Table of Contents Preamble 4 Key Revisions 5 Chapter 1. Summary of the Guidelines 7 Chapter 2. Clinical Diagnosis of Atherosclerosis 12 Chapter 3. Comprehensive Risk Assessment 14 3-1. Risk Factor Assessment 14 3-2. Disease Concept and Diagnostic Criteria for Metabolic Syndrome 27 Chapter 4. Comprehensive Risk Management 29 4-1. Absolute Risk of Atherosclerotic Cardiovascular Diseases (ASCVD) and Lipid-Management Targets 29 4-2. Lifestyle Modification 34 4-3. Drug Therapy 47 4-4. Managing Major High-Risk Conditions 59 4-5. Implementation of Comprehensive Risk Assessment and Management 66 Chapter 5. Familial Hypercholesterolemia 75 Chapter 6. Other Types of Primary Dyslipidemias 80 Chapter 7. Elderly 83 Chapter 8. Women 86 Chapter 9. Children 90 References 92 Appendix 1: Physical Activity Guidelines for Health Promotion 2013 137 Appendix 2: Exercise Guidelines for Health Promotion 2006 138 Appendix 3: Method for Achilles Tendon Radiography 139 Preamble Every 5 years, the JAS publishes guidelines for the treatment of dyslipidemia and atherosclerosis. To date, this society has released four such guidelines. Since 2007, the JAS has included objectives that consider all the risk factors for atherosclerotic cardiovascular diseases (ASCVD) and has accordingly been publishing manuals, such as the “Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases.” Because guidelines should be based on evidence of diagnoses and treatments that have already been validated, regular revisions are necessary to administer medical care of high quality. Apart from age, gender, and family history, for which clinical intervention is not possible, the major risk factors for ASCVD include diabetes, hypertension, smoking, and dyslipidemia. Dyslipidemia is a huge risk factor for coronary artery disease (CAD), a form of ASCVD, and in the current set of guidelines, we will be dealing with CAD as the main disease of interest. Nevertheless, other risk factors also ought to be thoroughly managed as part of the efforts for preventing ASCVD. In 1987, a consensus conference on hyperlipidemia was held at the JAS, and reference values for diagnosing hyperlipidemia were proposed. Although the reference values were established when there was a lack of evidence in Japan, it was an unprecedented proposal that provided the clinical limits of lipids for the prevention of ASCVD. In 1988, the evidence-based National Cholesterol Program (NCEP) was announced in the United States, and since then, the reference values have undergone several revisions. At that time, there was a strong momentum for the creation of a set of Japan-specific guidelines; therefore, the “Guidelines for Diagnosis and Treatment of Hyperlipidemia” were established in 1997. Following the publication of epidemiological studies, such as the Hisayama study, and observational studies, such as J-LIT, we gradually gathered sufficient evidence in our country. Subsequently, the “Guidelines for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases”, which took risk factors into consideration, were established in 2002. The “Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2007” were later published in 2007. A change of terms from “hyperlipidemia” to “dyslipidemia” and replacement of total cholesterol with LDL cholesterol (LDL-C) as the major risk factor were features of this guideline. Establishing LDL-C as the major risk factor has led to an even more direct approach toward managing the risk factors for ASCVD. Furthermore, raising the topic on the importance of measures against metabolic syndrome and smoking, which have gained considerable attention, serves as a reminder to pay attention also to measures for the prevention of ASCVD in our daily lives. For healthy individuals, the risk of ASCVD has traditionally been assessed through the relative risk; however, this was replaced by the use of absolute risk in the guidelines released in 2012. This change resulted in a higher awareness of the importance of combined risk factors. Considering the need to comprehensively manage the wide range of atherosclerotic risks, we have compiled information on the “Comprehensive Management of Atherosclerotic Cardiovascular Diseases” and have created charts, which incorporate the guidelines of various scientific societies. We have striven to include more updated information in the current revision; hence, you will find several newly introduced Clinical Questions (CQs), which are the mainstream of recent guidelines. Shizuya Yamashita President, the Japan Atherosclerosis Society Key Revisions 1. CQs and Systematic Review (SR) In the subsections on dyslipidemia in the assessment of risk factors, absolute risk of ASCVD, lipid management targets as well as drug therapy and diet therapy in improving lifestyle habits, we created CQs and performed an SR based on the MINDS method. For our SR, we essentially chose the literature published before the end of 2015. 2. Calculation of Absolute Risk Following the 2012 version, the assessment of risk has been performed using the absolute risk calculation described in this set of guidelines. The NIPPON DATA80, which was used to calculate the absolute risk in the 2012 version, was the result of baseline surveys conducted when statins were not available. It is suited to the observation of the natural course of disease, and the data are highly useful; however, using death instead of disease onset as the outcome and the absence of information on LDL-C and HDL-C are major issues, in addition to some others. SR indicated that the Suita study, which used CAD as its outcome, is most suitable for risk calculation in this set of guidelines. We believe that the determination of the incidence rate of CAD instead of the overall risk assessment has enabled a clearer demonstration of the importance of each risk. 3. Addition of High-Risk Conditions In view of the plan to compile an extensive list of risks for atherosclerosis, we included hyperuricemia and sleep apnea syndrome (SAS) as conditions to be considered. Although these conditions may contribute to atherosclerotic lesions to different extents, it is necessary to consider them from the perspective of comprehensive management. 4. Stricter LDL-C Control in High-Risk Conditions for Secondary Prevention For the secondary prevention of high-risk conditions, such as familial hypercholesterolemia (FH) and acute coronary syndrome (ACS), we proposed an even stricter LDL-C control level than the current LDL-C control level of 1.5 mm 3, 9), and assessment is especially important for some plaques that can possibly lead to cerebral embolism (e.g., echolucent plaques, ulcers, mobile lesions, and lipid-rich plaques). If short-axis scanning shows a buildup of plaque in ≥ 50% of the vascular lumen, then the degree of stenosis needs to be assessed. When the stenosis is significant (i.e., ≥ 70%), in addition to active medical treatment, carotid endarterectomy or carotid artery stenting should also be considered. Performing the assessment to determine the properties of the plaques and the percentage of stenosis in the same way as it is done in the carotid arteries is likewise important for arteries in the lower extremities 10). Furthermore, confirming the presence of collateral circulation, the patterns of blood flow waveforms and the below-knee transit time of vessel flow (TVF) would make it possible to estimate where the stenotic portions are 11). Ultrasonography is also a useful method for diagnosing atherosclerotic renal artery stenosis in the renal arteries 12, 13). 2) Computed Tomography (CT) CT is a method of examination that can diagnose arteriosclerosis in a short amount of time. It can also determine whether aneurysm is present by measuring the size of the artery. Furthermore, as the degree of calcification, fats, and fiber content can be estimated to some extent based on the CT number, it is an excellent means for confirming the presence of calcified lesions in the aorta and peripheral arteries. Multidetector CT (MDCT) offers superior imaging speed and spatial resolution, and by injecting a contrast medium through the peripheral veins, it enables the visualization of diseases in all the arteries and coronary arteries. It is commonly used to screen for CAD. It has excellent specificity 14–17), and organic coronary stenosis can almost be ruled out if no abnormalities are detected using this technique. 3) Magnetic Resonance Imaging/Angiography (MRI/MRA) MRI is especially useful for detecting lesions in the brain, which include ischemic changes and cerebral infarction. MRA provides an excellent means for visualizing stenosis and obstructive lesions in the intracranial arteries, carotid arteries, aorta, renal arteries and other blood vessels. Nowadays, non-contrast enhanced MRA is sometimes used in place of angiography. The properties of the plaques can also be assessed using MRI plaque imaging. 4) Catheterization To date, angiography using a catheter remains as one of the main methods for diagnosing arterial stenosis despite being an invasive examination. Stenotic portions are assessed on the basis of the percentage of stenosis, which is calculated using the luminal diameter of normal-appearing portions and stenotic portions. However, limitations such as eccentric plaques and compensatory remodeling hinder the accurate determination of plaque volume. Meanwhile, intravascular ultrasound (IVUS), optical coherence tomography (OCT) and the vascular endoscope are some other methods that provide an excellent assessment of the plaque volume as well as the properties of the plaques. 2. Vascular Function Tests 18) 1) Ankle–Brachial Index (ABI) and Toe–Brachial Index (TBI) ABI is the ratio of the blood pressure (BP) in the brachial artery to the BP at the ankle joint. This ratio is an indicator of narrowing of the central major arteries from the ankle joint or the presence of obstructive lesions and the degree of compensation by collateral circulation. Methods of measurement include the Doppler technique and the oscilloscope. The Korotkoff sounds should be verified when measuring the BP in the extremities using a sphygmomanometer and a stethoscope. On the other hand, the oscillometric method is employed when performing automated measurement using an automated sphygmomanometer or specialized equipment. Although the correlation between both methods is generally good, the precision of the oscillometric method is low when used in cases of critical limb ischemia. If the ABI is ≤ 0.9, then the presence of obstructive lesions in the lower extremities should be suspected 19, 20). TBI is the ratio of the BP in the brachial artery to the blood pressure at the toes. Measuring both the ABI and TBI allows us to gauge the peripheral artery obstructive lesions distal than ankle joints. The reference TBI value is ≥ 0.7, and the presence of obstructive lesions in the arteries of the lower extremities should be suspected if the resulting value is ≤ 0.6. It is necessary to note that diabetes patients and patients undergoing dialysis are prone to calcification in the walls of arteries below the knee, and hence, there are cases in which the ABI cannot be accurately measured. 2) Brachial-Ankle Pulse-Wave Velocity (baPWV) The pulse-wave velocity (PWV) produced by cardiac output reflects the stiffness of arteries 21). It can be easily determined by measuring the pulse waves in the extremities using a specialized device. However, it is necessary to note that the PWV is an indicator of arterial stiffness and does not necessarily reflect atherosclerosis. The PWV is the speed at which the aortic vibration (i.e., pulse wave) generated by the beating of the heart is transmitted to the peripheral artery. It is proportionate to the stiffness and thickness of the arterial walls. The carotid-femoral PWV (cfPWV) and baPWV are the two forms of PWV measurement. baPWV is currently being used in clinical practice in Japan. For baPWV, influences during BP measurement must be taken note of. Aging 22), hypertension 23), diabetes 24), and pulse rate 22) are CVD risk factors that have been reported to cause increased baPWV, and they show a good correlation with the Framingham Risk Score. A baPWV of 1,400 cm/sec corresponds to the moderate risk level in the Framingham Risk Score. 3) Stiffness Parameter β and Cardio-ankle Vascular Index (CAVI) Stiffness parameter β is an index that represents the localized intrinsic stiffness of the arterial walls. Arterial elasticity is hardly affected by BP, and stiffness parameter β has been designed as an index of arterial elasticity that is corrected using BP during measurement. It is calculated using the formula ln (Ps/Pd)/[(Ds-Dd)/Dd], with BP and changes in carotid artery caliber as the variables 25). Additionally, it has been reported that stiffness parameter β is correlated with carotid atherosclerosis 26, 27). The CAVI is an index that represents the elasticity of the entire artery, from its aortic root to the ankle, and it is derived by applying the concept of the stiffness parameter β to the long arteries. A feature of CAVI is its nondependence on BP during measurement 28). The CAVI increases with age 28), and patients with cerebral infarction, CVD 29), chronic kidney disease (CKD), and vasculitis have high CAVI values. It is also increased in patients who suffer from hypertension, diabetes, metabolic syndromes, sleep apnea syndrome (SAS), smoking, stress caused by disasters, etc., but at the same time, it has been reported that the CAVI improves with treatment of these contributing factors 25). Prospective surveys on cardiovascular events have revealed that a high CAVI value is associated with a high frequency of cardiovascular events 30). In addition to these, the central BP is also an index that reflects vascular function. 4) Vascular Endothelial Function Reactive hyperemia following a 5-minute avascularization in the forearm and certain drugs such as acetylcholine cause a vascular endothelium-dependent increase in blood flow, and vascular endothelial function is assessed by measuring the resulting increase in arterial diameter and blood flow. The first method of assessment is strain-gauge plethysmography, which measures the changes in circumference of the extremities as the arterial pulse is produced. The second method is flow-mediated dilatation (FMD), in which the changes in diameter of arteries in the upper arm are measured by ultrasonography. FMD is a test that assesses the extent of brachial artery dilation caused by reactive hyperemia after 5 minutes of forearm ischemia. The formula used for calculation is FMD (%) = (diameter of the most dilated blood vessel - resting blood vessel diameter)/resting blood vessel diameter × 100. The normal FMD value is ≥ 6–7%, and a malfunction in the endothelial cells results in poor production of nitric oxide (NO), which in turn lowers the amount of FMD. FMD starts decreasing from early stages of arteriosclerosis 31, 32), and it is therefore useful for the initial assessment of ASCVD. 3. Predicting the Risk for ASCVD by Assessing Arterial Walls It has been reported that IMT/plaque of carotid artery, ABI, baPWV, CAVI, FMD, and such are independent predictive factors of future risk for ASCVD. However, reports of other countries have revealed that adding the result of IMT measurement does not increase the ability of risk prediction by the Framingham Risk Score 33). Although there are reports on the significance of noninvasive arterial wall assessment in Japan 34), there is still a lack of sufficient evidence. Recent reports by Japan have shown that 35) when data from a meta-analysis that integrated personal-level data of 14,673 Japanese was used, the addition of baPWV to the classic risk factors increased the ability to predict the risk for CVD. These reports have particularly demonstrated the usefulness of baPWV in risk prediction for low-risk groups. In addition, it is suggested that a baPWV > 1,800 cm/s is a risk that is equivalent to the high-risk conditions 18, 21). However, baPWV that reflects a high risk may possibly be different in the target group, and further accumulation of data would be advantageous. To indicate the abnormal findings of these indices except ABI in the risk categories in this set of guidelines, which will lead to stricter management, more evidence needs to be built. Chapter 3. Comprehensive Risk Assessment 1. Risk Factor Assessment 1) Dyslipidemia CQ1. Is LDL-C a predictor of the ASCVD incidence and mortality in the Japanese people? Elevated LDL-C predicts the CAD incidence and mortality in the future. Among the types of stroke, LDL-C has been shown to be positively related to cerebral infarction and negatively related to hemorrhagic stroke, but in regard to the Japanese, the evidence cannot be considered adequate. (Evidence level: E-1b) Many epidemiological studies have been conducted in Europe and America, including the Framingham Study in the US. Similar to the results of these studies, the increase in hazard ratio for the CAD incidence and mortality following an elevation in LDL-C has been validated in cohort studies involving the Japanese 36–40). It was shown in the Circulatory Risk in Communities Study (CIRCS) that in comparison with the LDL-C 20 sticks in a meta-analysis. Furthermore, the relative risk of getting stroke and stroke-related death was 1.41 times higher for those who smoke ≤ 20 cigarettes a day and 1.56 times for those who exceed 20 sticks 112). Other than that, a metaanalysis of cohort studies in Japan have shown that for abdominal aortic aneurysm(AAA), the relative risk is 3.89 times higher for men and 4.30 times for women 113). The dose–response relationship has also been made apparent in the analysis. The association with PAD has also been shown in cohort studies, including the Framingham Study. Even in cross-sectional studies conducted in Japan, the proportion of PAD, as determined using the ABI, was shown to be 3.7 times higher in current smokers (4.2 times for those with ≥ 45 pack-years) and 3.7 times in ex-smokers. The dose–response relationship has similarly been demonstrated in these studies 114). On the other hand, for passive smokers, it has been revealed in a meta-analysis that the relative risks for CAD and stroke are 1.31 115) and 1.25 116), respectively. Smoking increases the risk for developing type 2 diabetes to 1.4 times 117), and the risk for metabolic syndrome increases in accordance with the number of cigarettes smoked 118). A meta-analysis has shown that smokers have lower HDL-C levels and higher LDL-C and TG levels, and the dose-response relationship has again been observed 119). Smoking by itself is not just a risk factor for ASCVD. It also increases the risk for diabetes, dyslipidemia and metabolic syndrome, in turn contributing to an added risk for ASCVD. Recently, new forms of tobacco (heat-not-burn tobacco products and electronic cigarettes, etc) that differ from the conventional combustion cigarette have been in circulation. As these new forms of tobacco have only been in circulation for a short period of time, their effects on health, such as the risk for ASCVD and related death, cannot be determined at this point of time. Nonetheless, although heat-not-burn tobacco products do not contain substances that are produced by combustion, users still inhale and exhale the aerosol generated by heating the tobacco leaves and additives, including nicotine 120). Moreover, from the fact that various carcinogens have been reported to be found in the aerosol, regardless of whether electronic cigarettes contain nicotine 121), the use of any of them has a possibility of adversely affecting health. 3) Hypertension [Statement] Blood pressures that exceed the optimal reading (i.e., systolic BP (SBP) 5% over 1 year 375). Therefore, maintaining an appropriate body weight is effective in improving serum lipid levels, and it is possible to prevent ASCVD by improving serum lipid levels. However, in such a case as sarcopenia and malnutrition in the elderly, caution should be exercised when decreasing the total energy intake, and the appropriate ratio and intake of nutrients should be considered. CQ8: Is limiting the percentage of energy derived from fat in the appropriate total energy intake effective in preventing ASCVD? Limiting the percentage of energy derived from fat in the total appropriate energy intake is effective in improving serum lipid levels. (Evidence level: 1, recommendation level: B) Although there is no direct evidence showing that limiting the percentage of energy derived from fat in the total appropriate energy intake suppresses ASCVD, lifestyle modifications including weight loss and modified and/or decreased fat intake may prevent ASCVD. (Recommendation level: A) There is no direct evidence showing that reduction of the percentage of energy derived from fat decreases ASCVD. However, many trials comparing low-fat* and low-carbohydrate meals in the appropriate total energy intake have been performed to reveal these effects on weight loss as the primary outcome and on ASCVD risk factors as the second outcomes in obese subjects with BMI more than 25 kg/m2. A meta-analysis of RCTs comparing ≥ 1 year outcomes of high-fat (> 30% of total energy intake) and low-fat diets in obese subjects with BMI > 25 kg/m2, found significant reductions of TC and LDL-C levels following a low-fat diets compared with high-fat diets. The TG levels were lower and the HDL-C levels were higher following a high-fat diet. The differences in TC and LDL-C levels observed in the two groups were abolished when total energy intake was restricted. A high carbohydrate intake was associated with an increase in the TG levels 376). Another meta-analysis of RCTs compared the effects of balanced diets (fat to 25–35% of total energy intake, and carbohydrate to 45–65% of total energy intake) with low-carbohydrate ( 12% of total energy intake, compared with ≤ 12%, but significant effects on the serum lipid levels have not been confirmed 436). Meta-analysis of RCT to analyze the effect of substitution of SFA with MUFA also did not have significant effect on serum lipid levels 382). The current evidence thus shows that increasing MUFA intake may improve serum lipid levels, but that this effect may disappear with excessive intake. CQ13. Is reducing the intake of trans fatty acids effective in preventing ASCVD? Reducing the intake of trans fatty acids is effective in preventing ASCVD. (Evidence level: 2, recommendation level: B) Trans fatty acids are constituents of naturally occurring foods such as beef, mutton, milk, and dairy products, and may also be industrially produced (hydrogenation) or refinement (deodorization or high-heat processing) of fat. Trans fatty acids produced by hydrogenation are contained in hard margarine, fatty spreads, and vegetable shortening, deep-fried food and confectionery made using these products. Trans fatty acids are also contained in refined vegetable oils such as salad oil. Industrially produced trans fatty acids increase LDL-C 437–441) and lipoprotein (a) [Lp(a)] which is a lipoprotein that promotes atherosclerosis 437, 442, 443) and decrease HDL-C 439, 442, 444), compared with other fatty acids, whereas the effect on TG is inconsistent 440–442). Cohort studies and their meta-analyses provide concordant evidence that the intake of trans fatty acids is associated with CAD 384, 438, 445–448). No significant relationship with ischemic stroke has been observed 447). A cross-sectional study reported high blood concentration of elaidic acid, an industrial trans fatty acid, in Japanese patients with metabolic syndrome or young Japanese patients with CAD 449). Currently, there is no consensus on whether naturally occurring trans fatty acids should be regarded in the same way as industrially produced ones 439, 444, 445, 450, 451). A meta-analysis of RCTs comparing the effects of vegetable oils containing industrially produced trans fatty acids with oils substituted with other fatty acids reported that TC, LDL-C, and TG levels were significantly decreased, and the HDL-C level significantly increased, when trans fatty acids were substituted with MUFA or PUFA 448). A meta-analysis of cohort studies in the same article found that substitution of trans fatty acids with SFA, MUFA or PUFA has decreased CAD risk 448). The average daily trans fatty acid intake of the Japanese is 0.92–0.96 g, or 0.44–0.47% of the total energy intake 452), which is lower than the 1.0 or presence of small dense LDL is confirmed using lipoprotein polyacrylamide gel disc electrophoresis (PAG). A survey of familial history is optional for this diagnosis. Table 17. Diagnostic criteria of FCHL Criteria (1) Familial combined hyperlipidemia is associated primarily with phenotype Ⅱb and possibly with phenotypes Ⅱa or Ⅳ (2) An apoprotein B/LDL-C ratio of > 1.0 or the presence of small dense LDL (particle size 0.05. Other indicators, such as apoE/B > 0.20 and apoE/CⅢ > 1.0 898), TC/apoB > 6.2 and TG/apoB 0.1 895), non-HDL-C/apoB > 3 900), and apoB48/TG > 0.11 901), have also been proposed. LDL-C levels are low on lipoprotein analysis using ultracentrifugation or HPLC. Ultracentrifugation can be used to confirm a significant increase of cholesterol in IDL fraction (1.006 65 years group, the relative risk of statin therapy on major coronary artery events was 0.81 (95% confidence interval [CI]: 0.76–0.88] (2005) 917), the relative risk on a major vascular event of statin and high-dose statin groups in subjects aged 66–75 years was 0.78 (95% CI: 0.74–0.83) relative to the control group or a low-dose statin group, and 0.84 (95% CI: 0.73–0.97) in the group > 75 years (2010). Both meta-analyses demonstrated that statin therapy showed increased effects than the control group, and that high-dose statins had greater effects than a low-dose statin group in preventing an event 918). A meta-analysis of 51,351 elderly subjects aged ≥ 60 years, including primary and secondary prevention patients, who received intervention with statins showed that statin therapy decreased total mortality by 15% (95% CI: 7–22%), death from CAD by 23% (95% CI: 15–29%), fatal and nonfatal myocardial infarction by 26% (95% CI: 22–30%), and fatal and nonfatal stroke by 24% (95% CI: 10–35%) compared to the placebo. However, the relative risk of cancer onset with statin therapy was 1.06 (95% CI: 0.95–1.18) relative to the placebo, and the difference was not statistically significant. There was no significant difference between statins and the placebo in terms of adverse events, such as a ≥ 3-fold increase of AST and ALT, ≥ 10-fold increase of CK or termination of the trial. However, muscle pain and gastrointestinal symptoms occurred significantly more often in the statin group. Moreover, new-onset diabetes was significantly higher in the statin group among those ≥ 65 years 919). A meta-analysis of CAD mortality risk in a secondary prevention intervention trial, including elderly subjects aged ≥ 65 years, showed that the effects of secondary prevention on the elderly are far greater than that would be predicted from the outcomes in younger individuals 920). As such, the secondary prevention effects of statin in the elderly with CAD history are evident and are recommended. The recently published J-STARS is a research study investigating the efficacy of 10 mg pravastatin on patients with ischemic stroke aged 45–80 years. Although no significant difference was found in terms of the primary endpoint, statins decreased the incidence of atherothrombotic cerebral infarction by 67% 921). Considering the mean patient age of 66 years in this study, approximately half of the subjects were presumed to be elderly, and considering that the effects of statin therapy were observed regardless of age group, these results suggest that statins are capable of preventing the recurrence of atherothrombotic cerebral infarction in the elderly. Meanwhile, the MEGA Study on primary prevention in the elderly showed that the concurrent risk of CAD and cerebral infarction decreased significantly in individuals aged ≥ 65 years [hazard ratio: 0.60 (0.39–0.93)], which was related to the efficacy of statin treatment in the elderly with high LDL-C 922). Another meta-analysis, involving only primary prevention studies, also indicated that statin administration lowered the risk of all-cause mortality, major cardiovascular events and major cerebrovascular events 923). Another meta-analysis of primary prevention including 24,674 elderly patients (mean age: 73 years, 43% women) confirmed that statins decreased myocardial infarction and stroke by approximately 40% and 25%, respectively 924). The efficacy of statin treatment has thus been established, at least for primary prevention in younger elderly patients. Consequently, pharmaceutical therapy can be recommended on the basis of the risk factors present. However, there is still a lack of strong evidence for primary prevention in the elderly aged ≥ 75 years. As there is no method of risk assessment for elderly patients aged ≥ 75 years, as indicated in Chapter 2, treatment should be given, or dismissed, at the discretion of the attending physician. In addition, as geriatric syndrome complications, such as frailty and sarcopenia, are common in elderly aged ≥ 75 years, it is important to confirm whether patients in this particular group have adequate protein intake when dietary counseling is provided. 2) The Effects of Statins in Dementia Prevention A selection of observational and interventional studies has attempted to investigate the effects of statin treatment on dementia prevention. However, many of these reports relate to subanalysis and secondary endpoints, and studies that set cognitive function as the primary endpoint involved sample sizes that were too small. An observational study suggested that statin treatment improves cognitive function 925), many research results do not support these effects 926, 927). A meta-analysis of interventional trials of four statins on patients with Alzheimer's disease patients in a recent Cochrane review, however, failed to demonstrate that statins could improve cognitive function 928). Therefore, we can conclude that the effects of statins in the prevention and treatment of Alzheimer's disease are not positive. Although there is no research data relating to the assessment of statin effects on vascular dementia, we do know that stroke increases dementia risk by approximately 2-fold and that statins decrease the incidence of stroke; consequently, the preventive effects of statins on vascular dementia incidence can be expected. However, there are some case reports in which statins decreased cognitive function, and must, therefore, be approached with caution. 3) Frailty, a New Risk Factor that should be Considered in the Elderly In the elderly, frailty is another factor which can require long-term care, much like dementia. In fact, there have been recent studies reporting that the incidence of cardiovascular events increases in elderly patients with frailty, or those who show vulnerability to acute stressors, a condition that appears with age. For example, White et al. conducted a prospective follow-up study dividing non-ST-elevating ACS patients aged ≥ 65 years into three groups: frail, pre-frail, and nonfrail groups using Fried criteria and found that the frail group had significantly higher primary endpoints of cardiovascular, myocardial infarction and stroke mortality than the nonfrail group (HR: 1.76; 95% CI: 1.36–2.28), and that all-cause mortality also increased significantly (HR: 1.98; 95% CI: 1.47–2.68) 929). In another study, Sergi et al. divided 1,567 nonfrail elderly patients aged 65–96 years into three groups: a group meeting 1 Fried criterion, a group meeting 2 Fried criteria and a third group that did not meet any of the criteria; these groups were followed-up for 4.4 years in relation to CAD, heart failure, stroke, PAD and cardiovascular death as the primary endpoints. Even after adjustment for the confounding factors, event incidence occurred significantly more frequently in the groups meeting 1 or 2 Fried criteria; in other words, those in the pre-frail groups, compared to the robust group 930). This suggested that frailty, characterized by low grip strength and slower walking speed, may represent a new risk factor for cardiovascular events in the elderly, and that there may be a need to make more comprehensive assessments that include geriatric syndromes such as frailty. Sarcopenia is a pathological condition related to frailty. Sarcopenia is characterized by decreased muscle mass associated with age, which decreases muscular strength and walking speed, and has been suggested to not only cause falls and fractures but also exert impact on cardiovascular events 931). Because statins cause muscle disorder as a side effect, it is concerned that long-term continuous use may be related to sarcopenia incidence. For example, Scott et al. showed that the use of statins in the community-dwelling elderly was linked to decreased leg muscle strength 932); however, a subsequent meta-analysis by Krishnan et al. concluded that the earlier study by Scott et al. was lacking in convincing evidence 933). Lynch et al. further reported that the use of statins in 3,422 elderly patients in rehabilitation (mean age = 81.4 years) was associated with an improvement in the activities of daily living 934). As such, at present, there is simply not enough evidence to support the fact that statin treatment increases the risk of sarcopenia. 4) The Advantages and Disadvantages of Statin Treatment during End-of-Life Care Sometimes doctors cannot decide whether or not a patient's medication should be continued or terminated, even during end-of-life care. Most clinical research tests the effects of pharmaceutical drugs by initiating them; however, Kutner et al. randomly assigned 381 patients estimated to have ≤ 1 year of life expectancy into two groups: one group for which treatment would be terminated and a second group that would continue taking the prescribed statin. These authors set death as the primary endpoint, and also studied quality of life (QOL) and financial effects. Results showed that there was no increase in deaths or cardiovascular events when statin treatment was terminated, and instead showed that QOL improved and that patients were able to save on their medical costs 935). At the end of life, it is sometimes difficult to continue taking medication due to decreased appetite or dysphagia; hence, it is logical that being able to decrease oral medication in a safe manner will lead to an improvement in patient QOL. Because statins in primary prevention are thought to take 3–4 years to have an effect upon the suppression of vascular events, the use of statins should only be considered in cases with at least ≥ 3 years of life expectancy. 3. Care of the Elderly For preventing ASCVD in the elderly and maintaining QOL, it is important to manage dyslipidemia, particularly hyper-LDL cholesterolemia, which is an important risk factor. At the same time, it is important to consider the increase in secondary dyslipidemia, which occurs with complications such as hypothyroidism. There are many aspects to carefully consider in providing treatment to the elderly, such as the comorbidities other than ASCVD that may impact upon vital prognosis, latent organ disorder, atypical symptoms, decreased organ spare ability, decreased drug metabolism ability, malnutrition, frailty, polypharmacy, and due to variability in physical functions, careful considerations should be paid to treatment. The basic treatment for dyslipidemia is dietary and exercise therapy for the elderly. Drug therapy should not be given at ease without implementing nonpharmaceutical therapies first. However, because adherence to strict diet therapies can worsen the nutritional state of the elderly, particularly in the latterstage elderly population, and because it is difficult for many to take on the same-level of physical activity as nonelderly adults for exercise therapy, it is best to make an intervention which is adapted to each individual's capacity. Pharmaceutical therapy should be prescribed with extreme care with the understanding that elderly patients are more prone to side effects. Chapter 8. Women [Statement] It is important to manage risk factors, such as hypertension, diabetes, and smoking regardless of menopause status. In particular, diabetes and smoking are related to an increased the coronary artery disease (CAD) risk in women than in men. (Evidence level: E-1a) The intensity of treatment for hypertension and diabetes should be personalized for each patient; however, smoking cessation is important for women across all age groups. (Evidence level: 2, recommendation level: A) In premenopausal women, lifestyle modification is the most important aspect of dyslipidemia treatment. (Evidence level: 2, recommendation level: A) Even before menopause, pharmacotherapy should be considered for high-risk women, such as those with familial hypercholesterolemia or CAD, and primary prevention subjects with high CAD risk. (Evidence level: 3, recommendation level: A) Lifestyle modification is the fundamental aspect of treatment for dyslipidemia in postmenopausal women; however, pharmacotherapy should be considered in patients with high CAD risk. (Evidence level: 2, recommendation level: A) 1. Current Status of ASCVD in Japanese Women According to the gender-specific causes of death in the 2014 Population Census of Japan, mortality rates for cardiovascular disease, including heart failure, and cerebrovascular disease in women is 26.8%, which is higher than the rate of 22.3% in men and the rate of 24.4% for malignant neoplasms 936). However, myocardial infarction incidence is lower in women than in men 937, 938) The epidemiological survey conducted in Japan between 1990 and the beginning of 2000 revealed that the age-adjusted incidence (100,000 persons/year) of myocardial infarction in women is 20–50% of that in men 98, 163, 939, 940). Although the incidence rate of myocardial infarction increases after menopause, the rate is still lower than that in men 163). According to the 2013 demographic statistics, mortality rate (per 100,000 persons) due to myocardial infarction in women is lower than that in men in the corresponding age groups: approximately 20% of the men's rate in the 50s, 20–30% in the 60s, and 37–48% even in their 70s 936). In contrast, it has been reported that the mortality rate after a coronary event is higher in women than in men among both Western 941–944) and Japanese subjects 945, 946). Aging among Japanese women is progressing and is accompanied by an increased morbidity and mortality due to myocardial infarction 163, 936). Thus, it is important to take future measures for prevention and care even in Japanese women. Among the Japanese, the age-adjusted incidence of cerebral infarction is higher than that of myocardial infarction. However, the incidence in women is approximately 50–70% of that in men 98, 939, 940, 947–949). The incidence rate of cerebral infarction in women increases with age, and it reaches 60–90% of that of the men for women aged ≥ 75 years. Compared to myocardial infarction incidence, the gender difference in the rate of cerebral infarction is small 163, 948, 949). Mortality rate due to cerebral infarction in women in 2013 (per 100,000 persons) is also lower than that in men 936). On the other hand, cross-sectional study of acute cerebral infarction reported that the duration of hospitalization is longer for women than for men and that patient status at the onset and after discharge is poorer for women than for men 950). Among the Japanese, cerebral infarction incidence is higher than that of myocardial infarction, and the gender differences in cerebral infarction incidence are smaller than that of myocardial infarction. Furthermore, proportion of older women continues to increase in Japan. Thus, the prevention and management of cerebral infarction among women is an important issue for the future. 2. Relationship between Risk Factors for Atherosclerosis and ASCVD in Women 1) Serum Lipids Age-related changes in serum lipid levels are significantly different between men and women. Total cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C) levels are higher in men than in women until the fourth decade of their lives; however, because of menopause, the levels become higher in women than in men after the age ≥ 50 years 85). High-densitylipoprotein cholesterol (HDL-C) levels are higher in women than in men among all age groups. Triglyceride (TG) levels are also higher in men than in women, but this increases with age in women, and the difference between genders diminishes after age 50 years 85). It is likely that the changes in serum lipid levels, especially changes in LDL-C after menopause, may influence the ASCVD risk in women. JALS-ECC 337), a longitudinal epidemiological study reported that CAD risk was significantly higher in the high-TC group than in the low-TC group after adjustment for multiple confounding factors in women. CIRCS also showed that myocardial infarction risk after adjustment of multiple factors increase 1.42 times with each increase LDL-C by 30 mg/dl 37). EPOCH-JAPAN studied the relationship between TC levels and CAD mortality risk, and found that the risk was significantly higher in the high-TC group than in the low-TC group for women aged between 40 and 69 years 951). The NIPPON DATA 80 also showed a significantly higher cardiovascular mortality risk among women with hypercholesterolemia group 54). However, in the Ibaraki Prefectural Health Study, no significant correlation was found between LDL-C and CAD mortality 38). Thus, cholesterol level is a significant risk factor for the CAD incidence among Japanese women, and also might be a risk factor related to CAD mortality. The JPHC Study 59) and EPOCH-JAPAN 951) examined the relationship between TC and cerebral infarction risk, and concluded that no significant correlation existed among women. Iso et al. reported that elevated TG level was also a significant risk factor for the incidence of myocardial infarction and ischemic cardiovascular diseases in women 88, 93). In addition, JALS-ECC 337) and CIRCS 63) reported that non-HDL-C is a significant risk factor for CAD incidence but not CAD mortality 66). Thus, abnormalities in TC, LDL-C, TG, and non-HDL-C levels might be an important risk factors of CAD for Japanese women. 2) Smoking The JPHC Study Cohort1 786) and Suita Study 108) found that the incidence rate of myocardial infarction was three to eight times higher among smokers than among nonsmokers even among women. In addition, CAD-related mortality risk was significantly higher in women smokers 952, 953). Meta-analyses involving studies conducted in Japan have reported that the influence of smoking on CAD risk in women is greater than that in men 954). JACSS, a multicenter collaborative research of acute coronary syndrome (ACS) in Japan, found that women who smoke had extremely higher ACS risk than men with smoking, with an odds ratio of 8.2 in women compared to that of 4.0 in men 955). Smoking is also a significant risk factor for cerebral infarction in women 108). Moreover, passive smoking increases cerebral hemorrhage risk but not cerebral infarction risk among Japanese women 956). Thus, smoking should be considered as an important risk factor for CAD and cerebral infarction among Japanese women. 3) Hypertension Epidemiological studies in Japan did not demonstrate that hypertension was a significant CAD risk factor in women 957, 958), although there was a trend for increase the CAD risk 958). However, it has been reported that hypertension was a significant risk factor for cerebral infarction incidence among women 857, 957, 958). NIPPON DATA 80, which studied the relationship between hypertension and cardiovascular mortality risk, reported that the association between the two was significantly stronger for in younger women aged 30–59 years than in women aged ≥ 60 years 959). Thus, hypertension is an important risk factor for cerebral infarction among women, and it is necessary to treat hypertension from a younger age. 4) Diabetes The JPHC 136, 146, 960), Hisayama 961), and Suita studies 962) reported that CAD and cerebral infarction risk as well as the related mortality risk were significantly higher among patients with diabetes than among those without. The NIPPON DATA 80 showed that CAD mortality risk was high among older women whose random blood glucose ≥ 200 mg/dL 161). JACCS reported that the odds ratio for myocardial infarction incidence for female diabetics was 6.12 compared to 2.90 for male diabetics, indicating a significant increased myocardial infarction risk among women 954). In the meta-analyses, including the research in Japan, it was reported that CAD risk and all-stroke risk were 44% 149) and 27% 150) higher, respectively for diabetic women than for diabetic men. 3. Primary and Secondary ASCVD Prevention in Women The fundamental strategy for ASCVD prevention is lifestyle modification. The Nurses' Health Study (NHS) in US revealed that the increasing of favorable lifestyle factors (e.g., smoking cessation, increase in physical activity, maintenance of ideal body weight, restriction of alcohol consumption, and healthy eating habits) were associated with lower risk of CAD 963) and sudden cardiac deaths 964). In addition, a collaborative analysis of NHS and Health Professionals Follow-up Study reported that the relative cerebral infarction risk among women who had all five factors described above was extremely low at 0.19, compared to women without any of favorable lifestyle factors 965). Moreover, NHS, which included young women aged 27–44 years, showed that CAD incidence was decreased by 98% who had six factors (the above described five factors plus restricted TV-watching time) compared with women without any of these factors 966). Thus, maintaining a healthy lifestyle from a younger age is quite important for preventing ASCVD in women. Although effect of smoking on CAD risk is greater for women than for men 953), this effect is diminished after smoking cessation 108). Because smoking has a negative effect on pregnancy 967) and smoking cessation decreases ASCVD risk regardless of age 107), it is extremely important for women to stop smoking from a younger age. Few large scale trials have investigated the primary prevention of CAD using statins in women. In the MEGA Study conducted in Japan, 68% subjects were postmenopausal women aged ≤ 70 years. In this study, statins did not decrease the risk of CAD and cerebral infarction significantly in women 41). However, in the sub-analysis among women, risk of CAD combined with cerebral infarction was significantly decreased among the women aged ≥ 55 years 620). In JUPITER, statins were administered to 3,426 female subjects, and the risks of unstable angina and reperfusion therapy were significantly decreased compared to the placebo group. However, significant risk reduction of myocardial infarction and cerebrovascular events was not observed in women with statin therapy 968). In addition, the risk for the primary endpoints that include these events was significantly lower among the women aged ≥ 65 years but not in women aged 35 mg/dL for HDL-C, and < 150 mg/dL for TG. When LDL-C is above the target level, blood glucose control is intensified and diet and exercise therapies for hyperlipidemia are added. For hypo-HDL-cholesterolemia and hypertriglyceridemia, the basic approach is to improve lifestyle habits 991). In Japan, the general consensus is that LDL-C should be maintained at least within the normal range (< 140 mg/dL); however, no explicit criteria are currently available for drug therapy for children 992). Therefore, it is important to take care of children's diets and continue with strict blood glucose control. 5. Maintaining Proper Body Weight with Appropriate Diet and Exercise Habits Pathological blood vessel changes associated with arteriosclerosis have been reported to gradually occur in childhood 993, 994). It is important to prevent such changes from occurring and progressing as much as possible. To achieve this, it is important to develop correct lifestyle habits (e.g., diet) and maintain a proper body weight from childhood. Even in children, obesity causes problems such as abnormal blood test values (e.g., adipocytokine secretion) and blood pressure 995, 996). Thus, obesity in children is also considered to promote ASCVD similar to that in adults, and attention paid to obesity during childhood helps reduce the risk of future lifestyle-related diseases. The 2015 Dietary Reference Intakes for Japanese 997) lists the desirable daily energy intake according to age and body size. Regarding nutritional balance, the target ratios of energy intake from fat and carbohydrates are 20–30% and 50–65%, respectively, which are same for all age groups (from 1 year to ≥ 70 years). Fat intake should be moderate because in recent years, due to the westernization of dietary habits, fat intake has increased. Therefore, it is recommended that individuals consume a well-balanced amount of fish, soybeans (products), vegetables, fruits, and seaweed, by utilizing Japanese food patterns as a main method, with no preference to a particular type of food. Care should also be taken to avoid excess salt intake. Because BMI percentile (or standard deviation) method is inappropriate to evaluate overweight and obesity in children, because of the large variability in body height, it is better to assess the percentage of overweight (POW) based on comparison with standard body weight 998). The POW is calculated as [(measured body weight–standard body weight)/standard body weight] × 100 (%). In general, elementary and junior high school students are classified as obese if the calculated POW is + 20% or higher (≥ 120% of the standard body weight) 998). Like in obese adults, LDL-C and TG tend to be high in obese children, whereas HDL-C tends to be low. Even if the calculated POW is not indicative of severe obesity (≥ 50%), the child is considered to be “obesity disease”, a target of treatment for reducing the severity of obesity, when he or she exhibits any obesity-related complications 996). In obesity, the energy intake is increased and exceeds the necessary level; it should be reversed to normal levels. Obese children should increase their vegetable intake and avoid certain drinks and seasonings. The degree of obesity improves more easily during childhood because body height continues to increase. Moreover, an exercise habit should be established at the same time as dietary restrictions. In particular, adequate guidance should be given to children who are obese or not accustomed to exercise. In cases of severe obesity, energy intake may also need to be restricted. Smoking is also an independent major risk factor for ASCVD, and smoking cessation is known to reduce the risk of developing such diseases. Because passive smoking has also been reported to increase the risk for CAD and diabetes, attention should be paid to smoking not only by the patient themselves but also by other family members.
