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2564-12-2011 ESC/EAS 2011 Guidelines for the management of dyslipidemias 1 European Heart Journal Advance Access Published June 28, 2011 2 Classes of recommendations Classes of recommendations Classes of recommendations Definition Class I ‘Everybody agrees’ Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective. Class II ‘Not everybody agrees’ Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure. Suggested wording to use Is recommended/is indicated Class IIa Weight of evidence/opinion is in favour of usefulness/efficacy. Should be considered Class IIb Usefulness/efficacy is less well established by evidence/opinion. May be considered Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. Is not recommended Class III ‘Everybody agrees’ 3 Levels of evidence Levels of evidence Level of Evidence A Data derived from multiple randomized clinical trials or meta-analyses. Level of Evidence B Data derived from single randomized clinical trials or large non-randomized studies. Level of Evidence C Consensus of opinion of the experts and/or small studies, retrospective studies, registries. 4 Risque de maladies cardiovasculaires fatales Risque à dix ans de maladies cardiovasculaires fatales pour la Belgique en fonction du sexe, de l’âge, de la pression systolique, du cholestérol et du statut tabagique Femme Homme 5 Relative Risk Chart < 40y 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. Please note that this chart shows RELATIVE not absolute risk. The risks are RELATIVE to 1 in the bottom left. Thus a person in the top right hand box has a risk that is 12 times higher than a person in the bottom left. ESC 2007 6 Recommendations for treatment targets for LDL-C Recommendations Classa Levelb Refc I A 15,32,33 In patients at VERY HIGH CV risk (established CVD, type 2 diabetes, type 1 diabetes with target organ damage, moderate to severe CKD or a SCORE level ≥10%) the LDL-C goal is <1.8 mmol/L (less than ~70 mg/dL) and/or ≥ 50% LDL-C reduction when target level cannot be reached. aClass of recommendation. of evidence. cReferences. bLevel CKD= chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; LDL-C = low-density lipoprotein-cholesterol 8 Recommendations for treatment targets for LDL-C Classa Levelb Refc In patients at HIGH CV risk (markedly elevated single risk factors, a SCORE level ≥5 to <10%) an LDL-C goal <2.5 mmol/L (less than ~100 mg/dL) should be considered. IIa A 15,16,17 In subjects at MODERATE risk (SCORE level >1 to ≤5%) an LDL-C goal < 3.0 mmol/L (less than ~115 mg/dL) should be considered. IIa C - Recommendations aClass of recommendation. of evidence. cReferences. bLevel CKD= chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; LDL-C = low-density lipoprotein-cholesterol 9 Intervention strategies as a function of total CV risk and LDL-C level LDL-C levels TOTAL CV risk (SCORE) % <70 mg/dL <1.8 mmol/L 70 to <100 mg/dL 1.8 to <2.5 mmol/L 100 to <155 mg/dL 2.5 to < 4.0 mmol/L 155 to < 190 mg/dL 4.0 to < 4.9 mmol/L <1 No lipid intervention No lipid intervention Lifestyle intervention Lifestyle intervention Classa/Levelb I/C I/C ≥ 1 to < 5 Lifestyle intervention Lifestyle intervention Classa/Levelb I/C I/C >5 to <10, or high risk Lifestyle intervention, consider drug* Lifestyle intervention, consider drug* Classa/Levelb IIa/A ≥10 or very high risk Lifestyle intervention, consider drug* Classa/Levelb IIa/A IIa/A Lifestyle intervention, and immediate drug intervention IIa/A I/C Lifestyle intervention, consider drug if uncontrolled IIa/A Lifestyle intervention, and immediate drug intervention IIa/A Lifestyle intervention, and immediate drug intervention I/A I/C Lifestyle intervention, consider drug if uncontrolled IIa/A Lifestyle intervention, and immediate drug intervention I/A Lifestyle intervention, and immediate drug intervention I/A >190 mg/dL >4.9 mmol/L Lifestyle intervention, consider drug if uncontrolled IIa/A Lifestyle intervention, consider drug if uncontrolled I/A Lifestyle intervention, and immediate drug intervention I/A Lifestyle intervention, and immediate drug intervention I/A *In patients with MI, statin therapy should be considered irrespective of LDL-C levels. of recommendation. bLevel of evidence. aClass CV = cardiovascular; LDL-C = low-density lipoprotein-cholesterol; MI = myocardial infarction. 10 Addendum II. Practical approach to reach LDL-C goal 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/mL <1.8 mmol/L (~70mg/dL) <2.5 mmol/L (~100mg/dL) <3 mmol/L (~115mg/dL) >6.2 >240 >70 >60 >55 5.2-6.2 200-240 65-70 50-60 40-55 4.4-5.2 170-200 60-65 40-50 30-45 3.9-4.4 150-170 55-60 35-40 25-30 3.4-3.9 130-150 45-55 25-35 10-25 2.9-3.4 110-130 35-45 10-25 <10 2.3-2.9 90-110 22-35 <10 - 1.8-2.3 70-90 <22 - - 11 12 LDL-C LDL-C: Percentage Change from Baseline at Week 6 (n=2240) Dose (mg) LS mean % change from baseline 0 10 20 40 80 Log scale -10 -20 -30 -40 -50 -60 rosuvastatin Jones et al. Am J Cardiol 2003: 93: 152-160 atorvastatin simvastatin pravastatin 13 SCORE 2011 Women High Risk 14 HDL-C: Percentage Change from Baseline at Week 6 (n= 2240) LS mean % change from baseline 12 10 8 6 4 2 0 10 rosuvastatin Jones et al. Am J Cardiol 2003: 93: 152-160 20 Dose (mg) atorvastatin 40 simvastatin 80 Log scale pravastatin 15 l’effet du cholestérol associé aux lipoprotéines de haute densité (HDL-C) sur le risque CV global Taux HDL-C, mg/dl Femme Homme 30 38 46 54 62 70 x 1,8 x 1,5 x 1,2 x 1 x 0,8 x 0,7 x 1,3 x 1,1 x 1 x 0,9 x 0,8 x 0,7 16 Statins Efficacy in clinical studies Statins are among the most studied drugs in CV prevention, and dealing with single studies is beyond the scope of the present guidelines. A number of large-scale clinical trials have demonstrated that statins substantially reduce CV morbidity and mortality in both primary and secondary prevention. Statins have also been shown to slow the progression or even promote regression of coronary atherosclerosis. 17 Statins Meta-analyses Current available evidence suggests that the clinical benefit is largely independent of the type of statin but depends on the extent of LDL-C lowering; therefore, the type of statin used should reflect the degree of LDL-C reduction that is required to reach the target LDL-C in a given patient. More details on this are provided in Addendum II to these guidelines. 18 Statins Meta-analyses - Type 2 Diabetes The recent finding that the incidence of diabetes may increase with statins should not discourage institution of treatment; the absolute reduction in the risk of CVD in high risk patients outweighs the possible adverse effects of a very small increase in the incidence of diabetes. 19 Cholesterol absorption inhibitors Efficacy in clinical studies Ezetimibe can be used as second-line therapy in association with statins when the therapeutic target is not achieved at maximal tolerated statin dose or in patients intolerant of statins or with contraindications to these drugs. 20 Management of hypertriglyceridaemia Pharmacological therapy As statins have significant effects on mortality as well as most CVD outcome parameters, these drugs are the first choice to reduce both total CVD risk and moderately elevated TG levels. More potent statins (atorvastatin, rosuvastatin, and pitavastatin) demonstrate a robust lowering of TG levels, especially at high doses and in patients with elevated TG. 21 Le risque sera également plus élevé qu’indiqué dans les tableaux pour : • Les personnes socialement défavorisées ; les privations induisent de nombreux autres facteurs de risque. • Les sujets sédentaires et ceux présentant une obésité abdominale ; ces caractéristiques déterminent de nombreux autres aspects des risques énumérés ci-dessous. • Les personnes diabétiques : une nouvelle analyse de la base de données SCORE indique que les personnes présentant un diabète avéré ont un risque nettement plus élevé ; cinq fois plus élevé pour les femmes et trois fois plus élevé pour les hommes. • Les personnes ayant un faible taux d’HDL-C ou d’apolipoprotéine A1 (apo A1), des taux élevés de TG, de fibrinogène, d’homocystéine, d’ apolipoprotéine B (apo B) et de lipoprotéine(a) (Lp(a)), une hypercholestérolémie familiale (HF) ou un taux élevé de hs-CRP ; ces facteurs indiquent un niveau de risque accru pour les deux sexes, pour toutes les tranches d’âge et pour tous les niveaux de risque. 23 • Les personnes asymptomatiques présentant des signes précliniques d’athérosclérose, par exemple la présence de plaques ou un épaississement de l’intima–média carotidienne détecté lors d’une échographie carotidienne. • Les personnes atteintes d’insuffisance rénale. • Les personnes ayant des antécédents familiaux de MCV précoce dont on considère qu’ils multiplient le risque par 1,7 chez les femmes et par 2,0 chez les hommes. • À l’inverse, le risque peut être inférieur à celui indiqué chez les personnes ayant des taux très élevés d’HDL-C ou des antécédents familiaux de longévité. 24 Risk factor management in coronary patients – results from a European wide survey EUROASPIRE III Professor David A Wood on behalf of the EUROASPIRE Investigators 25 Distribution of Age, Gender and Diagnostic Category 100 90 80 Gender Age Diagnostic category 70 60 50 40 30 20 10 0 Women (%) Mean age (years) Age < 60 yrs CABG PTCA (%) (%) (%) AMI (%) ISCHAEMIA (%) Survey 1 24,9 59,3 47,8 25,6 25,6 25,8 23,0 Survey 2 25,2 59,4 48,1 24,8 27,8 26,1 21,2 Survey 3 23,1 60,9 40,6 28,3 49,8 9,9 12,0 26 Prevalence of Smoking* * Self-reported smoking or CO in breath > 10 ppm 100% 90% 80% S2 vs. S1 : P=0.83 S3 vs. S2 : P=0.37 S3 vs. S1 : P=0.48 70% 60% 50% 40% P=0.64 30% 20% 10% 0% Czech Rep. Finland Survey 1 22,0% 12,8% 25,0% 16,8% 23,3% 18,6% 31,8% 13,3% 20,3% Survey 2 19,3% 21,6% 24,2% 16,8% 30,1% 15,1% 28,3% 14,6% 21,2% Survey 3 22,2% 16,8% 24,8% 18,4% 18,3% 14,0% 15,1% 12,0% 18,2% France Germany Hungary Italy NetherSlovenia lands ALL 27 Prevalence of Overweight* * Body mass index ≥ 25 kg/m² S2 vs. S1 : P=0.15 S3 vs. S2 : P=0.22 S3 vs. S1 : P=0.02 100% P=0.04 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% NetherSlovenia lands Czech Rep. Finland Survey 1 81,3% 79,3% 75,8% 82,4% 71,0% 81,4% 70,5% 73,8% 76,8% Survey 2 87,0% 78,4% 79,7% 82,7% 79,2% 71,7% 78,5% 78,7% 79,9% Survey 3 84,6% 77,2% 77,1% 85,3% 85,6% 81,3% 78,9% 84,4% 82,7% France Germany Hungary Italy ALL 28 Prevalence of Obesity* * Body mass index ≥ 30 kg/m² S2 vs. S1 : P=0.009 S3 vs. S2 : P=0.051 S3 vs. S1 : P=0.0002 100% 90% 80% 70% 60% P=0.0006 50% 40% 30% 20% 10% 0% Czech Rep. Finland Survey 1 31,4% 29,6% 33,4% 23,0% 23,3% 22,4% 18,9% 19,2% 25,0% Survey 2 40,1% 33,6% 37,5% 30,6% 36,8% 23,6% 28,2% 28,0% 32,6% Survey 3 37,9% 26,4% 36,8% 43,1% 49,3% 29,4% 26,5% 39,1% 38,0% France Germany Hungary Italy NetherSlovenia lands ALL 29 Prevalence of Raised Blood Pressure (1)* * SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg S2 vs. S1 : P=0.83 S3 vs. S2 : P=0.51 S3 vs. S1 : P=0.65 100% 90% 80% P=0.79 70% 60% 50% 40% 30% 20% 10% 0% Czech Rep. Finland Italy Nether lands Slovenia ALL Survey 1 60,1% 56,1% 48,4% 58,4% 50,6% 55,3% 54,0% 55,1% 54,6% Survey 2 46,9% 52,0% 55,5% 67,0% 40,4% 50,8% 54,4% 62,8% 54,0% Survey 3 62,5% 67,1% 48,1% 50,9% 46,3% 60,5% 59,6% 55,1% 55,2% France Germany Hungary 30 Therapeutic Control of Blood Pressure* * SBP/DBP < 140/90 mmHg for non-diabetics or < 130/80 mmHg for diabetics 100% 90% S2 vs. S1 : P=0.98 S3 vs. S2 : P=0.36 S3 vs. S1 : P=0.37 80% 70% P=0.57 60% 50% 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL Survey 1 34,4% 39,1% 47,9% 39,7% 44,0% 41,0% 43,3% 37,7% 41,0% Survey 2 47,2% 43,4% 36,7% 29,1% 55,0% 45,7% 43,5% 31,1% 41,2% Survey 3 30,1% 29,1% 44,1% 45,2% 44,1% 34,8% 35,3% 41,4% 38,7% 31 Prevalence of Raised Total Cholesterol* * Total cholesterol ≥ 4.5 mmol/L S2 vs. S1 : P<0.0001 S3 vs. S2 : P<0.0001 S3 vs. S1 : P<0.0001 P<0.0001 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL Survey 1 94,2% 93,7% 91,5% 94,3% 97,4% 96,9% 97,1% 95,5% 94,5% Survey 2 86,1% 63,8% 79,3% 83,4% 54,5% 72,5% 66,7% 82,2% 76,7% Survey 3 47,1% 28,2% 40,8% 49,4% 57,0% 48,8% 33,1% 41,8% 46,2% 32 Therapeutic Control of Total Cholesterol* 100% * Total cholesterol < 4.5 mmol/L S2 vs. S1 : P<0.0001 S3 vs. S2 : P<0.0001 S3 vs. S1 : P<0.0001 90% 80% P<0.0001 70% 60% 50% 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL Survey 1 4,6% 6,8% 14,2% 9,6% 4,8% 0,0% 7,9% 8,1% 8,4% Survey 2 17,3% 46,2% 23,4% 20,5% 31,4% 31,1% 40,0% 22,0% 28,7% Survey 3 55,8% 72,6% 62,4% 54,0% 48,7% 53,2% 68,9% 60,3% 57,3% 33 Prevalence of Diabetes* * Self-reported history of diagnosed diabetes 100% 90% S2 vs. S1 : P=0.21 S3 vs. S2 : P=0.02 S3 vs. S1 : P=0.001 80% 70% 60% P=0.004 50% 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL Survey 1 21,8% 15,4% 16,7% 13,5% 26,6% 17,2% 10,3% 17,4% 17,4% Survey 2 21,5% 18,7% 27,5% 13,5% 21,1% 21,8% 13,2% 23,8% 20,1% Survey 3 30,8% 19,1% 34,2% 22,6% 44,8% 21,7% 20,6% 18,8% 28,0% 34 Therapeutic Control of Diabetes* * Fasting glucose < 7 mmol/L in patients with history of diabetes 100% S2 vs. S1 : P=0.82 S3 vs. S2 : P=0.03 S3 vs. S1 : P=0.08 90% 80% 70% 60% 50% P=0.04 40% 30% 20% 10% 0% Czech Rep. Finland Survey 1 38,7% 34,4% Survey 2 29,9% 30,8% Survey 3 17,2% 40,0% France Germany Hungary Italy 15,1% 71,4% 20,4% 26,9% 42,3% 53,2% 27,8% 18,7% 25,4% 10,2% Netherlands Slovenia ALL 48,6% 39,1% 70,7% 72,7% 42,1% 33,3% 20,0% 21,5% 35 Medication Use: Antiplatelets S2 vs. S1 : P=0.29 S3 vs. S2 : P=0.0002 S3 vs. S1 : P<0.0001 P<0.0001 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL Survey 1 85,2% 82,2% 82,1% 82,9% 72,0% 86,1% 77,5% 79,4% 80,8% Survey 2 87,6% 81,9% 85,7% 86,3% 75,1% 91,5% 81,0% 82,3% 83,6% Survey 3 92,5% 96,4% 98,1% 91,8% 86,1% 98,0% 95,7% 92,4% 93,2% 36 Medication Use: Beta-Blockers S2 vs. S1 : P=0.001 S3 vs. S2 : P=0.0002 S3 vs. S1 : P<0.0001 100% P<0.0001 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL Survey 1 65,3% 77,8% 56,3% 43,6% 57,7% 49,2% 46,8% 51,8% 56,0% Survey 2 73,7% 87,9% 60,4% 68,1% 84,3% 61,2% 48,2% 65,7% 69,0% Survey 3 91,3% 95,8% 74,4% 85,0% 85,9% 87,6% 74,6% 87,0% 85,5% 37 Medication Use: ACE Inhibitors & Angiotensin II RA S2 vs. S1 : P<0.0001 S3 vs. S2 : P<0.0001 S3 vs. S1 : P<0.0001 100% P<0.0001 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL Survey 1 28,1% 17,3% 33,8% 31,4% 46,3% 31,8% 27,4% 31,2% 31,0% Survey 2 47,1% 31,0% 43,7% 50,6% 58,6% 53,5% 42,9% 63,0% 49,2% Survey 3 76,1% 59,3% 78,9% 72,8% 80,6% 70,9% 66,5% 83,0% 74,6% 38 Medication Use: Statins S2 vs. S1 : P<0.0001 S3 vs. S2 : P<0.0001 S3 vs. S1 : P<0.0001 100% P<0.0001 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Netherlands Slovenia ALL Survey 1 6,3% 34,9% 20,2% 31,1% 6,7% 6,8% 14,0% 23,2% 18,1% Survey 2 38,8% 62,6% 61,0% 65,6% 45,2% 57,0% 75,1% 56,3% 57,3% Survey 3 88,1% 95,2% 89,1% 85,4% 76,7% 90,0% 91,4% 90,1% 87,0% 39 Medication Use: Diuretics 100% S2 vs. S1 : P=0.30 S3 vs. S2 : P=0.02 S3 vs. S1 : P=0.002 90% 80% 70% 60% 50% P=0.006 40% 30% 20% 10% 0% Czech Rep. Finland France Germany Hungary Italy Nether-lands Slovenia ALL Survey 1 15,7% 12,0% 18,7% 14,5% 15,9% 17,6% 13,7% 14,3% 15,3% Survey 2 22,7% 12,4% 13,2% 32,7% 23,9% 16,3% 12,6% 14,3% 18,8% Survey 3 36,3% 10,8% 19,2% 33,8% 52,6% 20,4% 23,2% 29,1% 31,1% 40 Conclusions No change in blood pressure control despite increased use of anti-hypertensive medications 61% above therapeutic target (BP < 140/90 mmHg) Continuing improvement in lipid control with increased use of statins 42% above the 2003 therapeutic target (TC < 4.5 mmol/l) 41 Goals of treatment -BP < 140/90 mmHg in all hypertensive patients < 130/80 mmHg in hypertensive patients with diabetes or renal disease -Control of all cardiovascular risk factors ESH - ESC Guidelines, J Hypertens 2003 42 Patient 1 Patient 2 Patient 3 Sympathetic nervous system Renin-angiotensin system Total body sodium 43 Percentage of patients with normal blood pressure Drug A Drug B Drugs C 0 20 40 60 80 100 % 44 BP control rate during antihypertensive monotherapy Achieved BP: <140/90 mmHg 80 60 % 40 39 20 0 During monotherapy (diuretic, b-blocker, ACE inhibitor or Ca antagonist) Dickerson et al, Lancet, 1999 45 Percentage of patients with normal blood pressure Drug A Drug B Drugs A + B 0 20 40 60 80 100 % 46 Effects of two different drugs on BP separately and in combination (119 randomized placebo controlled trials) Placebosubtracted BP response. mmHg 0 "First" drug alone "Second" drug alone Combinati on -5 -10 -5 Systolic Diastolic Law et al, BMJ 200347 Advantages of fixed versus liberal combinations of two antihypertensive drugs Fixed * Liberal Simplicity of treatment + - Compliance + - Efficacy + + Tolerability +* - Price + - Flexibility - + Risk of administering contraindicated drug + - lower doses generally used in fixed-dose combinations 48 Pharmacological treatment of hypertension Consider : Blood pressure level before treatment Absence or presence of TOD and risk factors Choose between : Single agent at low dose Previous agent at full dose Two-drug combination at low dose If goal BP not achieved : Switch to Previous different combinati agent at low on at full If goal BP not achieved : dose dose Two-three drug combination Add a third drug at low dose Two-three drug combination 2003 European Society of Hypertension - European Society of Cardiology Guidelines for the Management of Arterial Hypertension, J Hypertens, 2003 49 Algorithm for treatment of hypertension Lifestyle modifications Not at goal BP (<140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease) Initial drug choices Hypertension without compelling indications Stage 1 hypertension (SBP 140-159 or DBP 90-99 mmHg) Thiazide-type diuretics for most, consider ACE inhibitor, ARB, b-blocker, CCB, or combination Hypertension with compelling indications Stage 2 hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACE inhibitor or ARB or bblocker or CCB) Drug(s) for the compelling indications Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, b-blocker, CCB) as needed Not at goal BP Optimize dosages or add additional drugs until goal BP is achieved Consider consultation with hypertension specialist The JNC VII Report, 2003 50 Normalization of BP Good tolerability Simple drug regimen SATISFACTION Day-to-day compliance Long-term compliance 51