDL-C, while the Mediterranean diet was more effective in reducing TG levels.[113] The cohort study of Adventist Health Study-2 showed that participants with a high animal protein intake had a 61% higher mortality rate than those with low intakes, while those consuming a high intake of nuts and seeds instead of meat as a source of protein had a 40% lower mortality risk than those with a low intake.[95] A cohort study among men in Finland showed that those with a high proportion of animal protein in their diet and a large meat intake had a higher risk of death.[114] A prospective cohort study in healthcare professionals in the United States showed that replacing animal protein with plant protein reduced cardiovascular mortality. Compared with plant protein, the intake of poultry and fish, dairy products, unprocessed red meat, eggs, and processed red meat increased the mortality rate by 6%, 8%, 12%, 19%, and 34%, respectively. In general, every 3% increase in energy replacement of animal protein with vegetable protein reduces the mortality rate by 10%.[94] Evidence for the effectiveness of dairy intake to reduce risk factors for ASCVD remains unclear. The dietary approaches to stop hypertension (DASH) diet, which includes low-fat dairy products, has been shown to lower blood pressure.[103] The PURE study showed that a daily intake of 2 servings of dairy products (about 500 mL) reduced the cardiovascular mortality rate by 23% compared with non-consumption of dairy products.[120] However, the results of the above-mentioned cohort study in the United States healthcare professionals showed that the cardiovascular mortality risk associated with the intake of dairy products increased by 11% compared with that associated with the intake of vegetable protein.[94]

Cholesterol and the risk of ASCVD

Among the sources of dietary cholesterol, meat (including poultry, red meat, processed meat products, and seafood) contributes approximately 42% of cholesterol intake, eggs account for 25%, and others account for about 33%. At present, the relationship between dietary cholesterol intake and cardiovascular disease and death remains unclear. Given the multiple confounding factors and varying results of observational studies, an association between dietary cholesterol and cardiovascular disease risk is generally not supported. However, the results of intervention studies and meta-analyses indicate that high cholesterol intake can lead to increased blood TC and LDL-C levels.[121] Over the past 20 years, the dietary cholesterol intake in the Chinese population has increased by 34%. At present, the average cholesterol intake for adults is 266.3 mg/d, equivalent to that for the United States. One-third of adults have a daily cholesterol intake above the previously recommended limit of 300 mg.[122] Although most current guidelines have removed this limit because of insufficient evidence, the potential risk of elevated blood cholesterol levels caused by excessive cholesterol intake cannot be overlooked. In 2019, the AHA made the following recommendations (for reference): Based on current guidelines for a healthy diet, 1 egg (585 mg of cholesterol/100 g of eggs) or the equivalent amount of cholesterol can be consumed per day; vegetarians having no other sources of cholesterol can increase their intake of dairy products and eggs appropriately; patients with hyperlipidemia, especially those at high risk of type 2 diabetes or heart failure, should be cautious when consuming high-cholesterol foods; and older people without hypercholesterolemia can increase their egg intake to no more than 2 eggs per day.[123]

Saturated and unsaturated fat and ASCVD risk

Trans fat and saturated fat are associated with an increased risk of total and cause-specific death. The replacement of 5% saturated fat with unsaturated fatty acids may reduce total mortality by 27%.[97] The results of the PURE study indicated that the consumption of saturated fat and unsaturated fat instead of refined carbohydrate reduced the incidence of stroke and the mortality rate.[98]

Trans fat (trans fatty acids) and ASCVD risk

Intake of trans fat may increase the risk of ASCVD. Studies have shown that trans fat is associated with an increased all-cause mortality rate.[97,99] Some food additives contain partially hydrogenated oils, which are the source of trans fatty acids.[102] One study found that the ban on trans fats in the food industry was associated with a reduction in stroke and myocardial infarction.[100] Trans fat has adverse effects on lipids and lipoprotein and can aggravate endothelial dysfunction as well as cause insulin resistance, inflammation, and arrhythmia.[101]

Salt and cardiovascular risk

The results of the DASH and TOHP studies showed that reducing daily sodium intake reduced blood pressure and the incidence of cardiovascular events.[103,104,115] Data from the National Health and Nutrition Examination Surveys (NHANES) showed that excessive sodium intake (>2 g/d (equivalent to 5 g of salt)) was associated with increased cardiovascular death.[105] A survey and analysis on sodium intake and cardiovascular death in multiple districts and counties of Shandong Province showed that in 2011, nearly 20% of cardiovascular death among people aged 25–69 could be attributed to increased SBP caused by high sodium intake (>2 g/d).[124] The global chronic disease prevention and control goals of the World Health Organization (WHO) include a reduction in the population sodium intake by 30% in 2025 compared with that in 2010.[125] In 2012, the dietary sodium intake in the Chinese population (5702 mg/standard person day, converted into 14.5 g of salt) was markedly higher than the recommended intake (Chinese guidelines recommend salt intake <6 g/d, while WHO guidelines recommend salt intake <5 g/d).[1] Measures such as reducing salt in cooking and avoiding high-salt foods can help lower blood pressure and reduce the risk of ASCVD. The PURE study findings posed a challenge to salt restriction. The study showed that the low sodium intake (<2 g/d) and high potassium intake (>3.5 g/d) recommended by the WHO were very rare in the study population (ie, only 0.002% met these criteria), and that moderate sodium intake (3–5 g/d) combined with high potassium intake was associated with the lowest risk of death and cardiovascular events.[116] Further evidence is needed to support these findings. In addition, the potassium intake of adults in China is generally lower than the level recommended by the WHO and the Chinese Nutrition Society. Therefore, encouraging an increased intake of foods naturally rich in potassium, such as fruit and vegetables, may help prevent cardiovascular disease.

Carbohydrates and ASCVD risk

High carbohydrate (ie, sugar) intake may increase the risk of ASCVD. Drinking just one sugar-sweetened beverage a day can increase the risk of diabetes by 20%.[106] Studies have shown that more than 10% of the energy consumed with added sugar per day is associated with an increased mortality rate.[107] Adults who are accustomed to consuming high-sugar beverages can use low-calorie sweetened beverages as an alternative, which provide sweetness while reducing caloric intake, and are beneficial in the transition to pure water.[108] The REGARDS study showed that the typical Southern American diet, which included fried foods, offal, processed meats, and sweetened beverages, significantly increased health risks. Among these, the risk of coronary heart disease increased by 56%, and the risk of stroke increases by 30%.[109] Consumption of fruit juices, sugary drinks, refined cereals, potatoes/chips, and sweets can increase the incidence of coronary events to a greater extent than the risk of eating animal products.[89] In addition, long-term low carbohydrate but high animal fat and protein consumption patterns are associated with an increased cardiac and non-cardiac mortality rate.[110–112] Atherosclerosis Risk in Communities (ARIC) study showed that low-carbohydrate diets containing animal-derived protein and fat (eg, lamb, beef, pork, and chicken) were associated with an increased mortality rate. In contrast, plant-derived sources (eg, vegetables, nuts, peanut butter, and whole wheat bread) were associated with reduced mortality. A meta-analysis of cohort studies, including the ARIC study, showed that high carbohydrate intake (energy supply >70%) and low carbohydrate intake (energy supply <40%) both increased the risk of death. Moderate carbohydrate intake can be defined as the consumption of 50%–55% of the energy supply as carbohydrate.[110] Data from the China Health and Nutrition Survey indicated that high-carbohydrate diets might be related to risk factors of cardiovascular disease, and it is therefore recommended to consume appropriate daily amounts of carbohydrates.[126] In addition, the consumption of beverages with artificial sweeteners has been shown to increase the risk of stroke, coronary heart disease, and all-cause death.[127]

Physical activity

 

-
Recommendations COR LOE
Adults should engage in at least 150 minutes of moderate-intensity physical activity or 75 minutes of high-intensity physical activity (or equivalent combination of moderate- and high-intensity physical activity) every week to reduce the risk of cardiovascular disease[128–133] I B
For adults who are unable to meet the minimum physical activity recommendations, some moderate- or high-intensity physical activity, even if less than the recommended amount, can also help to reduce the risk of cardiovascular disease[130,131] IIa B
Reducing sedentary behavior may help to reduce the risk of cardiovascular disease[128,134–136] IIa B
COR: Class of recommendation; LOE: Level of evidence.

Overview

Regular physical activity is the cornerstone of maintaining and improving cardiovascular health.[131] National survey data from 2014 showed that compliance with recommended physical activity levels was only 22.8% among individuals aged 20–59 years,[137] half of the same cohort in the United States population.[138] However, data from the China Health and Nutrition Survey indicate that from 1991 to 2011, physical activity in the Chinese population showed a downward trend.[1] The need for an increase in physical activity should be strenuously promoted.[139,140]

Meta-analyses and systematic reviews of observational studies support the proposal to increase aerobic exercise to reduce the risk of ASCVD.[128–133,141] Aerobic exercise is usually safe to perform[142] and can be in the form of brisk walking, jogging, swimming, cycling, dancing, or other activities. Individuals accustomed to a sedentary lifestyle should start physical activities at low intensity for short durations and proceed gradually.[143] It is not yet clear whether reaching an upper limit of activity or intensity for a prolonged duration will have adverse cardiovascular consequences.[144] However, very high-intensity physical activity is appropriate for only a small proportion of the population.[138] Older adults can choose yoga, tai chi, dancing, and other forms of more moderate activity to increase cardiopulmonary adaptability. For patients with reduced capacity for exercise, the type, intensity, and duration of physical activity should be individualized according to their condition.

Resistance exercise (eg, using fitness equipment or an elastic band) can improve body function,[141] help patients with diabetes to control blood sugar levels,[145,146] and lower blood pressure.[147] However, it remains unclear whether resistance exercise can reduce the risk of cardiovascular disease.[138]

A sedentary lifestyle is a health risk, and minimizing sedentary time may help reduce the risk of cardiovascular disease.[128,134–136]

The intensity of physical activity can be evaluated using several methods, such as the metabolic equivalent (MET). MET refers to the level of energy metabolism relative to physical activity at rest, expressed as energy consumption per unit time. One MET is equivalent to the activity intensity that consumes 3.5 mL of oxygen per kilogram of body weight per minute or consumes 1 kcal (1 kcal = 4.184 kJ) of energy per kilogram of body weight per hour. Low-, medium-, and high-intensity physical activities generally correspond to 1–2, 3–5, and ≥6 MET, respectively.

Supporting evidence

Moderate- to high-intensity physical activity reduces the risk of cardiovascular disease

Numerous studies have consistently shown that moderate- to high-intensity physical activities are associated with reduced risk of cardiovascular events and mortality rate.[128–133] A large prospective cohort study in China showed that both occupational and non-occupational physical activity is negatively correlated with the risk of cardiovascular disease, that is, the greater the amount of activity, the lower the risk of cardiovascular disease. Daily physical activity of 4 MET or higher intensity can reduce the risk of various cardiovascular diseases by 5%–12%.[148] Adults are recommended to take at least 150 minutes of moderate-intensity physical activity or 75 minutes of high-intensity physical activity every week. There is evidence that higher-intensity physical activity, such as more than 300 minutes of moderate or 150 minutes of high-intensity physical activity per week, further reduces the risk of cardiovascular disease. Further increases in physical activity to a very high level will bring sustained but gradually reduced additional benefits.[130,131,138] However, the potential risk associated with this level of activity is not clear, and it is not routinely recommended.

Regular physical activity can reduce the risk of cardiovascular disease

When moderate- to high-intensity physical activity is initiated, the benefits of reducing ASCVD risk appear and gradually increase.[131] Studies have shown that even if the activity amount is lower than the current recommended level, the cardiovascular protection effect is still significant.[149,150] Therefore, all adults should be encouraged to reach the recommended minimum activity amount, and those unable to do so should increase their activity amount step by step and according to their ability so as to minimize the risk of cardiovascular disease.[131]

Reducing sedentary behavior can reduce the risk of cardiovascular disease

Sedentary behavior refers to seated inactivity for a long duration in the awake state, with energy consumption typically less than or equal to 1.5 MET.[151] Sedentary behavior is associated with increased cardiac metabolism risk factors.[128,134–136] Individuals who seldom engage in moderate- to high-intensity physical activity typically have a higher risk of cardiovascular disease if they are sedentary.[128,135] Therefore, reducing sedentary behavior, especially among those who do not reach the current recommended physical activity amount, may help to reduce the risk of cardiovascular disease.[152]

Weight control

 

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Recommendation COR LOE
In individuals with overweight and obesity, comprehensive management measures such as limiting caloric intake and increasing physical activity are recommended to reduce and maintain weight so as to reduce the risk of cardiovascular disease[153,154] I B
COR: Class of recommendation; LOE: Level of evidence.

Overview

The proportion of overweight and obese adults in China has risen in recent years. Although the prevalence of overweight and obese is lower in the rural population, the increased rate is higher than that of urban residents.[1]

The risk of cardiovascular disease is increased in obese and overweight individuals.[155–160] A number of studies have shown that reducing and maintaining weight by restricting caloric intake and increasing physical activity can help reduce the risk of cardiovascular disease and even reduce all-cause death.[153,154] Although the use of drug intervention alone can reduce and maintain weight, the rate of associated adverse reactions is high, and any loss in weight can be difficult to maintain.[153] For patients with severe obesity, weight loss can be achieved through gastric volume reduction surgery, but this approach is generally unsuitable for primary prevention.[161]

Supporting evidence

A meta-analysis of 127 RCTs showed that restricting caloric intake and increasing physical activity for 12–18 months could effectively reduce and maintain body weight, reduce blood pressure, LDL-C, and blood glucose levels, and reduce the risk of new-onset diabetes without increasing the risk of other cardiovascular diseases.[153] Drug treatment for 12–18 months can also effectively reduce and maintain weight, although this benefit may be difficult to maintain because of adverse drug reactions. A meta-analysis of 54 RCTs involving 30,296 subjects found that low-fat and low-saturated-fat diets could reduce the risk of all-cause death by 18% and the risk of cardiovascular death by 7% independent from physical activity.[154] Individuals are recommended to take more than 150 minutes of moderate-intensity aerobic exercise per week as an initial weight-loss measure and 200–300 minutes of high-intensity physical activity per week to maintain weight. The caloric intake should be controlled at 1500–1800 kcal/d for men and 1200–1500 kcal/d for women. Very low caloric intake (<800 kcal/d) should be implemented only under professional supervision and is not routinely recommended.[162] Taken together, these measures can reduce body weight by 5%–10% within 6–12 months, for an average overall weight loss of approximately 8 kg. Although a slight rebound effect may be observed thereafter, continuous improvement in other cardiovascular disease risk factors can be expected.[153,154]

Smoking cessation

 

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Recommendations COR LOE
Smoking should be avoided in adults and adolescents to reduce the risk of cardiovascular disease and death[163–165] III B
Adults and adolescents should avoid exposure to secondhand smoke to reduce the risk of cardiovascular disease[166] III B
Smokers should quit smoking as soon as possible to reduce the risk of cardiovascular disease and death[167] III B
COR: Class of recommendation; LOE: Level of evidence.

Overview

The harmful effects of smoking on health are well established. Numerous observational studies have shown that smoking and secondhand smoke exposure are directly related to cardiovascular disease, lung cancer or chronic respiratory disease, liver cancer, and other types of cancer.[168] A cohort study showed that the risk of morbidity and mortality among those who quit smoking was significantly lower than that of current smokers. Smokers will benefit whenever they quit. The sooner a person quits smoking, the more he or she benefits.[169]

China has the largest number of smokers in the world. The burden of disease and economic loss caused by smoking is immense.[170] Quitting smoking is an important measure to prevent cardiovascular disease and other chronic diseases. Efforts to avoid smoking and secondhand smoke exposure should start with teenagers.[165,166] The risk of cardiovascular disease can return to normal 5 years after quitting smoking.

Helping smokers to quit smoking is key to the prevention and control of cardiovascular disease. Healthcare professionals should help smokers understand the dangers of smoking, increase their willingness to quit, provide help with quitting, and arrange follow-up visits. The degree of smoking dependence should be evaluated and treated, simple smoking cessation methods should be recommended, and pharmacological treatment should be offered when necessary.[171,172] Moreover, family members and friends of smokers should be invited to participate in smoking cessation programs to establish a positive and supportive environment.[173,174]

In 2015, 43.0% of male doctors in China were smokers. Healthcare professionals should not smoke. Those who do should quit smoking as soon as possible and become advocates of a non-smoking lifestyle. Increased publicity and implementation of smoking bans in public places are required. Medical institutions should take the lead in becoming smoke-free places. In addition to helping individuals to quit smoking, government bodies at all levels should be urged and supported to formulate effective smoking control laws and regulations for public places, public transportation, and office spaces to create a smoke-free environment for the public and to publicize the hazards of smoking.[173,174] Studies have shown that intervention by healthcare professionals in preventing and quitting smoking can help children and adolescents to understand the harm of smoking as well as help smokers to quit.[173]

Supporting evidence

Smoking increases the risk of cardiovascular disease and death

Smoking is an independent risk factor of cardiovascular disease and death, and the higher the smoking volume and the longer the smoking time, the higher the risk of cardiovascular disease incidence and death.[163–165] Even when adjusting for other risk factors, smoking among young people remains closely related to cardiovascular disease.[165] Therefore, young people are encouraged to avoid smoking.

Secondhand smoke exposure increases the risk of cardiovascular disease

The risk of cardiovascular diseases such as coronary heart disease and stroke is increased by exposure to secondhand smoke.[166–168] Studies have shown that for non-smokers, exposure to secondhand smoke increases the risk of coronary heart disease and stroke by 20%–30%.[168] Teenagers should also avoid exposure to secondhand smoke.

Benefits of smoking cessation

Smoking cessation can reduce the risk of cardiovascular disease and death.[164] One year after quitting smoking, the risk of death and recurrent cardiac events reduced by 50% in patients with coronary heart disease,[167] and the risk of mortality reduced by more than 70% in patients with myocardial infarction[175]; 15 years after smoking cessation, the mortality risk of patients with coronary heart disease and heart failure is similar to that of non-smokers.[167] Smokers should be aware of the benefits of not smoking and should be actively encouraged to quit smoking.

Control alcohol intake

 

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Recommendation COR LOE
Alcohol should be avoided to reduce the risk of cardiovascular disease and death[176–182] III B
COR: Class of recommendation; LOE: Level of evidence.

Overview

Excessive alcohol consumption increases the risk of cardiovascular disease,[176–183] and long-term excessive drinking or occasional heavy drinking can seriously affect health.

The “Chinese dietary guidelines (2016)” recommends that the daily alcohol intake should not exceed 25 g for men and 15 g for women.[117] Alcohol intake can be calculated as follows: alcohol content (% v/v) × amount consumed (mL)/100 × 0.8. Patients with hypertension, diabetes, atrial fibrillation, or impaired liver and kidney function as well as pregnant women and adolescents, are recommended to avoid consuming alcohol. The consumption of small amounts of alcohol is not recommended in the general population to prevent cardiovascular disease.

Supporting evidence

Excessive alcohol consumption increases the risk of cardiovascular disease and death. The number of deaths caused by long-term excessive drinking or occasional heavy drinking is as high as 3 million worldwide every year. Excessive drinking can lead to liver cirrhosis, cancer, and traffic accidents, and can increase the risk of atrial fibrillation, myocardial infarction, and heart failure.[176,177] Some studies have shown that alcohol consumption is closely related to hypertension, atrial fibrillation, and hemorrhagic stroke.[176] The relationship between alcohol and cardiovascular disease may vary depending on the type of alcohol consumed. A meta-analysis of observational studies showed a J-shaped curve relationship of red wine and beer with cardiovascular events; that is, moderate alcohol consumption was associated with the lowest risk of vascular events while excessive drinking increased the risk of vascular events. However, no J-shaped curve relationship was observed between the consumption of strong alcohol and the risk of cardiovascular events.[179] An analysis of 83 prospective studies involving more than 500,000 consumers of alcohol showed that people who consumed less than 100 g of alcohol per week had the lowest risk of death. On this basis, the incidence of stroke, myocardial infarction, heart failure, fatal hypertension disease, and aortic aneurysm in patients without a history of cardiovascular disease increased gradually with increasing alcohol consumption. For example, for a reference weekly alcohol intake ≤100 g, the life expectancy of adults aged over 40 years is shortened by 6 months or more as their weekly alcohol consumption doubles, suggesting that it may be safer to drink less than the current recommended standard.[182]

Maintain a healthy sleep pattern

 

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Recommendation COR LOE
Maintaining a healthy sleep pattern can reduce the risk of cardiovascular disease[184–187] IIa B
COR: Class of recommendation; LOE: Level of evidence.

Overview

Sleep is closely related to the risk of cardiovascular disease. Healthy sleep includes adequate sleeping time and good-quality sleep. Numerous observational studies and meta-analyses have shown that insomnia is associated with an increased risk of cardiovascular morbidity and mortality. Insufficient sleep time can increase the risk of hypertension, coronary heart disease, and heart failure, while the optimal sleep time of 7–8 hours per day with good sleep quality can significantly reduce the risk of cardiovascular disease.[184,186–191]

Supporting evidence

Cohort studies with a follow-up of more than 10 years showed that insomnia increased the risk of myocardial infarction and stroke,[189,190] and the incidence of heart failure.[191] In addition, a previous meta-analysis found that insomnia significantly increased the risk of cardiovascular death.[188] A prospective cohort study in the Netherlands included 17,887 healthy subjects without cardiovascular disease at baseline who were followed up for 12 years. The risk of cardiovascular disease and coronary heart disease has been shown to increase by 15% and 23%, respectively, for patients who achieved less than 6 hours of sleep per day compared with those who achieved 7–8 hours of sleep. In addition, based on a healthy diet, regular physical activity, non-smoking status, and other healthy lifestyle attributes, in healthy sleepers with sufficient sleep time and good quality sleep were compared with those having insufficient and poor quality sleep, the risk of combined cardiovascular events including myocardial infarction, stroke, and cardiovascular death was reduced by 65%, and the risk of cardiovascular death was reduced by 83%.[186]

Maintain a good mental state

 

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Recommendation COR LOE
Maintaining a good mental state can reduce the risk of cardiovascular disease[192–195] I B
COR: Class of recommendation; LOE: Level of evidence.

Overview

Mental and psychological abnormalities such as depression, anxiety, rage, and post-traumatic stress disorder are related to the incidence of cardiovascular disease.[196–200] Maintaining optimism contributes to maintaining cardiovascular health,[192,193,201] and a good mental state can also reduce the risk of cardiovascular disease and death.[192–195]

Supporting evidence

A meta-analysis of prospective cohort studies showed that a good mental state was positively correlated with a decreased rate of cardiovascular disease.[192] In a prospective cohort study involving 70,021 older women followed up for 8 years, participants with the highest optimism score had a 38% lower risk of cardiovascular death and 39% lower risk of stroke death than those having the lowest score.[194]

Blood pressure control

Lifestyle intervention is recommended to reduce blood pressure

 

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Recommendations COR LOE
Intake of fresh vegetables, fruits, legumes, nuts, whole grains, and fish is recommended to reduce blood pressure[202–207] I A
Restriction of sodium intake and gradual reduction of daily salt intake to <5 g/day are recommended[208,209] I B
Body weight control targets of BMI <24 kg/m2 and waist circumference <90/85 cm (male/female) are recommended[210–214] I B
At least 150 minutes of moderate-intensity physical activity or 75 minutes of high-intensity physical activity per week (or an equivalent combination of moderate- and high-intensity physical activity) are recommended[215–219] I A
Alcohol intake is not recommended[220–223] III B
BMI: Body mass index; COR: Class of recommendation; LOE: Level of evidence.

Overview

The most recent survey of the prevalence of major cardiovascular diseases in China showed that male sex, old age, overweight/obesity, family history of hypertension, low education level, smoking, and alcohol consumption were associated with increased risk of hypertension.[18]

Lifestyle intervention is feasible and effective for any individual with hypertension (including those with a level of high normal and those who require pharmacological intervention) at any time. The purpose of lifestyle intervention is to reduce blood pressure and control other cardiovascular disease risk factors. Intervention includes a healthy diet, salt reduction, alcohol restriction, weight loss, and physical activity.

Supporting evidence

Healthy diet

Studies have shown that the DASH diet can reduce SBP by 11.4 mmHg and DBP by 5.5 mmHg in patients with hypertension and by 6.7 and 3.5 mmHg, respectively, in the general population.[202] The DASH diet can effectively reduce the risk of coronary heart disease and stroke.[203,204] There remains a lack of research on interventions for hypertensive patients to follow the DASH diet, and the methods for assessing dietary compliance can vary considerably.[224] However, studies have found that people with high compliance with the DASH diet, the Chinese diet pagoda, and alternative healthy diets have a lower incidence of hypertension[225] and that the incidence of total death, cardiovascular events, and diabetes is also lower in these groups.[205,206] In an RCT including 85 patients with hypertension during pregnancy, 41 patients following the DASH diet had a significantly lower incidence of preeclampsia, preterm birth, and low birth weight infants.[207]

Salt reduction

In 2010, the global sodium intake per capita was 3.95 g/d, and 1.65 million people died from cardiovascular disease caused by increased sodium intake.[208] A diet high in sodium and low in potassium is an important risk factor for hypertension in the Chinese population. A reduction in sodium salt intake has an antihypertensive effect that can vary by the ethnic group but is particularly significant in Asian populations.[226] Observational studies also showed that although the incidence of stroke decreased with increased sodium intake in other countries, a positive correlation remained between sodium intake and stroke incidence in the Chinese population.[209]

Controlling sodium intake is particularly important in individuals with hypertension, and daily salt intake should be less than 5 g in this population. In addition to reducing salt in the cooking process, the use of sodium-containing sauces (eg, soy sauce, monosodium glutamate, and fish sauce) should be reduced. Furthermore, consumption of processed foods (eg, cakes, ham, and canned food) should be reduced. It is recommended to increase the consumption of fresh vegetables, fruits, low-fat dairy products, fish, whole grains, fiber, and foods rich in potassium and other minerals.

Weight loss

Overweight and obese individuals can experience blood pressure lowering when they lose 5%–10% of their body weight, regardless of whether they have diabetes. With an increase in weight loss,[210] blood pressure can be further reduced alongside improved control rate[211] and reduced numbers of antihypertensive drugs.[212] However, compliance with long-term weight loss treatment (>6 months) is significantly reduced, and blood pressure can increase with weight rebound.[227,228] For overweight or obese individuals with hypertension or high-normal blood pressure, weight loss has a distinct antihypertensive effect. In patients with hypertension (blood pressure >140/90 mmHg) and those receiving antihypertensive drugs, the blood pressure reduction is even greater.[213]

A Chinese cohort study showed that weight change could lead to greater changes in blood pressure in overweight or obese older individuals,[214] suggesting that this group in particular needs to control their weight more aggressively.

For obese patients who cannot lose weight through lifestyle modification, gastrectomy can significantly reduce body weight and blood pressure,[229] while the antihypertensive effect of weight loss medication is very limited.[230,231] Therefore, it is recommended to reduce weight to control BMI to <24 kg/m2 and waist circumference to <90/85 cm (male/female) in this patient group.

Physical activity

Blood pressure control can be improved through physical activity. Studies have shown that for middle-aged hypertensive patients, with an average blood pressure of 147/92 mmHg, blood pressure can be reduced by 6.1/3.0 mmHg through regular aerobic exercise (brisk walking, jogging, or cycling 3–5 times per week for 30–60 min each time).[215] Studies have also shown that aerobic exercise can reduce SBP by 3.84 mmHg and DBP by 2.58 mmHg in both hypertensive and normotensive persons.[216] A cohort study found that the reduction of incidence of cardiovascular disease and all-cause death in patients with hypertension was associated with regular physical activity.[217]

For patients with hypertension, resistance exercise can significantly reduce DBP, but its effect on SBP is weak.[232] Persisting in isometric resistance training (eg, plank support, wall squat, and hip bridge) for more than 8 weeks can achieve significant antihypertensive efficacy, especially in male hypertensive patients aged >45 years.[233]

No statistically significant difference in blood pressure changes has been observed between groups participating in the aerobic exercise group and those undertaking resistance exercise combined with aerobic exercise.[234] Of note, patients with hypertension should be cautious when performing high-intensity aerobic exercise.[235]

Changes in blood pressure can vary by the duration and frequency of physical activity.[236] In older patients, low-to-moderate-intensity physical activity for 12 weeks has a significant effect on improving arterial stiffness.[218] In older hypertensive patients, aerobic exercise (2–3 times per week, 20–30 min each time) can also reduce SBP.[219]

Therefore, both hypertensive and non-hypertensive individuals are recommended to perform moderate-intensity physical activities for 4–7 days per week and 30–60 minutes per day in addition to daily activities. Aerobic, resistance, or stretching exercises can be considered, whereas aerobic exercise is preferred and can be supplemented by anaerobic exercise. The appropriate intensity of physical activity must be personalized, and the maximum heart rate during activity is usually used to assess the intensity of physical activity. Moderate-intensity physical activity implies that the heart rate reaches 60%–70% of the maximum heart rate during activity. The maximum heart rate (times/min) can be approximated as 220 minus the person's age. High-risk patients must be evaluated before initiating activities. A typical physical activity plan consists of 3 stages: (1) preparatory activity: 5–10 minutes of mild warm-up activities; (2) training phase: 20–30 minutes of aerobic or endurance physical activity; and (3) relaxation phase: approximately 5 minutes in which the level of exertion is gradually reduced so that the reaction of the cardiovascular system and the heat production function of the body gradually stabilize.

Alcohol restriction

Restriction of alcohol intake is significantly associated with a decrease in blood pressure and has a significant dose-effect relationship. For hypertensive patients with high alcohol intake (daily intake >24 g), reducing alcohol intake can significantly reduce blood pressure.[220] When alcohol intake decreased by an average of 67% in a previous study, SBP was reduced by 3.31 mmHg, and DBP was reduced by 2.04 mmHg.[221] There is insufficient evidence at present to support the hypothesis that a small amount of alcohol consumption is beneficial to cardiovascular health. Studies show that cardiovascular health can be improved, and the risk of cardiovascular disease can be reduced even in light consumers of alcohol who further reduce their intake.[222] For individuals with high-normal blood pressure and a habit of alcohol drinking, reducing the amount of alcohol consumption does not result in a reduction in the incidence of hypertension.[223]

Patients with hypertension are recommended to avoid alcohol. If alcohol is consumed, the daily intake level should not exceed 25 g for males and 15 g for females.

Antihypertensive drug treatment

 

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Recommendations COR LOE
In addition to lifestyle changes, it is recommended that antihypertensive drugs should be given according to the overall risk profile of patients with hypertension to reduce the total risk of cardiovascular morbidity and mortality[237,238] I A
It is recommended to initiate antihypertensive drug treatment in high-risk patients with blood pressure >140/90 mmHg[238–241] I A
Initiation of antihypertensive drug treatment should be considered in patients with low or moderate risk of cardiovascular disease whose blood pressure exceeds 140/90 mmHg[241–243] IIa A
Initiation of antihypertensive drug treatment should be considered in high-risk patients with blood pressure 130–139/85–89 mmHg who have diabetes and/or CKD stage 3/4[244] IIb C
An optimal blood pressure target of <130/80 mmHg and an essential blood pressure target of <140/90 mmHg is generally recommended for hypertensive patients[237,245–248] I A
A blood pressure target of <130/80 mmHg is recommended for patients with diabetes[245,249–251] I A
A blood pressure target of <140/90 mmHg should be considered for older hypertensive patients[241] (the target should be individualized based on the tolerability of the individual patient) IIb B
Diuretics, β-receptor blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers are recommended as initial choices for antihypertensive therapy[237,250,252,253] I A
CKD: Chronic kidney disease; COR: Class of recommendation; LOE: Level of evidence.

Overview

Although active lifestyle intervention can effectively reduce blood pressure, most individuals with hypertension require antihypertensive medication in addition to lifestyle changes. Previous clinical trials on antihypertensive therapy have provided important evidence for determining the blood pressure target and selecting antihypertensive drugs.

Supporting evidence

Antihypertensive drug treatment can significantly reduce the risk of cardiovascular disease

The overall risk of cardiovascular, cerebrovascular, and renal complications and death in patients with hypertension can be significantly reduced using antihypertensive medication. A 10 mmHg reduction in SBP or a 5 mmHg reduction in DBP can reduce the incidence of major cardiovascular events by 20%, overall mortality rate by 10%–15%, stroke by 35%, coronary heart disease by 20%, and heart failure by 40%.[237,238] Regardless of the baseline blood pressure and/or cardiovascular risk level or the presence of diabetes or CKD, antihypertensive treatment for hypertensive patients of different ages, ethnicities, and genders can reduce the incidence of related events.[237,239] However, the benefit of antihypertensive medication for individuals with high-normal blood pressure is limited to those with coronary heart disease.

The efficacy and safety of intensive antihypertensive therapy

ACCORD,[245] SPRINT,[246] and SPS3[247] are recent studies of intensive blood pressure reduction (reducing SBP to <130 mmHg). The study populations were patients with diabetes, a high risk of cardiovascular disease, or lacunar infarction. Participants were randomized according to different blood pressure goals, and the blood pressure of the active intervention group was reduced to 119, 121, and 127 mmHg, respectively. Although there was no significant difference in the risk of primary endpoints in the ACCORD study, the incidence of stroke was significantly reduced in the intensive blood pressure-lowering group (40%).[245] In the SPRINT study,[246] there was a significant difference in the risk of primary endpoint events (hazard ratio (HR) = 0.75, 95% confidence interval (CI): 0.64–0.89, P < 0.001) in the intensive treatment group. In the SPS3 study,[247] the incidence of the primary endpoint (stroke) had a tendency to decrease (HR = 0.81, 95% CI: 0.64–1.03, P = 0.08). Although the unattended automatic blood pressure measurement method used in the SPRINT study was different from conventional blood pressure measurement, which may have affected the interpretation of data, the results of a subsequent meta-analysis continued to support the benefit of intensive antihypertensive therapy.[248]

Another meta-analysis showed that in patients with baseline SBP > 160 mmHg, the benefits on the incidence of major cardiovascular events and deaths per 10 mmHg reduction in SBP were similar to those in subjects with a baseline SBP of 130–139 mmHg. The study also showed that the incidence of cardiovascular events and death was reduced in people with SBP < 130 mmHg.[237] The results of this analysis showed that intensive reduction of SBP can not only benefit patients with cardiovascular comorbidities, diabetes, and CKD but also benefit patients without comorbidities. However, this patient group frequently has multiple cardiovascular risk factors.

The results of the ACCORD and SPRINT studies showed that although intensive blood pressure-lowering therapy can increase adverse events, it did not increase serious adverse events. However, a meta-analysis showed that when SBP was further reduced to <120 mmHg, the rate of withdrawal due to adverse events increased.[254]

Antihypertensive therapy for patients with grade 1 hypertension

Drug therapy for patients with grade 1 hypertension (140–159/90–99 mmHg) can reduce the incidence of cardiovascular complications.[238–240] Even patients with grade 1 hypertension without other comorbidities were shown to have a high risk of cardiovascular disease due to multiple risk factors or diabetes. Therefore, evidence from relevant studies is mainly limited to patients with a high risk of cardiovascular disease. Direct evidence for the initiation of antihypertensive drug treatment in patients with grade 1 hypertension and low- and moderate-risk primarily comes from the subgroup analysis of the HOPE3 study in patients with moderate risk of grade 1 hypertension (SBP > 143.5 mmHg, average blood pressure of 154.1 mmHg), in which the primary endpoint decreased significantly when SBP decreased by 6.0 mmHg.[241]

Antihypertensive therapy for patients with high-normal blood pressure

In a study among individuals with high-normal blood pressure without cardiovascular complications or diabetes, treatment with angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors for 2 years was found to reduce the incidence of hypertension.[255,256] However, the use of antihypertensive drugs in individuals with low- and moderate-risk of cardiovascular disease has not led to any benefit in cardiovascular endpoint events.[244] Although there is little evidence supporting the use of antihypertensive drugs in patients with high-risk and high-normal blood pressure without cardiovascular complications, the use of these medications is reasonable because blood pressure targets are usually stricter in patients with the blood pressure of 130–139/85–89 mmHg accompanied with diabetes or CKD stage 3/4.

There are differences in the effect of antihypertensive treatment in patients with different overall risks

Antihypertensive treatment for hypertensive patients based on total risk can reduce the incidence of total cardiovascular events. The efficacy varied depending on the total risk,[242,243] and the higher the baseline risk, the greater the absolute benefit of treatment, although a high residual risk remains. Regarding the impact of cardiovascular endpoint events, the benefits of antihypertensive therapy mainly derived from the reduction of stroke events regardless of the baseline risk. For patients with low cardiovascular risk, antihypertensive therapy has limited efficacy in reducing myocardial infarction, heart failure, cardiovascular death, and total death. For patients with blood pressure <140/90 mmHg, evidence for the benefit of antihypertensive drug treatment has only been observed in high-risk patients with coronary heart disease.[239]

Benefits of antihypertensive therapy in patients with diabetes

Studies have shown antihypertensive drug treatment can improve retinopathy in patients with type 1 diabetes and hypertension,[257] although evidence on cardiovascular outcomes in this population is lacking.

Large-scale clinical trials in patients with type 2 diabetes and hypertension have shown that antihypertensive treatment can significantly reduce cardiovascular complications and total deaths in this patient group.[249] In the ACCORD study, the incidence of total cardiovascular events tended to be reduced, while the incidence of stroke decreased significantly when SBP was reduced to 119 mmHg or lower.[245] A meta-analysis also showed that when the blood pressure in patients with type 2 diabetes was reduced to <130/80 mmHg, only the incidence of stroke was significantly reduced.[250,251]

Further analysis of the ACCORD study data showed that after excluding the interaction of hypoglycemic therapy, the overall incidence of cardiovascular events in patients with SBP < 130 mmHg decreased while cardiovascular events in patients with SBP < 120 mmHg tended to increase.[258] The evidence supporting DBP < 80 mmHg mainly derives from the ADVANCE and ACCORD studies, where DBP in the intensive blood pressure-lowering group decreased to below 80 mmHg.

Antihypertensive therapy in different age groups

A cohort study in individuals aged 40–69 years showed that the risk of fatal stroke and mortality from ischemic cardiovascular disease increased twofold every 10 mmHg increase in DBP from 115/75 mmHg. A positive correlation remained between blood pressure level and cardiovascular death in subjects aged 80–89 years, and the annual mortality rate increased with age. Age-specific deaths were similar for males and females.

It should be noted that the research on antihypertensive treatment in older hypertensive patients has not included frail older individuals so far. These trials included older hypertensive patients over 80 years of age with SBP > 160 mmHg. In other studies, older hypertensive patients had taking antihypertensive drugs at baseline, and they were grade 1 hypertension.[241] Studies have found that reducing SBP to <140 mmHg can reduce the incidence of cardiovascular events in this patient group. Blood pressure management in frail older people should avoid intolerance caused by excessive blood pressure lowering.

Cost-effectiveness of antihypertensive therapy in hypertensive patients of different ages and overall risk

The treatment cost-effectiveness ratio is optimal in high-risk patients, while in low-risk groups for cardiovascular disease, patients’ willingness to receive treatment and the treatment cost should be carefully considered.[259] The SPRINT study showed that the treatment cost-effectiveness ratio of the intensive treatment group was better than that of the standard treatment group.[260]

Efficacy of various antihypertensive drugs

The 5 classes of antihypertensive drugs have similar effects on reducing cardiovascular events,[237,250,252,253] and can be used as the initial choice of antihypertensive treatment. The benefits of antihypertensive therapy mainly come from the reduction of blood pressure per se. Different drugs have different effects on single endpoint events. β-receptor blockers have a weaker effect on stroke reduction compared with the 4 other types of antihypertensive drugs, while calcium channel blockers are less effective in preventing heart failure. Different drugs have different advantages for different groups of patients. Different drugs also have different effects with respect to target organ damage and adverse reactions. Polypills have a synergistic effect on lowering blood pressure and can improve patient compliance. Other antihypertensive drugs include α-receptor blockers, aldosterone receptor antagonists, renin inhibitors, and central nervous system inhibitors are not the first choice for treatment.

Lipid management

Recommended lipid measurement

 

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Recommendations COR LOE
Fasting venous blood should be used for blood lipid assessment[261] I C
TC should be used as an index to evaluate ASCVD risk I C
HDL-C should be used as an index to evaluate ASCVD risk I C
LDL-C should be used as an index to evaluate the risk of ASCVD and is a target of lipid-lowering therapy I C
TG should be used as a risk-enhancing factor for ASCVD risk assessment in some patients I C
Non-HDL-C can replace LDL-C[262–266] as a risk assessment index and intervention target of ASCVD, especially in very high-risk patients with high TG, diabetes, obesity, or very low LDL-C I C
As a reliable detection indicator for atherogenic lipoprotein particles, ApoB100 is superior to non-HDL-C as an ASCVD risk prediction and intervention indicator in patients with high TG, diabetes, obesity, or extremely low LDL-C, and can replace LDL-C[262–266] I C
Lp(a) measurement should be considered at least once in an adult's lifetime to identify individuals with very high Lp(a) level >430 nmol/L (180 mg/dL) who may have a high ASCVD risk equivalent to heterozygous FH[57,267–270] IIa C
Individuals with a family history of early-onset coronary heart disease and those at intermediate risk should be tested for Lp(a) as an enhancing risk factor[57,267–270] IIa C
ASCVD: Atherosclerotic cardiovascular disease; COR: Class of recommendation; FH: Familial hypercholesterolemia; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; LOE: Level of evidence; Lp(a): Lipoprotein-a; TC: Total cholesterol; TG: Triglycerides.

Overview

Blood lipid levels must be measured before assessing an individual's ASCVD risk. The Framingham risk assessment model and Pooled Cohort Equations require the measurement of TC and HDL-C.[9] In the ESC risk assessment model (SCORE), TC is an important assessment indicator for ASCVD, and HDL-C can further increase the accuracy of risk assessment.[33] LDL-C is used as a treatment target and an indicator of efficacy in all clinical intervention studies. It is also an important risk assessment factor in the ASCVD risk assessment model in China.[3] The risk assessment models in the ACC/AHA and ESC-related guidelines include only 2 blood lipid indicators, TC and HDL-C. These models were mainly derived from early (the 1970s and 1980s) cohorts, which focused on these 2 indicators. However, with a deepening understanding of dyslipidemia, other blood lipid parameters have been shown to have an independent predictive value for ASCVD risk. LDL-C, non-HDL-C, and ApoB typically have a good correlation, but in some patients with elevated TG (eg, those with obesity, metabolic syndrome, or diabetes), LDL-C cannot accurately reflect the risk of ASCVD because TG-rich lipoprotein particles are also an important component of atherogenic ApoB particles and the proportion of LDL particles in ApoB particles decreases when TG increases. Under these circumstances, the risk of ASCVD can be underestimated by measuring LDL-C alone.

Lp(a), consisting of apolipoprotein a (Apo(a)) bound to the surface of LDL particles, is atherogenic in a similar manner to LDL-C particles. Apo(a) is structurally similar to plasminogen and can thus bind to the plasminogen receptor to promote thrombosis. Lp(a) should be measured at least once in an individual's lifetime. If Lp(a) ≥430 nmol/L (180 mg/dL), the lifetime ASCVD risk is significantly increased and is equivalent to the risk associated with heterozygous FH. Although Lp(a) has not been included in the previous ASCVD risk assessment model, it was used as an enhancing factor for ASCVD risk assessment in the updated AHA and ESC guidelines.[9,33]

Supporting evidence

Venous blood is typically collected for blood lipid detection in patients who have fasted for at least 8 hours, as increased TG is typically observed in postprandial blood samples. Studies in European populations indicate that postprandial LDL-C levels are not significantly altered, and non-fasting lipid measurement may therefore be recommended.[271] However, studies in Chinese subjects have shown that LDL-C levels decrease significantly (0.24–0.56 mmol/L) at 2–4 hours after a standard meal[261,272] and the goal-attaining rate of lipid-lowering treatment may therefore be overestimated based on postprandial LDL-C levels. Therefore, it is recommended to continue using fasting venous blood for lipid detection as the basis for LDL-C target evaluation.

The currently recommended lipid-lowering target is controversial. Most guidelines recommend LDL-C as the primary target and non-HDL-C and ApoB as secondary targets. However, studies have shown that the predictive value of non-HDL-C and/or ApoB for ASCVD is superior to that of LDL-C.[262–266]

Some guidelines have therefore put non-HDL-C as the primary target.[273–276] The current guideline recommends using LDL-C as the primary target and non-HDL-C as a substitute target. However, for patients with diabetes, metabolic syndrome, obesity, or high TG level, non-HDL-C is the primary target. Observational studies have shown that reference to Lp(a) can increase the accuracy of ASCVD risk stratification.[57,267–270] Although it is not a target for lipid-lowering therapy at present, it is recommended to measure Lp(a) in patients with a moderate or high risk of ASCVD.

Recommended cholesterol-lowering targets

 

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Recommendations COR LOE
For patients with diabetes at high-risk of ASCVD, an LDL-C goal of <1.8 mmol/L (70 mg/dL) or LDL-C reduction of >50% from baseline[277–282] and non-HDL-C goal of <2.6 mmol/L (100 mg/dL) are recommended[283–286] I A
For patients without diabetes who are at high risk of ASCVD, an LDL-C goal of <2.6 mmol/L (100 mg/dL)[277–280,286,287] and non-HDL-C goal of <3.4 mmol/L (130 mg/dL) are recommended I A
For patients at moderate risk of ASCVD, an LDL-C goal of <2.6 mmol/L (100 mg/dL)[277–280,288,289] and non-HDL-C goal of <3.4 mmol/L (130 mg/dL) are recommended I A
For patients at low risk of ASCVD, an LDL-C goal of <3.4 mmol/L (130 mg/dL)[278] and a non-HDL-C goal of <4.2 mmol/L (160 mg/dL) should be considered IIa B
Patients with diabetes at high risk of ASCVD are those aged ≥40 years with diabetes or those aged 20–39 years with diabetes and high risk of ASCVD. ASCVD: Atherosclerotic cardiovascular disease; COR: Class of recommendation; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; LOE: Level of evidence.

Overview

Previous studies have confirmed that regardless of the method used, the lower the LDL-C level and the longer the duration of reduction, the greater the reduction in ASCVD risk. Currently, there is no lower limit for LDL-C at which a loss of association with ASCVD is observed. Therefore, all individuals can theoretically reduce their risk of ASCVD as long as they reduce their LDL-C level. However, considering the cost of drug treatment and potential adverse reactions, it is necessary to establish lipid-lowering goals according to the baseline risk of ASCVD.

Supporting evidence

The basis for setting blood lipid goals for ASCVD prevention is founded on data from RCTs, with contributing data from observational research and Mendelian randomization trials. Although these studies did not systematically seek to identify a specific target value of LDL-C, meta-analysis data showed that the greater and longer the decrease in LDL-C, the greater the decrease in ASCVD risk.[277–280] These studies did not identify a loss-of-effect threshold for LDL-C reduction or any adverse effects related to LDL-C lowering. A linear correlation exists between LDL-C lowering and relative risk reduction of ASCVD, indicating that the greater the decrease in LDL-C, the greater the decrease in ASCVD risk. However, when determining the goal of LDL-C, the cost-effectiveness of lipid-lowering should be considered. To ensure appropriate cost-effectiveness, 2 factors need to be considered: the absolute decrease in LDL-C after treatment and the baseline ASCVD risk of the patient. Therefore, the LDL-C target should be determined according to baseline ASCVD risk, meaning that the higher the baseline risk, the lower the LDL-C target. Although the LDL-C target should be the same for all patients at high risk of ASCVD, patients with diabetes have a greater risk of cardiovascular events and thus should have lower LDL-C targets. There is insufficient evidence for lipid-lowering treatment as primary prevention of ASCVD in older adults (aged over 75 years), meaning that a special recommendation has not been made for this patient population. In some patients, particularly those with elevated baseline TG (eg, patients with obesity, metabolic syndrome, or diabetes), LDL-C level cannot adequately represent all atherogenic lipoproteins, that is, lipoproteins containing ApoB. Under these circumstances, non-HDL-C can be used as an alternative index of lipoprotein containing ApoB for ASCVD risk assessment.

Although all studies with statin and non-statin have targeted LDL-C, there is evidence that non-HDL-C can better represent atherogenic lipoprotein particles.[263,264] A meta-analysis of statin therapy showed that, compared with LDL-C targets, non-HDL-C targets could better predict the residual risk of ASCVD.[265,266] Therefore, some guidelines and consensus statements recommend non-HDL-C as the primary target.[273–276] The currently recommended non-HDL-C target is an LDL-C target plus 0.8 mmol/L (0.8 mmol represents cholesterol carried by very low-density lipoprotein (VLDL) particles). However, the difference between non-HDL-C and LDL-C is influenced by baseline LDL-C and TG levels. A comparative study of LDL-C and non-HDL-C levels found that when LDL-C is 2.6 mmol/L, the corresponding non-HDL-C is 3.2 mmol/L, and the difference is 0.6 mmol/L,[283,284] which is consistent with results from related research in Chinese patients.[285] Therefore, when the LDL-C level is very low (<2.6 mmol/L), the corresponding value of the VLDL-C should be decreased simultaneously (<0.8 mmol/L). For example, the 2017 Diabetes Management Guidelines of the American Association of Clinical Endocrinologists established, for the first time, an LDL-C target value of 1.4 mmol/L for patients with an extremely high risk of ASCVD, with a corresponding non-HDL-C target of 2.1 mmol/L.[276] In view of the fact that Chinese clinicians are more accustomed to use LDL-C as the target, the current guideline continues to recommend LDL-C as the primary target and non-HDL-C as an alternative target. Non-HDL-C should be used as the primary target for people with elevated TG (eg, those with diabetes, metabolic syndrome, or obesity) and people with low LDL-C but a very high risk of ASCVD. The non-HDL-C target continues to be estimated by adding 0.8 mmol/L on the top of the LDL-C target.

Diet management in lipid-modifying therapy

 

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Recommendations COR LOE
Unsaturated fatty acids (eg, vegetable oils) should replace saturated fatty acids (eg, oil from animal sources or palm oil) to reduce serum cholesterol level[290,291] IIa A
Intake of trans fats (eg, hydrogenated vegetable oils) should be avoided[290,292] III A
People at low and moderate risk of ASCVD should consider restricting dietary cholesterol intake (<300 mg/d)[293–299] IIa B
People at high risk of ASCVD or those with hypercholesteremia should consider limiting dietary cholesterol intake (<200 mg/d)[297–299] IIa B
ASCVD: Atherosclerotic cardiovascular disease; COR: Class of recommendation; LOE: Level of evidence.

Overview

The most basic measure to reduce atherosclerotic lipoprotein levels is a lifestyle change, within which diet has the most significant impact on blood lipid levels.

Regarding dietary recommendations in the primary prevention of ASCVD, the established position recommends limiting the intake of saturated fatty acids and trans fats[290–292] and increasing the intake of fruits and vegetables, cereals, potatoes, and fish.[86] There are differences in the recommendations with respect to dietary cholesterol and eggs, including contradictory information in the dietary cholesterol recommendations of the United States Dietary Guidelines from 2015 to 2020. AHA/ACC guidelines indicate that cholesterol is not a nutrient of concern[300]; however, the healthy diet pattern indicates that cholesterol intake should be as low as possible.[301] Cholesterol, saturated fatty acids, and animal protein frequently coexist in the diet, meaning that it is difficult to identify foods with high cholesterol content but low saturated fatty acid content. Studies on dietary cholesterol and egg intake have been inconsistent with respect to the association between serum cholesterol levels and the risk of ASCVD. Different guidelines are based on different research data, leading to inconsistent conclusions.

Contrary to the decreasing trend observed in Europe and the United States, the incidence of cardiovascular disease in China is rising, as is the proportion of the population with dyslipidemia. From 2012 to 2014, the population LDL-C level increased by almost 50% compared with that in 2002.[21] These data highlight the importance of limiting high dietary cholesterol intake in China and not adhering to the dietary guidelines in Europe and the United States to relax the restrictions on cholesterol. It is recommended to set different dietary cholesterol and egg yolk intake standards for different groups of subjects. Populations at low and moderate risk for ASCVD should limit daily cholesterol intake to <300 mg; for high-risk individuals or those with elevated blood cholesterol levels, the daily cholesterol intake should be even lower (<200 mg).

Supporting evidence

The cholesterol content in the diet affects blood cholesterol levels

Most studies have found that dietary cholesterol is related to elevated plasma LDL-C levels. Studies have shown that when healthy young men consume 0, 1, 2, or 4 eggs a day to increase their cholesterol intake from 128 to 858 mg, their plasma LDL-C levels increase synchronously. For every 100 mg increase in dietary cholesterol, LDL-C increased by 1.5 mg/dL (0.04 mmol/L).[294] In women, the effect of dietary cholesterol on plasma cholesterol was even more significant. When consuming 0, 1, or 3 eggs a day to increase cholesterol intake from 108 to 667 mg, plasma LDL-C level increased by 2.1 mg/dL (0.05 mmol/L) for every 100 mg increase in dietary cholesterol.[293] The results of a meta-analysis showed that daily consumption of 1–3 yolks increased LDL-C by 4–12 mg/dL (0.10–0.31 mmol/L), a change likely to have a significant adverse effect over time. In the relationship between dietary cholesterol intake and blood cholesterol, the link between cholesterol intake and serum LDL-C is closer than that between cholesterol intake and HDL-C. Therefore, investigators suggest limiting egg consumption.[302] Another meta-analysis showed a 200-mg reduction in cholesterol intake reduced blood cholesterol by approximately 4 mg/dL (0.1 mmol/L).[303] In 2020, the AHA issued scientific recommendations on dietary cholesterol and cardiovascular disease in which high dietary cholesterol was related to elevated blood cholesterol levels. However, considering that a specific dietary cholesterol level was not easy to implement, the document only recommends adherence to a generally healthy diet, such as the Mediterranean diet or DASH diet.[123]

Egg intake and dietary cholesterol affect the risk of ASCVD

A prospective study involving 5672 female patients with diabetes found that every intake of 200 mg/d cholesterol or 1000 calories/d increased the risk of cardiovascular disease by 37%.[295] Another study reported that egg intake increased the risk of new-onset diabetes.[296] The influence of diet on clinical endpoints is difficult to evaluate in RCTs, meaning that most data are derived from observational studies. The results are thus influenced by a number of confounding factors, and contradictions can frequently appear. The baseline cholesterol level can affect dietary choices, for example, people with high baseline cholesterol levels may consume fewer eggs or high-cholesterol foods, while those with low baseline cholesterol levels may not. When the heterogeneity of included studies is high, and other confounding factors are not fully controlled, the ability to reach a consistent conclusion is limited.[121] By removing extreme dietary groups in a 2019 meta-analysis of 6 high-quality cohort studies, the cholesterol content of each study was uniformly quantified, and different models were used to control the influence of other dietary components, especially the total calorie consumption and baseline cholesterol level of individuals. The results showed a dose-dependent relationship between dietary cholesterol content and the number of eggs consumed and the occurrence of cardiovascular disease and all-cause mortality. For every 300 mg increase in daily dietary cholesterol intake, the risk of coronary heart disease increased by 17%, while all-cause mortality increased by 18%.[297] Other meta-analyses in which cholesterol or egg intake did not affect the risk of cardiovascular disease did not control baseline cholesterol levels and total calories.[304–306]

Data from Mendelian randomized trials indicate that dietary cholesterol affects ASCVD risk

Mendelian randomized trial data show that mutations in NPC1L1, a gene related to intestinal cholesterol absorption, can lead to decreased LDL-C levels. When the LDL-C level of NPC1L1 mutation carriers decreased by an average of 12%, the risk of coronary heart disease decreased by 53%.[298] Another Mendelian study reported that when NPC1L1 mutation and HMGCR mutation related to cholesterol synthesis led to the same decrease in LDL-C, the same level of decrease in coronary heart disease risk was observed.[299] Inhibiting both the absorption of intestinal cholesterol and the synthesis of cholesterol in the liver is therefore suggested to reduce the risk of ASCVD, which indirectly supports a restriction on cholesterol intake.

Cholesterol-lowering pharmacotherapy

 

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Recommendations COR LOE
For all individuals at high risk of ASCVD, lifestyle intervention is recommended I B
Moderate-intensity statin therapy should be prescribed as the initial lipid-lowering treatment[281,288,307–310] I A
If targets are not achieved with moderate-intensity statin therapy, combination with ezetimibe is recommended[311,312] I B
For patients with initial LDL-C >4.9 mmol/L and other cardiovascular disease risk factors, the addition of PCSK9 monoclonal antibody should be considered if goals are not achieved with combination therapy of moderate-intensity statin and ezetimibe[313,314] IIa B
Ezetimibe should be considered in patients with moderate to high risk of ASCVD who cannot tolerate statins[311] IIa C
Patients at high risk of ASCVD who cannot tolerate statins may consider PCSK9 monoclonal antibody for treatment[313,314] IIb C
Moderate-intensity statins or statins combined with ezetimibe should be considered for non-dialysis CKD patients[312,315] IIa B
It is not recommended to use statins to prevent ASCVD in patients with CKD on continuous dialysis[316,317] III A
Other cardiovascular risk factors include hypertension, smoking, family history of premature coronary heart disease, and obesity. ASCVD: Atherosclerotic cardiovascular disease; CKD: Chronic kidney disease; COR: Class of recommendation; LDL-C: Low-density lipoprotein cholesterol; LOE: Level of evidence; PCSK9: Proprotein convertase subtilisin/kexin9.

Overview

Healthy lifestyle is firstly recommended for the primary prevention of ASCVD, including diet, physical activity, weight control, smoking cessation, and alcohol restriction. Medication should be considered when blood lipid targets cannot be achieved with improvements in lifestyle. Cholesterol-lowering drugs play an important role in the prevention of ASCVD. According to the mechanism of action, these drugs can be divided into statins that inhibit cholesterol synthesis, ezetimibe and bile acid sequestrants that inhibit cholesterol absorption, and proprotein convertase subtilisin/kexin9 (PCSK9) inhibitors that inhibit LDL receptor degradation. These types of drugs are commonly used to lower cholesterol. In addition, specific medications are available for homozygote FH, including microsomal TG transfer protein (MTTP) inhibitors (eg, lomitapide) that inhibit VLDL secretion by the liver and ApoB100 antisense oligonucleotides (eg, mipomersen) that inhibit VLDL apolipoprotein production. Homozygous FH is a rare form of dyslipidemia that requires specialized treatment according to specific disease guidelines not discussed here. Of note, the heterozygous FH phenotype is more common, and its treatment measures are the same as those for ordinary high-risk groups.

Statins have the strongest evidence for primary prevention of ASCVD. Numerous studies have demonstrated that statins can significantly reduce the risk of ASCVD in high-, moderate-, and even low-risk groups. The mean baseline LDL-C level of the study populations ranged from 192 mg/dL (4.9 mmol/L) to 108 mg/dL (2.8 mmol/L), including high-, moderate-, and low-risk groups. These results indicated that statins could significantly reduce the risk of ASCVD and that the greater the reduction in LDL-C, the greater the reduction in the risk of ASCVD. Although statins form the basis of cholesterol-lowering therapy, the effect on LDL-C reduction can only be increased by up to 6% when the dose of statin is doubled.

Statins are associated with potential adverse effects such as liver damage, myopathy, and new-onset diabetes. Considering that Chinese patients are less tolerant to high-dose statins compared with patients in Europe and the United States, the use of moderate-intensity statins is recommended over high-dose statins in China. Non-statins, such as ezetimibe and PCSK9 monoclonal antibody, can be used alone or in combination for patients who cannot tolerate statins or cannot achieve the LDL-C target using statins alone. Xuezhikang has been shown to have a good safety profile and has demonstrated clinical benefits in a secondary prevention study in the Chinese population,[318] and can be used as a moderate-intensity cholesterol-lowering drug or as an alternative treatment for patients with statin intolerance.

Given the good efficacy and tolerability of non-statin drugs, combinations of moderate-intensity statins and non-statin drugs have become the most commonly used treatment approach to achieve the goal of intensive cholesterol reduction. For high-risk patients, only high-dose statins such as atorvastatin 80 mg or rosuvastatin 20 mg can achieve a 50% reduction in LDL-C. However, Chinese patients can rarely tolerate long-term use of high-intensity statins. Combinations of most moderate-intensity statins with ezetimibe 10 mg or PCSK9 monoclonal antibody alone can achieve this goal.[319] In view of the high price of PCSK9 monoclonal antibody, the recommended order of cholesterol-lowering drugs is as follows: moderate-intensity statins, and for those who do not meet the LDL-C target, ezetimibe should be added; for high-risk patients with LDL-C >4.9 mmol/L and in combination with other cardiovascular risk factors, statins combined with PCSK9 monoclonal antibody may be considered [Table 5].

Table 5 - Dosage and combination drug selection of drugs with different cholesterol-lowering intensities
Cholesterol-lowering intensity Drugs with dosage and combination drug selection
Low intensity (LDL-C decreased by <30%) Simvastatin 10 mg
Pravastatin 10–20 mg
Lovastatin 10–20 mg
Fluvastatin 40 mg
Pitavastatin 1 mg
Xuezhikang 1.2 g
Ezetimibe 10 mg
Moderate intensity (LDL-C decreased by 30%–49%) Atorvastatin 10–20 mg
Rosuvastatin 5–10 mg
Simvastatin 20–40 mg
Pravastatin 40 mg
Lovastatin 40 mg
Fluvastatin sustained-release tablets 80 mg
Pitavastatin 2–4 mg
Simvastatin 10 mg + ezetimibe
Pravastatin 20 mg + ezetimibe
Lovastatin 20 mg + ezetimibe
Fluvastatin 40 mg + ezetimibe
Pitavastatin 1 mg + ezetimib
Xuezhikang 1.2 g + ezetimibe
High-intensity (LDL-C decreased by 50%–60%) Atorvastatin 40–80 mg
Rosuvastatin 20 mg
Simvastatin 20–40 mg + ezetimibe
Pravastatin 40 mg + ezetimibe
Lovastatin 40 mg + ezetimibe
Fluvastatin 80 mg + ezetimibe
Pitavastatin 2–4 mg + ezetimibe
Atorvastatin 10–20 mg + ezetimibe
Pravastatin 5–10 mg + ezetimibe
PCSK9 monoclonal antibody
Ultra-high-intensity (LDL-C decreased by > 60%) Atorvastatin 40–80 mg + ezetimibe
Pravastatin 20 mg + ezetimibe
moderate-dose statin + PCSK9 monoclonal antibody
Ezetimibe + PCSK9 monoclonal antibody
LDL-C: Low-density lipoprotein cholesterol; PCSK9: Proprotein convertase subtilisin/kexin 9.

Supporting evidence

Statins and primary prevention of ASCVD

There is abundant evidence that statins play a beneficial role in the primary prevention of ASCVD. The WOSCOPS study included patients with an average LDL-C of 192 mg/dL (4.9 mmol/L) but without established cardiovascular disease. In this study, pravastatin 40 mg was found to reduce the incidence of primary endpoint events by 31%, cardiovascular mortality rate by 32%, and all-cause mortality rate by 22%.[307] The 5-year mortality rate for non-fatal myocardial infarction and coronary heart disease was as high as 7.9%. In the general population, patients with baseline LDL-C >190 mg/dL (4.9 mmol/L) have a 5-fold higher risk of ASCVD within 30 years compared with those with LDL-C <130 mg/dL (3.4 mmol/L),[43] indicating that active cholesterol-lowering therapy is needed when LDL-C >190 mg/dL (4.9 mmol/L). In subjects with low LDL-C and moderate-risk cardiovascular disease in the HOPE3 study, the average LDL-C level of the population was 127.8 mg/dL (3.3 mmol/L) at enrollment. Rosuvastatin 10 mg was shown to reduce the risk of cardiovascular disease by 24%.[288] The results of the JUPITER study showed that even in low-risk groups with low baseline blood lipid levels (LDL-C 108 mg/dL (2.8 mmol/L)), rosuvastatin 20 mg also reduced the incidence of composite cardiovascular events by 46%. A post hoc analysis of the JUPITER study showed that the treatment group could be divided into groups with LDL-C reduction ≥50% and <50% according to the difference in response to rosuvastatin. Compared with the placebo group, the incidence of primary endpoint events in these groups was reduced by 57% and 39%, respectively,[320] suggesting that the decrease in LDL-C of >50% can be regarded as the target of intensive cholesterol reduction.

The results of the first study on cholesterol-lowering therapy for primary prevention of cardiovascular disease in an Asian population showed that compared with a diet control group, the incidence of the first coronary heart disease event in the group with pravastatin 10–20 mg and diet control was reduced by 33%.[308] Primary prevention studies among patients with diabetes and hypertension have also confirmed that those at high risk of cardiovascular disease can benefit from moderate-intensity statin therapy.[281,309,310]

The results of a meta-analysis showed that the risk of cardiovascular disease and the risk of all-cause mortality was decreased by 21% and 12%, respectively, for each 1 mmol/L decrease in LDL-C for 5 years, regardless of the presence or absence of baseline cardiovascular disease, baseline cardiovascular disease risk,[278] baseline LDL-C level,[286] or type and dose of statins.[287]

There is little evidence on the primary prevention of cardiovascular disease with statins in older patients. The PROSPER study included patients aged 70–82 years, of whom 50% were at high risk of cardiovascular disease, 50% had established cardiovascular disease.[321] The results showed that the risk of major adverse cardiovascular events (MACE) in the pravastatin 40 mg group was 15% lower than that in the placebo group.[321] In 2019, a meta-analysis of 28 studies on statins showed that both the group over 75 years of age and the 4 groups under 75 years of age might benefit from statins treatment; however, a downward trend in the benefit was observed in the 2 older groups (70–75 years and >75 years) without baseline cardiovascular disease.[322]

CKD is a risk factor for ASCVD, and the effect of statins on reducing the risk of ASCVD is also influenced by renal function. Statins can significantly reduce the risk of cardiovascular disease in patients with mild to moderate renal insufficiency,[323] although the cardioprotective effect is reduced in patients with severe renal insufficiency.[316,317] The results of a meta-analysis showed that the reduction of cardiovascular risk by statins decreased with decreasing eGFR levels.[315]

Non-statins and primary prevention of ASCVD

The results of the EWTOPIA75 study showed that ezetimibe 10 mg reduced the risk of sudden cardiac death, myocardial infarction, and coronary revascularization by 34% in people aged ≥75 years without coronary heart disease.[311] Ezetimibe may therefore be used as the primary preventive medication of ASCVD in the elderly.

Few studies have examined the primary prevention of cardiovascular disease using statins combined with non-statin drugs. The SHARP study evaluated the effect of lipid-lowering combination therapy on cardiovascular protection in patients with CKD.[312] Patients with moderate to severe CKD (including dialysis and non-dialysis patients) but without established cardiovascular disease were enrolled in this study, in which simvastatin 20 mg combined with ezetimibe 10 mg was compared with placebo. Although the average LDL-C of the combined treatment group was only 0.85 mmol/L lower than that of the placebo group, the risk of non-fatal myocardial infarction, cardiac death, non-hemorrhagic stroke, and revascularization was 17% lower in the combined treatment group. Simvastatin 20 mg combined with ezetimibe 10 mg can therefore reduce the risk of ASCVD in patients with moderate to severe CKD.[312]

Evidence on the role of pure PCSK9 inhibitors in the primary prevention of ASCVD is currently lacking. Two short-term exploratory studies among ASCVD high-risk populations and ASCVD patients found that the addition of PCSK9 inhibitors to statin therapy significantly reduced the risk of cardiovascular events. In the OSLER study, 4465 patients who had completed the phase 2 or 3 study of evolocumab were enrolled and were randomly assigned in a 2:1 ratio to conventional statin treatment + evolocumab group and a conventional statin treatment group. The average follow-up time was 11.1 months, and the results showed that evolocumab reduced the level of LDL-C by 61%, from a median of 120 mg/dL (3.1 mmol/L) to 48 mg/dL (1.2 mmol/L). The rate of cardiovascular events at 1 year decreased by 53%. Cardiovascular risk factors were present in 80% of the study population, and 20% had established coronary heart disease.[313]

The data from this study can therefore be regarded as evidence of primary prevention in patients with a high risk of ASCVD. In the ODDYSSEY study, 2341 patients at high risk of ASCVD (70% of them had coronary heart disease) were randomly assigned in a 2:1 ratio to conventional statin treatment + alirocumab group or conventional statin treatment group. Over a period of 78 weeks, the results showed that the LDL-C level of the alirocumab group was 62% lower and the risk of cardiovascular adverse events was 48% lower than that of the conventional statin treatment group. Only 30% of the study participants met the primary prevention standard of ASCVD.[314]

TG management and primary prevention of ASCVD

 

-
Recommendations COR LOE
For patients at high risk of ASCVD, high-dose ethyl eicosapentaenoate (2 g, twice daily) should be considered for further reduction of the risk of ASCVD if TG >2.3 mmol/L after moderate-dose statin treatment[324,325] IIa B
For patients at high risk of ASCVD, fenofibrate may be considered for further reduction of the risk of ASCVD if TG >2.3 mmol/L after moderate-dose statin treatment[326,327] IIb B
ASCVD: Atherosclerotic cardiovascular disease; COR: Class of recommendation; LOE: Level of evidence; TG: Triglycerides.

Overview

TG-rich VLDL particles and remnant particles transport most of TG present in the circulation. Elevated TG is associated with an increased risk of ASCVD, although the significance of correlation disappears after adjusting for non-HDL-C.[55] The effect of fibrate on ASCVD risk reduction is proportional to the amplitude of non-HDL-C reduction, which is identical to the mathematical correlation between LDL-C reduction and ASCVD risk decline.[279] These observations indicate that the impact of TG-lowering on ASCVD is achieved by reducing non-HDL-C, including TG-rich lipoproteins. Data from Mendelian studies also support a causal relationship between TG and coronary heart disease, although it should be noted that the candidate genes also have an impact on HDL-C, LDL-C, and Lp(a). A Mendelian randomized study in 2019 found that TG-lowering lipoprotein lipase (LPL) variants and LDL-C-lowering LDL receptor variants were associated with a similar risk reduction of ASCVD when the variants led to a similar reduction in ApoB level.[328] The causal relationship between TG-rich lipoprotein and its remnant and ASCVD may be determined by ApoB lipoprotein particles rather than by TG. A 2019 meta-analysis found that even after adjusting for the effect of LDL-C, the decrease in TG with TG-lowering drugs, including fibrates, nicotinic acid, and omega-3 fatty acids was still associated with a decrease in MACE.

Elevated TG is closely related to poor lifestyle and diet. Physical activity and diet control can reduce obesity and insulin resistance, thereby effectively reducing TG. Alcohol consumption is an important risk factor for elevated TG and should be restricted in individuals with high TG.

In addition to limiting fatty acid intake, the focus is required on reducing the intake of refined carbohydrates. For example, the consumption of low-sugar foods rich in cellulose (eg, whole grains) should be increased.

Supporting evidence

Fibrates and primary prevention of ASCVD

FIELD[326] and ACCORD[329] are RCTs of fibrates and clinical endpoint events. The FIELD study enrolled patients with type 2 diabetes, of which 78% had no history of cardiovascular disease at enrollment. In this study, the incidence of primary and secondary endpoint events decreased by 25% and 11%, respectively, in the population with primary prevention,[326] indicating that fenofibrate can reduce cardiovascular events in patients with a high risk of ASCVD. The ACCORD study was the first large-scale RCT of statins combined with fibrates. The study subjects had type 2 diabetes, and 74% had no history of cardiovascular disease. Subjects were randomized to fenofibrate or placebo based on simvastatin treatment. No statistically significant difference in the incidence of primary and secondary endpoint events was observed between the 2 groups. Further analysis on the subgroup population with TG ≥204 mg/dL (2.3 mmol/L) and HDL-C ≤34 mg/dL (0.88 mmol/L) found that fenofibrate reduced the incidence of composite endpoint events by 31%.[329] These findings indicated that statins combined with fibrates could reduce cardiovascular events in patients with diabetes that have high TG and low HDL-C. Meta-analysis data showed that fibrates reduced cardiovascular events in subjects with high TG and low HDL-C.[330–332] In general, the current evidence for risk reduction in cardiovascular events with fibrates was far less than that of statins.

The effect of omega-3 fatty acids on cardiovascular disease

Several large-scale randomized trials have shown that low-dose omega-3 fatty acids (1 g/d) do not reduce cardiovascular risk in patients at high risk of ASCVD.[333–335] The effect of n-3 fatty acids may be related to the dose and source. In the JELIS study, 18,645 patients with hypercholesterolemia were randomly assigned to 1.8 g eicosapentaenoic acid (EPA) or placebo on top of statin treatment. EPA decreased MACE by 19% compared with the placebo (P = 0.011).[324] The REDUCE-IT study included patients with elevated TG (1.7–5.6 mmol/L) after statin treatment who received icosapent ethyl 4 g/d or placebo (mineral oil) as intervention. Compared with the placebo group, the icosapent ethyl 4 g/d group had a 25% lower incidence of MACE (P < 0.001).[325] Of note, 70.7% of patients in this study were in the secondary prevention group, and only 29.3% were in the primary prevention group. The STRENGTH study included patients with a high risk of ASCVD whose TG remained high after statin treatment. Participants were randomized to high-dose n-3 fatty acids (EPA + docosahexaenoic acid 4 g/d) or placebo (corn oil) treatment.[336] At approximately 5 years of follow-up, the study was terminated because no statistically significant difference in the incidence of cardiovascular events was observed between the 2 groups. The preventive effect of omega-3 fatty acids on ASCVD may therefore be related not only to the dose but also to the source of omega-3 fatty acids.

Management of type 2 diabetes

 

-
Recommendations COR LOE
Adults with type 2 diabetes are recommended to adopt a diet that is beneficial to cardiovascular health to improve the control of glucose, weight, and other ASCVD risk factors[337,338] I A
Adults with type 2 diabetes should perform at least 150 minutes of moderate-intensity physical activity or 75 minutes of high-intensity physical activity every week to improve the control of glucose, weight, and other ASCVD risk factors[339,340] I A
For adult patients with type 2 diabetes, metformin should be initiated as a first-line treatment alongside lifestyle intervention to improve glycemic control and reduce cardiovascular risk[341–344] IIa B
For adult patients with type 2 diabetes and additional ASCVD risk factors, even where glucose is controlled by lifestyle improvement and metformin use, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor with cardiovascular benefits may be considered to reduce the risk of cardiovascular disease[345,346] IIb B
For adult patients with type 2 diabetes and additional ASCVD risk factors, even where glucose is controlled by lifestyle improvement and metformin use, a glucagon-like peptide-1 (GLP-1) receptor agonist with cardiovascular benefits should be used to reduce the risk of cardiovascular disease[347] IIa B
ASCVD: Atherosclerotic cardiovascular disease; COR: Class of recommendation; LOE: Level of evidence.

Overview

Type 2 diabetes is one of the main risk factors for ASCVD.[35] Long-term intensive, comprehensive treatment for ASCVD risk factors for patients with type 2 diabetes can significantly reduce the incidence of cardiovascular events.[348,349] In addition, data from the Daqing Diabetes Prevention Study and long-term follow-up showed that for people with impaired glucose tolerance, comprehensive lifestyle interventions such as appropriate control of carbohydrate and alcohol intake, increased vegetable intake, and reasonable physical activity can help delay impaired glucose tolerance from developing into diabetes and can reduce the incidence of cardiovascular events and deaths.

Supporting evidence

Adherence to a diet beneficial to cardiovascular health is an important method for the treatment of type 2 diabetes mellitus

The Mediterranean, DASH, and vegetarian diets have been shown to increase weight loss and improve glycemic control in patients with type 2 diabetes.[337,338,350] Furthermore, studies have confirmed that the risk of cardiovascular disease and related death in patients with type 2 diabetes can be significantly reduced by following a healthy diet.[348]

The types of carbohydrates consumed are particularly important for controlling type 2 diabetes. Whole grains rich in dietary fiber should be consumed, while refined carbohydrates such as polished rice and noodles should be avoided.[351] A prospective cohort study in diabetes patients in the United States showed that higher intake of unsaturated fatty acids was associated with lower total and cardiovascular mortality rates, indicating that the type of fat intake also plays an important role in the prevention of cardiovascular disease in patients with type 2 diabetes.[352] Chinese cohort studies showed that red meat intake was associated with an increased risk of type 2 diabetes,[353] while a cohort study in the United States showed that reducing red meat intake could improve blood glucose control.[354] Furthermore, a prospective cohort study in Sweden showed that the consumption of fish in patients with type 2 diabetes was associated with decreased incidence of myocardial infarction.[355] Finally, a Japanese cohort study in Asian patients with diabetes showed that increased intake of meat was associated with an increased incidence of cardiovascular disease in this patient population.[356] Weight loss is a standard treatment for patients with type 2 diabetes; overweight and obese individuals should lose weight.[210,357–359] An appropriate nutrition plan should be formulated under the guidance of healthcare professionals.

Physical activity contributes to the control of blood glucose and cardiovascular risk factors in patients with type 2 diabetes

A meta-analysis of RCTs showed that physical activity could reduce the level of glycosylated hemoglobin in patients with diabetes.[360] Compared with a single type of physical activity, aerobic exercise combined with resistance training significantly improves blood glucose control and promotes weight loss.[339,340] Sports training can improve cardiac autonomic nerve function in patients with type 2 diabetes.[361] A prospective cohort study found that a healthy lifestyle, including moderate- to high-intensity physical activity, was associated with a lower incidence and mortality rate of cardiovascular disease.[362] In addition, RCT data showed that both long-term moderate-intensity continuous training and high-intensity intermittent training, when combined with resistance training, can reduce the carotid intima-media thickness in patients with type 2 diabetes. Furthermore, high-intensity intermittent training can improve the peripheral artery stiffness indices and distensibility coefficient.[363]

Among older adults with type 2 diabetes, particularly those combined with other comorbidities, simple physical activities such as walking can be beneficial. Younger individuals who are relatively healthy should be encouraged to participate in a variety of physical activities. In addition to regular physical activity programs, increased daily physical activity (eg, climbing stairs, walking, or cycling) should be encouraged.

Metformin treatment is associated with reduced cardiovascular risk

In the UK Prospective Diabetes Study, overweight patients with newly diagnosed type 2 diabetes were randomly divided into 2 groups. Compared with conventional therapies such as lifestyle improvement, metformin reduced the incidence of diabetes-related microvascular and macrovascular complications by 32%, incidence of myocardial infarction by 39%, and all-cause mortality rate by 36%.[341] A 2016 systematic review and meta-analysis of hypoglycemic therapy for type 2 diabetes supported metformin as first-line treatment for type 2 diabetes. Benefits of metformin treatment include a reduction in glycosylated hemoglobin level, weight control, and improved ASCVD outcomes, with acceptable safety and low cost.[342] Metformin use is associated with an increased risk of lactic acidosis and is therefore contradicted in patients with stage 4 CKD (eGFR < 30 mL·min−1·1.73 m−2). For most patients with type 2 diabetes with no contraindications, it is recommended to initiate metformin therapy alongside lifestyle intervention. In younger patients or those with only slightly elevated glycosylated hemoglobin, lifestyle intervention for 3–6 months can be attempted first, followed by timely initiation of metformin treatment based on the blood glucose level.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors can reduce the risk of cardiovascular events in patients with type 2 diabetes who are at high risk of ASCVD

SGLT-2 inhibitors act on the proximal tubules of the kidney, inhibiting the reabsorption of glucose, promoting the excretion of glucose from the urine, and thus reducing blood glucose levels. Studies have shown that the use of SGLT-2 inhibitors such as empagliflozin, canagliflozin, and dapagliflozin can significantly reduce the incidence of composite cardiovascular events and heart failure hospitalization rates in patients with type 2 diabetes.[345,346,364–368] Although most studies included subjects with cardiovascular disease at baseline, SGLT-2 inhibitor use has been proven to reduce the hospitalization rate for heart failure and can thus be extended to the primary prevention population.[346,369–372] In the Canagliflozin Cardiovascular Assessment Study (CANVAS) and Dapagliflozin Effect on Cardiovascular Events (DECLARE) trials of canagliflozin and dapagliflozin, respectively, 34.4% and 59.4% of participants were type 2 diabetes patients with high-risk factors who had not yet developed ASCVD. The results of these trials showed that SGLT-2 inhibitors could reduce the risk of hospitalization for renal failure and heart failure in this patient population and may be considered for primary prevention of cardiovascular disease.[345,346]

Glucagon-like peptide-1 (GLP-1) receptor agonists can reduce the risk of cardiovascular events in patients with type 2 diabetes at high risk of ASCVD

GLP-1 receptor agonists can enhance insulin secretion, inhibit glucagon secretion, delay gastric emptying, and reduce food intake through central inhibition of appetite in a glucose-dependent manner. Some GLP-1 receptor agonists (eg, liraglutide, albiglutide, semaglutide, and dulaglutide) can reduce the risk of ASCVD in adults with type 2 diabetes.[347,373–375] In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER), Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6), and Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) clinical trials of GLP-1 receptor agonists, 27.6%, 27.8%, and 68.5% of participants were patients with type 2 diabetes who had high-risk factors but had not yet developed ASCVD. Among these trials, only REWIND provided evidence that GLP-1 receptor agonists can be used for the primary prevention of cardiovascular disease in patients with type 2 diabetes.[347,373–377]

Based on the current evidence, SGLT-2 inhibitors or GLP-1 receptor agonists with evidence of cardiovascular benefits may be used for primary prevention of cardiovascular disease in patients with type 2 diabetes with cardiovascular risk factors, if available and affordable, in addition to lifestyle intervention and metformin treatment, independent of the level of blood glucose.

Use of aspirin

 

-
Recommendations COR LOE
Low-dose aspirin may be considered for the primary prevention of ASCVD among patients aged 40–70 years who are at very high risk of ASCVD and at least 1 enhancement factor but no high bleeding risk[378–385] IIb A
Low-dose aspirin is not recommended for routine primary prevention among patients at low to moderate risk of ASCVD III A
Low-dose aspirin is not recommended for primary prevention of ASCVD in patients aged below 40 years or over 70 years[386] III B
Low-dose aspirin is not recommended for primary prevention of ASCVD in patients with a high risk of bleeding[387] III C
Low-dose aspirin is defined as 75–100 mg/d.
Assessment of high bleeding risk is described in the section “Bleeding risk assessment”. ASCVD: Atherosclerotic cardiovascular disease; COR: Class of recommendation; LOE: Level of evidence.

Overview

Aspirin reduces the risk of thrombosis by irreversibly inhibiting cyclooxygenase-1 activity and thromboxane A2-dependent platelet aggregation, but it can increase the risk of bleeding, especially in the gastrointestinal tract.[388] Although aspirin has been widely used in the primary and secondary prevention of ASCVD, accumulating evidence indicates that its use in primary prevention should be individualized based on the patient's risk-benefit profile.

Supporting evidence

Benefits of aspirin

Aspirin is used in the secondary prevention of ASCVD,[8,389] but its role in primary prevention remains controversial. To date, no large-scale prospective clinical studies evaluating the efficacy and safety of aspirin in the primary prevention of ASCVD have been conducted in Chinese patients. Recent international guidelines have different recommendations on primary prevention use of aspirin, and European guidelines do not recommend aspirin for the primary prevention of ASCVD.[8] Data from a meta-analysis of studies published before 2016 showed that the main benefit of aspirin use is a reduction in the risk of myocardial infarction, particularly non-fatal myocardial infarction, ischemic stroke, and all-cause mortality. However, these benefits come at the cost of a higher risk of severe bleeding, especially gastrointestinal bleeding. Relevant guidelines in China and the United States recommend the use of aspirin in patients with a high risk of ASCVD.[390,391] Data from randomized studies published after 2016 indicate that the benefits of aspirin in the prevention of ischemic events are decreasing,[392–394] particularly for non-fatal myocardial infarction and ischemic stroke. Compared with blood pressure management and cholesterol-lowering treatment, aspirin has less benefit for the primary prevention of ASCVD but increased bleeding risk.[378–385] The results of recently published studies (eg, ASCEND, ARRIVE, and ASPREE)[386,392–394] further support to lower the COR of aspirin use, indicating the importance of weighing the risk of ischemia versus bleeding in the use of aspirin for primary prevention.

Assessment of ischemia risk

The importance of antiplatelet therapy in the prevention and treatment of ASCVD lies in the ability to reduce acute thrombotic events. Identifying patients at high risk of ischemia is the first step in the treatment algorithm; for example, the benefit-risk ratio is increased for prophylactic use of aspirin in patients at high risk of ASCVD.[390,395] The incidence of ischemic events observed in previous studies has a good correlation with the estimated ASCVD risk. Therefore, aspirin use is beneficial in patients with a 10-year ASCVD risk ≥10%.[391,396] However, in recent randomized studies, the incidence of observed ischemic events was lower than expected.[393] Therefore, the target population for primary prevention is individuals with a high risk of ischemia. Enhancement factors such as a family history of premature cardiovascular disease, poor control of cholesterol, blood pressure, and glucose level, or significantly higher CAC score (see “assessment of cardiovascular risk” section) should be considered in addition to conventional risk stratification.[397] Although the benefit-risk ratio of aspirin is decreasing, there remains a group of patients who may derive cardiovascular benefits from the prophylactic use of aspirin. Prophylactic use of low-dose aspirin is a treatment strategy for patients with high-risk ASCVD and enhancement factors.[398] Aspirin is not recommended for patients with low-risk ASCVD.[393]

Bleeding risk assessment

When considering the prophylactic use of aspirin, a bleeding risk assessment should be performed. Aspirin can increase the risk of severe bleeding, especially gastrointestinal bleeding, but not fatal bleeding.[384,387,394] In a previous meta-analysis study, aspirin did not increase the risk of intracranial hemorrhage compared with placebo; the incidence of epidural and subdural hemorrhage was 1 case per 1000 person-years. Subgroup analysis shows that Asian participants and those with low body weight were at higher risk of intracranial hemorrhage.[399] Predictors of bleeding include but are not limited to previous gastrointestinal bleeding or peptic ulcer disease, history of major bleeding, low body weight, age >70 years, thrombocytopenia, coagulation dysfunction, CKD, and use of concomitant medications that increase the risk of bleeding (eg, non-steroid anti-inflammatory drugs, steroids, non-vitamin K antagonists, oral anticoagulants, and warfarin).[387] The use of proton pump inhibitors to prevent gastrointestinal bleeding may be considered in patients taking aspirin for primary prevention.[400,401]

Optimal dose of aspirin

Aspirin use in primary prevention has a low benefit to risk, meaning that a dosage ≤100 mg/d is recommended. Meta-analysis data indicate that the ASCVD risk-benefit of low-dose aspirin is equivalent to that of high-dose aspirin, but patients taking high-dose aspirin have a greater bleeding risk.[389] Although the benefit-risk ratio of low-dose aspirin appears to vary according to body weight,[402] prospective studies are needed for further confirmation of this effect. The current recommended dose of aspirin for primary prevention of ASCVD is 75–100 mg/d.

Age consideration

Bleeding risk is greater than the expected benefit of aspirin use for primary prevention of ASCVD in patients aged over 70 years, and routine use is therefore not recommended in this patient population.[386] For patients aged <40 years, there is insufficient evidence to determine the risk-benefit ratio of conventional aspirin use. For patients aged between 40 and 70 years, individualized assessment and discussion of the risk-benefit profile should be conducted based on the ASCVD risk assessment algorithm and bleeding risk to determine whether prophylactic use of low-dose aspirin is warranted.

Funding

None.

Author Contributions

Writing Group Members: Jing Liu (Beijing Anzhen Hospital, Capital Medical University), Yihong Sun (China-Japan Friendship Hospital), Daoquan Peng (Second Xiangya Hospital of Central South University), Yuqing Zhang (Fuwai Hospital, Chinese Academy of Medical Sciences), Jing Liu (Peking University People's Hospital)

Core experts: Runlin Gao (Fuwai Hospital, Chinese Academy of Medical Sciences), Dong Zhao (Beijing Anzhen Hospital, Capital Medical University), Ji-Guang Wang (Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine), Ping Ye (Second Medical Center, General Hospital of Chinese People's Liberation Army), Yifang Guo (Hebei General Hospital), Xinchun Yang (Beijing Chaoyang Hospital Affiliated to Capital Medical University), Luyuan Chen (Guangdong General Hospital), Jianjun Li (Fuwai Hospital, Chinese Academy of Medical Sciences), Xiang Cheng (Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology)

Expert Committee Members (arranged in alphabetical order by pinyin of last name): Huiping Bian (Qinghai Province Cardiovascular and Cerebrovascular Disease Specialist Hospital), Jun Cai (Fuwai Hospital, Chinese Academy of Medical Sciences), Guiying Chen (First Affiliated Hospital of Harbin Medical University), Hong Chen (Peking University People's Hospital), Jiyan Chen (Guangdong General Hospital), Xiaoping Chen (China-Japan Friendship Hospital), Zhenyue Chen (Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine), Luyuan Chen (Guangdong General Hospital), Xiang Cheng (Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology), Ruozhu Dai (Quanzhou First Hospital Affiliated to Fujian Medical University), Rongjing Ding (Peking University People's Hospital), Shifang Ding (General Hospital of Central Theatre Command), Xugang Dong (First Affiliated Hospital, Sun Yat-sen University), Zhiqing Fan (Daqing Oilfields General Hospital), Yingqing Feng (Guangdong General Hospital), Xianghua Fu (Second Hospital of Hebei Medical University), Runlin Gao (Fuwai Hospital, Chinese Academy of Medical Sciences), Jianjun Guo (Capital Institute of Physical Education), Yifang Guo (Hebei General Hospital), Yaling Han (General Hospital of Northern Theater Command), Jingbo Hou (Second Affiliated Hospital of Harbin Medical University), Dayi Hu (Peking University People's Hospital), Kai Huang (Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology; Liyuan Cardiovascular Clinical Center, Tongji Medical College, Huazhong University of Science and Technology), Linong Ji (Peking University People's Hospital), Shaobin Jia (General Hospital of Ningxia Medical University), Hong Jiang (People's Hospital of Wuhan University), Zhi-Cheng Jing (Peking Union Medical College Hospital, Chinese Academy of Medical Sciences), Liwen Li (Guangdong General Hospital), Chunjian Li (Jiangsu Province Hospital), Jianjun Li (Fuwai Hospital, Chinese Academy of Medical Sciences), Ling Li (First Affiliated Hospital of Zhengzhou University), Xiaodong Li (Shengjing Hospital of China Medical University), Xinli Li (First Affiliated Hospital of Nanjing Medical University), Yi Li (General Hospital of Northern Theater Command), Yuming Li (Teda International Cardiovascular Hospital), Chun Liang (Shanghai Changzheng Hospital), Jing Liu (Peking University People's Hospital), Jing Liu (Beijing Anzhen Hospital, Capital Medical University), Peiliang Liu (Liaoning Jinqiu Hospital), Changsheng Ma (Beijing Anzhen Hospital, Capital Medical University), Xiaoping Meng (Affiliated Hospital of Changchun University of Chinese Medicine), Guang Ning (Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine), Yi Ning (Meinian Institute of Public Health, Peking University Health Science Center), Daoquan Peng (Second Xiangya Hospital of Central South University), Xiaoyong Qi (Hebei General Hospital), Peng Qu (Second Affiliated Hospital of Dalian Medical University), Yuqin Shen (Tongji Hospital Affiliated to Tongji University), Xubo Shi (Beijing Tongren Hospital Affiliated to Capital Medical University), Yihong Sun (China-Japan Friendship Hospital), Yida Tang (Peking University Third Hospital), Dongwei Wang (Zhengzhou Central Hospital), Ji-Guang Wang (Shanghai Institute of Hypertension, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine), Lemin Wang (Tongji Hospital Affiliated to Tongji University), Shouli Wang (People's Liberation Army Strategic Support Force Characteristic Medical Center), Xiaozeng Wang (General Hospital of Northern Theater Command), Yongjian Wu (Fuwai Hospital, Chinese Academy of Medical Sciences), Dan Xiao (Tobacco Medicine and Tobacco Cessation Centre, China-Japan Friendship Hospital, National Respiratory Medical Center), Xinhua Xiao (Peking Union Medical College Hospital, Chinese Academy of Medical Sciences), Biao Xu (Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School), Juntang Xu (Peking University People's Hospital), Chenghui Yan (General Hospital of Northern Theater Command), Lixia Yang (920 Hospital of Joint Logistic Support Force of Chinese People's Liberation Army), Xinchun Yang (Beijing Chaoyang Hospital Affiliated to Capital Medical University), Ping Ye (Second Medical Center, Chinese People's Liberation Army General Hospital), Miao Yu (Peking Union Medical College Hospital, Chinese Academy of Medical Sciences), Jinming Yu (School of Public Health, Fudan University), Jinqing Yuan (Fuwai Hospital, Chinese Academy of Medical Sciences), Zuyi Yuan (First Affiliated Hospital of Xi’an Jiaotong University), Cuntai Zhang (Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology), Jian Zhang (General Hospital of Northern Theater Command), Junjie Zhang (Nanjing First Hospital), Ruiyan Zhang (Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine), Xiaofei Zhang (Beijing Tsinghua Changgung Hospital affiliated to Tsinghua University), Yaojun Zhang (Xuzhou Third People's Hospital), Yuqing Zhang (Fuwai Hospital, Chinese Academy of Medical Sciences), Dong Zhao (Beijing Anzhen Hospital, Capital Medical University), Wenhua Zhao (National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention), Shenghua Zhou (The Second Xiangya Hospital of Central South University), Yingsheng Zhou (Beijing Anzhen Hospital, Capital Medical University), Yujie Zhou (Beijing Anzhen Hospital, Capital Medical University)

Conflicts of Interest

None.

Editor note: Yaling Han is the Editor-in-Chief of Cardiology Discovery; Runlin Gao and Dayi Hu are Honorary Editors-in-Chief of Cardiology Discovery; Changsheng Ma and Ji-Guang Wang are associate editors of Cardiology Discovery; Jun Cai, Xiang Cheng, Zhi-Cheng Jing, Yi Li, Jing Liu, Yida Tang, Chenghui Yan, Zuyi Yuan and Yuqing Zhang are the members of the editorial board of Cardiology Discovery. The article was subject to the journal's standard procedures, with peer review handled independently of these editors and their research groups.

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Keywords:

Cardiovascular disease; Primary prevention; Guideline

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