ESC/EAS Guidelines on the management of dyslipidaemias

Transcription

1 EuroHeartCare Glasgow March Management of patients with dyslipidaemia: latest guidelines with a focus on ESC/EAS Guidelines on the management of dyslipidaemias Ian Graham Trinity College Dublin, Ireland Chair JTF Guidelines on CVD Prevention Member JTF on CVD Prevention Member Task Force ESC/EAS Guidelines for the management of dyslipidaemias

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3 Dyslipidaemia guidelines. EAS/ESC Joint Lipid Guidelines - my main focus. JTF Joint European Guidelines on the prevention of CVD in clinical practice - complementary. Canadian Cardiac Society Lipid update, published. U.S. ATP- where, oh where, are they?

4 The European Guidelines on Cardiovascular Disease Prevention in Clinical Practice Chairperson Joep Perk Linneaus University Institute for Health and Caring Sciences Campus Kalmar, Sweden European Heart Journal doi:.9/eurheartj/ehs9

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6 JTF: The Deal and developments The deal: the partners will help us to ensure compatibility between the Joint Guidelines and those of their specialist bodies Generally successful with regards to lipids: essentially similar categories of risk and targets New developments since Lipid Guidelines include: Introduced the GRADE system of grading evidence High and low risk countries re-defined Concept of risk age introduced

7 Canadian Society of Cardiology lipid update Can J Cardiol :9:- Uses the GRADE system to assess evidence, like JTF LDL remains the primary target; essentially similar to Europe for high risk persons- LDL=/<, or % reduction Increased emphasis on high risk people, and on health behaviour Screen: All men >, all women >, everyone if other risk factors levels of risk (now in Europe) Also uses cardiovascular age, as JTF

8 ESC/EAS Guidelines for the Management of Dyslipidaemias European Heart Journal & Journal of Atherosclerosis

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10 European Heart Journal doi:.9/eurheartj/ehr8 ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Developed with the special contribution of: European Association for Cardiovascular Prevention & Rehabilitation Authors/Task Force Members: Željko Reiner* (ESC Chairperson) (Croatia) Alberico L. Catapano* (EAS Chairperson)* (Italy), Guy De Backer (Belgium), Ian Graham (Ireland), Marja-Riitta Taskinen (Finland), Olov Wiklund (Sweden), Stefan Agewall (Norway), Eduardo Alegria (Spain), M. John Chapman (France), Paul Durrington (UK), Serap Erdine (Turkey), Julian Halcox (UK), Richard Hobbs (UK), John Kjekshus (Norway), Pasquale Perrone Filardi (Italy), Gabriele Riccardi (Italy), Robert F. Storey (UK), David Wood (UK). European Heart Journal (), 9 88

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12 Guidelines on Prevention SCORE,HeartScore Evidence based reviews Research Guidelines 9,98,,, EuroAspire SURF Audit Implementation PIC

13 ESC/EAS Dyslipidaemia guidelines. Why and for whom?. Grading evidence. Total risk- why and how?. HDL and risk. Categories of risk. Intervention thresholds related to risk. Which lipids to measure and when 8. Secondary hyperlipidaemia 9. TARGETS. Diet and lifestyle. Drug treatment. Women. Older persons. Additional information. Implementation

14 Why new guidelines? The Joint European Guidelines on CVD Prevention already cover different CVD risk factors, including dyslipidaemias. But there was a demand for more detail on lipid management as well as hypertension and diabetes- hence separate Guidelines- BUT The deal is that this is a partnership and that the specialist Guidelines will, as far as possible, compatible with the joint Guidelines

15 Dyslipidaemia guidelines - for whom did we write them? Primarily for cardiologists and GPs But also for internists, diabetologists and allied health care professionals, including nurse specialists

16 Dyslipidaemia guidelines what should they look like? Information overload! Pub med:,9 Guidelines, of which 8, are on CVD and, on lipids! Simple, user-friendly guidelines with most recent data and details concerning lipids Clear and explicit recommendations Need for compatibility with forthcoming guidelines- th Joint TF on CVD prevention(), diabetes () and hypertension ()

17 Dyslipidaemia guidelines what should they look like? Prevention and management of dyslipidaemias should always be considered within the broader framework of CVD prevention and therefore the assessment of total CVD risk is necessary Target values are not the only aspect! Evidence based upon independent research (credible, trustworthy) levels of evidence and classes of recommendations

18 Grading the evidence The ESC system appropriately gives the highest grading to randomized control trials and meta-analyses- BUT This will always give a higher grading to drugs compared to lifestyle measures- therefore JTF and CCS also use the GRADE system (do it/don t do it) Different types of evidence are needed when considering, for example, lifestyle measures, causality, screening and diagnostic techniques as opposed to therapeutic interventions The ESC grading was eventually accepted and implemented throughout the lipid guidelines

19 Classes of recommendations Classes of recommendations Classe I Class II Class IIa Class III Class IIb Definition Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective. Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure. Weight of evidence/opinion is in favour of usefulness/efficacy. Usefulness/efficacy is less well established by evidence/opinion. Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. Suggested wording to use Is recommmended/ is indicated. Should be considered. May be considered. Is not recommended. European Heart Journal (), 9 88

20 Levels of evidence Level of Evidence A Data derived from multiple randomized clinical trials or meta-analyses. Level of Evidence B Data derived from a single randomized clinical trial or large non-randomized studies. Level of Evidence C Consensus of opinion of the experts and/ or smal studies, retrospective studies, registries. European Heart Journal (), 9 88

21 The importance of total risk assessment Atherosclerosis is usually the product of several interacting risk factors- for example- WHO gets the statin? year old woman, cholesterol 8 but no other risk factors, or a year old man, cholesterol but smoker with hypertension Total risk assessment should aid logical management

22 Impact of combinations of risk factors on year risk of CVD death- who gets the statin? SEX AGE CHOL BP SMOKE RISK % F 8 NO? F YES? M NO? M 8 YES?

23 Impact of combinations of risk factors on year risk of CVD death- who gets the statin? SEX AGE CHOL BP SMOKE RISK % F 8 NO F YES M NO 8 M 8 YES

24 Risk assessment The lipid guidelines continue to recommend the use of the SCORE charts New information on HDL cholesterol has been added, with new HDL charts HDL is an independent predictor of risk at all risk levels and at all levels of cholesterol. Its use usefully re-classifies people close to the threshold of intervention This is better seen using the new version of HeartScore, the interactive electronic version of SCORE

25 SCORE chart: year risk of fatal cardiovascular disease (CVD) in populations at high CVD risk Systolic blood pressure (mmhg) Women Men Non-smoker Smoker Age Non-smoker Smoker SCORE % and over %-% %-9% %-% % % < % -year risk of fatal CVD in populations at High CVD risk Cholesterol (mmol/l) 8 8 mg/dl European Heart Journal (), 9 88

26 European Heart Journal (), 9 88 SCORE chart: year risk of fatal cardiovascular disease (CVD) in populations at low CVD risk % and over %-% %-9% %-% % % < % SCORE -year risk of fatal CVD in populations at Low CVD risk Non-smoker Smoker Women Systolic blood pressure (mmhg) Cholesterol (mmol/l) Age Non-smoker Smoker Men mg/dl

27 CVD Mortality Rate Relative Risks Compared to the lowest total Chol Quartile and the highest HDL quartile Relative Risk HDL..... HDL HDL HDL TOT TOT Total Cholesterol TOT TOT HDL

28 HDL =.8mmol/l HDL =.mmol/l HDL =.mmol/l HDL =.8mmol/l

29 Risk function without high-density lipoprotein-cholesterol (HDL-C) for men in populations at high cardiovascular disease risk Non-smoker Smoker Without HDL HDL.8 HDL. HDL. HDL Age Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Systolic blood pressure (mmhg) Without HDL HDL.8 HDL. HDL. HDL Total Cholesterol (mmol/l) European Heart Journal (), 9 88

30 Risk function without high-density lipoprotein-cholesterol (HDL-C) for women in populations at high cardiovascular disease risk Non-smoker Smoker Without HDL HDL.8 HDL. HDL. HDL Age Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Without HDL HDL.8 HDL. HDL. HDL Systolic blood pressure (mmhg) Total Cholesterol (mmol/l) European Heart Journal (), 9 88

31 Relative risk chart This chart may be used to show younger people at low absolute risk that, relative to others in their age group, their risk may be many times higher than necessary. This may help to motivate decisions about avoidance of smoking, healthy nutrition and exercise, as well as flagging those who may become candidates for medication. Non-smoker Smoker 8 8 Systolic blood pressure (mmhg) Cholesterol (mmol/l) Please note that this chart shows RELATIVE not absolute risk. The risks are RELATIVE to in the bottom left. Thus a person in the top right hand box has a risk that is times higher than a person in the bottom left. European Heart Journal (), 9 88

32 Using the risk charts Detailed instructions and lists of qualifiers are given in the text of the Guidelines and in the reserve slides in this set Risks will be overestimated if mortality has declined and underestimated if it has increased. Solutions: Recalibrate or use appropriate local cohort data such as NORRISK Low and high risk countries have been re-defined in JTF

33 NEW: categories of risk. VERY HIGH RISK: Documented CVD, Diabetes type or type with target organ damage, CKD with GFR<, SCORE % or more. HIGH RISK: Markedly elevated single risk factors, SCORE -%. MODERATE RISK: SCORE -%, modified by family history, abdominal obesity, activity and other risk factors. LOW RISK: SCORE <%

34 Priorities: JTF: categories of risk: Very high Risk: High Risk: Moderate Risk: Low Risk: Subjects with any of the following: Documented CVD Diabetes ( or) with one or more RFs &/or target organ damage Patients with moderate to severe CKD (GFR <ml/min/.m) SCORE =/>% Subjects with : Markedly elevated single risk factors such as: familial dyslipidaemias severe hypertension. SCORE of =/>% and <% Diabetes ( or ) without CV RFs or target organ damage Mod CKD (GFR -9) SCORE is =/> and <% at years, further modulated by: family history of premature CAD, abdominal obesity, physical activity pattern SCORE less than % and free of qualifiers HDL-C, TG, hscrp social class

35 New: Intervention thresholds and strategies are defined by baseline risk and by LDL cholesterol level

36 Intervention strategies as a function of total CV risk and LDL-C level Total CV risk (SCORE) % < mg/dl <.8 mmol/l to < mg/dl.8 to <. mmol/l LDL-C levels to < mg/dl. to <. mmol/l to < 9 mg/dl. to <.9 mmol/l < No lipid intervention No lipid intervention Lifestyle intervention Lifestyle intervention > 9 mg/dl >.9 mmol/l Lifestyle intervention, consider drug if uncontrolled Class/Level I/C I/C I/C I/C IIa/A to < Lifestyle intervention Lifestyle intervention Lifestyle intervention, consider drug if uncontrolled Lifestyle intervention, consider drug if uncontrolled Lifestyle intervention, consider drug if uncontrolled Class/Level I/C I/C IIa/A IIa/A I/A > to <, or high risk Lifestyle intervention consider drug* Lifestyle intervention consider drug* Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention Class/Level IIa/A IIa/A IIa/A I/A I/A or very high risk Lifestyle intervention consider drug* Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention Lifestyle intervention and immediate drug intervention Class/Level IIa/A IIa/A I/A I/A I/A European Heart Journal (), 9 88

37 Which lipid measure when? Evidence-based guidance is given as to when to measure lipids, and which to measure- total cholesterol, LDL-C, TG, HDL-C, non-hdl-c, Apo-B, Lp(a), apo B/apo Aratio, non-hdl-c/hdl-c ratio Total cholesterol is used in the SCORE charts, but otherwise the primary measure for risk stratification, management decisions and treatment targets is LDL-C

38 Don t be caught out by secondary hypercholesterolaemia! Hypothyroidism Nephrotic syndrome Pregnancy Cushing syndrome Anorexia nervosa Immunosuppressant agents Corticosteroids European Heart Journal (), 9 88

39 Recommendations for treatment targets for LDL-C Recommendations Class Level In patients at VERY HIGH CV risk (established CVD, type diabetes, type diabetes with target organ damage, moderate to severe CKD or a SCORE level %) the LDL-C goal is <.8 mmol/l (less than ~ mg/dl) and/or % LDL-C reduction when target level cannot be reached. I A In patients at HIGH CV risk (markedly elevated single risk factors, a SCORE level to < %) an LDL-C goal <. mmol/l (less than ~ mg/dl) should be considered. IIa A In subjects at MODERATE risk (SCORE level > to %) an LDL-C goal <. mmol/l (less than ~ mg/dl) should be considered. IIa C European Heart Journal (), 9 88

40 Targets JTF Smoking No exposure to tobacco in any form Diet Healthy diet- low in saturated fat with a focus on wholegrain products, vegetables, fruit and fish Physical Activity. to hours moderately vigorous physical activity per week or - minutes most days Body weight Blood pressure BP </9 BMI -. Waist circumference <9 cm (men) or <8 cm (women) Lipids Very high risk: LDL<.8mmol/l or >% reduction High risk: LD <.mmo/l Low to moderate risk: LDL<mmol/l HDL cholesterol: No target, but >.mmol/l in men and >.mmol/l in women indicates lower risk Triglycerides: No target but <.mmol/l indicates lower risk and higher levels indicate a need to look for other risk factors Diabetes HbAC: <%, BP< /8

41 Dyslipidaemia guidelines- Summary. EAS/ESC Joint Lipid Guidelines - my main focus. JTF Joint European Guidelines on the prevention of CVD in clinical practice - complementary. Canadian Cardiac Society Lipid update, published. U.S. ATP- where, oh where, are they?

42 ESC/EAS Dyslipidaemia guidelines: Summary. Why and for whom?. Grading evidence. Total risk- why and how?. HDL and risk. Categories of risk. Intervention thresholds related to risk. Which lipids to measure and when 8. Secondary hyperlipidaemia 9. TARGETS. Diet and lifestyle. Drug treatment. Women. Older persons. Additional information. WILL THEY IMPACT ON MANAGEMENT?. Implementation

43 Thank you

44 Reserve slides

45 Risk levels - mortality or morbidity? Clinicians like systems that estimate risk of total (fatal +non-fatal) CVD events- BUT This is less simple than generally thought- the definitions of non-fatal events vary widely and are affected by changes in diagnostic tests and ascertainment rates The SCORE risk of CVD mortality of % corresponds to % for total hard (Monica defined) F+NF CVD events- multiply by

46 Recommendations for lipid analyses as treatment target in the prevention of CVD Recommendations Class Level LDL-C is recommended as target for treatment. I A TC should be considered as treatment target if other analyses are not available. IIa A TG should be analysed during the treatment of dyslipidaemias with high TG levels. Non-HDL-C should be considered as a secondary target in combined hyperlipidaemias, diabetes, the MetS or CKD. IIa IIa B B Apo B should be considered as a secondary treatment target. IIa B HDL-C is not recommended as a target for treatment. III C The ratios apo B/apo A and non-hld-c/hdl-c are not recommended as targets for treatment. III C European Heart Journal (), 9 88

47 Impact of specific lifestyle changes on lipid levels () Lifestyle interventions to reduce TC and LDL-C levels Magnitude of the effect Level of evidence Reduce dietary saturated fat +++ A Reduce dietary trans fat +++ A Increase dietary fibre ++ A Reduce dietary cholesterol ++ B Utilize functional foods enriched with phytosterols +++ A Reduce excessive body weight + B Utilise soy protein products + B Increase habitual physical activity + A Utilize red yeast rice supplements + B Utilize polycosanol supplements - B European Heart Journal (), 9 88

48 Impact of specific lifestyle changes on lipid levels () Lifestyle interventions to reduce TG levels Magnitude of the effect Level of evidence Reduce excessive body weight +++ A Reduce alcohol intake +++ A Reduce intake of mono- and disaccharides ++ A Increase habitual physical activity ++ A Reduce total amount of dietary carbohydrate ++ A Utilize supplements of n- polyunsaturated fat ++ A Replace saturated fat with mono-or polyunsaturated fat + B European Heart Journal (), 9 88

49 Impact of specific lifestyle changes on lipid levels () Lifestyle interventions to increase HDL-C levels Magnitude of the effect Level of evidence Reduce dietary trans fat +++ A Increase habitual physical activity +++ A Reduce excessive body weight ++ A Reduce dietary carbohydrates and replace them with unsaturated fat ++ A Use alcohol with moderation ++ B Among carbohydrate-rich foods prefer those with low glycaemic index and high fibre content + C Quit smoking + B Reduce intake of mono- and disaccharides + C European Heart Journal (), 9 88

50 Dietary recommendations to lower TC and LDL-C To be preferred To be used with moderation Cereals Whole grains Refined bread, rice and pasta, biscuits, corn flakes Vegetables Legumes Raw and cooked vegetables All (including soy and soy protein) Fruit Fresh and frozen fruit Dried fruit, jelly, jam, canned fruit, sorbets, popsicles To be chosen occasionnaly in limited amounts Pastries, muffins, pies, croissants Vegetables prepared in butter or cream Sweets and sweeteners Non-caloric sweeteners Sucrose, honey, fructose, glucose, chocolate, candies Cake, ice creams Meat and fish Lean and oil fish, poultry without skin Lean cuts of beef, lamb, pork or veal, seafood, shellfish Sausages, salami, bacon, spare ribs, hot dogs, organ meats Dairy food and eggs Skimmed milk and yogurt, egg white Low fat milk, low fat cheese and other milk products Regular cheese, cream, egg yolk, whole milk and yoghurt Cooking fat and dressings Vinegar, ketchup, mustard, fat-free dressings Vegetable oils, soft margarines, salad dressing, mayonnaise Butter, solid margarines, trans fats, palm and coconut oils; lard, bacon fat, dressings made with egg yolks Nuts/seeds All Coconut Cooking procedures Grilling, boiling, steaming Stir-frying, roasting Frying European Heart Journal (), 9 88

51 Summary of lifestyle measures and healthy food choices for managing total cardiovascular risk () Dietary recommendations should always take into account local food habits; however, interest in healthy food choices from other cultures should be promoted. A wide variety of foods should be eaten. Energy intake should be adjusted to prevent overweight and obesity. Consumption of fruit, vegetables, legumes, nuts, wholegrain cereals and bread, fish (especially oily) should be encouraged. Saturated fate should be replaced with the above foods and with monounsaturated and polyunsaturated fats from vegetable sources, in order to reduce energy intake from total fat to < % of energy, saturated fat to < % of total energy, trans fats to < % of total energy, and dietary cholesterol to < mg/day. European Heart Journal (), 9 88

52 Summary of lifestyle measures and healthy food choices for managing total cardiovascular risk () Salt intake should be reduced below g/day by avoiding table salt and limiting salt in cooking, and by choosing fresh or frozen unsalted foods; many processed and convenience foods, including bread, are high in salt. For those who drink alcoholic beverages, moderation should be advised (< - g/day for women and < - g/day for men) and patients with hupertriglyceridaemia (HTG) should abstain. The intake of beverages and foods with added sugars, particularly soft drinks, should be limited, particularly for patients with HTG. Physical activity should be encouraged, aiming at regular physical exercice for at least minutes/day every day. Use and exposure to tobacco products should be avoided. European Heart Journal (), 9 88

53 Recommendations for the pharmacological treatment of hypercholesterolaemia Recommendations Class Level Prescribe statin up to the highest recommended dose, or highest tolerable dose to reach the target level. I A In the case of statin intolerance, bile acid sequestrants or nicotinic acid should be considered. A cholesterol absorption inhibitor, alone or in combination with bile acid sequestrants or nicotinic acid, may also be considered in the case of statin intolerance. If target level is not reached, statin combination with a cholesterol absorption inhibitor or bile acid sequestrant or nicotinic acid may be considered. IIa IIb IIb B C C European Heart Journal (), 9 88

54 LDL % A systematic review and meta-analysis on the therapeutic equivalence of statins A A A A8 F F F8 L L L L8 P P P S S S S8 R R R R P P P ATOR FLUVA LOVA PRAVA SIMVA ROSU PITA Weng TC, et al. J Clin Pharm Ther. ;;9- Mukhtar RY, et al. Int J Clin Pract. ;9():9- European Heart Journal (), 9 88

55 Management of dyslipidaemia in women Statin treatment is recommended for primary prevention of CAD in high risk women. Statins are recommended for secondary prevention in women with the same indications and targets as in men. Lipid-lowering drugs should not be given when pregnancy is planned, during pregnancy or during the breast feeding period. European Heart Journal (), 9 88

56 Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Peturrson H et al, J Eval Clin Practice HUNT study;8:9-8 Inverse relation between ccholesterol and total mortality in women

57 Recommendations for treatment of dyslipidaemia in the elderly Recommendations Class Level Treatment with statins is recommended for elderly patients with established CVD in the same way as for younger patients. I B Since elderly people often have comorbidities and have altered pharmacokinetics, it is recommended to start lipid-lowering medication at a low dose and then titrate with caution to achieve target lipid levels which are the same as in the younger subjects. I C Statin therapy may be considered in elderly subjects free of CVD, particularly in the presence of at least one other CV risk factor besides age. IIb B European Heart Journal (), 9 88

58 Summary of dyslipidaemia in MetS and in type diabetes Dyslipidaemia in MetS represents a cluster of lipid and lipoprotein abnormalities including elevation of both fasting and postprandial TGs, apo B, and small dense LDL, and low HDL-C and apo A. Non-HDL-C or apo B are good surrogate markers of TRLs and remnants and are a secondary objective of therapy. Non-HDL-C <. mmol/l (less than ~ mg/dl) or apo B < mg/dl is desirable. Increased waist circumference and elevation of TGs seems to be a simple tool to capture the high risk subjects with MetS. Atherogenic dyslipidaemia is one of the major risk factors for CVD in people with type diabetes. European Heart Journal (), 9 88

59 Recommendations for treatment of dyslipidaemia in diabetes Recommendations Class Level In all patients with type diabetes and in the presence of microalbuminuria and renal disease, LDL-C lowering (at least %) with statins as the first choice (eventually drug combination) is recommended irrespective of the basal LDL-C concentration. I C In patients with type diabetes and CVD or CKD, and in those without CVD who are over the age of years with one or more other CVD risk factors or markers of target organ damage, the recommended goal for LDL-C is <.8 mmol/l (less than ~ mg/dl) and the secondary goal for non-hdl-c is <. mmol/l ( mg/dl) and for apo B is < 8 mg/dl. I B In all people with type diabetes LDL-C <. mmol/l (less than ~ mg/dl) is the primary target. Non-HDL-C <. mmol/l ( mg/dl) and apo B < mg/dl are the secondary targets. I B European Heart Journal (), 9 88

60 Hints to help adherence to lifestyle changes Develop a good alliance with the patient. Make sure that the patient understands how lifestyles affect cardiovascular disease and use this to gain commitment to the change in behaviour. Explore potential barriers to the change. Design with the patient a lifestyle change plan that is realistic and encouraging. Reinforce the patient s efforts to change. Involve other experts wherever needed and possible. Arrange a schedule of follow-up visits. European Heart Journal (), 9 88

61 Tips to help compliance with multiple drug therapies Simplify the dosing regimen if possible by reducing daily doses and concomitant medications. Choose cheaper alternatives. Provide clear written and oral instructions. Undertake a dialogue with the patient regarding adherence. Tailor the regimen to the patient s lifestyle and needs. Involve the patient as partner in the treatment. Use behavioural strategies (reminder systems, cues, selfmonitoring, (feedback, reinforcement). European Heart Journal (), 9 88

62 OK, but- Will the lipid guidelines impact on optimal CV risk management? The relevance of total CVD risk assessment is affirmed More detail on the impact of HDL cholesterol on risk Refinement of risk categories to levels Management stratified by total risk and LDLC level More aggressive LDLC targets for very high risk subjects More detail on women and older persons Hopefully yes, BUT-

63 Guidelines are irrelevant unless used Guidelines alone are good for the vanity of the authors and bad for rain forests; they are a waste of time without a defined implementation strategy (Ian Graham)

64 Dyslipidaemia Guidelines- additional information. Causes of high triglycerides and treatment. Drug treatment of low HDL-C. Drug combinations for mixed hyperlipidaemia. Dx and management of familial hyperlipidaemia. Frequency of monitoring lipids and enzymes. Valvular disease. A-I immune disease 8. CKD 9. PAD and stroke. HIV. Adherence to lifestyle advice and drug treatments

65 How to use the risk estimation charts The low risk charts should be considered for use in Belgium, France, Greece, Italy, Luxembourg, Spain, Switzerland and Portugal and also in countries which have recently experienced a substantial lowering of the CV mortality rates (see (CVD statistics) for recent mortality data). The high risk charts should be considered in all other countries of Europe. NOTE that several countries have undertaken national recalibrations to allow for time trends in mortality and risk factor distributions. Such charts are likely to represent current risk levels better. To estimate a person s year risk of CVD death, find the table for their gender, smoking status, and age. Within the table find the cell nearest to the person s blood pressure and TC. Risk estimates will need to be adjusted upwards as the person approaches the next age category. Low risk persons should be offered advice to maintain their low risk status. While no threshold is universally applicable, the intensity of advice should increase with increasing risk. Relative risks may be unexpectedly high in young persons, even if absolute risk levels are low. The relative risk chart (figure page ) may be helpful in identifying and counselling such persons. The charts may be used to give some indication of the effects of reducing risk factors, given that there will be a time lag before risk reduces and that the results of randomized controlled trials in general give better estimates of benefits. Those who stop smoking in general halve their risk. The presence of additional risk factors increases the risk (such as low HDL- C, high TG). European Heart Journal (), 9 88

66 Qualifiers The charts can assist in risk assessment and management but must be interpreted in the light of the clinician s knowledge and experience and of the patient s pre-test likelihood of CVD. Risk will be overestimated in countries with a falling CVD mortality, and underestimated in countries in which mortality is increasing. At any given age, risk estimates are lower for women than for men. This may be misleading since, eventually, at least as many women as men die of CVD. Inspection of the charts indicates that risk is merely deferred in women, with a -year-old woman resembling a -year-old man in terms of risk. European Heart Journal (), 9 88

67 Risk will also be higher than indicated in the charts in: Socially deprived individuals; deprivation drives many other risk factors. Sedentary subjects and those with central obesity; these characteristics determine many of the other aspects of risk listed below. Individuals with diabetes: re-analysis of the SCORE database indicates that those with known diabetes are at greatly increased risk; five times higher in women and three times higher in men. Individuals with low HDL-C or apolipoprotein A (apo A), increased TG, fibrinogen, homocysteine, apolipoprotein B (apo B), and lipoprotein(a) [Lp(a)] levels, familial hypercholesterolaemia (FH), or increased hs-crp; these factors indicate a higher level of risk in both genders, all age groups and at all levels of risk. As mentioned above, supplementary material (see Addendum I) illustrates the additional impact of HDL-C on risk estimation. Asymptomatic individuals with preclinical evidence of atherosclerosis, for example, the presence of plaques or increased carotid intima-media thickness (CIMT) on carotid ultrasonography. Those with impaired renal function. Those with a family history of premature CVD, which is considered to increase the risk by.-fold in women and by.-fold in men. Conversely, risk may be lower than indicated in those with very high HDL-C levels or a family history of longevity. European Heart Journal (), 9 88

68 Recommendations for lipid profiling in order to assess total CV risk Condition Class Level Lipid profiling is indicated in subjects with: Type diabetes mellitus I C Established CVD I C Hypertension I C Smoking I C BMI kg/m or waist circumference > 9 cm (9 cm c ) for men, > 8 cm for women I C Family history of premature CVD I C Chronic inflammatory disease I C Chronic kidney disease I C Family history of familial dyslipidaemia I C Lipid profiling may be considered in men > and women > years of age. IIb C European Heart Journal (), 9 88

69 Recommendations for lipid analyses for screening for CVD risk Recommendations Class Level TC is recommended to be used for the estimation of total CV risk by means of the SCORE system. LDL-C is recommended to be used as the primary lipid analysis for screening and risk estimation. I I C C TG adds information on risk and is indicated for risk estimation. I C HDL-C is a strong risk factor and is recommended to be used for risk estimation. I C Non-HDL-C should be considered as an alternative risk marker, especially in combined hyperlipidaemias, diabetes, the MetS or CKD. Lp(a) should be recommended in selected cases at high risk and in subjects with a family history of premature CVD. Apo B should be considered as an alternative risk marker, especially in combined hyperlipidaemias, diabetes, the MetS or CKD. The ratio apo B/apo A combines the risk information of apo B and apo A and may be recommended as an alternative analysis for risk screening. The ration non-hdl-c/hdl-c may be recommended as an alternative analysis for risk screening. IIa IIa IIa IIb IIb C C C C C European Heart Journal (), 9 88

70 Recommendations for lipid analyses for characterization of dyslipidaemias before treatment Recommendations Class Level LDL-C is recommended to be used as the primary lipid analysis. I C TG adds information to risk and is indicated for diagnosis and choise of treatment. I C HDL-C is recommended to be analysed before initiation of treatment. I C Non-HDL-C should be recommended for further characterization of combined hyperlipidaemias and dyslipidaemia in diabetes, the MetS or CKD. Apo B should be recommended for further characterization of combined hyperlipidaemias and dyslipidaemia in diabetes, the MetS or CKD. Lp(a) should be recommended in selected cases at high risk and in subjects with a family history of premature CVD. TC may be considered but is usually not enough for the characterization of dyslipidaemia before initiation of treatment. IIa IIa IIa IIb C C C C European Heart Journal (), 9 88

71 Percentage reduction of LDL-C requested to achieve goals as a function of the starting value STARTING LDL-C % REDUCTION TO REACH LDL-C mmol/l ~ mg/dl <.8 mmol/l (~ mg/dl) <. mmol/ (~ mg/dl) < mmol/l (~ mg/dl) >. > > > > <..9 9 <.8. 9 < European Heart Journal (), 9 88

72 Possible causes of HTG () Genetic predisposition Obesity Type diabetes Alcohol consumption Diet high in simple carbohydrates Renal disease Hypothyroidism Pregnancy (physiological TG concentrations double during the third trimester) Autoimmune disorders, such as paraproteinemia or SLE European Heart Journal (), 9 88

73 Possible causes of HTG () Multiple medications, including: Cortisosteroids, Oestrogens, especially those taken orally, Tamoxifen, Antihypertensives: e.g. β-adrenergic blocking agents (except carvedilol), thiazides, Isotretinoin, Bile acid-binding resins, Ciclosporin, Antiretroviral regimen (protease inhibitors), Psychotropic medications: phenothiazine, second-generation antipsychotics. European Heart Journal (), 9 88

74 Recommendations for drug treatment of HTG Recommendations Class Level In particular high risk patients, lowering of HTG by using the following drugs: is recommended: fibrates should be considered: nicotinic acid nicotinic acid + laropiprant IIa C n- fatty acids IIa B statin + nicotinic acid IIa A statin + fibrate IIa C may be considered: combinations with n- fatty acids I IIa IIb B B B European Heart Journal (), 9 88

75 Recommendations if drug treatment of low HDL-C is considered Recommendations Class Level Nicotinic acid is currently the most efficient drug to raise HDL-C and should be considered. IIa A Statins and fibrates raise HDL-C with similar magnitude and these drugs may be considered. The efficacy of fibrates to increase HDL-C may be attenuated in people with type diabetes. IIb IIb B B European Heart Journal (), 9 88

76 Definition of central obesity Waist circumference Caucasians (Europids) South Asians, Chinese, Japanese Ethnic south and Central Americans Sub-Saharan Africans Eastern Mediterranean and Middle East (Arabic) populations Men 9 cm; women 8 cm Men 9 cm; women 8 cm Use South Asian recommendations until more specific data are available Use European data until more specific data are available Use European data until more specific data are available European Heart Journal (), 9 88

77 Summary of the efficacy of drug combinations for the management of mixed dyslipidaemias In combined dyslipidaemia an increase of HDL-C and a decrease of TG, on top of the LDL-C reduction that can be achieved with a statin, may be considered. Therefore a combination of statin with nicotinic acid can be considered, but the adverse effect of flushing may affect compliance. A combination of statins with fibrates can also be considered while monitoring for myopathy, but the combination with gemfibrozil should be avoided. If TG are not controlled by statins or fibrates, prescription of n- fatty acids may be considered to decrease TG further, and these combinations are safe and well tolerated. European Heart Journal (), 9 88

78 Genetic disorders of lipoprotein metabolism Disorder Prevalence Gene(s) Effect on lipoproteins HeFH I in LDLR PCSK9 APO B LDL HoFH I in LDLR LDL FCH I in / USFI + modifying genes Familial dysbetalipoproteinaemia I in APO E Familial lipoprotein lipase deficiency Tangier disease (analphalipoproteinaemia) Familial LCAT deficiency (fish eye disease) I in LPL APO C LDL, VLD APO B I in ABC-i HDL I in LCAT HDL IDL and chylomicron remnants (VLDL) chylomicrons and VLDL European Heart Journal (), 9 88

79 Diagnostic criteria for the clinical diagnosis of HeFH according to MedPed and WHO Family history Clinical history Physical examination LDL-C Criteria First-degree relative known with premature CAD and/or first-degree relative with LDL-C > 9th centile First-degree relative with Tx and/or children < 8 with LDL-C > 9th centile. Score Patient has premature CAD Patient has premature cerebral/peripheral vascular disease Tx Arcus cornealis below the age of years > 8. mmol/l (more than ~ mg/dl) mmol/l (~ -9 mg/dl).-. mmol/l (~ 9-9 mg/dl).-.9 mmol/l (~ -89 mg/dl) Definite FH Score > 8 Probable FH Score -8 Possible FH Score - No diagnosis Score < European Heart Journal (), 9 88

80 Recommendations for detection and treatment of patients with HeFH Recommendations Class Level FH is suspected in patients with CVD aged < years among men or < years among women, in subjects with relatives with premature CVD or in subjects with known FH in the family. It is recommended to confirm the diagnosis with clinical criteria or whenever the resources are available with DNA analysis. Family screening is indicated when a patient with HeFH is diagnosed; if resources are available it is recommended to perform this as cascade screening. In HeFH high dose statin is recommended and whenever needed in combination with cholesterol absorption inhibitors and/or a bile acid sequestrant. Children of parents with FH are recommended: to be diagnosed as early as possible, to be educated to adopt a proper diet, to receive pharmacological treatment in late childhood or in adolescence. I I I I I C C C C C Children with HoFH need special attention already from the first year of life. I C Treatment is aimed at reaching the LDL-C goals for high risk subjects (<. mmol/l, less than ~ mg/dl) or in the presence of CVD of very high risk subjects (<.8 mmol/l, less than ~ mg/dl). If targets cannot be reached, maximal reduction of LDL-C should be considered using appropriate drug combinations in tolerated doses. IIa C European Heart Journal (), 9 88

81 Recommendations for treatment of dyslipidaemia in HF or valvular disease Recommendations Class Level n- PUFAs g/day may be considered to be added to optimal treatment in patients with HF (NYHA classification II-IV). Cholesterol-lowering therapy with statins is not indicated in patients with moderate to severe HF (NYHA classification III-IV). Lipid-lowering treatment is not indicated in patients with valvular disease without CAD. IIb III III B A B European Heart Journal (), 9 88

82 Recommendations for treatment of dyslipidaemia in autoimmune diseases Recommendations Class Level As yet there is no indication for the preventive use of lipid-lowering drugs only on the basis of the presence of autoimmune diseases. III C European Heart Journal (), 9 88

83 Recommendations for lipid lowering drugs in patients with moderate to severe CKD (stages, GFR 89 ml/min/. m) Recommendations Class Level CKD is acknowledged as a CAD risk equivalent; in these patients LDL-C reduction is recommended as the primary target of therapy. LDL-C lowering reduces CVD risk in CKD subjects and should be considered. Statins should be considered to slow the rate of kidney function loss modesty function loss modestly and thus protect against the development of ESRD requiring dialysis. Since statins have a beneficial effect on pathological proteinuria (> mg/day) they should be considered in patients with stage - CKD. In moderate to severe CKD statins as monotherapy or in combination with other drugs should be considered to achieve LDL-C <.8 mmol/l (less than ~ mg/dl). I IIa IIa IIa IIa A B C B C European Heart Journal (), 9 88

84 Recommendations for treatment of dyslipidaemia in transplant patients Recommendations Class Level Global CV risk management strategies are a priority in transplant patients. I C Statins should be considered as the first-line agents in transplant patients. Initiation should be at low doses with careful up-titration and with caution regarding potential drug-drug interactions, particularly for those on ciclosporin. In patients who are intolerant of statins or those with significant dyslipidaemia and high residual risk despite a maximally tolerated dose of statin, alternative or additional therapy may be considered: ezetimibe for those where high LDL-C is the principal abnormality; fibrates or nicotinic acid for those where hypertriglyceridaemia and/or low HDL-C is the principal abnormality. IIa IIb B C European Heart Journal (), 9 88

85 Recommendations for lipid-lowering drugs in patients with PAD Recommendations Class Level PAD is a high risk condition, and lipid-lowering therapy (mostly statins) is recommended in these patients. I A Statin therapy is recommended to reduce the progression of carotid atherosclerosis. I A Statin therapy is recommended to prevent the progression of aortic aneurysm. I C European Heart Journal (), 9 88

86 Recommendations for lipid-lowering drugs for primary and secondary prevention of stroke Recommendations Class Level Statin therapy to reach established treatment goals is recommended in patients at high global risk. I A Statin therapy is recommended in patients with other manifestations of CVD. I A Statin therapy is recommended in patients with a history of non-cardioembolic ischaemic stroke or TIA. I A European Heart Journal (), 9 88

87 Recommendations for lipid-lowering drugs in HIV patients Recommendations Class Level Lipid-lowering therapy, mostly statins, should be considered in HIV patients with dislipidaemia to achieve the LDL-C goal as defined for high risk subjects. IIa C European Heart Journal (), 9 88

88 Summary of recommendations for monitoring lipids and enzymes in patients on lipid-lowering therapy () How often should lipids be tested? Testing lipids Before starting lipid-lowering drug treatment, at least two measurements should be made, with an interval of - weeeks, with the exception of conditions where immediate drug treatment is suggested such as in ACS. How often should patients s lipids be tested after starting lipid-lowering treatment? 8 (± ) week after starting drug treatment. 8 (± )weeks after adjustements to treatment until within the target range. How often should cholesterol or lipids be tested once a patient has reached target or optimal cholesterol? Annually (unless there is adherence problems or another specific reason for more frequent reviews). European Heart Journal (), 9 88

89 Summary of recommendations for monitoring lipids and enzymes in patients on lipid-lowering therapy () How often should liver enzymes (ALT) be routinely mesured in patients taking lipid lowering drug? Before treatment. 8 weeks after starting drug treatment or after any dose increase. Annually thereafter if liver enzymes are < x ULN. What if liver enzymes becomes raised in a person taking lipid-lowering drugs? If < x ULN: Continuous therapy Recheck liver enzymes in - weeks. If values rise to x ULN: Stop statin or reduce dose, recheck liver enzymes within - weeks. Cautious reintroduction of therapy may be considered after ALT has returned to normal. ACS ALT CK ULN = acute coronary syndrome = alanine aminotransferase = creatine phosphokinase = upper limit of normal Monitoring liver and muscle enzymes How often should CK be measured in patients taking lipidlowering drugs? Pre-treatment Before starting treatment. If baseline CK level > x ULN, do not start drug therapy; recheck. Monitoring Routine monitoring of CK is not necessary. Check CK if patient develops myalgia. Increase alertness regarding myopathy and CK elevation in patients at risk such as: elderly patients, concomitant interfering therapy, multiple medications, liver or renal disease. What if CK becomes raised in a person taking lipid-lowering drugs? If > x ULN: Stop treatment, check renal function and monitor CK every weeks. Consider the possibility of transient CK elevation for other reasons such as muscle exertion. Consider secondary causes of myopathy if CK remains elevated. If x ULN: If no muscle symptoms, continue statin (patients should be alerted to report symptoms; consider further checks of CK). If muscle symptoms, monitor symptoms and CK regularly. European Heart Journal (), 9 88

90 European Heart Journal doi:.9/eurheartj/ehr9 ESC/EAS Guidelines for the management of dyslipidaemias: Addenda The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) Developed with the special contribution of: European Association for Cardiovascular Prevention & Rehabilitation Authors/Task Force Members: Željko Reiner* (ESC Chairperson) (Croatia) Alberico L. Catapano* (EAS Chairperson)* (Italy), Guy De Backer (Belgium), Ian Graham (Ireland), Marja-Riitta Taskinen (Finland), Olov Wiklund (Sweden), Stefan Agewall (Norway), Eduardo Alegria (Spain), M. John Chapman (France), Paul Durrington (UK), Serap Erdine (Turkey), Julian Halcox (UK), Richard Hobbs (UK), John Kjekshus (Norway), Pasquale Perrone Filardi (Italy), Gabriele Riccardi (Italy), Robert F. Storey (UK), David Wood (UK). European Heart Journal (), 9 88

91 Inhibitors and inducers of enzymatic pathways involved in statin metabolism CYP substrates Inhibitors Inducers CYPA Atorvastatin, lovastatin, simvastatin CYPC9 Fluvastatin, rosuvastatin, pitavastatin Transporter protein substrates MDR/P-gp Atorvastatin, lovastatin, pravastatin, simvastatin, pitavastatin OATPB All statins Ketoconazole, itraconazole, fluconazole,erythromycin, clarithromycin, tricyclic antidepressants, nefazodone, venlafaxine, fluvoxamine, fluoxetine, sertraline, cyclosporin A, tacrolimus, mibefradil, amiodarone, danazol, diltiazem, verapamil, protease inhibitors, midazolam, corticosteroids, grapefruit juice, tamoxifen Ketoconazole, fluconazole, amiodarone, sulfaphenazole, oxandrolone, dronedarone, warfarin Inhibitors Ritonavir, ciclosporin, verapamil, erythromycin, ketoconazole, itraconazole, quinidine, elacridar Ciclosporin, rifampicin, gemfibrozil, gemfibrozil-o-glucuronide, clarithromycin, erythromycin, roxithromycin, telithromycin, indinavir, ritonavir, saquinavir Phenytoin, phenobarbital, barbiturates, rifampin, dexamethasone, cyclophosphamide, carbamazepine, omeprazole, St John s Wort Rifampicin, phenobarbital, phenytoin Inducers Rifampicin, St John s Wort UGT substrates Inhibitors Inducers Atorvastatin, lovastatin, pravastatin, simvastatin Gemfibrozil, ciclosporin Rifampicin European Heart Journal (), 9 88

92 Recent developments in CVD prevention in Europe 99 First Joint Task Force Recommendations 99 Joint European Societies Implementation Group on Coronary Prevention EUROASPIRE I 998 Second Joint Task Force Recommendations 999- EUROASPIRE II Joint European Societies CVD Prevention Committee Third Joint Task Force Recommendations - EUROASPIRE III Fourth JointTask Force Recommendations Fifth Joint Task Force Recommendations