I

II

STATEMENT OF INTENT This guideline was developed to be a guide for best clinical practice in the management of dyslipidaemia. It is based on the best available evidence at the time of development. Adherence to this guideline does not necessarily lead to the best clinical outcome in individual patient care. Thus, every health care provider is responsible for the management of his/her unique patient based on the clinical presentation and management options available locally. REVIEW OF THE GUIDELINE This guideline was issued in 2011 and will be reviewed in 2016 or earlier if important new evidence becomes available. CPG Secretariat Health Technology Assessment Unit Medical Development Division Level 4, Block EI, Parcel E Government Offices Complex 62590 Putrajaya, Malaysia Available on the following websites: http://www.malaysianheart.org http://www.moh.gov.my http://www.acadmed.org.my

SUMMARY Total cholesterol (TC) and High Density Cholesterol (HDL-C) can be measured in the fasting and non fasting states. Triglycerides (TG) is best measured in a fasting sample. Low Density Cholesterol (LDL-C) is calculated using the Friedwalds equation. When TG > 2.3mmol/l, non HDL-C is a better indicator of total atherogenic burden. Dyslipidaemias may be primary or secondary. Target of therapy: LDL-C should be the primary target of therapy I,A Non HDL-C should be an alternative primary target of therapy in patients with TG > 4.5 mmol/l I,A Individuals should be risk stratified. I,C (See Table 1, pg 3 and Fig 1A & B, 2A & B, pg 30-31) Diabetes is a Coronary Heart Disease (CHD) risk equivalent. I,A Target lipids levels will depend upon the individuals global risk. CVD and CHD risk equivalents LDL-C < 2.6 mmol/L with (High Risk): an option of <2.0 mmol/L1,A Individuals with a 10 year risk score of 10 20% (Intermediate Risk): LDL-C < 3.4 mmol/L1,A Individuals with a 10 year risk score of < 10% (Low Risk): LDL-C < 4.1 mmol/lL IIa,C Therapeutic Lifestyle Changes (TLC) should be an integral component of lipid management in all patients.1,B (Table 3, pg 4) Individuals with Cardiovascular Disease (CVD) and CHD risk equivalents should be treated aggressively with drug therapy from the outset.1,A (Table 1&2, pg 3; Flowcharts I-IV, pg5-8) Statins are the drug of choice for reducing LDL-C.1,A Fibrates and nicotinic acid may be considered for increasing HDL-C and reducing TG after LDL-C treatment goal has been achieved. IIa, B Some individuals may require combination therapy to achieve lipid target goals. Control of glycaemia alone is inadequate in preventing cardiovascular (CV) events.1,A Concomitant treatment of dyslipidaemia, hypertension and other metabolic abnormalities are also important. 1,A
2

Table 1: Major Risk Factors for CVD (other than LDL Cholesterol) Positive Risk Factors Male 45 years of age Female 55 years of age or premature menopause without hormonal replacement therapy Hypertension Current cigarette smoking Family history of myocardial infarction or sudden death prior to age 55 in a male parent or male first degree relative and prior to age 65 in a female parent or other female first degree relative HDL-C < 1.0 mmol/L Negative Risk Factors HDL > 1.6 mmol/L Table 2 : Recommendations for Drug Therapy for Dyslipidaemia
Medications Grades of recommendation/ Levels of evidence I, A Comments

Statins

Ezetimibe

IIa, B IIa, C

Reduction of LDL-C. Increase dose till target levels are achieved or till tolerated As an addition to statins if target LDL-C is not achieved As monotherapy in statin intolerant individuals As monotherapy to increase HDL-C and/or lower TG in individuals with mildly raised LDL-C As part of combination therapy with statins to increase HDL-C and lower TG after LDL-C target is achieved or almost achieved As monotherapy to increase HDL-C and/or lower TG in individuals with mildly raised LDL-C As part of combination therapy with statins to increase HDL-C and lower TG after LDL-C target is achieved or almost achieved
3

Fibrates

IIa,B IIa, B

Nicotinic Acid

IIa,B IIa, B

Table 3 : Recommendations for Therapeutic Lifestyle Changes

Grade of Recommendation Level of Evidence Diet Saturated Fats and Trans-fatty acids Cholesterol Monounsaturated fats Polyunsaturated fats Dietary Fiber Plant stanols Soy protein Omega 3 fatty acids I, B I,B I,B I,B I,B IIb, B IIb, B IIa, B IIb,B Comments

< 7% of calorie intake < 200 mg /day Up to 10% of calories Up to 20% of calories 20-30 gm/day 2-3 gm /day 25-50 gm/day A dose of 3-9 gm/day to lower TG levels A dose of 0.75-1 gm/day as secondary prevention to prevent sudden death 25-35% of calories 50-60% of calories About 15% of calories Avoid Assess BMI and waist circumference at each visit. Encourage a weight reduction of 0.5-1kg/week in the overweight and obese. The initial goal should be to reduce body weight to < 10% of baseline. Encourage aerobic exercises such as brisk walking, jogging, cycling and swimming

Total fats Carbohydrates Proteins Anti-oxidants Weight Reduction Goal: BMI : 18.5- <23 kg/ m2 Waist circumference >90 cm in males and < 80 cm in females Exercise Goal: 30-45 min per session, at least 5 times a week Smoking Goal: Complete cessation

I,B I,B I,B III,A I,C I,B

I,B

I,B I,C

Enquire about smoking status at each visit and encourage complete cessation. Avoid exposure to environmental tobacco smoke at work and at home 4

FLOWCHART I: HIGH RISK INDIVIDUALS LIPID MANAGEMENT OF PERSONS WITH CVD OR CHD RISK EQUIVALENTS (Adapted and modified from ATPIII)139 In these high risk individuals the recommended LDL-C goal is < 2.61,A mmol/L with an optional goal < 2.0 mmol/L1,A
CVD + CHD Risk Equivalents LDL-C < 2.6mmol/L TLC + Control Other Risk Factors * LDL-C 2.6mmol/L

3 months LDL-C 2.6mmol/L

LDL-C < 2.6mmol/L

TLC Therapeutic Lifestyle Changes * Start statins to achieve LDL-C target goal < 2.0 mmol/L1,A ** Consider LDL-C target goal < 2.0 mmol/L in very high risk individuals eg individuals with ACS, recurrent cardiac events, CHD with T2DM and those with multiple poorly controlled risk factors1,A *** Other therapeutic options include increasing the dose of statin, changing to high intensity statin or combination therapy, intensifying diet therapies, weight reduction, exercise or adding drugs to lower TG and / or increase HDL-C.

FLOWCHART II: INTERMEDIATE RISK INDIVIDUALS LIPID MANAGEMENT OF PERSONS WITH MULTIPLE RISK FACTORS, 10-YEAR RISK 10-20 PERCENT (Adapted and modified from ATPIII)139 The LDL-C goal is < 3.4 mmol/L. I,A Drugs can be considered after a trial of TLC if the LDL-C level is 3.4 mmol/L.

LDL-C < 3.4mmol/L Control other Risk Factors Healthy lifestyle* Reevaluate in 1 year

LDL-C 3.4mmol/L

TLC 3 months LDL-C 3.4mmol/L

LDL-C < 3.4mmol/L

TLC Therapeutic Lifestyle Changes The LDL-C goal is < 3.4 mmol/L. Drugs can be considered after a trial of TLC if the LDL-C level is 3.4 mmol/L. * In patients at intermediate risk of CVD, the presence of high risk features such as a family history of premature CVD, evidence of subclinical atherosclerosis or high hs-CRP may warrant statin therapy to lower LDL-C target < 2.6 mmol/L.

FLOWCHART III: LOW RISK INDIVIDUALS LIPID MANAGEMENT OF PERSONS WITH MULTIPLE (2+) RISK FACTORS, 10-YEAR RISK < 10 PERCENT (Adapted and modified from ATPIII)139 In these individuals the LDL-C goal is < 3.4mmol/L. Drug therapy can be considered if LDL-C level is 4.1 mmol/L after a trial of TLC.

LDL-C < 3.4mmol/L Control other Risk Factors Healthy lifestyle* Reevaluate in 1 year

LDL-C 3.4mmol/L

TLC 3 months LDL-C 4.1mmol/L

LDL-C < 4.1mmol/L

TLC Therapeutic Lifestyle Changes * Patients at low risk of CVD with at least 2 other risk factors but with evidence of subclinical atherosclerosis, high hs-CRP or positive family history of premature CVD should be considered an LDL-C goal of < 2.6 mmol/L.

FLOWCHART IV: LOW RISK INDIVIDUALS LIPID MANAGEMENT OF PERSONS WITH 0-1 RISK FACTOR (Adapted and modified from ATPIII)139 In these individuals, the LDL-C goal is < 4.1 mmol/L. Drug therapy can be considered if the LDL-C level is 4.9 mmol/L after a trial of TLC. If LDL-C is 4.1-4.9 mmol/L, drug therapy is optional depending on clinical judgment.
0-1 Risk Factors 10-yr risk usually <10% LDL-C < 4.1mmol/L Control other Risk Factors Healthy lifestyle* Reevaluate in 1 year LDL-C 4.1mmol/L

LDL-C < 4.1 mmol/L

TLC 3 months

LDL-C 4.1-< 4.9mmol/L

LDL-C 4.9mmol/L

Patients at low risk of CVD with 0 to 1 risk factor but with evidence of subclinical atherosclerosis should be considered for a lower LDL-C target < 2.6 mmol/L.

MESSAGE FROM THE AMERICAN COLLEGE OF CARDIOLOGY The American College of Cardiology heartily congratulates the National Heart Association of Malaysia along with the Ministry of Health of Malaysia and the Academy of Medicine for the creation of this important Clinical Practice Guideline for the management of dyslipidemias. Appreciating that in Malaysia cardiovascular disease is the leading cause of death in both men and women and that dyslipidemia is both readily identifiable and treatable offers the ideal opportunity to translate known cardiovascular science to the bedside. This CPG focusing on lipid management should become a cornerstone for practitioners in Malaysia in their mission to combat cardiovascular disease. Seminal work by Ford reported in the New England Journal of Medicine points out that both primary risk factor modifications along with adherence to secondary prevention measures has markedly decreased mortality and morbidity of cardiovascular disease.1 Risk factor modification has a much greater impact on population health than invasive or interventional cardiac procedures. Evidence based lipid management is a major component of the worldwide success in decreasing mortality and morbidity of cardiovascular disease along with hypertension control, tobacco cessation, diabetic care along with increasing exercise and successful treatment of obesity. I again congratulate my Malaysian colleagues and encourage enthusiastic application of this seminal work to improve the health of the great people of Malaysia. Sincerely,

Ralph Brindis, MD, MPH, MACC, FSCAI Immediate Past President, American College of Cardiology

Reference: 1. Ford ES, Ajani UA, Croft JB et al Explaining the Decrease in U.S. Deaths from Coronary Disease, 1980-2000. N Engl J Med 2007;356:23882398.
10

Members of the Expert Panel Chairperson: Dr Robayaah Zambahari Secretary : Dr R. Jeyamalar Consultant Cardiologist, Institute Jantung Negara, Kuala Lumpur Consultant Cardiologist, Sime Darby Medical Center, Subang Jaya, Selangor

Members (in alphabetical order) Dr Abdul Rashid Rahman Consultant Physician, Cyberjaya University College of Medical Sciences, Cyberjaya, Selangor Dr Chan Siew Pheng Consultant Endocrinologist, Sime Darby Medical Center, Subang Jaya, Selangor Consultant Cardiologist Pantai Medical Center Consultant Cardiologist Institute Jantung Negara, Kuala Lumpur Consultant Physician, Hospital Tuanku Jaafar, Seremban (HTA trained) Consultant Cardiologist, Sarawak General Hospital, Kuching Consultant Cardiologist, University Malaya Medical Center Consultant Endocrinologist, Hospital Putrajaya, Putrajaya

Dr Khoo Kah Lin Dr Rosli Mohd Ali

Dr Sree Raman

Dr Sim Kui Hian

Dr Wan Azman Dr Zanariah Hussein

11

External Reviewers (in alphabetical order): Pn Che Zuraini Sulaiman Dr Chia Yook Chin Dr Ghazali Ahmad Kutty Dr Hashim Noh Pharmacist Universiti Malaya Medical Centre Consultant Primary Care Physician Universiti Malaya Medical Centre Consultant Nephrologist Hospital Kuala Lumpur General Practitioner, Klinik Young, Newton and Partners Kuala Lumpur/Petaling Jaya Consultant Cardiologist Hospital Sultanah Aminah Johor Consultant Geriatrician Hospital Kuala Lumpur, Kuala Lumpur Consultant Physician Hospital Sultanah Rahimah, Klang Family Medicine Specialist, Klinik Kesihatan Jelapang, Ipoh, Perak Consultant Endocrinologist Hospital Universiti Sains Malaysia, Kota Baru, Kelantan General Practitioner, LW Medical Associates Kuala Lumpur Consultant Cardiologist Hospital Universiti Sains Malaysia, Kota Baru, Kelantan

Dr Lee Chuey Yan Dr Lee Fatt Soon

Dr Santha Kumari Dr V Paranthaman

Dr Wan Mohamad Wan Bebakar Dr Wong Kai Fatt

Dr Zurkarnai Yusof

12

RATIONALE AND PROCESS OF GUIDELINE DEVELOPMENT Rationale: In Malaysia, cardiovascular disease (CVD) is the leading cause of death in both men and women1. CVD includes coronary heart disease (CHD), cerebrovascular disease and peripheral arterial disease. CHD is a spectrum ranging from stable angina to acute coronary syndromes (ACS). Malaysians develop ACS at a younger age when compared to people in Thailand, mainland China and western countries. Our local NCVD-ACS Registry, showed that most patients (96.8%) had at least one established cardiovascular risk factorhypertension (72.6%), dyslipidaemia (55.9%) and /or diabetes (55%)3. In preventing CVD, efforts should be aimed at reducing global risks. The Clinical Practice Guideline (CPG) is on management of dyslipidaemia. The last CPG (3rd edition) was published in 2004. Thus the need for an update. Objectives: The objective of this CPG is to: provide guidance on the best treatment strategies for managing dyslipidemia utilizing and optimizing existing health resources. This CPG has been drawn up by a committee appointed by the National Heart Association of Malaysia, Ministry of Health and the Academy of Medicine. It comprises cardiologists, endocrinologists and general physicians from the government and private sectors as well as from the Universities. Process: Evidence was obtained by systematic review of current medical literature on dyslipidaemia using the usual search engines PubMed, Medscape and Ovid. The other international guidelines (American and European) on the subject were also studied. After much discussion, the draft was then drawn up by the members of the Expert Panel and submitted to the Technical Advisory Committee for Clinical Practice Guidelines, Ministry of Health Malaysia and key health personnel in the major hospitals of the Ministry Of Health and the Private Sector for review and feedback. The clinical questions were divided into major subgroups and members of the Expert Panel were assigned individual topics. The
13

group members met several times throughout the development of the guideline. All retrieved literature were appraised by individual members and subsequently presented for discussion during group meetings. All statements and recommendations formulated were agreed collectively by members of the Expert Panel. Where the evidence was insufficient the recommendations were derived by consensus of the Panel. The draft was then sent to local external reviewers for comments. It was also sent to the American College of Cardiology and the European Society of Cardiology for feedback. The level of recommendation and the grading of evidence used in this guideline was adapted from the American Heart Association and the European Society of Cardiology (ACC/ESC) and outlined on page 15. In the text, this is written in black on the left hand margin. In the Summary and Key Recommendations, it is written as a superscript immediately after the therapeutic agent or at the end of the statement as applicable. Clinical Questions Addressed: What is the current evidence on the management of patients with dyslipidaemia? Which management and recommendations are most applicable to our local setting? Target Group: This guideline is directed at healthcare providers including general practitioners, medical officers, pharmacists, general and family physicians, cardiologists and endocrinologists. Target Population: All individuals. Period of Validity of the Guidelines: This guideline needs to be revised at least every 5 years to keep abreast with recent developments and knowledge. Applicability of the Guidelines: This guideline was developed taking into account our local health resources. Blood chemistry for lipid profiles, liver and renal function tests can be done in all government health facilities. The medications recommended are approved for use in Malaysia. This guideline aims to educate health care professional on strategies to optimize existing resources in the management of dyslipidemia.

14

Implementation of the Guidelines: The implementation of the recommendations of a CPG is part of good clinical governance. To ensure successful implementation of this CPG we suggest: increasing public awareness of CVD and its prevention continuing medical education and training of healthcare providers. monitoring lipid levels in the population through National health surveys which will now be conducted every 5 years and through the NCVD ACS/PCI registry. clinical audit at hospital level- documentation of target LDL-C levels. GRADES OF RECOMMENDATIONS AND LEVELS OF EVIDENCE
GRADES OF RECOMMENDATION Conditions for which there is evidence and/or general agreeI ment that a given procedure/therapy is beneficial, useful and/ or effective. Conditions for which there is conflicting evidence and/or diverII gence of opinion about the usefulness/efficacy of a procedure/ therapy. II-a II-b III Weight of evidence/opinion is in favor of its usefulness/efficacy. Usefulness/efficacy is less well established by evidence/opinion Conditions for which there is evidence and/or general agreement that a procedure/therapy is not useful/effective and in some cases may be harmful.

LEVELS OF EVIDENCE Data derived from multiple randomized clinical trials or meta A analyses Data derived from a single randomized clinical trial or large B non randomized studies Only consensus of opinions of experts, case studies or standard C of care Adapted from the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC)
15

TABLE OF CONTENTS Statement of Intent Summary Flowcharts I,II,III and IV Message from Director General of Health Members of the Expert Panel External Reviewers Rationale and Process of Guideline Development Grades of Recommendation and Levels of Evidence 1. 2. 3. 4. 5. 6. Introduction Measurement of Lipids and Apoproteins Classification of Dyslipidaemias Dyslipidaemia as a Risk factor for CVD Other Risk Factors for CVD Global Cardiovascular Risk Assessment 6.1 Risk Stratification 6.2 Diabetes mellitus and Dysglycaemia as CHD risk equivalents 6.3 Targets of therapy Prevention of CVD Management of Dyslipidaemia 8.1 Therapeutic Lifestyle Changes 8.2 Lipid lowering Drug Therapy 8.3 LDL Apheresis Management in Specific Conditions 9.1 Specific Lipid Disorders 9.2 Diabetes Mellitus 9.3 Coronary Heart Disease 9.4 Hypertension 9.5 Stroke 9.6 Renal Disease Management in Specific Groups 10.1 Women 10.2 Children and Adolescents 10.3 Elderly Adherence, Compliance and Quality Assurance References Appendixes Acknowledgement Disclosure Statements Source of Funding
16

1 2 5-8 9 11 12 13-15 15 17 17-19 19-22 22-24 24-27 27-34 27-32 32-34 34 35 36-47 36-39 40-47 47 47-60 47-52 52-54 54-56 56-57 57 58-60 61-63 61 61-62 62-63 63-64 65-79 80-84 85 85 85

7. 8.

9.

10.

11. 12. 13. 14. 15. 16.

1. INTRODUCTION In 2009, cardiovascular disease (CVD) was the leading cause of death in both men and women1. CVD includes coronary heart disease (CHD), cerebrovascular disease and peripheral arterial disease. CHD is a spectrum ranging from stable angina to acute coronary syndromes (ACS). The peak incidence of ACS in Malaysia was in the 51-60 year age group and the male to female ratio was 3:12. The mean age in the local NCVD-ACS Registry 2006 was 58.1 years.3 This is younger than that noted in neighbouring countries such as Thailand (65 years) 4, China (63 years) 5 and in the western population (GRACE Registry- 66 years6, Canada- 68 years7). In the NCVD-ACS Registry, most patients (96.8%) had at least one established cardiovascular risk factor hypertension (72.6%), dyslipidaemia (55.9%) and/or diabetes (55%)3. In the prevention of CVD, efforts should be aimed at reducing global risks. This guideline emphasizes: a multifactorial approach that addresses all risk factors. This is because the benefits of modifying several risk factors simultaneously are synergistic. that preventing CVD should be directed at global CVD burden rather than CHD alone. In the management of dyslipidaemia the following changes have been made: identification of those at high risk this includes individuals with established CVD, diabetes, multiple risk factors and established renal disease. emphasizes the importance of a family history of premature CVD and familial dyslipidaemia treatment targets. The objectives of this CPG is to: provide guidance on the best treatment strategies for managing dyslipidemia utilizing and optimizing existing health resources.

17

2. MEASUREMENT OF LIPIDS AND APOLIPOPROTEINS Serum lipid levels are affected by several factors: acute stress or illness, eg fever, surgery, acute myocardial infarction. drugs eg beta-blockers, thiazides, steroids. 2.1 Lipids TC, HDL-C, LDL-C and TG Total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) can be measured both in the fasting and in the non fasting states. Triglycerides (TG) however should be measured after 1012 hours of fasting. TG levels are influenced by alcohol intake in the preceding 24 hours and by smoking during the fasting state. Low density lipoprotein cholesterol (LDL-C) is calculated using the Friedewald equation: LDL-C (mmol/l) = TC HDL-C - TG / 2.2 If TG > 4.5mmol/L, this formula is not valid. LDL-C may also be measured directly although these methods are not well standardized and not routinely performed. 2.2 Lipids non HDL-C More recent data suggest that when TG > 2.3mmol/l, LDL-C calculation using the above formula may not be accurate. Cholesterol rich remnant lipoproteins - small Very Low Density Lipoprotein (VLDL) and Intermediate Density Lipoproteins (IDL) - are also significantly elevated.8,9 In this situation, LDLC measurement alone does not reflect the entire atherogenic lipoprotein fraction and Non-HDL-C is more representative of the atherogenic burden.10 This can be calculated by the following formula: Non-HDL-C(mmol/l) = TC HDL-C Non HDL-C levels can be calculated from a non-fasting serum. It is a target of therapy in patients with TG > 4.5mmol/l.

18

Measurements made from whole blood differs slightly from that obtained from plasma or serum. TC, TG and HDL-C measured using desktop machines are acceptable when performed according to specifications. Lipid levels especially TG show biological variability. Because of this and laboratory variability more than one measurement is required in borderline cases. 2.3 Apolipoproteins (Appendix I, pg 80) Apoproteins are proteins attached to lipid particles to form lipoproteins. There are several apolipoproteins. Apo B is a better indicator of CVD risk than LDL-C alone.11-14 It is found in chylomicrons, VLDL, IDL, LDL and Lp(a) particles. Since each of these particles contains a single Apo B molecule, measurement of Apo B represents the total atherogenic burden. Apo B measurement has been standardized, automated and can be done in the non-fasting state. It is not routinely measured. Key messages: TC and HDL-C can be measured in the fasting and non fasting states. TG is best measured in a fasting sample. LDL-C is calculated using the Friedwalds equation. When TG > 2.3mmol/l, non HDL-C is a better indicator of total atherogenic burden.I,A 3. CLASSIFICATION OF DYSLIPIDAEMIAS Dyslipidaemia is defined as lipid values outside the norm. Based on therapeutic considerations, dyslipidaemias may be classified as follows (Table 4): Table 4: Classification of Dyslipidaemias Hypercholesterolemia Mixed Hyperlipidemia Hypertriglyceridemia Low HDL Cholesterol Lipoprotein LDL LDL + VLDL VLDL HDL
19

Serum Lipid TC TC and TG TG and or HDL-C TC and or TG

Table 5: Primary Dyslipidaemia

Risk of CHD Common (polygenic) Hypercholesterolemia Familial Combined Hyperlipidemia Risk of Pancreatitis Plasma Cholesterol Plasma Triglyceride Serum Physical signs (if present) Corneal Arcus Xanthelasma Corneal Arcus Xanthelasma Tendon xanthomata, (finger extensor, Achilles tendons) Corneal Arcus, Xanthelasma, Aortic stenosis Tuberous xanthomata, (elbows), striae xanthomata, (palm creases) tendon xanthomata Eruptive xanthomata, (buttocks, elbows) retinal lipemia, hepatosplenomegaly Eruptive xanthomata, (buttocks, elbows) retinal lipemia, hepatosplenomegaly -

or

or

Familial Hypercholesterolemia

Remnant Hypercholesterolemia

Chylomicronemia Syndrome

or

Familial Hypertriglyceridemia

High HDL-C Low HDL-C

20

or

Dyslipidaemias may be primary or secondary in etiology. (Tables 5 & 6). In the following situations, secondary causes of dyslipidaemia should be considered: When TC exceeds 7.0 mmol/l, exclude conditions such as primary hypothyroidism, nephrosis, obstructive liver disease. Cushings syndrome (including subclinical disease) can lead to lipid abnormalities in 40-70% of patients.15 Patients on exogenous steroids may also develop secondary dyslipidemias. Hypothyroidism is another important cause.16 It is more prevalent in the elderly in whom a high index of suspicion may be necessary for diagnosis.17 When TG exceeds 4.5 mmol/l, exclude secondary causes such as alcoholism. When there is high TG with low HDL-C, insulin resistance states such as type 2 Diabetes (T2DM) and metabolic syndrome have to be considered Failure to respond to anti-lipid therapy. In patients with a family history of T2DM or a past history of thyroid disease. Table 6: Causes of Secondary Dyslipidaemias
DISORDER Metabolic / Endocrine Hypothyroidism T2DM Metabolic Syndrome Cushings Syndrome Renal End stage renal disease Nephrotic syndrome Hepatic Obstructive liver disease Primary biliary cirrhosis Drugs Alcohol Thiazide diuretics Beta blockers CHOLESTEROL TRIGLYCERIDES HDLCHOLESTEROL

or
21

Key messages: Dyslipidaemias may be primary or secondary to nephrotic syndrome, obstructive liver disease, hypothyroidism, Cushings syndrome, drugs, alcoholism and insulin resistance states such as T2DM and metabolic syndrome. 4. DYSLIPIDAEMIA AS A RISK FACTOR FOR CVD Dyslipidaemia has been identified as one of the main risk factors for CVD. Our local NCVD ACS Registry showed that dyslipidaemia was present in 55% of our patients3. Specific lipid abnormalities implicated are: 4.1. Elevated LDL-C levels LDL-C has been shown to be atherogenic in epidemiological studies. There is a direct relationship between levels of LDL-C (or TC) and the rate of new onset CHD in men and women who were initially free from CHD.18-21 In people with established CHD, elevated LDL-C correlates with recurrent cardiac events.22,23 There is a near absence of clinical CHD in populations with very low levels of serum cholesterol throughout their life (TC<3.9mmol/L or LDL-C< 2.6 mmol/L).24,25 The risk for CHD appears to increase progressively above these levels. At levels of LDL-C above 3.4 mmol/L, atherogenesis proceeds at a significant rate particularly in the presence of other major risk factors.26 Randomized controlled trials have repeatedly shown that lowering of LDL-C reduces CVD events in both primary and secondary prevention.27-34 Studies have also shown that LDL-C particle concentration and size are important predictors of CVD.34,35,36 However measurement of these are not widely available and are not standardized. Thus LDL-C should be the primary target for cholesterol therapy. Meta- analysis have shown that reducing LDL-C by 1% reduces CHD risk by 1%.37

22

4.2. Low HDL-C levels There is substantial data linking a low HDL-C level (< 1.0 mmol/L) with increased risk of CHD.18,38,39,40 A 1% decrease in HDL-C, in epidemiological studies, has been associated with 2-3% increase in CHD risk.40 Clinical trials using pharmacotherapy to increase HDL-C levels have, however, showed mixed results. 41,42,43 4.3. Elevated TG levels Data suggest that a raised TG level indicates a modest but highly significant association with CHD.44,45,46 This suggests that some TG-rich lipoproteins are atherogenic. Weight reduction and drug therapies (fibrates, nicotinic acid and statins) reduce remnant lipoproteins and are accompanied by a reduced risk for CHD.43,47,48 4.4. Elevated Non-HDL-C levels Non HDL-C reflects the concentration of cholesterol within all lipoprotein particles considered atherogenic. Many studies have demonstrated that non HDL-C is a better predictor of CV risk than is LDL-C and may be especially true in statin-treated patients.49,50,51 4.5. Atherogenic Dyslipidaemia This consists of low HDL-C, raised TG and small dense LDL particles.52,53 The LDL-C levels are usually normal but there is a higher proportion of small dense LDL particles which are more atherogenic. Although epidemiological data indicates that the ratio of TC/ HDL-C is a CVD risk marker, there have been no outcome studies to support using this as a target of therapy. 4.6 Lipoprotein Lp(a) Elevated levels of Lp(a) have been shown to be related to cardiovascular risk in some but not all studies.54,55

23

Key messages: LDL-C should be the primary target of therapy I,A Non HDL-C should be an alternative primary target of therapy in patients with TG > 4.5 mol/L I,A 5. OTHER RISK FACTORS FOR CVD More than 90% of CVD can be explained by 9 to 10 modifiable risk factors dyslipidaemia, hypertension, smoking, diabetes, abdominal obesity, psychosocial stress, low intake of fruits and vegetables, alcohol intake and physical inactivity.56,57(Appendix II, pg 80) 5.1. Age The incidence of CVD increases with age.18 This is due to the combined effects of age related changes in the vascular system as well the duration of exposure to adverse risk factors.

5.2. Gender The incidence of CVD is about 3-4 times higher in men than women in the middle decades of life and approximately twice as high in the elderly.18 5.3. Hypertension Both elevated systolic and diastolic blood pressures are linked with increased CVD risk.58,59,60 From epidemiological data, elevated systolic blood pressure appears to be more important when compared to diastolic blood pressure as a risk factor especially in middle aged and elderly individuals.61-64 The presence of left ventricular hypertrophy is associated with increased CV risk. 5.4. Smoking This is an important CV risk factor and cause of mortality in both men and women.65,66,67 The incidence and mortality of CVD is 2-3 times as high in cigarette smokers compared to non smokers.68,69
24

The risk of developing CVD is directly related to the number of cigarettes smoked.70,71 The relative risk of CV events is greater in younger than in older patients although the absolute excess mortality related to smoking increases with age.68,70 Smoking interacts in a multiplicative manner with other risk factors ie the risk is higher than that would have resulted from simply adding together the independent risks.72,73 In individuals who discontinue smoking, the risk decreases within a year or two of stopping and the curve flattens out within 4 years although the relative risk remains slightly higher compared to never-smokers.74,75 5.5. Family History of Premature CVD Familial and genetic factors may play an important role in the determination of some major risk factors, especially hypertension, lipid abnormalities and glucose intolerance. In addition there appears to be a familial predisposition to CVD.76,77,78 The presence of premature CVD in first degree male relatives below the age of 55 years or female relatives below the age of 65 years is a recognized independent risk factor for CVD.79 This risk is greater when more family members are affected and the younger their age of onset of CVD.

5.6 Others Other risk factors include: 5.6.1 Lifestyle Risk Factors - Abdominal obesity: Risk for CVD is increased although a recent analysis seems to indicate that abdominal obesity just helps to identify high risk individuals with metabolic abnormalities. In Asians, a waist circumference of > 90 cm in men and > 80 cm in women has been found to be associated with increased CV risk.80-84 (Appendix III, pg 81)

25

- Physical Inactivity: Numerous studies have shown that physical inactivity is associated with increased mortality and CVD.85,86,87 - Intake of fruits and vegetables: Low intake (less than 5 servings a day) increases CV risk.88 5.6.2.: Risk Markers The following risk markers maybe helpful in intermediate risk patients to determine the intensity of therapeutic targets. - Inflammatory markers (hs-CRP) Pathological studies strongly support a role for inflammation in the pathogenesis of the early stages of atherosclerosis, plaque progression and rupture. One such acute phase reactant is high sensitivity C-reactive protein (hs-CRP). Data show that an elevated level of hs-CRP identifies healthy individuals who are at an increased risk of an initial and recurrent cardiac events.89-93 Results of a recent trial indicated that healthy persons with LDL-C levels in the normal range but with elevated hs-CRP benefited from statins.94 - Hemostatic markers An elevated level of fibrinogen has been associated with an increased risk for coronary events.95,96 - Subclinical atherosclerosis Individuals with subclinical atherosclerotic disease are at increased risk for major coronary events.97 Subclinical atherosclerosis may be identified by the: presence of abnormalities in the resting and / or stress ECG measurement of the ankle / brachial blood pressure (ABI) (a level of less than 0.9 is significant) measurement of carotid intima-medial thickness (IMT) by ultrasound (more than 75th percentile for age and sex) measurement of coronary calcium score by computed tomography (CT) non invasive imaging of the coronary arteries by CT angiography.
26

These tests may be used for risk stratification in individuals at intermediate risk. Patients with subclinical atherosclerotic disease may warrant a more aggressive preventive treatment strategy.

Key messages: Increasing age, male gender, hypertension, smoking and a family history of premature CVD are major independent risk factors for CVD. Diabetes is a CHD risk equivalent I,A 6. GLOBAL CARDIOVASCULAR RISK ASSESSMENT Based on the Malaysian National Health and Morbidity Survey 2006, the prevalence of dyslipidaemia in Malaysians above the age of 40 years was 28%98. All adults above the age of 40 years should have a complete fasting lipid profile (TC, LDL-C, HDL-C, TG). If the levels are normal, then screening should be done annually. Individuals who already have evidence of atherosclerosis or are at high risk of developing CVD, should have a complete lipoprotein profile earlier in life. This includes individuals with a family history of premature CVD, genetic dyslipidaemias, metabolic syndrome, T2DM and abdominal obesity. 6. 1 Risk Stratification Individuals with CVD and CHD risk equivalents belong to the highest risk category. The CHD risk equivalents are: Other clinical forms of atherosclerotic disease (atherosclerosis in any vascular bed - aorta including abdominal aortic aneurysm, carotid, cerebral and peripheral vessels) T2DM Multiple risk factors that confer a 10 year risk for CVD > 20% These individuals are at high risk of developing CVD . They should be screened for the traditional risk factors and treated appropriately.
27

Table 7: Major Risk Factors for CVD (Other than LDL Cholesterol) Positive Risk Factors Male 45 years of age Female 55 years of age or premature menopause without hormonal replacement therapy Hypertension Current cigarette smoking Family history of myocardial infarction or sudden death prior to age 55 in a male parent or male first degree relative and prior to age 65 in a female parent or other female first degree relative HDL-C < 1.0 mmol/L Negative Risk Factors HDL > 1.6 mmol/L In all other patients, their global CVD risk should be determined. There are several risk equations that may be used.99 (Appendix IV, pg 82). All have some limitations and difficulty to extrapolate to our local population. Until local data are available we recommend adopting the latest (2008) Framingham CV risk score.100 This estimates CVD risk while the earlier version (2002) provides a risk estimate of hard CHD events ie cardiac death and nonfatal myocardial infarction. The intensity of risk reduction therapy is dependent on an individuals global risk of developing CVD. In determining CV risk the following steps are taken: Count the number of major risk factors for CVD (Table 7,pg 28). In individuals with more than 2 risk factors, calculate the 10year CVD risk using the Framingham score sheets (Figures 1A & B, 2A & B, pg 30-31). The vascular age can also be determined (Figure 1C and 2C, pg 32) In individuals with 0 1 risk factors, the CV risk score need not be calculated since the 10-year CVD risk is <10%.

28

Other risk factors not included in the general risk profile that should be taken into account in evaluating risk include: Clinical features of insulin resistance such as abdominal obesity, elevated triglycerides, and dysglycaemia (See Section 6.2) ECG evidence of left ventricular hypertrophy hs-CRP levels Evidence of subclinical atherosclerosis Chronic kidney disease (GFR<60ml/min) Chronic autoimmune inflammatory disorders such as systemic lupus erythematosis and rheumatoid arthritis Chronic HIV infection These individuals are at high risk of developing CVD. They should be screened for the traditional risk factors and treated appropriately. Individuals with 0-1 risk factor almost always have a 10 year CVD risk <10%. Individuals with 2 or more risk factors can fall into one of the following risk categories for developing CVD over 10 years: > 20% 10-20 % < 10% Those individuals with a 10-year risk of developing CVD of > 20% have a very high risk and are therefore considered as CHD risk equivalents. (see 6.1) Determining an individuals global CVD risk will guide LDL-C target goal and management strategies. (Table 8, pg 34) The 10 year risk calculation is to be performed at the outset to help guide the intensity of cholesterol lowering therapy. It cannot be used to track changes in risk over time as risk factors are modified. In calculating the risk scores (Figures 1A & B, 2A & B, pg 30-31), the TC and HDL-C should be the average of at least 2 measurements. The average baseline blood pressure (BP) must be obtained from an average of several readings. A smoker means any cigarette smoking in the past month.
29

Figure 1A: Estimation of 10 year CVD Points for MEN (Framingham Point Scores) 100
Points Age,y HDL-C TC SBP (not treated) <120 <4.2 4.2-<5.2 5.2-<6.3 6.3-<7.4 >7.4 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75+ 120-129 130-139 140-159 160+ 120-129 130-139 140-159 160+ Yes Yes <120 No No SBP (treated) Smoker Diabetes

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Points allotted 35-39 30-34

1.6+ 1.3-1.6 1.2-<1.3 0.9-<1.2 <0.9

Grand Total :_____________points

Figure 1B: CVD Risk for Men100

Total Points <-3or less -2 -1 0 1 2 3 4 5 6 7 10 year Risk % <1 1.1 1.4 1.6 1.9 2.3 2.8 3.3 3.9 4.7 5.6
30

Total Points 8 9 10 11 12 13 14 15 16 17 18+

10 year Risk % 6.7 7.9 9.4 11.2 13.2 15.6 18.4 21.6 25.3 29.4 >30

Figure 2A: Estimation of 10 year CVD Points for WOMEN (Framingham Point Scores) 100
Points -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 Points allotted 50-54 55-59 60-64 65-69 70-74 75+ 40-44 45-49 35-39 1.6+ 1.3-1.6 30-34 1.2-<1.3 0.9-<1.2 <0.9 5.2-<6.3 6.3-<7.4 >7.4 150-159 160+ 140-149 150-159 160+ <4.2 4.2-<5.2 120-129 130-139 140-149 120-129 130-139 Yes Yes <120 No No Age,y HDL-C TC SBP (not SBP treated) (treated) <120 Smoker Diabetes

Grand Total :_____________points

Figure 2B: CVD Risk For Women100

Total Points <-2 -1 0 1 2 3 4 5 6 7 8 9 10 year Risk % <1 1.0 1.2 1.5 1.7 2.0 2.4 2.8 3.3 3.9 4.5 5.3 Total Points 10 11 12 13 14 15 16 17 18 19 20 21+ 10 year Risk % 6.3 7.3 8.6 10.0 11.7 13.7 15.9 18.5 21.5 24.8 28.5 >30

31

Figure 1C : Heart Age/ Vascular Age for Men100

Points <0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 >17 Heart age, y <30 30 32 34 36 38 40 42 45 48 51 54 57 60 64 68 72 76 >80

Figure 2C : Heart Age/ Vascular Age for Women100

Points <1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15+ Heart age, y <30 31 34 36 39 42 45 48 51 55 59 64 68 73 79 >80

32

6.2. Diabetes mellitus and Dysglycaemia as CHD risk equivalents Patients with type 2 diabetes mellitus (T2DM) and impaired glucose tolerance (IGT) have an increased risk of cardiovascular events.101,102 These patients have higher mortality and a higher incidence of recurrent cardiac events.103 The two main types of DM (type 1 and type 2) have different patterns of dyslipidaemia. Type 2 diabetes (T2DM) may be associated with insulin resistance, as in some individuals with the metabolic syndrome. The current definition of metabolic syndrome (2009) includes any 3 or more of the following (including those on treatment)*: Elevated Waist circumference (Asian cut-off) : - females >80cm - males >90cm Elevated TG > 1.7 mmol/L Reduced HDL-C < 1.3 mmol/L (female) or < 1.0 mmol/L (male) Elevated blood pressure (BP): - Systolic BP > 130 and / or diastolic BP > 85 mmHg Disorders of glycaemia: - T2DM, or - impaired glucose tolerance (IGT) [Fasting plasma sugar < 7.0 mmol/L and 2 hours after 75 gm glucose load: 7.8 11.1 mmol/L], or - impaired fasting glucose (IFG) [Fasting plasma sugar: 6.1 7.0 mmol/L]

*Adapted from Joint Interim Statement (Joint Interim Statement of International Diabetes Federation Task Force on Epidemiology and Prevention, National Heart Lung Blood Institute (NHLBI), American Heart Association (AHA), World Heart Federation (WHF), International Atherosclerotic Society (IAS and International Association for Study of Obesity (IASO) Circulation 2009:120:1640-1645

Proatherogenic risk markers like elevated Lp(a), prothrombotic risk markers eg. raised PAI-1, increased fibrinogen and endothelial dysfunction are found in insulin resistance states and contribute to the increased CV risk. These associated abnormalities of insulin resistance can be present for up to 10 years before detection of the glycaemic disorder.
33

I,A

Individuals with type 1 diabetes are more likely to have elevated TC, with rise in LDL-C and increased TG. These lipid abnormalities can be fully corrected with good glycaemic control with insulin. Individuals with T2DM have the atherogenic dyslipidaemia. Improvement of glycaemic control may not fully correct this dyslipidaemia.104 Some studies show better correlation of non HDL-C than LDL-C to coronary mortality.10 (see 4.4. & 4.5) 6.3. Target Lipid Levels

I,A I,A

LDL-C is the primary target for therapy. The target LDL-C level will depend on the individuals global risk. (see Table 8) Table 8: Target LDL-C levels
Global Risk 0-1 risk factor a 2 or more risk factors b CVD and CVD risk Equivalents LDL-C levels to initiate Drug therapy 4.9 c 3.4 c 2.6 2.0 to < 2.6 Target LDLC levels (mmol/l) < 4.1 3.4d < 2.6e < 2.0f

a Almost all individuals with 0-1 risk factor have a 10 year risk < 10%, thus 10 year risk assessment in individuals with 0-1 risk factor is not necessary. b These include individuals with multiple risk factors but a 10 year risk of CVD of < 20%. c After 8-12 weeks of TLC. d An optional target of <2.6mmol/L in certain high risk individuals. See flowchart II & III, pg 4 e The lower the LDL-C achieved, the greater the CV benefits seen. f Consider LDL-C target goal < 2.0 mmol/LI,A in very high risk individuals eg individuals with ACS, recurrent cardiac events, CHD with T2DM and those with multiple poorly controlled risk factors See Flowcharts I-IV, pg 5-8.

Key messages: Individuals should be risk categorized I,C (Table 7, pg 28, Fig 1A & B, 2A & B, pg 30-31). Target lipids levels will depend upon the individuals global risk. Individuals with CVD and CHD risk equivalents should be treated aggressively with drug therapy I,A (Table 8, pg 34; Flowcharts I-IV, pg 5-8).
34

7. PREVENTION OF CVD Prevention can be divided into: Primary prevention is the prevention of occurrence of CVD events in people without CVD. Secondary prevention is the prevention of progression of CVD and its complications in people with established CVD or CVD risk equivalents.

Strategy of primary prevention The strategy is based on a: Population based strategy This strategy is aimed at educating the public concerning CVD, its presentation and complications, cardiac risk factors, and the importance of maintaining a healthy lifestyle, which is a healthy diet, weight control, increased physical activity and the avoidance or cessation of smoking. These measures should be started early in life. Mass screening for dyslipidaemia is not advocated as it is not cost effective and there may be inadequate follow-up and counseling. Individual based strategy The aim is to identify individuals at risk of developing CVD and modifying their risk factors. This would include all individuals above the age of 40 years. (See Section 6). Strategy of secondary prevention This is aimed at individuals with established CVD or with CVD risk equivalents. In these high-risk persons, drug therapy should be initiated together with therapeutic lifestyle changes (TLC).

35

8. MANAGEMENT OF DYSLIPIDAEMIA 8.1. THERAPEUTIC LIFESTYLE CHANGES Introduction Therapeutic lifestyle changes (TLC) refer to dietary modification, weight reduction, regular physical activity, cessation of smoking and alcohol restriction. TLC is an integral component of the treatment of dyslipidaemia. It should precede or be initiated together with drug therapy and is directed especially at individuals who are obese, who smoke and who seldom exercise. For patients without CVD or CVD risk equivalents, emphasis should be placed on TLC. 8.1.1. Dietary Modification
I,B

This is aimed at optimizing lipid levels while maintaining a balanced diet. It is encouraged to refer an individual to a dietician for medical nutrition therapy. Dietary therapy can lower TC by 10-15% and occasionally >20%.105 Dietary therapy is continued indefinitely. (Appendix V, pg 83) The intake of food high in cholesterol content must be reduced.106-109 A high intake of saturated fatty acids (SFA) and trans fatty acids (TFA) raise LDL-C levels while a high intake of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) lower LDL-C and reduce CV risk.106,110,111 Thus both PUFA and MUFA should be encouraged in place of SFA and TFA. SFA should not be replaced with carbohydrates. A high intake of carbohydrate (> 60% of total caloric intake) results in a reduction of HDL-C and a rise in TG levels.112,113 In individuals with the metabolic syndrome a lower carbohydrate intake is important. The use of viscous (soluble) forms of dietary fibre (oats, pectin, guar and psyllium) of at least 510 gm per day is encouraged as they have been shown to reduce LDL-C levels.114,115,116

I,B

I,B

IIa,B

36

IIb,B

Plant stanol/sterol esters (23 gm/day) also have a LDL-C lowering effect117 which is dose related but there is inter-individual variation in their response. Plant sterols and stanols are not routinely recommended for the prevention of CVD since there are no CV outcome data. High intake of soy protein (25-50 gm/day) can cause small reductions in LDL-C.106 8.1.2. Weight Reduction

IIb,B

I,B

This is important in overweight and obese individuals particularly those with the metabolic syndrome. Weight reduction helps to lower TG and increase HDL-C levels, in addition to enhancing the cholesterol (TC and LDL-C) lowering effects of dietary modification.118 A weight reduction of 0.5-1.0 kg per week is recommended. According to the Asia Pacific Western Pacific Regional World Health Organization, the recommended BMI in Asians is 18.5 - < 23 kg/ m2 and a waist circumference < 90 cm for males and < 80 cm for females.81 8.1.3. Physical Activity

I,B

I,B

Physical activity and weight reduction enhance the lipid-lowering effects of dietary therapy. They also improve cardiovascular fitness, lower BP, increase insulin sensitivity, increase HDL-C levels and decrease TG levels.119,120 Such activities include aerobic exercises such as brisk walking, jogging, cycling, swimming. Exercise needs to be regular and adequate (30-45 minutes per session at least 5 times a week). 8.1.4. Cigarette Smoking Smoking is one of the major risk factors for CVD and must be stopped. Even passive smokers are at high risk of developing CVD. The decline in CVD risk begins within a year or two after smoking cessation.74,75
37

I,A

I,B

8.1.5. Alcohol Restriction of alcohol is advised in patients with dyslipidaemia as it increases plasma TG levels.121,122 Moderate alcohol consumption (not more than 14 units for males and 7 units for female per week) increases HDL-C and apo A-I and is associated with a reduction in all cause mortality.123-127 Over-consumption is however associated with a higher mortality rate. High intake of alcohol elevates BP and can precipitate acute pancreatitis in individuals with high TG levels. Nondrinkers should therefore not be encouraged to start alcohol consumption to improve their dyslipidaemia. (1 unit of alcohol is equivalent to 250 ml of beer, 100 ml of wine and 30 ml of whisky) 8.1.6. Miscellaneous Omega3 polyunsaturated fatty acids are useful in individuals with high TG and can be considered in addition to fibrates or nicotinic acid. For lowering TG, a dose of 3-9 gm/day of omega-3 fatty acids is required In patients with CVD, omega-3 fatty acids (dose of 0.75 gm-1 gm/day) has been shown to reduce sudden cardiac death, CHD mortality and total mortality although a recent trial showed no benefit.128,129,130 It is recommended to increase intake of omega-3-fatty acids by eating more fish, walnuts, flaxseed oil and green, leafy vegetables.128,131

I,A

IIa,B

IIb,B

III,B

The importance of the following in treating dyslipidaemia remains uncertain : - trans-fatty acids, essential fatty acids (linoleic acid, linolenic acid), and lecithin. The use of antioxidants (such as vitamin C, E, beta carotene, bioflavonoids) selenium and Coenzyme Q-10 has not been shown to be effective in preventing or treating CVD. Foods, vitamins and minerals which act as antioxidants include Co-enzyme Q10, ginkgo, green tea, Vitamin A (Beta-carotene), Vitamin C, Vitamin E.132,133
38

III,A

III,B

None of the formulations of garlic have been shown to produce a statistically significant effect on the cholesterol level.134 Guggulipid has not been found to be effective in lowering LDL-C levels and may cause a hypersensitivity rash in some individuals.135 8.1.7. Assessing response to TLC The lipid profile should be measured 6-12 weeks after initiating TLC. Generally, TLC may reduce lipid levels (at best) up to 20%. For individuals who attain target lipid levels, they should continue these lifestyle changes life-long to maintain these effects. They can be assessed every 6 months with a full lipoprotein analysis. On the other hand, if these levels are not achieved, patient compliance should be re-assessed and TLC intensified. They are then reassessed after 6-12 weeks. There is a genetically determined inter-individual variability in the response to diet. Thus poor response to TLC is not always due to non-compliance. For individuals at low risk, failure to achieve a defined target value for LDL-C does not necessarily mean that dietary therapy be replaced by drug therapy. Whatever reduction that is achieved will help lower the risk of CVD especially with the concomitant adoption of a healthy lifestyle. When a decision has been made to start drug therapy, TLC must still be continued indefinitely because it provides substantial additive LDL-C lowering effects.136 Key messages: A multifactorial lifestyle approach is recommended to reduce the risk of CVD. I,B In patients without CVD or CHD risk equivalents, a period of at least 6-12 weeks is given to assess the effectiveness of TLC before considering drug therapy. I,C

39

8.2. DRUG THERAPY

I,A

Therapeutic Lifestyle Change forms an integral component in the management of dyslipidaemia. In secondary dyslipidaemia, efforts should be made to correct the underlying cause. 8.2.1 Lipid Lowering Drugs In those with established CVD / CHD risk equivalents, drug treatment will need to be initiated in conjunction with TLC (Table 8, pg 33). There are 5 major groups of anti-lipid drugs. (Table 9, pg 41) 8.2.1.1 HMG CoA Reductase Inhibitors (Statins) Statins are inhibitors of HMG CoA reductase , the rate limiting enzyme in hepatic cholesterol synthesis. They are the most effective drug class and the treatment of choice in reducing LDL-C. They are suitable first-line agents in familial hypercholesterolemia, for primary prevention of CVD, secondary prevention of CVD and CHD equivalents. They have moderate effect in lowering TG and in elevating HDL-C. Treatment is initiated at the recommended starting dose with the evening meal or at bed time except for long-acting statins that can be taken at any time. The dose is then adjusted accordingly to achieve target levels. Serum lipids and alanine aminotransferase should be measured at 6-8 weeks after starting treatment and thereafter as necessary especially when doses are increased.

I,A

III,C

Statin therapy is contraindicated in pregnancy and lactation. It should not be prescribed to women of child bearing potential unless adequate contraception is taken.

40

Table 9: Major Anti Lipid Drug Classes (Adapted from ATPIII)139

Drug Class HMG-CoA Reductase Inhibitors (statins) Lipid Effects LDL-C 18-55% HDL-C 5-15% TG 7-30% Side Effects -Myopathy -Increased liver Enzymes Contraindications Absolute: -Active or chronic liver disease Relative: -Concomitant use of certain drugs* Absolute: -Severe hepatic disease -Severe renal disease Relative: -Concomitant use of certain drugs** Absolute: -Dysbetalipoproteinemia -Tg > 4.5 mmol/l Relative: -Tg > 2.3 mmol/l Absolute: -Chronic-liver disease -Severe Gout Relative: -Diabetes (high doses only) -Hyperuricemia -Peptic-Ulcer Disease

Fibric-Acid Derivatives (Fibrates)

LDL-C 5-20% HDL-C 10-35% TG 20-50%

-Dyspepsia -Gallstones -Myopathy

Bile-Acid Sequestrants (Resins)

LDL-C 15-30% HDL-C 3-5% TG /

-GIT distress -Constipation -***Decreased absorption of certain drugs

Nicotinic Acid (Niacin)

LDL-C 5-25% HDL-C 15-35% TG 20-50%

-Flushing -Hyperglycemia -Hyperuricemia (or gout) -Upper-GIT distress -Hepatotoxicity -Headache -Abdominal pain -Diarrhea

Cholesterol Absorption Inhibitors****

*

LDL-C 18-25% HDL-C 3-5% TG 8-14%

cyclosporin, macrolide antibiotics, various anti fungal agents and cytochrome P-450 inhibitors (fibrates and nicotinic acid should be used with appropriate caution) ** gemfibrozil and repaglinide140 *** Paracetamol, NSAIDs, anticoagulant, valproate, digitalis, thiazides, thyroxine, raloxifene, propranolol and tricyclic antidepressants. **** usually used in combination with statins.

These data are derived from short-term clinical trials meant for drug registration. In real life long term use, the amount of lipid change achieved may be less than this.

41

Recent concern about statin and new onset diabetes has not been substantiated. In fact statins have been proven to prevent CV events in diabetics with no overt CVD.137,138 There is no evidence that patients on statins have increased risk of cancer, poor memory and renal toxicity. The routine use of Co enzyme Q 10 to prevent muscle toxicity is unproven and therefore not recommended. Recommended Dosages for Statins*
Drug Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin
* As stated in MIMS,Malaysia

Recommended initiating dose 20 mg 20 mg 20 mg 20 mg 10 mg 10 mg

Usual dose range 10-80 mg/day in single or divided doses 10-40 mg daily 5-80 mg once daily 20-80 mg/day single or divided doses 10-80 mg once daily 10-20 mg once daily

8.2.1.2. Fibric Acid Derivatives (Fibrates) Fibrates are Peroxisome Proliferator Activated Receptor (PPAR) agonist which in turn stimulates synthesis of fatty acid oxidation. Fibrates are particularly useful in individuals with combined (mixed) dyslipidaemia and hypertriglyceridaemia as they reduce serum TG levels and increase HDL-C effectively. Fibrates are alternative treatment in individuals with mild to moderate hypercholesterolemia who are statin intolerant.
IIa,B

In men with established CHD with low LDL-C and HDL-C, fibrates have been shown to improve CV outcome. In individuals with T2DM, fibrates reduced the composite endpoint of CV death, CV events and the need for coronary and carotid revascularization.43,47

42

IIa,B

Doses of fibrates need to be adjusted in the presence of CKD. Serum alanine aminotransferase should be monitored when starting therapy or when doses are increased. Recommended Dosages for Fibrates*
Drug Bezafibrate Fenofibrate Gemfibrozil Ciprofibrate Recommended Dosage 200 mg daily increasing to a maximum dose of 200 mg tds (regular) or 400 mg daily (sustained release) 300 mg daily or in divided doses (regular) or 200 mg daily (micronised) or 160 mg daily (supra) 600-1500 mg daily in divided doses (regular) or 900 mg daily (sustained release) 100 mg daily

* As stated in MIMS,Malaysia

8.2.1.3. Bile Acid Sequestrants (Resins)

IIa,B

Bile acid sequestrants bind to bile acids to promote their secretion into the intestines. They are effective in lowering LDL-C. Resins may increase TG and HDL-C slightly. Monotherapy has a modest effect on CHD in primary prevention. Resins are therefore not suitable as monotherapy in combined hyperlipidaemia. Combination with a statin may be necessary in severe hypercholesterolaemia. Other medications should be taken 1 hour before and / or 4 hours after resins. This class of drug is currently not available in the Malaysian market. 8.2.1.4. Nicotinic Acid (Niacin) and its derivatives Nicotinic acid decrease mobilization of free fatty acids from adipose tissues. It is very effective in increasing HDL-C and also effectively lowers both TC and TG levels. It is also the first to show mortality reduction in individuals with CHD.48

IIa,B

43

However its side effects (particularly flushing and gastrointestinal side effects) tend to limit compliance. Acipimox is a derivative of nicotinic acid which produces fewer side effects (especially less cutaneous flushing) and does not worsen glucose tolerance. Tredaptive is a combination of modified release nicotinic acid and laropiprant (a prostaglandin inhibitor) which will reduce the flushing caused by nicotinic acid. Recommended Dosages: Nicotinic acid (Niacin) is available as capsules of 100 mg or 500mg, and sustained release form: - starting dose: 150-300 mg daily in divided doses, titration of dose up to 2g/day (Usual dose) It should be taken with meals to reduce gastrointestinal side effects. Acipimox is currently not available in the Malaysian market. 8.2.1.5 Cholesterol Absorption Inhibitors Cholesterol absorption inhibitors selectively block intestinal absorption of both dietary and biliary cholesterols and other phytosterols. This leads to a reduction in hepatic cholesterol delivery - a mechanism which complements the action of statins. It is indicated as monotherapy for primary hypercholesterolemia in patients who cannot tolerate statin or fibrate. It can also be used in combination with statins to further lower LDL-C. When used with statins, the lipid lowering effects appears to be synergistic. Recommended Dose: Ezetimibe 10 mg daily 8.2.2. Recommended Drug Treatment for Dyslipidaemia The choice of drugs will depend on the type of dyslipidaemia. (Table 10, pg 45)

44

Table 10: Suggested Drug Therapy for Dyslipidaemia

Lipid Values LDL-C > 3.4 mmol/l TG < 2.3 mmol/l Initial Drug Statins Suggested Addition (in order of preference) Resin Ezetimibe Fibrates Nicotinic Acid Fibrates Nicotinic Acid

LDL-C 3.4 mmol/l TG : 2.3-5.7 mmol/l HDL-C < 1.0 mmol/l TG < 5.7 mmo/l If: LDL-C < 2.6 mmol/l If: LDL-C > 2.6 mmol/l TG > 5.7 mmol/L

Statins

Statins Statins Fibrates

Fibrates Nicotinic Acid Fibrates Nicotinic Acid Nicotinic Acid Statins Omega 3 FA

I,A

IIa, B

LDL-C reduction with statin treatment remains the cornerstone of lipid lowering therapy to reduce risk of CVD. If target lipid goals have not been achieved after 8-12 weeks of optimal monotherapy, combination therapy is suggested (Table 10, pg 45). Combination of statin and cholesterol absorption inhibitors have been shown to reduce CV events and renal outcomes in patients with CKD.141 Some combination therapies carry a potential for adverse effects, especially myositis (particularly combination of fibrates plus statins) although the incidence is still low (0.5 - 2.5%). For monotherapy, the incidence of myopathy is 0.1 - 0.5%.142,143 The combination of gemfibrozil and statin is discouraged. If used, caution and close monitoring should be stressed. 8.2.3. Monitoring and Duration of Therapy It should be stressed that these individuals will be on lifelong therapy. It is therefore important to assess them on a regular basis,
45

ie. in terms of response to treatment and to look out for possible side-effects related to the drugs. After starting drug therapy, LDL-C level should be measured at 6-8 weeks and drug doses titrated if necessary. Once target lipid levels are achieved, a 4-6 monthly follow up is recommended. Monitoring of ALT is necessary if statins and fibrates are used for treatment. Liver function tests should be carried out before and within 1-3 months of starting treatment. Statins should be discontinued if transaminase levels rise to at 3 times the upper limit of normal. If the levels are elevated between 2 to 3 times upper limit of normal, the trend should be monitored at monthly intervals. If the levels are stable, they only need be checked periodically or if the dose of statin or fibrate is increased. If myositis is suspected, then creatine kinase levels should be measured. If the level is more than 10 times the upper limit of normal, then the drug should be discontinued. 8.2.4 Pharmacoeconomics of Lipid Lowering Therapy The economic implication of treating dyslipidaemia should not be judged only by the direct out of pocket cost. Dyslipidaemia leads to major CV events which have economic implications. The incidence of CVD and CKD in the country is on the rise and so is the cost associated with it. As such the economic implication of treating dyslipidaemia must be looked at from the perspective of total cost (direct and intangible cost) instead of just direct out of pocket cost. Local data is lacking at this present time. Cost effective analysis of major lipid lowering trials have shown that although direct short term cost may be higher, the incremental cost effectiveness ratio (derived from the ratio of cost over Quality Adjusted Life Years) is favorable even for patented statins.144 A substantial proportion of statin acquisition cost was offset by reduction in health care resource use as a consequence of lesser CV events. Even taking into consideration the cost of patented statin and measurement of hs- CRP, statin use is cost effective even in primary prevention of medium risk individuals. 145 This is also true for fibrate treatment in T2DM.146 Cost effective analysis showed that prescribing generic statins may not necessarily translate into the most cost effective option for treating dyslipidemia.147
46

Key messages: Statins are the drug of choice for reducing LDL-C in a wide range of dyslipidaemic patients. I,A Fibrates and nicotinic acid may be considered for increasing HDL-C and reducing TG after LDL-C treatment goal has been achieved. IIa,B Some individuals may require combination therapy to achieve lipid target goals 8.3 LDL-C APHERESIS
IIa,B

LDL-C apheresis is indicated in patients with homozygous familial hypercholesterolemia (FH) who do not respond satisfactorily to maximum multiple drug therapy.148-153 This form of treatment may also be considered in individuals with severe heterozygous FH and progressive coronary artery disease who do not achieve target lipid levels with maximal drug therapy (high intensity statin at maximal dose with ezetimibe).148-153 In some patients with very high LDL-C levels, despite aggressive treatment with medications plus LDL-C apheresis, progression of atherosclerosis may occur but at a lesser extent.154,155 9. MANAGEMENT IN SPECIAL CONDITIONS 9.1. Specific Lipid Disorders 9.1.1. Elevated TG There is evidence of a strong association between TG levels and CVD.44,45,46 This may in part be due to its association with the other CV risk factors found in the metabolic syndrome. Very high serum TG (> 5.7 mmol/L) can give rise to acute pancreatitis and needs urgent and definitive treatment. High (2.3-5.7 mmol/L) and borderline high levels (1.7-2.3mmol/L) of TG are a common association with low HDL cholesterol, small dense LDL particles and insulin resistance.

IIa,B

47

9.1.1.1. Targets of therapy

I,A

In individuals with elevated TG, the primary target of therapy remains achieving LDL-C goal depending upon the individuals global risk. (Table 8, pg 34) In individuals where the TG > 2.3 mmol/L, non HDL-C is more representative of all atherogenic lipoproteins than LDL-C. (see also section 2 and 4.4) In these individuals, the secondary target of therapy is non HDL-C as listed in Table 11, pg 48. Another secondary target of therapy is TG < 1.7 mmol/L. Table 11: Targets of LDL-C and non HDL-C
Global Risk Target LDLC levels (mmol/L) < 4.1 < 3.4** 2.0 to < 2.6 < 2.0 non HDL-C levels corresponding to LDL-C goals (mmol/L) < 4.9 < 4.1 < 3.4 < 2.6

I,A

0-1 risk factor 2 or more risk factors* CHD and CHD risk Equivalents
* **

These include individuals with multiple risk factors but a 10 year risk of CVD of < 20% Optional target <2.6mmol/L in certain high risk individuals. See Flowchart II & III

9.1.1.2. Classification of TG (see Table 12, pg 48) With reference to Table 12, pg 50: Factors contributing to elevated TG include: obesity and overweight, physical inactivity, cigarette smoking, excessive alcohol intake, high carbohydrate intake (>60% of energy intake), T2DM, chronic kidney disease, nephrotic syndrome, Cushings disease, lipodystrophy, pregnancy and various drugs {corticosteroids, beta-blockers, retinoids, oral estrogens (not transcutaneous estrogen), tamoxifen, protease inhibitors for AIDS}.
48

Genetic disorders associated with high TG (familial combined hyperlipidaemia, familial hypertriglyceridaemia and familial dysbetalipoproteinaemia)

9.1.1.3. Management of elevated TG (see Appendix VI, pg 78)

I,A

In individuals with mixed hyperlipidaemia, the primary target of therapy is to achieve LDL-C goal. In those individuals with: TG between 2.3 and 4.5mmo/l the secondary target of therapy is non HDL-C TG > 4.5mmol/L, the primary target of therapy is non HDL-C. Once LDL-C target has been achieved, the next step is to target TG < 1.7 mmol/L. a) Borderline high TG (1.72.3 mmol/L)

A target value of TG < 1.7 mmol/L can usually be achieved by:

I,B

b)

Lifestyle changes of weight reduction, low carbohydrate diet, control of diabetes or insulin resistance, exercise, reduction of alcohol intake and cessation of smoking.106,109,112,113,118-121 Medications are rarely required. High TG ( 2.35.7 mmol/L)

I,B I,B

I,A IIa,B

Treatment should include: Lifestyle changes as outlined above. Ensure diabetes if present is controlled. Drug therapy should be considered in high risk individuals. There are two options to achieve targets139: intensifying statin therapy if LDL-C target not achieved156 adding fibrates or niacin as a combination therapy to statin157,158,159 caution should be exercised when gemfibrozil is used in combination with statins because of the significant risk of rhabdomyolysis.141,142
49

Table 12: Classification of TG (Adapted from ATPIII)139

Classification of serum TG Normal TG (< 1.7 mmol/L) Borderline High TG (1.7-2.3 mmol/L) Acquired causes - Overweight and obesity - Physical inactivity - cigarette smoking - excess alcohol intake - high carbohydrate intake (> 60% of total energy) Secondary causes Genetic causes various genetic polymorphism Acquired causes - same as for borderline high TG (usually combined with foregoing causes) Secondary causes Genetic causes - familial combined hyperlipidemia -familial hypertriglyceridemia -polygeneic hypertriglyceridemia - familial dysbetalipoproteinemia Usually combined causes - same as for high TG Familial lipoprotein lipase deficiency Familial apolipoprotein C-11 deficiency Marker for atherogenic dyslipidemia - elevated small LDL particles - Low HDL-C Marker for the metabolic syndrome - elevated BP - insulin resistance and glucose intolerance - prothrombotic state - proinflammatory state Elevated atherogenicremnant lipoproteins Marker for other components of atherogenic dyslipidemia (see above) Marker for the metabolic syndrome (see above) Causes of elevated TG Clinical significance

High TG (2.3-5.7 mmol/L)

Very high TG ( 5.7mmol/L)

Metabolic syndrome,T2DM and increased risk for CHD Increased risk for acute pancreatitis Chylomicronemia syndrome - eruptive skin xanthomas - hepatic steatosis - lipemia retinalis - mental changes - high risk for pancreatitis

50

There are no clinical trial evidence that show a reduction in CVD events with drug therapy in individuals with only elevated TG both in primary and secondary prevention. (Appendix VI, pg 84) c) Very high TG > 5.7 mmol/L:

When TG is extremely high (>10mmol/L) treatment goal is to prevent acute pancreatitis. Treatment include: Start with a fibrate or nicotinic acid - Gemfibrozil and Fenofibrate lower TG by about 70%.43,47,160,161 - Nicotinic acid is effective at doses of above 2gm per day.139,162 very low fat diets (< 15% of calorie intake) and lifestyle changes (See Section 8.1)106,111,139 Severe hypertriglyceridaemia associated with uncontrolled diabetes warrants initiation of insulin therapy. The TG level will improve but may not normalize. Fish oils which contain long chain omega-3 polyunsaturated fatty acids can also lower TG. Doses of 3 to 9 gm per day can lower TG by up to 50%.139,163 They can be considered as an addition to fibrate or nicotinic acid. Statins are not useful as a first line therapy in this situation. In these individuals, it is difficult to achieve target values of TG (< 1.7mmol/L). Levels of TG < 2.3 mmol/L are acceptable. 9.1.2. Low HDL-C and High TG: Low HDL-C and high TG are seen in insulin resistance states and very high carbohydrate intakes.
I,A

I,B I,B I,B

IIa,B

IIa,B I,A

Treatment of this dyslipidaemia in individuals with CVD or CHD risk equivalents is aimed at lowering LDL-C to target.164 The choice of anti lipid drug will depend upon the level of LDL-C (Table 10, pg 45). If the HDL-C is still low despite adequate TLC then consider, fibrates or niacin if LDL-C is < 2.6mmol/L.43,47,160,161,162 statin if LDL-C is > 2.6mmol/L 165,166

51

9.1.3. Isolated Low HDL-C Individuals with isolated low HDLC have HDL-C < 1.0 mmol/L and TG < 1.7 mmol/L. Low HDL-C is an independent major risk factor for CVD.18,38,39 The major causes are obesity, physical inactivity, cigarette smoking and genetic factors. There are however no large outcome studies to date showing that increasing HDL-C improves CVD outcomes. 164 Treatment for isolated low HDL-C is mainly aimed at those individuals with CVD or CHD risk equivalent.
I,A

Statin is still the mainstay of treatment even in patients with low LDL-C (<2.6 mmol/L). Statin trials have showed that lowering LDLC in persons with isolated low HDL-C, significantly reduces CVD risk.166 Fibrates have also been shown to reduce major CVD events in persons with isolated low HDL-C.43,47,160,161 This benefit has been attributed in part to the HDL-C raising effects of fibrates. Key messages: In patients with isolated hypertriglyceridemia, isolated low HDL-C or its combination, the primary goal of treatment is lowering LDL-C to target.I,A The other targets of therapy are lowering non HDL-C (if TG > 2.3mmol/L) to target, maintaining TG < 1.7 mmol/L and HDL-C > 1.0 mmol/L.

IIa,B

9.2. Diabetes Mellitus (T2DM) Diabetes (T2DM) is a CHD risk equivalent. Recent long-term follow up studies showed that the benefits of intensive glucose control was not apparent early on but a legacy effect of a significant reduction in CV events was realized only 9-10 years after good glycaemic control.167,168 Despite this, the CV risk still remains high when compared to non-diabetics. Thus efforts must also be directed to control hypertension, lipids and other abnormalities.
169

52

Optimal Lipid values in individuals with diabetes are:

I,A

Primary target : - LDL-C < 2.6 mmol/L (<1.8 mmol/L for DM with established CVD) Secondary target: - Non-HDL-C < 3.4 mmol/L (when TG > 2.3 mmol/L) - HDL-C > 1.0 mmol/L (male) and > 1.2 mmol/L (female) - TG < 1.7 mmol/L

These targets are usually not achievable by TLC or glucose control. Improvement of glycaemic control alone will not fully correct the atherogenic dyslipidaemia. (See Table 13, pg 53) Table 13: Lipid Lowering Drug Therapy In Diabetics
Lipid Goal Lower LDLC Initial Drug Statins Suggested Addition In order of preference Fibrates Ezetimibe Resins Statins***

Increase HDL-C Lower TG Treat Combined Hyperlipidemia

* ** ***

Fibrates* or, Nicotinic Acid** Fibrates Statins***

Fibrates Nicotinic Acid

statins should be the initial drug if LDL-C goal is not achieved. with careful monitoring and keeping the dose < 1.5 gm / day. high doses may be required.

I,A

Statins should be initiated for all individuals above the age of 40 years with T2DM regardless of baseline LDL-C.170 Target should be to LDL-C <2.6 or 30-40% below baseline LDLC.169,170 For those with T2DM and with established CVD, LDL-C should be <1.8 mmol/L.169

I,A

53

I,B

If drug-treated patients do not reach targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of 3040% from baseline is an alternative therapeutic goal.170 In patients with high TG, reduction of carbohydrate intake is emphasized.112,113 Sub group analysis of recent outcome studies using combination therapy of statins and fibrates to achieve lipid targets have shown benefit in atherogenic dyslipidaemia.170 Key messages: Control of glycaemia alone is inadequate in preventing CV events. Concomitant treatment of dyslipidaemia, hypertension and other metabolic abnormalities are also important.I,A Target LDL-C goal in individuals with diabetes is <2.6 mmol/L. I,A In the presence of established CVD, LDL-C should be <1.8 mmo/L. I,A

I,B

IIa,B

9.3 Coronary Heart Disease (CHD) Patients with CHD may present as stable angina or as acute coronary syndromes (ACS). ACS is a spectrum of disease ranging from unstable angina (UA), non ST elevation myocardial infarction (NSTEMI) to ST elevation myocardial infarction depending on the acuteness and severity of the coronary occlusion. 9.3.1. Acute Coronary Syndromes (ACS)
I,A

Early initiation of statin therapy soon after admission for ACS is safe and improves outcome regardless of baseline LDL-C levels in patient with ACS.32,171-175 These benefits are independent of the lipid lowering effects of statins. Patient with ACS should be treated with a higher intensity statins. More aggressive lipid lowering further lowers cardiovascular event rates.32,171,172,176-179
54

I,A

I,C

Lipid management includes: Assessment of a fasting lipid profile for all patients, within 24 hours of hospitalization. Statins, in the absence of contra-indications, regardless of baseline LDL-C and diet modifications, should be initiated soon after admission and continued indefinitely to provide life long benefits.180-182 Statin treatment should not be delayed until lipid levels are available or management of other modifiable risk factors. Lipids should be re-tested about 2-3 months after the start of statin therapy.

I,A

I,A IIa,B

LDL-C level should be targeted <2.0mmol/L for most patients. Patients with low HDL-C may benefit from fibrates or nicotinic acid.43,162 9.3.2. Coronary Revascularizations

IIa,B

Pre-treatment with statins 7 days prior to elective PCI has been shown to reduce post-procedure MI.183 A loading dose of statins pre-procedure has also been shown to reduce post procedure MI in individuals who are statinnave and those already on regular statins.184,185 All cardiac patients post-revascularization (CABG, PCI) should be on long term statin therapy, the dose being adjusted to achieve target lipid levels.186,187 9.3.3 Stable CAD Stable CAD refers to stable angina, asymptomatic myocardial ischemia and coronary atherosclerosis detected by coronary or CT Angiogram. In individuals with stable CAD, PCI did not confer additional CV benefits when added to optimal medical therapy as an initial management strategy.188. Those individuals who had undergone
55

IIa,B

IIa,A

PCI however, had improvement in their quality of life during follow up.189
I,A

Irrespective of the baseline LDL-C level, statin therapy reduces the risk of major CV events by 24%.29 Individuals with stable CAD should be treated with optimal medical therapy using a combination of antiplatelet agents, statins, -blockers and angiotensin converting enzymes inhibitors.190 Statin therapy should always be considered for individuals with stable coronary artery disease . Therapy should aim at statin dosages documented to reduce morbidity and mortality in clinical trials. Key messages: Statins should be started early in individuals with ACS, and on all post revascularisation individuals irrespective of their baseline cholesterol levels.I,A In high risk individuals, high intensity statin treatment confers more benefit. I,A Statins are an integral component of optimal medical therapy in CAD individuals. I,A 9.4. Hypertension CV risk depends not only on blood pressure but also on associated risk factors, clinical conditions and target organ damage.191

I,A

I,A

I,A

I,A

Hypertensive individuals without established CVD but with moderate to high CV risk ( 10% risk of events in 10 years) should also be considered for statin therapy irrespective of baseline LDL-C levels.192 The choice of antihypertensive agent should be individualized. Certain antihypertensive agents may have an adverse effect on lipid levels eg high dose thiazides increases TC, LDL-C and TG levels, -blockers with no intrinsic sympathetic activity reduce HDL-C and increase serum TG. These effects are modest and should not affect the selection of an antihypertensive agent.139
56

Key messages: Hypertension and elevated cholesterol levels often coexist and synergistically increase the risk of developing CVD and treatment of both conditions reduces CVD events. Statins should be considered in high risk hypertensive individuals. I,A 9.5 Stroke Recent studies have shown an association between raised serum lipids and risk of ischaemic stroke.193
I,B

Statins have been shown to prevent ischaemic stroke in high risk individuals.29,194 Individuals with Ischaemic stroke or transient ischaemic attacks benefit from lipid modifying therapy.181,194,195 High intensity statins has been found to prevent recurrent stroke7. In-hospital lipid testing should be performed in individuals with ischaemic stroke and TIA.196,197

I,B

I,A

Statin therapy should be considered in individuals with LDL-C 2.6 mmol/L 198,199. Key messages: Statins have been shown to reduce the incidence of ischaemic strokes when used in high risk individuals. I,B Lipid lowering therapy with statins should be considered in all individuals with previous ischaemic stroke or transient ischaemic attack. I,B

57

9.6. Renal disease Chronic Kidney Disease (CKD) is associated with significant CV morbidity and mortality.200,201 Mortality increases progressively with worsening renal function. The risk of death from CVD is higher than the risk of eventually requiring renal replacement therapy.202,203 Currently, there are differing views about recognizing CKD as a CHD Risk Equivalent although all stages of CKD including individuals with asymptomatic microalbuminuria are at increased CVD risk. 139,200,204-209 They should be screened for traditional risk factors and treated according to their determined risk. Dyslipidaemia occurs in all stages of CKD, on dialysis, after renal transplantation and in individuals with the nephrotic syndrome. In individuals with CKD and in those on dialysis, the main lipid abnormalities are elevated levels of TG, low levels of HDL-C and elevated levels of Lp (a).The TC is usually normal or low. A number of studies have shown that in these individuals, lower levels of TC are associated with increased mortality most likely due to the adverse effects of malnutrition and chronic inflammation.210-217 In the nephrotic syndrome both TC and LDL-C are elevated. The lipid abnormalities may improve or resolve following resolution of the nephrosis. If the dyslipidaemia still persists, drug therapy should be considered. Caution must be exercised when starting anti lipid drug therapy in individuals with renal insufficiency. The use of fibrates in these individuals carries a higher risk of rhabdomyolysis and there is no proven long term CV benefits.218
IIb,B

In individuals with very high TG levels (more than 5.7 mmol/L), low dose fibrates may be initiated cautiously to prevent pancreatitis.43,47,160,161 Omega 3 Fish oils (at a dose of 4 gm/day) may also be used.219 Statins have been shown to have differential effects on the kidney. Some statins reduce proteinuria and slow the rate of progression of renal disease while others have been neutral.220,221

IIa,B IIa,B

58

I,B

In individuals with CHD and mild to moderate CKD, statins have been shown to be beneficial.29,218 A recently presented large prospective trial in patients with stages 3-5 CKD without CHD, showed that the use of a statin and ezetimibe combination resulted in a significant reduction in atherosclerotic events. A third of these patients were on dialysis and they did not show any benefit, a finding consistent with that of previous studies.141,222,223 The immunosuppresive drugs used post renal transplants or for underlying renal disease are associated with dyslipidaemia. Individuals receiving statins and fibrates in combination with cyclosporin should be closely monitored for myositis. The initiating dose of anti lipid drugs in patients with CKD should be lower. (Table 14, pg 60). Key messages: Individuals with CKD have high CV Risk. Statins have been found to be beneficial in individuals with CHD and mild to moderate CKD.I,B In individuals on dialysis, the benefits of lipid lowering therapy are doubtful.IIb,B Statins are safe in CKD.I,B Fibrates should be used cautiously in individuals with CKD and very high TG.IIb,B

IIa,B

IIb,B

59

Table 14. Dosing Modifications for Lipid-Lowering Drugs in CKD224

Agent Mild GFR 6090 ml/ min/1.73 m2 Moderate GFR 1559 ml/ min/1.73 m2 Severe GFR <15 ml/ min/1.73 m2 Notes

STATINS Atorvastatin Fluvastatin No No No Not defined No Not defined to 50% dose to one-half at GFR <30 ml/ min/1.73 m2 dose to one-half at GFR <30 ml/ min/1.73 m2 Start at 10 mg/day for GFR <60 ml/ min/1.73 m2 Contraindicated for GFR <30 ml/ min/1.73 m2, max dose 10 mg/day Start at 5 mg if GFR <10 ml/min/1.73 m2

Lovastatin

No

to 50%

Pravastatin

No

No

No

Rosuvastatin

No

510 mg

Avoid

Simvastatin

No

No

to 50%

NONSTATINS Nicotinic acid Cholestyramine Colesevelam Ezetimibe Fenofibrate Gemfibrozil No No No No to 50% No No No No No to 25% No to 50% No No No Avoid No May serum creatinine NLA recommends a dose of 600 mg/ day for GFR 1559 ml/min/1.73 m2 and avoiding use for GFR <15 ml/ min/1.73 m2 34% kidney excretion Not absorbed Not absorbed

60

10. MANAGEMENT IN SPECIAL GROUPS 10.1. Women Women develop heart disease about 10 to 15 years later than men.225 There are no gender differences in the risk factors that predispose to CVD although women with T2DM are at higher risk of CVD than men.226-230 In premenopausal women, CVD tends to occur in those with T2DM and multiple risk factors.
I,A

In secondary prevention, women have similar benefits on CVD outcomes as men.29,33,231 Statins should be the drug of first choice.29,33,231 Statins should not be used in women who are pregnant, intend to become pregnant or who are breast feeding. In women who have normal LDL-C but low HDL-C and high TG, fibrates may be used.47 In primary prevention, the cornerstone of management is lifestyle modification with advice on a healthy diet and physical activity. Women at high risk who do not achieve their target levels should be considered for pharmacological intervention although there is little data on the effect of lipid lowering therapy on CVD events for primary prevention in women. Current practice is to treat these women in the same manner as men based on extrapolation of benefit in men at similar risk.232 Women with genetic dyslipidaemias such as familial hypercholesterolemia with very high levels of TC or LDL-C may be considered for lipid lowering therapy from the outset. 10.2. Children & Adolescents Atherosclerosis begins in childhood, the rate of progression depending on the presence and number of risk factors and their severity.233-237 Risk factors for atherosclerosis in children include:
61

III,C

IIb,B

I,B

IIa,C

IIa,B

obesity and the metabolic syndrome238 T2DM post organ transplantation systemic lupus erythematosis nephrotic syndrome HIV infections

These risk factors have been shown to persist into adult life and lead to premature CVD. Screening begins with an assessment of family history for CVD or genetic dyslipidaemia.239 In addition, obese and overweight children and those with the risk factors mentioned above should also have a full lipoprotein profile, BP measurement and a fasting glucose assessment. Children whose lipid levels are significantly elevated should be referred to specialists interested in this field.
I,B

The main approach is a healthy lifestyle with appropriate diet, maintenance of desirable weight and regular exercise. In children with elevated cholesterol levels, statins are the drug of choice.240 There has been limited data on the use of niacin, fibric acid derivatives and ezetimibe in children. When prescribing drugs in children, the need for life long therapy and its associated health risks and drug exposure during unplanned pregnancy in individuals of child bearing age need to be considered. Patients should be extensively counseled prior to initiation of drug therapy.

I,A

IIb,B

I,A

10.3. Elderly (> 65 years) Increasing age is a major risk factor for CVD and death. For secondary prevention, the elderly derive a greater absolute benefit from lipid lowering therapy.241,242

62

Thus, they should not be deprived from lipid lowering therapy solely on the basis of their age although there is limited clinical trial data in patients over the age of 80 years. Renal function should be assessed and drug dosages adjusted accordingly. The benefits of lipid lowering therapy for primary prevention in elderly individuals with no other risk factors besides dyslipidaemia are less well established. Global risk assessment using standard risk factors as mentioned earlier is generally less reliable in older persons. Clinical judgement and consideration of co-morbid factors, co-existing disease and functional age become essential in deciding the need for drug therapy in this situation. (see Table 8, pg 34) Key messages: Women and the elderly with CHD and CHD risk equivalent should be treated in the same manner as man. I,A Children with very high cholesterol levels benefit from statin therapy. I,A 11. ADHERENCE, COMPLIANCE AND QUALITY ASSURANCE It has been well documented that there is a lack of adherence to cardiovascular preventive therapy. This is due to both physician factors (not initiating treatment, not achieving treatment goals, not checking on drug compliance) and patient factors (non compliance). Lack of adherence threatens the success of the guideline recommendation and implementation. Clinical trials have shown that the amount of risk reduction achieved is related to the level of adherence to treatment.243,244,245 More importantly, lack of adherence leads to missed opportunity for the risk reducing benefits of the treatment, thus creating enormous costs to the health system for treating CV events that could have been prevented.
63

To improve adherence and compliance the following are recommended: Patient factors - Simplify medication regimens using wherever possible drugs with a single daily or twice daily dosing - Give clear instructions - Encourage the support of the family - Involve patients in their care through self-monitoring - Remind patients that lipid lowering drugs are not a substitute for dietary and lifestyle interventions Physician Factors - Teach physicians to implement lipid treatment guidelines - Educate patients to prompt preventive care - Remind patients of appointments and follow-up missed appointments Health Delivery System - Involve pharmacists and other health care deliverers in patient education - Use mass media for patient education - Disseminate clinical guidelines and clinical pathways to health care providers - Standardize reference values in all laboratories to recommended Malaysian guidelines

Adherence to therapy should be checked periodically. Some suggested indicators as audit for lipid lowering therapy are: Measurement of lipid values Risk categorization of patients Appropriate usage of drug therapy Achieving primary lipid target goal: LDL-C to target Achieving secondary lipid target goals: HDL-C and TG to target

64

12. REFERENCES 1. 2. Number of discharges and deaths in government hospitals. Health Informatics Centre, Planning and Development Division, Ministry of Health Malaysia, July 2010. Azman W, Ramesh S V, Zambahari R et al on behalf of the ACCORD investigators. Malaysia-ACute CORonary syndromes Descriptive study (ACCORD): Evaluation of the compliance with existing guidelines in patients with Acute Coronary Syndrome (Unstable Angina and Non-ST elevation Myocardial Infarction). Personal communication. WA Wan Ahmad, KH Sim (Eds). Annual Report of the NCVD-ACS Registry, Year 2006. Kuala Lumpur, Malaysia: National Cardiovascular Disease Database 2008, Assessed at www.acrm.org.my Chaowalit N, Yipintsoi T, Tresukosol D et al for the Thai Acute Coronary Syndrome Registry. Prognostic value of selected presenting features of acute coronary syndrome in predicting in-hospital adverse events: insight from the Thai Acute Coronary Syndrome Registry. Intern Med 2009; 48 : 639-46. Song XT, Chen YD, Pan WQ for the CRACE Investigators. Gender based differences in patients with acute coronary syndrome: finding from Chinese Registry of Acute Coronary Events (CRACE). Chin Med J 2007; 120 :1063-7. The Global Registry of Acute Coronary Events. Assessed at: www.outcomesumassmed.org/grace/ Yan AT, Yan RT, Tan M; et al, Canadian Acute Coronary Syndromes 1 and 2 Registry Investigators. Management patterns in relation to risk stratification among patients with non-ST elevation acute coronary syndromes. Arch Intern Med 2007; 167 : 1009-1016. Senti M, Pedro-Botet J, Nogues X, Rubies-Prat J. Influence of intermediatedensity lipoproteins on the accuracy of the Friedewald formula. Clin Chem 1991; 37: 1394-1397. Abate N, Vega GL, Grundy SM. Variability in cholesterol content and physical properties of lipoproteins containing apolipoprotein B-100. Atherosclerosis 1993; 104 : 159-71. Brunzell JD, Davidson M, Furberg CD et al. Lipoprotein management in patients with cardiometabolic risk. Consensus from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 2008; 31: 811-822. Barter PJ, Ballantyne CM, Carmena R, et al. ApoB versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/tencountry panel. J Intern Med 2006; 259 : 247-258. Pischon T, Girman CJ, Sacks FM et al. Non-high density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men. Circulation 2005;112: 337583. Lamarche B, Moorjani S, Lupien PJ et al. Apolipoprotein A-1 and B levels and the risk of ischemic heart disease during a five-year follow-up of men in the Quebec Cardiovascular Study. Circulation1996 ; 94:273278. Walldius G, Jungner I, Holme I et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001; 358:20262033. Colao A, Gaillard R .Novel insights in the management of Cushings syndrome. Neuroendocrinology 2010; 92 : suppl 1;6-132. 65

3. 4.

5. 6. 7.

8. 9. 10.

11. 12. 13. 14. 15.

16. Lithell H,Boberg J,Hellsing K et al. Serum lipoprotein and apolipoprotein concentrations and tissue lipoprotein lipase activity in overt and subclinical hypothyroidism: The effects of substitution therapy. Eur J Clin Invest 1981; 11: 3-10. 17. Sawin CT, Castelli WP,Hershman JM et al. The aging thyroid.Thyroid deficiency in the Framingham Study. Arch Intern Med 1985; 145 :1386-1388. 18. Wilson PWF, DAgostino RB, Levy D et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837-47. 19. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results I: Reduction in the incidence of coronary heart disease. JAMA 1984;251:351-64. 20. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results II: The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984;251:365-74. 21. Stamler J, Wentworth D, Neaton JD for the MRFIT Research Group. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356 222 primary screenees of the Multiple Risk Factor Intervention Trial. (MRFIT) JAMA 1986; 256 : 2823-8. 22. Pekkanen J, Linn S, Heiss G et al. Ten year mortality from cardiovascular disease in relation to cholestrol level among men with and without preexisting cardiovascular disease. N Eng J Med 1990;322:1700-7. 23. Wong ND, Wilson PWF, Kannel WB. Serum cholesterol as a prognostic factor after myocardial infarction: the Framingham study. Ann Intern Med 1991; 115 : 687-93. 24. Keys A, Arvanis C, Blackburn H. Seven countries: a multivariate analysis of death and coronary heart disease. Cambridge MA: Harvard University Press, 1980;381. 25. Peoples Republic of China United States Cardiovascular and Cardiopulmonary Epidemiology Research group. An epidemiological study of cardiovascular and cardiopulmonary disease risk factors in four populations in the Peoples Republic of China: baseline report from P.R.C.-U.S.A. Collaborative study. Circulation 1992;85:1083-96. 26. Law MR. Lowering heart disease risk with cholesterol reduction: evidence from observational studies and clinical trials. Eur Heart H Suppl 1999; (suppl S) :S3-8. 27. Turner RC, Millns H, Neil HA et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23). Br Med J 1998; 316:823828. 28. Lee ET, Howard BV, Wang W et al. Prediction of coronary heart disease in a population with high prevalence of diabetes and albuminuria: the Strong Heart Study. Circulation 2006; 113:28972905. 29. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:722. 30. Sever PS, Dahlof B, Poulter NR et al for the ASCOT Investigators: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian cardiac outcomes trial-lipid lowering arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361:11491158. 31. Pedersen TR, Faergeman O, Kastelein JJP et al. Bendiksen FS, Lindahl, C, Szarek M, Tsai J: High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL Study: a randomized controlled trial. JAMA 294:24372445, 2005. 66

32. Cannon CP, Braunwald E, McCabe CH, et al Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495 1504, 2004. 33. LaRosa JC, Grundy SM, Waters DD et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352:14251435. 34. Sacks FM, Pfeffer MA, Moye LA et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335:10011009. 35. Cromwell WC, Otvos JD. Low-density lipoprotein particle number and risk for cardiovascular disease. Curr Atheroscler Rep 2004; 6:381387. 36. Mora S, Szklo M, Otvos J et al. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA) Atherosclerosis 2007; 192: 211217. 37. El Harchaoui K, van der Steeg WA, Stroes ES et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: the EPIC Norfolk prospective population study. J Am Coll Cardiol 2007; 49:547553. 38. Gordon DJ. Cholesterol lowering reduces mortality: the statins. In: Grundy SM ed. Cholesterol lowering therapy: evaluation of clinical trial evidence. New York: Marcel Dekker Inc., 2000:299-311. 39. Assmann G, Schulte H, von Eckardstein A, Huang Y. High density lipoprotein cholesterol as a predictor of coronary heart disease risk: the PROCAM experience and pathophysiological implications for reverse cholesterol transport. Artherosclerosis 1996;124 (suppl 6) :S11-20. 40. Gordon DJ, Rifkind BM. High-density lipoprotein -- the clinical implications of recent studies. N Engl J Med 1989;321:1311-1316. 41. Barter PJ,Caulfield M, Erikkson M et al for the ILLUMINATE Investigators. Effects of Torcetrapib in Patients at High Risk for Coronary Events. N Engl J Med 2007; 357:2109-2122. 42. Cannon CP, Shah S, Dansky HM et al for the DEFINE Investigators. Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease. N Engl J Med 2010; 363:2406-2415. 43. Rubins HB, Robins SJ, Collins D, et al., for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of highdensity lipoprotein cholesterol. N Engl J Med 1999;341: 410-8. 44. Sarwar N, Danesh J, Eiriksdottir G et al Triglycerides and the Risk of Coronary Heart Disease: 10 158 Incident Cases Among 262 525 Participants in 29 Western Prospective Studies. Circulation 2007;115:450-458. 45. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting Triglycerides and Risk of Myocardial Infarction, Ischemic Heart Disease, and Death in Men and Women JAMA. 2007;298(3):299-308. 46. Bansal S, Buring JE, Rifai N et al. Fasting Compared With Nonfasting Triglycerides and Risk of Cardiovascular Events in Women JAMA. 2007;298(3):309-316. 47. The FIELD Study Investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366: 1849 - 1861. 48. PL Canner, KG Berge, NK Wenger et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986; 8:12451255. 67

49. Lu W, Resnick HE, Jablonski KA, et al. Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes: the Strong Heart Study. Diabetes Care 2003;26:16 23. 50. Liu J, Sempos C, Donahue R et al. Joint distribution of non-HDL and LDL cholesterol and coronary heart disease risk prediction among individuals with and without diabetes. Diabetes Care 2005;28:1916 21. 51. Kastelein JJP, van der Steeg WA, Holme I et al for the IDEAL and TNT study groups.. Lipids, Apolipoproteins, and Their Ratios in Relation to Cardiovascular Events With Statin Treatment. Circulation 2008;117:3002-3009. 52. Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol 1998;81:18B-25B. 53. Krauss RM. Atherogenicity of triglyceride rich lipoproteins. Am J Cardiol 1998;81:13-17B. 54. Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302:412 23. 55. Nordestgaard BG, Chapman MJ, Ray K et al. Lipoprotein (a) as a cardiovascular risk factor : current status. Eur Heart J 2010: 31: 2844-2853. 56. Yusuf S, Hawken S, Ounpuu S, on behalf of the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937-952. 57. ODonnel MJ, Xavier D, Liu L et al on behalf of the INTERSTROKE Investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010;376 : 112-123. 58. van den Hoogen PCW, Feskens EJM, Nagelkerke NJD et al for the Seven Countries Research Group. The relation between blood pressure and mortality due to coronary heart disease among men in different parts of the world. N Engl J Med 2000;342:1-8. 59. Franklin SS, Lopez VA, Wong ND et al. Single versus combined blood pressure components and risk for cardiovascular disease: the Framingham Heart Study. Circulation. 2009; 119: 243250. 60. Schillaci G, Pirro M, Mannarino E. Assessing Cardiovascular Risk : Should We Discard Diastolic Blood Pressure?Circulation 2009; 119: 210 - 212. 61. Staessen JA, Gasowski J, Wang JG et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet 355, 865872 (2000). 62. Franklin SS, Jacobs MJ, Wong ND et al. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives. Hypertension 37, 869874 (2001). 63. Asia Pacific Cohort Studies Collaboration. Blood pressure and cardiovascular disease in the Asia Pacific region. J. Hypertens. 21, 707716 (2003). 64. Psaty BM, Furberg CD, Kuller et al. Association between blood pressure level and the risk of myocardial infarct, stroke and total mortality. Arch Intern Med 2001;161:1183-1192. 65. Doll R, Peto R. Mortality in relation to smoking: 20 years observation on male British doctors. Br Med J 1976;2:1525-36. 66. Doll R, Gray R, Hafner B, Peto R. Mortality in relation to smoking: 22 years observations on female British doctors. Br Med J 1980;280:967-71. 67. LaCroix AZ, Lang J, Scherr P et al. Smoking and mortality among older men and women in three communities. N Eng J Med 1991;324:1619-25. 68

68. Teo KK, Ounpuu S, Hawken S et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a casecontrol study. Lancet 2006; 368: 647658. 69. Wannamethee G, Shaper AG, Macfarlane PW, Walker M. Risk factors for sudden cardiac death in middle-aged British men. Circulation 1995; 91; 17491756. 70. Willett WC, Green A, Stampfer MJ et al. Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med 1987; 317 :13031309. 71. Burns DM. Epidemiology of smoking-induced cardiovascular disease. Prog Cardiovasc Dis 2003; 46:1129. 72. Metz L, Waters DD. Implications of cigarette smoking for the management of patients with acute coronary syndromes. Prog Cardiovasc Dis 2003; 46: 19. 73. Nakamura K, Barzi F, Lam T et al. Cigarette smoking, systolic blood pressure, and cardiovascular diseases in the Asia-Pacific Region. Stroke 2008; 39: 16941702 74. Kenfield S, Stampfer M, Rosner B, Colditz G. Smoking and smoking cessation in relation to mortality in women. JAMA 2008;299, 20372047. 75. Lightwood JM, Glantz SA. Short-term economic and health benefits of smoking cessation: myocardial infarction and stroke. Circulation 1997; 96: 10891096 76. Phillips RL, Lilienfeld AM, Diamond EL, Kagan A. Frequency of coronary heart disease and cerebrovascular accidents in parents and sons of coronary heart disease index cases and controls. Am J Epidemiol 1974;100:87-100. 77. Barrett Connor E, Khaw K-T. Family history of heart attack as an independent predictor of death due to cardiovascular disease. Circulation 1984;69:1065-9. 78. Chow CK, Islam S, Bautista L et al. Parental History and Myocardial Infarction Risk Across the World. The INTERHEART Study. J Am Coll Cardiol 2011;57:619-627. 79. Lloyd Jones DM, Nam B-H, DAgostino R B et al. Parental Cardiovascular Disease as a Risk Factor for Cardiovascular Disease in Middle-aged Adults A Prospective Study of Parents and Offspring. JAMA 2004;291 : 2204-2211. 80. WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 2004;363 : 15763. 81. Asia Pacific Cohort Studies Collaboration. Body mass index and cardiovascular disease in the Asia-Pacific Region: an overview of 33 cohorts involving 310 000 participants. Int J Epidem 2004; 33 : 751-758. 82. Zhang C,Rexrode KM, van Dam RM et al. Abdominal Obesity and the Risk of AllCause, Cardiovascular, and Cancer Mortality. Sixteen Years of Follow-Up in US Women Circulation 2008;117:1658-1667. 83. Jacobs EJ, Newton CC, Wang Y et al.Waist Circumference and All-Cause Mortality in a Large US Cohort. Arch Intern Med 2010;170 :1293-1301. 84. Wildman RP, McGinn AP, Lin J et al. Cardiovascular Disease Risk of Abdominal Obesity vs. Metabolic Abnormalities. Obesity (19 August 2010) | doi:10.1038/ oby.2010.168 85. Barengoa NC, Hub GC, Lakkaa TA. Low physical activity as a predictor for total and cardiovascular disease mortality in middle-aged men and women in Finland. Eur Heart J 2004; 25 : 22042211. 86. Hu G, Tuomilehto J, Borodulin K , Jousilahti P. The joint associations of occupational, commuting, and leisure-time physical activity, and the Framingham risk score on the 10-year risk of coronary heart disease. Eur Heart J 2007; 28 : 492-498.

69

87. Mora S, Cook N, Buring JE et al .Physical Activity and Reduced Risk of Cardiovascular Events. Potential Mediating Mechanisms. Circulation. 2007;116: 2110-2118. 88. Dauchet L, Amouyel P, Hercberg S, Dallongeville, J. Fruit and Vegetable Consumption and Risk of Coronary Heart Disease: A Meta-Analysis of Cohort Studies. J. Nutr 2006; 136: 2588-2593. 89. Iso H, Cui R, Date C et al. C-reactive protein levels and risk of mortality from cardiovascular disease in Japanese: The JACC Study. Atherosclerosis 2009; 207 : 291-297. 90. Hamer M, Chida Y, Stamatakis E. Utility of C-Reactive Protein for Cardiovascular Risk Stratification Across Three Age Groups in Subjects Without Existing Cardiovascular Diseases. Am J Cardiol 2009; 104 : 538-542. 91. The Emerging Risk Factors Collaboration. C-reactive protein concentration and the risk of coronary heart disease, stroke, and mortality. Lancet 2010; 375:132140. 92. Ridker PM, Buring JE, Shih J et al. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 1998;98:731-3. 93. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-843. 94. Ridker PM, Danielson E, Fonseca FAH et al for the JUPITER Study Group. Rosuvastatin to Prevent Vascular Events in Men and Womenwith Elevated C-Reactive Protein. N Engl J Med 2008; 359 :2195207. 95. Fibrinogen Studies Collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 2005;294:1799-1809. 96. Woodward M, Tunstall-Pedoe H, Rumley A, Lowe GDO. Does fibrinogen add to prediction of cardiovascular disease? Results from the Scottish Heart Health Extended Cohort Study. Br J Haematol 2009;146:442-446. 97. Smith SC Jr, Greenland P, Grundy SM. Beyond secondary prevention: identifying the high risk patient for primary prevention: executive Summary: AHA Conference Proceedings: Prevention Conference V. Circulation 2000;101:111-6. 98. Institute of Public Health (IPH) 2008. The Third National Health and Morbidity Survey 2006 Vol 2. Ministry of Health Malaysia. Pg 199-316 ISBN 978-983-388730-09. 99. Greenland P, Alpert JS, Beller GA et al. 2010 ACCF/AHA Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults: Executive Summary. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2010; 56:2182-2199. 100. DAgostino Sr RB, Vasan RS, Pencina MJ et al. General Cardiovascular Risk Profile for Use in Primary Care. The Framingham Heart Study. Circulation. 2008;117:743-753. 101. Kannel WB, Mc Gee DL. Diabetes and glucose tolerance as risk factors for cardiovascular disease: The Framingham Study. Diabetes Care 1979;2:120-6.

70

102. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A meta-regression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999; 22: 233-40. 103. Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with Type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34. 104. Joint Interim Statement (Joint Interim Statement of International Diabetes Federation Task Force on Epidemiology and Prevention, National Heart Lung Blood Institute (NHLBI), American Heart Association (AHA), World Heart Federation (WHF), International Atherosclerotic Society (IAS) and international Association for Study of Obesity (IASO) Circulation 2009: 120: 1640-1645. 105. Jenkins DJA, Kendall CWC, Faulkner DA et al. Assessment of the longerterm effects of a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia. Am J Clin Nutr 2006; 83:582-591. 106. Lichtenstein AH, Appel LJ, Brands M et al. Diet and Lifestyle Recommendations Revision 2006 .A Scientific Statement From the American Heart Association Nutrition Committee Circulation 2006;114:82-96.) 107. Oh K, Hu FB, Manson JE et al Dietary Fat Intake and Risk of Coronary Heart Disease in Women: 20 Years of Follow-up of the Nurses Health Study. Am J Epidemiol 2004; 161 : 672-679. 108. Tanasescu M, Cho E, Manson JE, Hu FB. Dietary fat and cholesterol and the risk of cardiovascular disease among women with type 2 diabetes. Am J Clin Nutr 2004; 79: 999-1005. 109. Siri Tarino PW, Sun Q, Hu FB, Krauss R. Saturated fat, carbohydrate, and cardiovascular disease. Am J Clin Nutr 2010; 91: 502-509. 110. Mozaffarian D, Katan MB, Ascherio A et al. Trans fatty acids and cardiovascular disease. N Engl J Med 2006;354:1601-13. 111. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003;77:1146-1155. 112. Appel LJ, Sacks FM, Carey VJ et al. for the OmniHeart Collaborative Research Group. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA. 2005; 294: 24552464. 113. Johnson RK, Appel LJ, Brands M et al on behalf of the American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism and the Council on Epidemiology and Prevention Dietary Sugars Intake and Cardiovascular Health. A Scientific Statement From the American Heart Association.Circulation. 2009;120:1011-1020. 114. Hu FB, Willett WC. Optimal diets for prevention of coronary heart disease. JAMA 2002; 288: 25692578. 115. Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr 1999; 69: 3042. 116. Wang L, Gaziano JM, Liu S et al. Whole- and refined-grain intakes and the risk of hypertension in women. Am J Clin Nutr 2007; 86 : 472-479. 117. Racette SB, Lin X, Lefevre M et al.: Dose effects of dietary phytosterols on cholesterol metabolism: a controlled feeding study. Am J Clin Nut. 2010; 91, 3238. 71

118. Laimer MW, Engl J, Tshoner A et al. Effects of weight loss on lipid transfer proteins in morbidly obese women. Lipids 2009; 44:1125-30. 119. Stoedefalke K. Effects of exercise training on blood lipids and lipoprotein s in children and adolescents. J Sports Sc Med 2007; 6 : 313-318. 120. Kraus WE, Houmard JA, Duscha DA et al. Effects of the Amount and Intensity of Exercise on Plasma Lipoproteins. N Engl J Med 2002; 347:1483-1492. 121. Ginsberg H, Olefsky J, Farquhar JW, et al. Moderate ethanol ingestion and plasma triglyceride levels: a study in normal and hypertriglyceridemic persons. Ann Intern Med 1974; 80:143-9. 122. Taskinen MR, Valimaki M, Nikkila EA, et al. Sequence of alcohol induced initial changes in plasma lipoproteins (VLDL and HDL) and lipolytic enzymes in humans. Metabolism 1985; 34:112-9. 123. Pownall HJ, Ballantyne C, Kimball K, et al. Effect of moderate alcohol consumption on HTG: a study in the fasting state. Arch Intern Med 1999; 159:981-7. 124. Hvidtfeldt UA, Tolstrup JS, Jakobsen MU et al. Alcohol Intake and Risk of Coronary Heart Disease in Younger, Middle-Aged, and Older Adults. Circulation 2010;121:1589-1597. 125. Castelnuovo AD, Costanzo S, Bagnardi V et al. Alcohol Dosing and Total Mortality in Men and Women. An Updated Meta-analysis of 34 Prospective Studies. Arch Intern Med. 2006; 166 : 2437-2445. 126. Fuchs CS, Stampfer MJ, Colditz GA et al. Alcohol consumption and mortality among women. N Engl J Med 1995; 332 :1245-1250. 127. Corrao G, Bagnardi V, Zambon A, La Vecchia C. A meta-analysis of alcohol consumption and the risk of 15 diseases. Prev Med 2004; 38 : 613-619. 128. Burr ML, Fehily AM, Gilbert JF et al. Effects of changes in fat, fish and fibre intakes on death and myocardial infarction: Diet and Reinfarction Trial (DART). Lancet 1989; 2: 757-61. 129. GISSIPrevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI Prevenzione trial. Lancet 1999; 354:447-55. 130. Galan P, Kesse-Guyot E, Czernichow S et al for the Su.Fol.Om Collaborative Group.Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial. Br Med J 2010; 341:c6273. 131. Appel LJ, Moore TJ, Obarzanek E et al for the DASH Collaborative Research Group. A Clinical Trial of the Effects of Dietary Patterns on Blood Pressure. N Engl J Med 1997; 336 : 1117-1124. 132. Lonn E, Bosch J, Yusuf S et al for the HOPE and HOPE-TOO Trial Investigators. Heart Outcome Prevention Evaluation & Heart Outcome Prevention Evaluation The Ongoing Outcome Trial. Effects of long term vitamin E supplementation on cardiovascular event and cancer : a randomized controlled trail. JAMA 2005; 293: 1338-47. 133. Heart Protection Study Collaboration Group. MRC/BHF Heart protection study of antioxidant vitamin supplementation in 20,536 high risk individuals: a randomized placebo controlled trail. Lancet 2002; 360 : 23-33. 134. Gardner CD, Lawson LD, Block E et al. Effect of Raw Garlic vs Commercial Garlic Supplements on Plasma Lipid Concentrations in Adults With Moderate Hypercholesterolemia: A Randomized Clinical Trial. Arch Intern Med 2007; 167:346-353. 135. Szapary PO, Wolfe MC, Bloedon LT et al. Guggulipid in the treatment of hypercholesterolemia. A randomized controlled trial. JAMA 2003; 290: 765-72. 72

136. Hunninghake DB, Stein EA, Dujovne CA et al. The efficacy of intensive dietary therapy alone or combined with lovastatin in outpatients with hypercholesterolaemia. New Engl J Med 1993; 328:1213-9. 137. Collins R, Armitage J, Parish S et al .MRCBHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebocontrolled trial.Lancet 2003; 361:2005-2016. 138. Colhoun HM, Betteridge DJ, Durrington PN et al for CARDS Investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004 ;364:685-96. 139. Executive summary of the Third Report of the National cholesterol Education program (NCEP) Expert Panel on detection, evaluation and treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation 2002; 106; 3143 -3421. 140. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003; 46:347-57. 141. SHARP Collaborative Group, Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease, Am Heart J 2010; 160 : 785-794. Results assessed at www.ctsu.ox.ac.uk 142. Hodel C. Myopathy and rhabdomyolysis in lipid-lowering drugs. Toxicol. Lett 2002;128:159-68. 143. Mantel - Teeuwisse AK, Klungel OH, Herrings RM, von Puijenbroek EP, Porsius AJ, de Boer A. Myopathy due to statin / fibrate use in the Netherlands. Ann Pharmacother 2002; 36: 1957-1960. 144. Plosker GL, Lyseng- Williamson KA. Atorvastastin : a pharmacoeconomic review of its use in the primary and secondary prevention of cardiovascular events. Pharmacoeconomics 2007;25(120):1031-53. 145. Choudhry NK, Patrick AR, Glynn RJ, Avorn J. The cost-effectiveness of C-reactive protein testing and rosuvastatin treatment for patients with normal cholesterol levels. J Am Coll Cardiol 2011; 57: 784-791. 146. Carrington M, Stewart S. Is fenofibrate a cost saving for middle- aged individual with type 11 diabetes ? An economic analysis of the FIELD study. Int J Cardiol 2008;,127: 51-56. 147. Tran YB, Frial T, Miller PS. Statins cost effectiveness : a Canadian analysis of commonly prescribed and brand name statins. Can J Clin Pharmcol. 2007; 14: 205- 214. 148. Vella A, Pineda AA, OBrien T. Low-density lipoprotein apheresis for the treatment of refractory hyperlipidemia. Mayo Clin Proc 2001;76:103946. 149. Forms of Therapeutic Hemopheresis. Summary Report of the Working Party on Medical Treatment of the Federal Committee of Physicians and Health Insurance Companies on the Deliberations Pursuant to 135 para 1 of the Code of Social Law, vol V (SGB V), 2003. 150. Civiera F, for International Panel on Management of Familial Hypercholesterolemia. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis 2004;173:5568.

73

151. Kavey R-EW, Allada V, Daniels SR, et al. Cardiovascular risk reduction in highrisk pediatric patients. A Scientific Statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; the Interdisciplinary Working Group on Quality of Care and Outcomes Research. Circulation 2006; 114:271038. 152. Szczepiorkowski ZM, Bandarenko M, Kim HC, et al. Guidelines on the use of therapeutic apheresis in clinical practice: evidence-based approach from the apheresis applications committee of the American society for apheresis. J Clin Apher 2007; 22 :10675. 153. Kroon A, Aengevaeren WRM, Van Der Werf T et al. Effect of Aggressive Versus Conventional Lipid Lowering Treatment on Coronary Atherosclerosis. LDLApheresis Atherosclerosis Regression Study (LAARS). Circulation 1996; 93:18261835. 154. Thompson GR et al. Review: Efficacy criteria and cholesterol targets for LDL apheresis. Atherosclerosis 2010; 208 : 317-321. 155. Stefanutti C. The 2009 2nd Italian Consensus Conference on LDL-apheresis. Nutr, Metabolism & Cardio Dis 2010; 20, 761-762. 156. Stein EA, Lane M, Laskarzewski P. Comparison of statins in hypertriglyceridemia. Am J Cardiol 1998;81:66B-69B. 157. The ACCORD Study Group. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. N Engl J Med 2010; 362:1563-1574. 158. Van JT, Pan J, Wasty T, et al. Comparison of extended-release niacin and atorvastatin monotherapies and combination treatment of the atherogenic lipid profile in diabetes mellitus. Am J Cardiol 2002;89:1306-8. 159. Brown GB, Zhao X-Q, Chait A et al. Simvastatin and Niacin, Antioxidant Vitamins, or the Combination for the Prevention of Coronary Disease. N Engl J Med 2001; 345:1583-1592. 160. Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998; 98:2088-93. 161. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;317:1237-45. 162. Chapman MJ, Assmann G, Fruchart JC et al. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acida position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 2004; 20:12531268. 163. Harris WS, Miller M, Tighe AP, et al Omega-3 fatty acids and coronary heart disease risk: clinical and mechanistic perspectives. Atherosclerosis 2008; 187: 1224. 164. Briel M, Ferreira-Gonzalez I,You JJ et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. Br Med J 2009; 338:b92. 165. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357:1301-10. 166. deGoma EM, Leeper NJ, Heidenreich PA . Clinical Significance of High-Density Lipoprotein Cholesterol in Patients With Low Low-Density Lipoprotein Cholesterol. J Am Coll Cardiol 2008; 51 : 49-55. 74

167. Holman RR, Paul SK, Bethel A et al. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Engl J Med 2008; 359:1577-1589. 168. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive Diabetes Treatment and Cardiovascular Disease in Patients with Type 1 Diabetes. N Engl J Med 2005; 353:2643-2653. 169. UK Prospective Diabetes Study Group. Association of Glycaemia with macrovascular and microvascular complication of Type 2 diabetes (UKPDS 35). Br Med J 2000;321:405-12. 170. Clinical Practice Guidelines on the Management of Type 2 Diabetes Mellitus (4th Edition)2009. Assessed at www.acadmed.org.my 171. American Diabetes Association. Standards of Medical Care in Diabetes2011. Diabetes Care 2011; 34:S11-S61. 172. Fonarow GC, Wright S, Spencer FA at el. Effect of statins use within the first 24 hours of admission for AMI on early morbidity and mortality. Am J Cardiol 2005; 96: 611-6. 173. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: a randomized controlled trial. JAMA 2001; 285 : 17118. 174. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes. JAMA 2004; 292 : 130716. 175. Briel M, Schwartz GG, Thompson PL, et al. Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes: a meta-analysis of randomized controlled trials. JAMA 2006; 295 : 2046-56. 176. Hulten E, Jackson JL, Douglas K et al. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med 2006; 166 : 1814-1821. 177. Ray KK, Cannon CP, McCabe CH, et al. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes. Results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2005 ; 46 : 140510. 178. Hiro T, Kimura T, Morimoto T et al. Effect of Intensive Statin Therapy on Regression of Coronary Atherosclerosis in Patients With Acute Coronary Syndrome: A Multicenter Randomized Trial Evaluated by Volumetric Intravascular Ultrasound Using Pitavastatin Versus Atorvastatin. J Am Coll Cardiol 2009; 54 : 293302. 179. Gibson CM, Pride YB, Hochberg CP et al. Effect of Intensive Statin Therapy on Clinical Outcomes Among Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome. PCI-PROVE IT: A PROVE ITTIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis In Myocardial Infarction 22) Substudy. J Am Coll Cardiol 2009; 54 : 22905. 180. De Backer G, Ambrosioni E, Borch-Johnsen K et al. European guidelines on cardiovascular disease prevention on clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J. 2003; 24 : 1601-1610. 181. Smith SC Jr, Allen J, Blair SN et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease 2006 update: endorsed by the National Heart, lung, and Blood Institute. Circulation 2006; 113 : 2363-2372. 182. Ridker PM, Cannon CP, Morrow D et al C Reactive protein levels and outcomes after statins therapy. N Engl J Med 2005; 352 : 20-28. 75

183. Pasceri V,Patti G, Nusca A, et al. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention. Results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2004;110: 674-8. 184. Briguori C,Visconti G,Focaccio A et al. Novel Approaches for Preventing or Limiting Events (NAPLES) II Trial: Impact of Loading Dose of Atorvastatin on Periprocedural Myocardial Infarction. J Am Coll Cardiol 2009; 54 : 2157-2163. 185. Di Sciascio G, Patti G, Pasceri V et al. Efficacy of Atorvastatin Reload in Patients on Chronic Statin Therapy Undergoing Percutaneous Coronary Intervention. Results of the ARMYDARE- CAPTURE (Atorvastatin for Reducti on of Myocardial Damage during Angioplasty) Randomized Trial. J Am Coll Cradiol 2009; 54 : 558-564. 186. Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low dose anticoagulation on obstructive changes in saphenous vein coronary-artery bypass grafts. N Engl J Med 1997;336:153162. 187. Serruys PW, de Feyter P, Maccaya C et al. for the LIPS Investigators. Fluvastatin for Prevention of Cardiac Events Following Successful First Percutaneous Coronary Intervention. JAMA 2002;287:3215-22. 188. Boden WE, O Rouke RA, Teo KK et al.Optimum medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007: 356 : 1503-16. 189. Weintraub WS, Spertus JA, Kolm P et al. Effect of PCI on Quality of Life in Patients with Stable Coronary Disease. N Engl J Med 2008: 359 : 677-687. 190. Fraker TD Jr, Fihn SD writing on behalf of the 2002 Chronic Stable Angina Writing committee. 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of patients with Chronic Stable Angina. A report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines Writing Group to Develop the Focused Update of the 2002 Guidelines for the Management of Patients with Chronic Stable Angina. J Am Coll Cardiol 2007; 50; 2264-2274. 191. Malaysian Clinical Practice Guidelines. Management of hypertension 3rd ed. Feb 2008. 192. Sever PS, Dahlof B, Poulter NR et al for ASCOT Investigators.Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58. 193. Stamler J, Vaccaro O, Neaton J et. al. Multiple Risk Factor Intervention Trial Research Group . Diabetes, other risk factors and cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16: 434-444. 194. Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 2009; 8:453-463. 195. Ovbiagele B, Kidwell CS, Saver JL. Expanding indications for statins in cerebral ischemia: a quantitative study. Arch Neurol 2005; 62: 67-72. 196. Smith EE, Abdullah AR, Amirfarzan H, Schwamm LH. Serum lipid profile on admission for ischemic stroke.: failure to meet National Cholesterol Education Program Adult Treatment Panel (NCEP-ATPIII) guidelines. Neurology 2007; 68: 660-665.

76

197. Smith EE, Pan W, Olson DW, Reeves MJ et al. Frequency and determinents of lipid testing in ischemic stroke and transient ischemic attack: findings from get with the guidelines stroke. Stroke 2010; 41: 232-238. 198. Sacco RL, Adams R, Albers G et al. Guidelines for prevention of strokes in patients with ischemic stroke or transient ischemic attack. Stroke 2006; 37: 577-617. 199. Adams RJ, , Albers G, Alberts MJ et al. American Heart Association, American Stroke Association. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke 2008; 39:1647-1652. 200. Sarnak, MJ, Levey, AS, Schoolwerth AC, Coresh J. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 2003; 108: 2154-2169. 201. Collins AJ, Foley RN, Herzog C et al. Excerpts from the US Renal Data System 2009 Annual Data report: Atlas of end-stage renal disease in the United States. Am J Kidney Dis 2010; 55(1 Suppl 1):S1-A7. 202. Foley RN, Murray AM, Li S et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 2005; 16:489-495. 203. Keith DS, Nichols GA, Gullion CM et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 2004; 164:659-663. 204. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002; 39 suppl1 : S1-S266. 205. Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004; 110:588-636. 206. Levey AS, Beto JA, Coronado BE et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: what do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis 1998; 32:853-906. 207. Wattanakit K, Coresh J, Muntner P et al. Cardiovascular Disease among adults with chronic kidney disease, with or without prior myocardial infarction. J Am Coll Cardiol 2006; 48 : 1183 -1189. 208. Genest J, McPherson R, Frohlich j et al. 2009 Canadian Cardiovascular Society/ Canadian guidelines for the diagnosis and treatment of dyslipidaemia and prevention of cardiovascular disease in the adult-2009 recommendations. Can J Cardiol 2009; 25 : 567-579. 209. NICE clinical guideline 67. Lipid Modification: Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Assessed at www.nice.uk.org/cg067 210. Weiner, DE, Sarnak, MJ. Managing dyslipidemia in chronic kidney disease. J Gen Intern Med 2004; 19:1045 -1052. 211. Lo JC, Go AS, Chandra M et al. GFR, body mass index, and low high-density lipoprotein concentration in adults with and without CKD. Am J Kidney Dis 2007; 50:552-558. 77

212. Lowrie EG, Lew NL. Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990; 15:458-482. 213. Degoulet P, Legrain M, Reach I. Mortality risk factors in patients treated by chronic hemodialysis. Report of the Diaphane collaborative study. Nephron 1982; 31:103-110. 214. Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients. Kidney Int 2002; 61:1887-1893. 215. Liu Y, Coresh J, Eustace J et al. Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition. JAMA 2004; 291:451-459. 216. Kalantar-Zadeh K, Horwich TB, Fonarow GC et al. A low rather a high serum LDL cholesterol is associated with increased mortality in hemodialysis patients even after controlling for inflammation. J Am Soc Nephrol 2004; 15:173A-459. 217. Habib AN, Baird BC, Leypoldt JK et al. The association of lipid levels with mortality in patients on chronic peritoneal dialysis. Nephrol Dial Transplant 2006; 21:28812892. 218. Pierides AM, Alvarez-Ude F, Kerr DN. Clofibrate-induced muscle damage in patients with renal failure. Lancet 1975; 2:1279-1282. 219. Harper CR, Jacobsen TA. Managing Dyslipidemia in Chronic Kidney Disease. J Am Coll Cardiol 2008; 51 ; 2375-2384. 220. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta analysis. Kidney Int 2001; 59 : 260-269. 221. de Zeeuw D. Different renal protective effects of atorvastatin and rosuvastatin in diabetic and non-diabetic renal patients with proteinuria. Results of the PLANET trials. 2010 European Renal Association-European Dialysis and Transplant Association Congress; June 27, 2010; Munich, Germany. 222. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353:238-248. 223. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009; 360:1395-1407 224. K/DOQI clinical practice guidelines for managing dyslipidemia in chronic kidney disease Am J Kidney Dis 2003;41(Suppl 3):S1-S237. 225. Douglas PS, Ginsburg GS. The evaluation of chest pain in women. N Engl J Med 1996; 334 : 1311-5. 226. Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA. 1999; 281 : 1291-7. 227. Lee WL, Cheung AM, Cape D, Zinman B. Impact of diabetes on coronary artery disease in women and men: a meta analysis of prospective studies. Diabetes Care 2000; 23 : 962-8. 228. Orchard TJ. The impact of gender and general risk factors on the occurrence of atherosclerotic vascular disease in non-insulin-dependent diabetes mellitus. Ann Med 1996; 28 : 323-33. 229. Laing SP, Swerdlow AJ, Slater SD et al. The British Diabetic Association Cohort Study II: cause specific mortality in patients with insulin treated diabetes. Diabet Med 1999; 16 : 466-71. 230. Huxley R, Barzi F, Woodward M .Excess risk of fatal coronary heart disease associated with diabetes in men and women: meta-analysis of 37 prospective cohort studies. Br Med J 2006; 332 : 73-78. 78

231. Nissen SE, Tuzcu EM, Schoenhagen P et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291 : 10711080. 232. Malaysian Clinical Practice Guidelines for Prevention of CVD in Women, 1ST ed 2008. 233. Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking: a preliminary report from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. JAMA. 1990; 264: 30183024. 234. McGill HC Jr, McMahan CA, Zieske AW et al. Effects of nonlipid risk factors on atherosclerosis in youth with a favorable lipoprotein profile. Circulation. 2001; 103: 15461550. 235. Newman WP III, Freedman DS, Voors AW et al. Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis: the Bogalusa Heart Study. N Engl J Med. 1986; 314: 138144. 236. Mc Crindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo controlled trial. J Pediatr 2003;142:74-80. 237. Berenson GS, Srinivasan SR, Bao W et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults: the Bogalusa Heart Study. N Engl J Med. 1998; 338: 16501656. 238. Freedman DS, Dietz WH, Srinivasan SR, Berenson GS. The relation of overweight to cardiovascular risk factors among children and adolescents: the Bogalusa Heart Study. Pediatrics. 1999; 103 (pt 1): 11751182. 239. American Academy of Pediatrics. National Cholesterol Education Program: report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992; 89: 525584. 240. McCrindle BW, Urbina EM, Dennison BA et al. Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents: A Scientific Statement From the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, With the Council on Cardiovascular Nursing. Circulation 2007;115:1948-1967. 241. Secondary Prevention of Coronary Heart Disease in the Elderly (With Emphasis on Patients >=75 Years of Age): An American Heart Association Scientific Statement From the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac Rehabilitation,and Prevention. Circulation 2002; 105:17351743. 242. Streja D, Streja E. Management of dsyslipidemia in the elderly. In: Hershman J, ed. Endocrinology of Aging. www.endotext.org/aging/aging4/agingframe4.htm Accessed 2nd April, 2010. 243. Anonymous. Coronary Drug Project Research Group. Influence of adherence to treatment and response of cholesterol on mortality in the Coronary Drug Project. N Engl J Med 1980;303: 1038-41. 244. Anonymous. Compliance and adverse event withdrawal: their impact on the West of Scotland Coronary Prevention Study. Eur Heart J 1997;18:1718-24. 245. Chia YC. Review article. Understanding patient management: the need for medication adherence and persistence. Malaysian Family Physician 2008: 3 (1): 1985-2274. Assessed at www.e-mfp.org.my/2008v3n1/index.htm 246. Hu FB, Stampfer MJ, Rimm EB et al. A prospective study of egg consumption and risk of cardiovascular disease in men and women. JAMA 1999; 281 : 1387-1394 247. Scrafford CG, Tran NL, Barraj L, Mink P. Egg consumption and CHD and Stroke mortality: A prospective study of US adults. Public Health 2011; 14 : 261- 270. 79

APPENDIX I: APOLIPOPROTEINS : MAJOR CATEGORIES

MAJOR CLASSES Apo A Apo B Apo C Apo D Apo E Apo H SUBCLASSES/ISOFORMS apo A-I, apo-II, apo A-IV, apo A- V apo B-48, apo B-100 apo C-I, apo C-II, apo C-III, apo C-IV apo E-2, apo E-3, apo E-4

APPENDIX II: RISK FACTORS FOR MI AND STROKE IN THE INTERHEART AND INTERSTROKE STUDIES*
INTERSTOKE (all stroke; 3000 cases, 3000 controls)* 34.6% (30.4-39.1) 18.95 (15.3-23.1) 26.5% (18.8-36.0) INTERHEART (acute myocardial infarction; 15152 cases, 14820 controls)** 17.9% (15.7-20.4) 35.7% (32.5-39.1) 20.1% (15.3-26.0)

Hypertension Smoking Waist-to-hip (abdominal obesity) Diet Diet risk score Fruits and vegetables daily Regular physical activity Diabetes Alcohol intake Psychosocial factors All psychosocial factor Psychosocial stress Depression Cardiac causes Ratio of apolipoproteins B to A1
*

18.8% (11.2-29.7) .. 28.5% (14.5-48.5) 5.0% (2.6-9.5) 3.8% (0.9-14.4) .. 4.6% (2.1-9.6) 5.2% (2.7-9.8) 6.7% (4.8-9.2) 24.9% (15.7-37.1)

13.7% (9.9-18.6) 12.2% (5.5-25.1) 9.9% (8.5-11.5) 6.7% (2.0-20.2) 32.5% (25.1-40.8) .. .. .. 49.2% (43.8-54.5)

Yusuf S, Hawken S, Ounpuu S, on behalf of the INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364:937-952. ** O Donnel MJ, Xavier D, Liu L et al on behalf of the INTERSTROKE Investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010;376 : 112-123

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APPENDIX III: BODY MASS INDEX Calculation of body mass index (BMI) is one way of determining the ideal weight for an individual. BMI is the relationship of body weight to height. Increased BMI is associated with increased mortality and morbidity. The predictive value of BMI is enhanced by taking the waist circumference into consideration as well. Body Mass Index = (Weight in kg) (Height in m)2
CLASSIFICATION OF WEIGHT BY BMI CLASSIFICATION Underweight Normal range Overweight Pre-Obese Obese I Obese II Obese III BMI (Kg / m2) < 18.5 18.5-22.9 > 23.0 23.0-27.4 27.5-34.9 35.0-39.9 > 40.0 Increased Moderate Severe Very Severe Risk of co-morbidities Low (but increased risk of other clinical problems) Average

(Adapted from Malaysian Clinical Practice Guidelines on the Management of Obesity 2003. Assessed at www.acadmed.org.my)

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APPENDIX IV: COMPARISON OF GLOBAL CORONARY AND CARDIOVASCULAR RISK SCORES94

PROCAM (Men) 5,389 35 to 65; Mean: 47 10 10.2 10.8 Mean: 52 Mean: 63 >45; >50; 24,558 10,724 Reynolds (Women) Reynolds (Men)

Framingham

SCORE

Sample size

5,345

205,178

Age (y)

30 to 74;

19 to 80;

Mean: 49

Mean : 46

Mean follow-up ,y

12

13

Risk factors considered

82

Age, sex, total cholesterol, HDL cholesterol, smoking, systolic blood pressure, antihypertensive medications Fatal/nonfatal MI or sudden cardiac death (CHD and CVD combined) MI, ischemic stroke, coronary revascularization, cardiovascular death (CHD and CVD combined) http://www. reynoldsriskscore.org/

Age, sex, total-HDL cholesterol ratio, smoking, systolic blood pressure

Age, LDL cholesterol, HDL cholesterol, smoking, systolic blood pressure, family history, diabetes, triglycerides

Age, HbA1C (with diabetes), smoking, systolic blood pressure, total cholesterol, HDL cholesterol, hsCRP, parental history of MI at <60 y of age

Age, systolic blood pressure, total cholesterol, HDL cholesterol, smoking, hsCRP, parental history of MI at <60 y of age

Endpoints

CHD (MI and CHD death)

Fatal CHD

MI, stroke, coronary revascularization, cardiovascular death (CHD and CVD combined) http://www. reynoldsriskscore.org/

URLs for risk calculators

http://hp2010. nhlbihin.net/ atpiii/calculator. asp?usertype=prof

http://www. heartscore. org/pages/ welcome.aspx

http://www.chdtaskforce.com/ coronary_risk_ assessment.html

APPENDIX V: LIPID LOWERING DIET

PRINCIPLE Decrease dietary cholesterol AMOUNT < 200 mg / day COMMENT Reduce intake of organ meat (offal) eg liver, heart, brains, kidney. Limit to 3 oz once fortnightly. A small amount of prawn / crab / oysters / cockles may be taken once or twice a week if desired. Modify cooking methods grill /steam / boil / bake / microwave to reduce use of oils and fats. Avoid oily / fatty food eg deep fat fried foods. Minimize the use of following butter, hard margarine, full cream milk (including condensed milk) cream, high fat cheese, fatty meats, bacon and sausages, coconut oil, santan, products containing hydrogenated oil and some non dairy creamers. Choices may include the following: olive oil, sunflower oil, corn oil, palm oil, soybean oil, peanut oil and polyunsaturated margarine.

Decrease total fat/oil

< 30% of total energy

Types: a) saturated fat

7-10% (not more than 10% of total calorie intake)

b)mononunsaturated and polyunsaturated oils/margarine Increase intake of complex carbohydrate / grains and fiber

Not more than 6 teaspoonsfuls per day to be used in cooking or as a spread 20-25 gm fiber / day. Include 2-3 servings of fruit and 3-4 servings of vegetables and 5 -7 servings per day of grains 2-3 servings per day

Sources of complex carbohydrates/grains: rice, bread, pasta, noodles and tuber Sources of fiber: fruits, vegetables, pulses, legumes and unrefined cereals.

Choose food high in protein but low in saturated fat

Choices may include: chicken without skin, fish, Legumes and pulse (tofu, dhal, green peas and beans), egg whites, lean meat, skim milk and milk products (low fat milk may be used but some low fat milk may contain up to 50% of its original fat).

Consuming an egg a day does not substantially increase CVD risk.246,247 The method of cooking the egg is important. *Adapted and modified from Lichtenstein AH, Appel LJ, Brands M et al. Diet and Lifestyle Recommendations Revision 2006. A Scientific Statement From the American Heart Association Nutrition Committee Circulation 2006;114:82-96.

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APPENDIX VI: CONVERSION TABLE

(<1.14mmol/L) (<1.7mmol/L)

(1.7-2.3mmol/L)

(2.3-5.7mmol/L)

(5.7mmol/L)

*Adapted from Miller M, Stone NJ, Ballantyne C et al Triglycerides and Cardiovascular Disease: A Scientific Statement from the American Heart Association. Circulation 2011; 123: 2292-2333

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ACKNOWLEDGMENTS The committee of this guideline would like to express their gratitude and appreciation to the following for their contribution: Technical Advisory Committee, Clinical Practice Guidelines, Ministry of Health for their valuable input and feedback Panel of external reviewers who reviewed the draft DISCLOSURE STATEMENT The panel members have no potential conflict of interest to disclose. SOURCES OF FUNDING This CPG was made possible by an unrestricted educational grant to NHAM from Pfizer (M) Sdn Bhd. There was total editorial independence and the funding body did not influence the content of this guideline.

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