2016 ESC/EAS Guideline in Dyslipidemias: Impact on Treatment& Clinical Practice

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1 2016 ESC/EAS Guideline in Dyslipidemias: Impact on Treatment& Clinical Practice Nattawut Wongpraparut, MD, FACP, FACC, FSCAI Associate Professor of Medicine, Division of Cardiology, Department of Medicine Faculty of Medicine Siriraj Hospital

2 Objective 2016 ESC/EAS Dyslipidemias guideline Current target when Rx dyslipidemias patients Evidence based on efficacy and Safety What has changes?

3 Recommendation Class: Definitions Eur Heart J 2016: doi / eurheartj/ ehv272

4 Level of Evidence: Definitions Eur Heart J 2016: doi / eurheartj/ ehv272

5 Causes of death worldwide [Mackay 2004:E] Deaths (2002)* *Population: Age 60 years; CHD is the second leading cause of death in persons years. Mackay J, et al. Deaths from coronary heart disease. In: The Atlas of Heart Disease and Stroke. Geneva: World Health Organization; 2004:46-49.

6 Lipoproteins in Atherosclerosis: Response-to-Retention Model 1,2 1 ApoB lipoprotein retention Lipoprotein modification 2 Inflammatory response 3 Macrophage recruitment Foam cell formation Lesion progression 4 SMC migration Fibrous cap formation Macrophage necrosis 1 Modified lipoprotein ApoB lipoproteins in plasma 2 Macrophage Fibrous cap 3 Foam cell SMCs 4 Growth factors Cytokines Plaque necrosis with cholesterol crystals Apo = apolipoprotein; SMC = smooth muscle cell. 1. Tabas I et al. Circulation. 2007;116: Sherer Y et al. Nat Clin Pract Rheumatol. 2006;2:

7 Atherothrombosis Plaque Rupture Thrombosis Atherosclerosis Stable angina Intermittent Claudication Critical Limb Ischemia MI ACS Stroke/TIA Acute limb ischemia CV death Stary HC. Circulation 1995; Fuster V, et al. Vasc Med1998; 3: 231-9

8 General Concepts of Reperfusion Therapy Myocardial salvage is defined as the difference between the actual and potential infarct size : The initial area at risk during acute coronary occlusion. Gersh BJ, Stone GW, White HD, Homes DR Jr. JAMA 293:979, 2005.

9 Consequences of the reperfusion at various time after coronary adhesion Robbins and Cotran PATHOLOGIC BASIS OF DISEASE 8 th edition, 2009

10 Ischemic Cardiomyopathy- Disease that utilize high cost/resource but still has a poor outcome Cost Mortality (Baht) MADIT 1 NEJM 1996; 335: ; DINAMIT NEJM 2004; 351: , STICH NEJM 2011; 364:

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13 Risk Estimation Eur Heart J 2016: doi / eurheartj/ ehv272

14 Risk Categories Eur Heart J 2016: doi / eurheartj/ ehv272

15 ESC/EAS 2011 Guidelines for the Management of Dyslipidemia Very High Risk Documented cardiovascular disease by Invasive or noninvasive testing for atherosclerosis Previous MI Acute coronary syndrome Coronary revascularization Ischemic stroke Peripheral artery disease Type 2 DM, or type 1 DM with target organ damage (such as microalbuminuria). Type 2 DM with CVD or CKD. Type 2 DM aged >40 yr with at least 1 other CV risk factor. Moderate-to-severe CKD (glomerular filtration rate <60 ml/min/1.73 m 2 ) 10-year risk SCORE 10% Cardiovascular Risk Levels High Risk Markedly elevated single risk factors (eg, familial dyslipidemia and severe hypertension) 10-year risk SCORE 5% to <10% Moderate Risk 10-year risk SCORE 1% to <5% Low Risk 10-year risk SCORE <1% ESC guideline 2011 Management for Dyslipidaemias. EHJ 2011; 32:

16 Cardiovascular Event Rate, % Risk Pattern for Subsequent CV Events Over a Range of LDL-C Values LDL, mg/dl CHD + Diabetes CHD + MS or IFG CHD No MS or IFG Diabetes No CVD No Diabetes No CVD CV = cardiovascular; CHD = coronary heart disease; MS = metabolic syndrome; IFG = impaired fasting glucose; CVD = CV disease. 1. Robinson JG et al. Am J Cardiol. 2006;98:

17 Proportional Reduction in Vascular Event Rate (95% CI), % CTT Meta-analysis: Proportional Reduction in Major Vascular Events vs Absolute LDL-C Reduction More vs less (5 trials) Statin vs control (21 trials) % risk reduction per 1 mmol/l (39 mg/dl) P< Mean LDL-C Difference Between Treatment Groups, mg/dl CTT = Cholesterol Treatment Trialists; CI = confidence interval. 1. Cholesterol Treatment Trialists (CTT) Collaboration. Lancet. 2010;376:

18 Lipid Analysis Eur Heart J 2016: doi / eurheartj/ ehv272

19 Non HDL-C Is a Risk Factor for CHD Non HDL-C represents the cholesterol content of all apob-containing lipoproteins, including VLDL, IDL, LDL, Lp(a), and chylomicrons and chylomicron remnants 1,2 Non HDL-C = total cholesterol HDL-C 1 When TG levels are 200 mg/dl, non HDL-C may better represent the concentration of all atherogenic lipoproteins than does LDL-C alone 1 Multiple prospective cohort studies have shown that non HDL-C may be superior to LDL-C for CV risk assessment 3 Non HDL-C 1,3,4 HDL-C 1,5 Chylomicrons TG C apob-48 Chylomicron remnants TG C apob-48 VLDL TG C apob- 100 IDL TG C apob- 100 Large buoyant LDL C apob- 100 Small dense LDL C apob- 100 C Lp(a) apob- 100 HDL C apo A1 Adapted with permission from Walldius G et al. 6 Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature CAD. CHD = coronary heart disease; ApoB = apolipoprotein B; VLDL = very low-density lipoprotein; IDL = intermediate-density lipoprotein; Lp(a) = lipoprotein (a); TG = triglyceride; CV = cardiovascular; C = cholesterol; CAD = coronary artery disease. 1. NCEP ATP III Expert Panel. Circulation. 2002;106: Rana JS et al. Curr Opin Cardiol. 2010;25: Hoenig MR. Vasc Health Risk Manag. 2008;4: Chapman M et al. Eur Heart J Suppl. 2004;6(suppl A):A43 A Barter P. In: Ballantyne CM. Clinical Lipidology: A Companion to Braunwald s Heart Disease. Saunders, an imprint of Elsevier Inc; 2009: Walldius G et al. J Intern Med. 2004;255:

20 Previous Guideline Recommendations for Managing LDL-C in Patients With CHD (Stable or ACS) Previous Guideline Risk Group Classification Recommended LDL-C Goal or Treatment NCEP ATP III Very high risk a LDL-C <100 mg/dl (<70 mg/dl is a therapeutic option) (2004 update) 1 High risk b LDL-C <100 mg/dl Current Guidelines European 2012 CVD Prevention Guidelines 2 ACC/AHA 2013 Blood Cholesterol Guideline 3 Risk Group Classification Very high risk c Clinical ASCVD d (high risk) Recommended LDL-C Goal or Treatment LDL-C <1.8 mmol (<~70 mg/dl) or a 50% LDL-C reduction when target level cannot be reached Aged 75 years: high-intensity statin therapy (anticipated to achieve 50% LDL-C reduction from untreated baseline) e Aged >75 years OR not a candidate for high-intensity statin: moderate-intensity statin therapy (anticipated to achieve 30% to <50% LDL-C reduction from untreated baseline) e a Established CVD plus multiple risk factors (especially diabetes); severe and poorly controlled risk factors (especially cigarette smoking); multiple risk factors of the metabolic syndrome; patients with ACS. 1 b CHD or CHD risk equivalent (diabetes, other atherosclerotic disease [eg, peripheral arterial disease, >50% carotid artery stenosis], or 10-year risk for hard CHD >20%). 1 c Documented CVD by invasive or noninvasive testing, previous MI, ACS, coronary or other revascularization procedure, ischemic stroke, PAD, diabetes mellitus with 1 cardiovascular risk factor and/or target organ damage, severe CKD, or a calculated 10-year risk SCORE 10%. 2 d Clinical ASCVD includes ACS, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or PAD presumed to be of atherosclerotic origin; high-risk individuals include those with ASCVD, those with LDL-C 190 mg/dl, and individuals with diabetes. 3 e Clinicians treating high-risk patients who have a less-than-anticipated response to statins may consider the addition of a nonstatin cholesterol-lowering therapy. 3 CHD = coronary heart disease; ACS = acute coronary syndrome; NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III; CVD = cardiovascular disease; ACC = American College of Cardiology; AHA = American Heart Association; ASCVD = atherosclerotic CVD; MI = myocardial infarction, PAD = peripheral artery disease; CKD = chronic kidney disease; SCORE = Systematic Coronary Risk Evaluation; TIA = transient ischemic attack. 1. Grundy SM et al. Circulation. 2004;110: Perk J et al. Eur Heart J. 2012;33: Stone NJ et al. Circulation. 2014;129(suppl 2):S1 S45.

21 Key point from American Guideline Standpoint Science is not compare treating to target of each LDL level systematically but comparing high versus nonhigh intensity statin Establishment of a specific target level of LDL would be arbitrary because risk is continuous and express by regression line

22 Proportional Reduction in Vascular Event Rate (95% CI), % CTT Meta-analysis: Proportional Reduction in Major Vascular Events vs Absolute LDL-C Reduction More vs less (5 trials) Statin vs control (21 trials) % risk reduction per 1 mmol/l (39 mg/dl) P< Mean LDL-C Difference Between Treatment Groups, mg/dl CTT = Cholesterol Treatment Trialists; CI = confidence interval. 1. Cholesterol Treatment Trialists (CTT) Collaboration. Lancet. 2010;376:

23 TNT (Treating to New Targets) Patient population: CHD LDL-C: mg/dl TGs 600 mg/dl Screening and wash-out (n=18 469) Open-label run-in (n= ) Baseline Primary efficacy outcome measure: Occurrence of a major CV event: CHD death Nonfatal, non-procedure-related MI Resuscitated cardiac arrest Fatal or nonfatal stroke Double-blind period (n=10 001) LDL-C: <130 mg/dl Atorvastatin 10 mg n=5006 Atorvastatin 10 mg LDL-C target: 100 mg/dl n=4995 Atorvastatin 80 mg LDL-C target: 75 mg/dl 1 8 weeks 8 weeks Median follow-up=4.9 years LaRosa JC, et al. N Engl J Med 2005;352:

24 Cumulative incidence (%) TNT Incidence of major CVD events Atorvastatin 10 mg (n=5006). Mean LDL-C during study 101 mg/dl Atorvastatin 80 mg (n=4995). Mean LDL-C during study 77 mg/dl 22% RRR HR % CI 0.69 to 0.89 (p<0.001) ARR=2.2% NNT 45 over 4.9 years Time (years) Atorvastatin 80 mg reduced the risk of hospitalization for HF by 26% (HR 0.74; 95% CI ; p=0.01) relative to atorvastatin 10 mg LaRosa JC, et al. N Engl J Med 2005;352: From New England Journal of Medicine, LaRosa JC, et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease, 352, Copyright (2005) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

25 Patients (%) TNT Increasing LDL-C Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5 (<64 mg/dl) (64 <77 mg/dl) (77 <90 mg/dl) (90 <106 mg/dl) ( 106 mg/dl) p<0.0001* 10 8 p<0.0001* p<0.01* p<0.05* 0 *p-value for trend across LDL-C (continuous variable) Major CV events CHD death Nonfatal MI Stroke LaRosa JC, et al. Am J Cardiol 2007;100: Reprinted from American Journal of Cardiology, Vol 100, LaRosa JC et al. Safety and Efficacy of Atorvastatin-Induced Very Low-Density Lipoprotein Cholesterol Levels in Patients With Coronary Heart Disease (a Post Hoc Analysis of the Treating to New Targets [TNT] Study), Copyright (2007), with permission from Elsevier

26 Risk reduction vs atorvastatin 10 mg (%) TNT: High-intensity atorvastatin 80 mg reduced CV events vs moderate-intensity atorvastatin in patients with CHD 0 Fatal or nonfatal Nonfatal MI 1 stroke 1 Revasc. 2 Hosp. for CHF 1 Angina % p= % p= % p= % 26% p=0.01 p< Mean LDL-C values during the study were 77 mg/dl for atorvastatin 80 mg and 101 mg/dl for atorvastatin 10 mg 1. LaRosa JC, et al. N Engl J Med 2005;352: Data on file. Pfizer Inc, New York, NY

27 PROVE-IT TIMI 22: Atorvastatin for reduction of CV risk in patients with ACS Study design highlights Patient population: Enrolled at 349 sites in eight countries Men and women, aged 18 years Hospitalized for an ACS in the preceding 10 days Total-C 240 mg/dl or total-c 200 mg/dl if receiving lipid-lowering therapy Primary endpoint: Time to the first occurrence of a major CV event 4162 patients Double-blind period Atorvastatin 80 mg/day Pravastatin 40 mg/day Mean 2-year follow-up (925 primary events) Cannon CP, et al. N Engl J Med 2004;350:

28 Death or major CV event (%) PROVE-IT: Atorvastatin reduces CV risk in patients with ACS PROVE-IT: atorvastatin 80 mg reduced the risk of death or a major CV event by 16% (p=0.005) compared with pravastatin 40 mg in patients with ACS Incidence of death or major CV events * 16% RRR 95% CI 5 to 26% (p=0.005) ARR 3.9% NNT 26 over 2 years *Major CV events: MI, unstable angina requiring hospitalization, revascularization, and stroke 5 0 Pravastatin 40 mg (n=2063). Median LDL-C 95 mg/dl Atorvastatin 80 mg (n=2099). Median LDL-C 62 mg/dl Time (years) Cannon CP, et al. N Engl J Med 2004;350:

29 Death, MI, or rehospitalization for ACS (%) PROVE-IT: Benefit of atorvastatin over pravastatin was evident at 30 days PROVE-IT: atorvastatin 80 mg reduced the composite triple endpoint (death, MI, or rehospitalization for ACS) within 30 days of randomization This benefit remained stable from 30 days onward ARR 1.2% NNT=83 over 30 days 28% RRR HR % CI 0.52 to 0.99 (p=0.046) 1 0 Pravastatin 40 mg (n=2063). Mean LDL-C at 30 days=88 mg/dl Atorvastatin 80 mg (n=2099). Mean LDL-C at 30 days=60 mg/dl Time (days following randomization) Ray K, et al. JACC 2005;46:

30 MIRACL: Atorvastatin for reduction of CV events in patients with ACS Patient population: Enrolled at 122 sites Men and women with unstable angina or non-q-wave acute MI Randomized within hours of hospital admission 3086 patients Atorvastatin 80 mg/day 16-week double-blind treatment phase Placebo plus usual care Primary end point: Time to first ischemic event* *Death, nonfatal acute MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia Schwartz GG, et al. JAMA 2001;285:

31 MIRACL: Atorvastatin reduces stroke within 16 weeks in patients with ACS MIRACL: Atorvastatin 80 mg reduced the risk of fatal or non-fatal stroke by 50% (p=0.045) compared with placebo Atorvastatin 80 mg (n=1538) Placebo (n=1548) Fatal or nonfatal stroke % RRR HR % CI, (p=0.045) Nonfatal stroke % RRR HR % CI, (p=0.048) Patients experiencing strokes over 16 weeks (%) Schwartz GG, et al. JAMA 2001;285:

32 Treatment Goal for LDL Eur Heart J 2016: doi / eurheartj/ ehv272

33 Treatment Target and Goals for CV disease prevention Eur Heart J 2016: doi / eurheartj/ ehv272

34 Impact of Life style Change on Lipid Level Eur Heart J 2016: doi / eurheartj/ ehv272

35 Impact of Life style Change on Lipid Level Eur Heart J 2016: doi / eurheartj/ ehv272

36 Dietary Recommend to Lower LDL Eur Heart J 2016: doi / eurheartj/ ehv272

37 Treatment Goal for LDL Eur Heart J 2016: doi / eurheartj/ ehv272

38 Meta-Analysis of Therapeutic Equivalent Dose of Statins Weng TC et al. J Clin Pharm Ther 2010; 35: , Mukhtar RY et al. Int J Clin Prac 2005; 59: , Eur Heart J 2016: doi / eurheartj/ ehv272

39 Atorvastatin is well tolerated across the dosage range Data from a pooled analysis involving patients from 49 trials AE, % Atorvastatin 10 mg (n=7258) Atorvastatin 80 mg (n=4798) Placebo (n=2180) Withdrawals due to treatmentrelated AEs Serious treatment-related nonfatal AEs Myalgia Treatment-related myalgia Persistent ALT or AST >3 ULN * Persistent CK >10 ULN * Rhabdomyolysis Albuminuria Hematuria *Based on the number of patients with laboratory measurements CK, creatine kinase Newman C, et al. Am J Cardiol 2006;97:61 67

40 High-intensity atorvastatin is well tolerated in patients aged 65 years Pooled analysis of data from 50 randomized clinical trials AE, % Atorvastatin 10 mg (n=2042) Atorvastatin 80 mg (n=1698) Placebo (n=995) Treatment-related AEs Withdrawals due to treatment-related AEs Serious, treatmentrelated nonfatal AEs Death Hey-Hadavi JH, et al. Am J Geriatr Pharmacother 2006;4:

41 Pharmacologic treatment of Hypercholesterolemia Eur Heart J 2016: doi / eurheartj/ ehv272

42 What has change? Focus on specific LDL cholesterol target Patients at very high risk for cardiovascular events to an LDL cholesterol target < 70 mg/dl, or to achieve at least a 50% reduction in LDL cholesterol if baseline levels range between 70 and 135 mg/dl (class 1, level of evidence B). Patient with high risk for cardiovascular events, the LDL cholesterol target <100 mg/dl, or with the aim of achieving at least a 50% reduction in LDL cholesterol if baseline levels range between 100 and 200 mg/dl (class I, level of evidence B). DM without target organ damage and moderate CKD are placed in high risk ESC/EAS recommending the highest dose tolerable to achieve treatment goals (class I, level of evidence A). For patients who are statin intolerant, ezetimibe or a bile-acid sequestrant should be considered (class IIa, level of evidence C), while statins and ezetimibe can be considered for patients not at goal (class IIa, level of evidence B). Indication for PCSK9 inhibitors

43 Drug Treatment of Hypertriglyceridaemia Eur Heart J 2016: doi / eurheartj/ ehv272

44 Drug Treatment of Low HDL Eur Heart J 2016: doi / eurheartj/ ehv272

45 Treatment of Dyslipidemia in DM Eur Heart J 2016: doi / eurheartj/ ehv272

46 Patients with major CV events (%) TNT: High- vs moderate-intensity atorvastatin reduces major CV events in patients with CHD and diabetes Subgroup analysis 1501 patients in TNT had diabetes (and stable CHD) Incidence of major CV events Atorvastatin 10 mg (n=753). Final mean LDL-C 99 mg/dl Atorvastatin 80 mg (n=748). Final mean LDL-C 77 mg/dl 25% RRR HR % CI 0.58 to 0.97 (p=0.026) ARR 4.1% NNT 24 over 4.9 years Time (years) 6 Shepherd J, et al. Diabetes Care 2006;29: American Diabetes Association, Effect of Lowering LDL Cholesterol Substantially Below Currently Recommended Levels in Patients With Coronary Heart Disease and Diabetes, American Diabetes Association, Copyright and all rights reserved. Material from this publication has been used with the permission of American Diabetes Association.

47 Rate of acute cardiac events (%) PROVE-IT: Atorvastatin reduces acute cardiac events in patients with ACS and diabetes PROVE-IT (sub-analysis): Atorvastatin 80 mg reduced the risk of acute cardiac events by 25% (p=0.03) compared with pravastatin 40 mg in a post-hoc analysis of patients with recent ACS and type 2 diabetes 30 Incidence of acute cardiac events * 25% *Death, MI, and unstable angina requiring hospitalization % Median LDL-C at 30 days: 57 mg/dl 26.6% Median LDL-C at 30 days: 81 mg/dl Atorvastatin 80 mg Pravastatin 40 mg n=499 n=479 RRR (p=0.03) ARR 5.5% NNT 18 over 2 years Ahmed S, et al. Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial. European Heart Journal, 2006, 27(19), , by permission of Oxford University Press

48 Lipid Lowering for Primary and Secondary Prevention of stroke Eur Heart J 2016: doi / eurheartj/ ehv272

49 SPARCL: High-intensity atorvastatin for reduction of CV events in high-risk patients with previous stroke/tia Patient population: Enrolled at 205 sites worldwide Men and women with previously documented TIA or stroke A modified Rankin Score of 3 LDL-C levels 100 mg/dl and 190 mg/dl Primary endpoint: Time to the first occurrence of a fatal or nonfatal stroke 4731 patients Double-blind period Atorvastatin 80 mg/day Placebo Median follow-up 4.9 years Amarenco P, et al. N Engl J Med 2006;355:

50 Fatal or nonfatal stroke (%) SPARCL: High-intensity atorvastatin reduces stroke in high-risk patients with previous stroke/tia SPARCL: atorvastatin 80 mg provided 16% RRR in the primary endpoint of fatal or nonfatal stroke in patients with recent stroke or TIA and no CHD compared with placebo (p=0.03) Incidence of fatal or nonfatal stroke ARR 2.2%; NNT=45 over 5 years 16% RRR HR % CI 0.71 to 0.99 (p=0.03) 4 0 Placebo (n=2366). Mean LDL-C during study 128 mg/dl Atorvastatin 80 mg (n=2365). Mean LDL-C during study 73 mg/dl Time (years since randomization) Amarenco P, et al. N Engl J Med 2006;355: From New England Journal of Medicine, Amarenco P, et al. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack, 355, Copyright (2006) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

51 Lipid Lowering in Patients with PAD Eur Heart J 2016: doi / eurheartj/ ehv272

52 Conclusion Very high risk patients: LDL-C goal <70 mg/dl or a reduction of at least 50% if baseline LDL-C between mg/dl High risk patients: LDL-C goal <100 mg/dl or a reduction of at least 50% if baseline LDL-C between mg/dl High dose atorvastatin (80/40) showed feasibility to reach the 50% reduction target as well as reduction in CV events as evidence by TNT, MIRACLE, PROVE-IT, SPARCL trial etc Guideline recoomend maximal tolerated dose of statin to achieve treatment goal High intensity of atorvastatin is well tolerated