The 2009 Canadian Lipid Guidelines Milan Gupta MD

The 2009 Canadian Lipid Guidelines Milan Gupta, MD Department of Medicine, Mc. Master University Division of Cardiology, William Osler Health Centre Division of Cardiology / CV Surgery, University of Toronto

Disclosures Honoraria Abbott, Astellas, Astra. Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Glaxo. Smith. Kline, IMI, Merck Schering, Novartis, Pfizer, Roche, sanofi-aventis, Servier, Solvay Research Astra. Zeneca, Bristol Myers Squibb, GSK, IMI, Pfizer, sanofi-aventis Equity None

2009 Lipid Guidelines n Care Gap n Secondary Prevention n Primary Prevention and Risk Assessment

Relationship Between Proportional Reduction in Events and Optimal LDL-C Reduction at 1 Year A prospective meta-analysis of data from 90, 056 individuals from 14 trials of statins 1 A 1 mmol/L (39 mg/d. L) reduction in LDL-C was associated with a… 40 30 20 10 0 -10 50 Proportional reduction in event rate (% SE) 50 23% reduction in major coronary events 0. 5 1. 0 (19) (38) 1. 5 (58) Reduction in LDL-C mmol/L (mg/d. L) 2. 0 (77) 21% reduction in major vascular events 40 30 20 10 0 -10 0. 5 (19) 1. 0 (38) 1. 5 (58) Reduction in LDL-C mmol/L (mg/d. L) Adapted from Baigent C, et al, Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2005; 366: 1267– 1278. 2. 0 (77)

2006 CCS Dyslipidemia Guidelines Risk level High* Moderate‡§ Low‡§ Recommendations 10 -year CAD risk >20% and 10%-19% and <10% and Treatment targets†: Primary: LDL-C <2. 0 mmol/L Secondary: TC: HDL-C <4. 0 Treat when: LDL-C ≥ 3. 5 mmol/L or TC: HDL-C ≥ 5. 0 Treat when: LDL-C ≥ 5. 0 mmol/L or TC: HDL-C ≥ 6. 0 High risk patients should lower LDL-C by at least 50% Low-Moderate risk, patients should lower LDL-C by at least 40% May initiate treatment at lower or higher levels if family history or other investigations indicate elevated or reduced risk. Optimal apo B < 1. 2 g/L low risk, <1. 05 g/L intermediate risk, < 0. 85 g/L in high risk patients. * Mc. Pherson R, Frohlich J, Fodor G, Genest J. Canadian Cardiovascular Society position statement – Recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol 2006; 22(11): 913 -927.

CHRC High-Risk Registries: VP and GOALL Patients are Not Reaching LDL Targets Adapted from Yan A, , et al; Vascular Protection (VP) and Guidelines Oriented Approach to Lioid Lowering (GOALL) Registries Investigators. Am J Med 2006; 119: 676 -683

Statin therapy associated with low risk Review of placebo-controlled statin monotherapy* trials; N = 74, 102 Outcome Statin (%) Placebo (%) RD P value Statin better Myalgias 15. 4 18. 7 2. 7 0. 37 CK elevations 0. 9 0. 4 0. 2 0. 64 Rhabdomyolysis 0. 2 0. 1 0. 4 0. 13 Hepatotoxicity 1. 4 1. 1 4. 2 <0. 01 AE discontinuation 5. 6 6. 1 -0. 5 Placebo better 0. 80 *Atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin CK = creatine kinase AE = adverse events -30 -15 0 15 30 Risk difference per 1000 patients (RD) (95% CI) Kashani A et al. Circulation. 2006; 114: 2788 -97.

2009 Lipid Guidelines n Care Gap n Secondary Prevention n Primary Prevention and Risk Assessment

Primary Endpoint CV Death or Non-fatal MI or Non-fatal Stroke 35 Placebo n = 732 (29. 3%) 30 Per cent 25 Rosuvastatin n = 692 (27. 5%) 20 15 Hazard ratio = 0. 92 95% CI 0. 83 to 1. 02 p = 0. 12 10 5 0 0 No. at risk Placebo Rosuvastatin 6 2497 2514 2315 2345 12 18 24 30 Months of follow-up 2156 2207 2003 2068 1851 1932 1431 1484 36 811 855 Kjekshus J et al, N Engl J Med 2007; 357

GISSI-HF – Co-Primary Endpoints (i) All cause mortality and (ii) All cause mortality or hospitalizations for cardiovascular reasons Placebo (n=2289) n (%) HR* CI p value 657 (29) 644 (28) 1. 00 [95. 5% CI 0. 90 -1. 12] 0. 94 1305 (57) 1283 (56) 1. 01 [99% CI 0. 91 -1. 11] 0. 90 Rosuvastatin (n=2285) n (%) Primary Endpoints All-cause mortality or CV hospitalisations HR – Hazard Ratio; CI – Confidence Interval *adjusted HR GISSI-HF Investigators. Lancet 2008; doi: 10. 1016/S 01. 40 -6736(08)61240 -4

4 D study in diabetic hemodialysis patients: no benefit of statin therapy 60 Placebo 50 p=0. 37 40 Atorvastatin Cumulative incidence of 30 primary endpoint 20 (%) 10 0 0 1 2 3 4 5 6 Time (years) No. at risk: Placebo 636 532 383 252 136 51 19 Atorvastatin 619 515 378 252 136 58 29 4 D=Die Deutsche Diabetes Dialyse Studie Wanner C et al. N Engl J Med 2005; 353: 238– 248

AURORA: primary endpoint Kaplan-Meier estimate of time to first major CV event 40 Placebo 35 30 Cumulative incidence of primary endpoint (%) Rosuvastatin 25 20 15 10 HR=0. 96 (95% CI 0. 84– 1. 11) P=0. 59 5 0 0 No. at risk: Rosuvastatin Placebo 1390 1384 1 3 4 2 Years from randomization 1152 1163 962 952 826 809 551 534 5 148 153

2009 Lipid Guidelines n Care Gap n Secondary Prevention n Primary Prevention and Risk Assessment

What does the Framingham Risk Score not include? Genetic risk Impaired glucose (non-diabetic) Abdominal obesity Ethnic origin Socioeconomic status Measures of psychosocial stress Diet Level of exercise Alcohol consumption Novel biomarkers Atherosclerosis imaging

Risk charts in different ethnic groups Risk of CHD and stroke relative to Caucasian whites CHD Stroke Potential mechanisms Risk Charts South Asians or body fat and insulin resistancerelated factors Smoking, cholesterol Underestimate African American Greater salt-sensitive HBP & diabetes paradoxical healthy lipid profile Substantial obesity/ Social Good prediction Mexican American or or obesity rates & physical activity May overestimate Chinese or cholesterol, Sat. fat hypertension and intracerebral haemorrhage May overestimate

Lifetime Risk Men (n = 3564) 70 Women 69 60 70 (n = 4362) 60 50 46 Adjusted cumulative 40 incidence 30 of CVD (%) 20 36 50 50 40 39 30 50 27 20 10 5 10 8 0 0 50 60 70 ≥ 2 Major RFs 1 Major RF 80 90 50 Attained age (years) ≥ 1 Elevated RF ≥ 1 Not optimal RF *Optimal RF defined as total cholesterol <4. 65 mmol/L BP <120/80 mm. Hg, nonsmoker, nondiabetic 60 70 80 90 All optimal RFs Lloyd-Jones DM et al. Circulation. 2006; 113: 791 -8.

Fully Adjusted Relative Risk hs. CRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated PHS 1997 WHS 2000 HPFUS 2004 EPIC-N 2005 UK 2000 Strong 2005 < 1 mg/L MONICA 2004 Kuopio 2005 ARIC 2004 Iceland 2004 NHS 2004 CHS 2005 PIMA 2005 FHS 2008 1 to 3 mg/L > 3 mg/L

JUPITER Multinational, randomized, double-blind, placebo-controlled trial of rosuvastatin in the prevention of FIRST major cardiovascular events among individuals with low LDL and elevated hs. CRP No prior CVD or DM Men ≥ 50, Women ≥ 60 LDL <130 mg/d. L (3. 36 mmol/L) hs. CRP ≥ 2 mg/L Rosuvastatin 20 mg (n=8, 901) 4 -week run-in Placebo (n=8, 901) MI Stroke Unstable angina CVD Death CABG/PTCA Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela Ridker PM et al. Circulation 2003; 108: 2292 -7.

JUPITER -1° Composite Endpoint of Non-Fatal MI, Non. Fatal Stroke, UA/Revascularization and CV Death Cumulative Incidence 0. 08 HR 0. 56, 95% CI 0. 46 -0. 69 p<0. 00001 0. 06 Placebo 251/8, 901 - 44% Number Needed to Treat (NNT 5) = 25 0. 04 Rosuvastatin 142/8, 901 0. 02 0. 00 0 1 Number at Risk Rosuvastatin Placebo 8, 901 8, 631 8, 621 8, 412 8, 353 2 Follow-up (Years) 6, 540 6, 508 3, 893 3, 872 1, 958 1, 963 3 1, 353 1, 333 4 983 955 544 534 157 174 Ridker PM et al. N Engl J Med 2008; 359: 2195 -207.

Ridker et al NEJM 2008 JUPITER Secondary Endpoint – All Cause Mortality HR 0. 80, 95%CI 0. 67 -0. 97 P= 0. 02 0. 06 Placebo 247 / 8901 0. 04 0. 03 0. 02 Rosuvastatin 198 / 8901 0. 00 0. 01 Cumulative Incidence 0. 05 - 20 % 0 Number at Risk Rosuvastatin 8, 901 Placebo 8, 901 1 2 3 4 Follow-up (years) 8, 847 8, 852 8, 787 8, 775 6, 999 6, 987 4, 312 4, 319 2, 268 2, 295 1, 602 1, 614 1, 192 1, 196 683 684 227 246

Guidelines for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease 2009 www. ccs. ca

2009 Canadian Dyslipidemia Guidelines Committee Jacques Genest, MD Ruth Mc. Pherson, MD, Ph. D Jiri Frohlich, MD Todd Anderson, MD Norm Campbell, MD André Carpentier, MD Patrick Couture, MD Robert Dufour, MD George Fodor, MD Gordon Francis, MD Steven Grover, MD Milan Gupta, MD Robert A. Hegele, MD David C. Lau, MD Lawrence Leiter, MD Gary F. Lewis, MD Eva Lonn, MD G. B. John Mancini, MD Dominic Ng, MD, Ph. D Glen J. Pearson, Pharm D Allan Sniderman, MD James M. Stone, MD, Ph. D Ehud Ur, MD

Stakeholders in the Elaboration of Canadian Lipid Guidelines C-Change: Canadian Cardiovascular Harmonization of National Guidelines Endeavor. Canadian Association of Cardiac Rehabilitation Canadian Cardiovascular Society Canadian College of Family Physicians Canadian Council for Tobacco Control Canadian Council of Cardiovascular Nurses Canadian Diabetes Association Canadian Hypertension Society Canadian Medical Association Canadian Obesity Network Canadian Pharmacist Association Canadian Society for Exercise Physiology Canadian Stroke Network Canadian Working Group on Dyslipidemias Obesity Canada Public Health Agency of Canada Royal College of Physicians and Surgeons of Canada Canadian Institutes of Health Research (CIHR)

Criteria Used for Evaluation of Evidence Recommendation Grade Class I Evidence and/or general agreement that a given diagnostic procedure/treatment is beneficial, useful and effective Class II Conflicting evidence and /or a divergence of opinion about the usefulness /efficacy of the treatment Class II a Weight of evidence in favor Class II b Usefulness/efficacy less well established I IIa IIb III Class III Evidence that the treatment is not useful and in some cases may be harmful Level of Evidence Level A A Data derived from multiple randomized clinical trials (RCT) or meta-analysis Level B Data derived from a single RCT or large non-randomized studies Level C Consensus of opinion by experts and/or small studies, retrospective studies, registries C

Screening C Men over 40 and postmenopausal women Anyone with atherosclerosis regardless of age Anyone with diabetes regardless of age Family history of premature CVD Arterial hypertension (Check metabolic disorder, dyslipidemia) Inflammatory diseases (lupus, rheumatoid arthritis, psoriasis) Children of patients with severe dyslipidemia HIV infection with HAART therapy Clinical hyperlipidemias (xanthomas, xanthelasmas, premature arcus corneus) • Erectile dysfunction • Chronic renal disease • • •

Risk Assessment CV risk assessment remains imperfect • Framingham Risk Score (CVD) – FRS has been shown to underestimate the risk of some patients (e. g. , the young and women, and possibly those with the metabolic syndrome) • Reynolds Risk Score (CVD) – Is an alternative and includes family history and hs. CRP – Web-based version www. reynoldsriskscore. org We now recommend cardiovascular risk (total CVD) assessment, not only CAD, as CHEP and CDA do.

Metabolic Syndrome • • • C Association of several metabolic abnormalities Uniform classification remains elusive International Diabetes Federation classification Higher long-term risk than FRS estimates Measuring hs. CRP may help stratify risk • “ We recommend that clinical judgement be used to move up an FRS-determined score category based on his or her “load” of metabolic risk factors or the severity of the metabolic syndrome”

Recommended Lifestyle Changes • Smoking cessation, including the use of pharmacological therapy, as required • A diet low in sodium and simple sugars, with substitution of unsaturated fats for saturated and trans fats and increased consumption of fruits and vegetables • Caloric restriction to achieve and maintain ideal body weight • Moderate to vigorous exercise for 30 -60 minutes on most, and preferably all, days of the week • Psychological stress management Genest J et al. Can J Cardiol 2009; 25: 567 -79.

High Risk Level • Documented evidence of atherosclerosis • Diabetic adults over 45 (men), 50 (women) • FRS or RRS 10 year risk score > 20% – Requires intensive lifestyle modification advice – Requires pharmacological lowering of LDL-C

End-stage renal disease or congestive heart failure due to systolic dysfunction: • New studies on statins and heart failure • Statins may not reduce risk in advanced heart failure (CORONA, GISSI HF) A • Similar results for hemodialysis patients (AURORA, 4 D trials): no effect on CVD Use clinical judgment A

Target Levels Risk Level Initiate treatment if: Primary LDL-C Primary Alternate High Consider treatment in all patients <2 mmol/L CAD, PVD Or ↓ 50% LDL-C Apo. B<0. 80 Atherosclerosis Most Pts with Diabetes FRS>20% Class I Level A A A RRS>20%

Moderate Risk Levels Major health concern among midlife Canadians • FRS 10 -19% at 10 years Family history and high hs. CRP modulate risk o Reynolds Risk Score potentially useful o • Requires lifestyle changes • May require pharmacological therapy

Which Moderate Risk Patients Warrant Treatment? • LDL-C > 3. 5 mmol/L • TC: HDL ratio > 5. 0 • Those with a definite family history of premature CVD* • Those with multiple features of the metabolic syndrome* In moderate risk patients not fitting the above criteria, if male > 50 or female >60, consider testing hs. CRP • If hs. CRP > 2, consider treatment (Class IIA, Level B) Subjects should be free of acute illness and the lower of 2 hs. CRP values, taken at least 2 weeks apart, should be used. Genest J et al. Can J Cardiol 2009 Oct; [in press].

Target Levels Risk Level Initiate treatment if: Primary LDL-C Primary Alternate High Consider treatment in all patients <2 mmol/L CAD, PVD Or ↓ 50% LDL-C Apo. B<0. 80 Atherosclerosis Most Pts with Diabetes FRS>20% Class I Level A A A RRS>20% Moderate (strive towards ) FRS 10 -19% LDL-C>3. 5 mmol/L TC/HDL >5. 0 hs. CRP >2 men 50+, women 60+ Family history and hs. CRP modulate risk <2 mmol/L Or ↓ 50% LDL-C Apo. B<0. 80 A A Class IIA Level A Class IIA Level A

Low Risk Level § Framingham Risk Score < 10% § Pharmacological treatment for severe genetic dyslipidemia C § Use clinical judgment, proper timing § Careful family history for added risk factors § RRS can re-classify low-risk patients

Risk Assessment and Treatment Targets Risk Assessment HIGH FRS > 20% RRS > 20% Initiate/consider treatment if any of the following: • • CAD PVD Atherosclerosis Most Diabetic Patients Primary Target LDL-C Primary Alternate Apo. B < 2 mmol/L or ↓ LDL-C 50% Apo. B < 0. 80 (consider treatment in all patients) Moderate FRS 10 -19% • • LDL-C > 3. 5 mmol/L TC/HDL-C > 5. 0 hs. CRP > 2 mg/L * Family history A A (strive towards ) LOW FRS < 10% • LDL-C > 5. 0 mmol/L ↓ LDL-C 50% A * Only screen for hs. CRP in men ≥ 50 and women ≥ 60 if they do NOT already have CVD, diabetes, multiple risk factors, family history or hyperlipidemia Genest J et al. Can J Cardiol 2009 Oct; [in press].

Residual Risk (When LDL-C at target) OPTIONAL Secondary Targets Test Cut-point TC/HDL-C >4. 0 • Niacin • Fibrate Non HDL-C >3. 5 mmol/L • Niacin • Fibrate Apo B/AI >0. 8 Triglycerides >1. 7 mmol/L hs. CRP >2. 0 mg/L Genest J et al. Can J Cardiol 2009 Oct; [in press]. Intervention • Niacin • Ezetimibe • Fibrate • Niacin • Statin • Ezetimibe