2009 ccs can lipid guidelines slide kit

Guidelines for the diagnosis and Treatment of Dyslipidemia

and Prevention of Cardiovascular Disease 2009

2009 Canadian Lipid Guidelines

Jacques Genest MD Ruth McPherson MD PhD Jiri Frohlich MD

Todd Anderson MD Norm Campbell MD André Carpentier MDPatrick Couture MD Robert Dufour MDGeorge Fodor MD Gordon Francis MDSteven Grover MD

Milan Gupta MDRobert A. Hegele MDDavid C. Lau MD Lawrence Leiter MD Gary F. Lewis MD Eva Lonn MD G.B. John Mancini MD Dominic Ng MD PhD Glen J. Pearson Pharm D Allan Sniderman MD James M. Stone MD, PhDEhud Ur MD

Conflict of Interest Statements• Conflict of Interest Statement• The elaboration of these guidelines was done without financial or logistical support from pharmaceutical companies. Under no circumstances were funds requested nor received for work related to these recommendations

by members of the writing group or Review Panelists. The logistical support of the Canadian Cardiovascular Society, Canadian Vascular Coalition and the Canadian Institutes of Health Research is acknowledged. • The authors have declared the following duality/conflicts of interest:• Dr. Jacques Genest reports receiving honoraria (speaker’s fees, advisory boards, consultant meetings) from Astra-Zeneca (significant), Glaxo-Smith-Kline, Merck-Frosst, Pfizer, and Schering-Plough; research support from

Astra-Zeneca (significant), Merck-Schering Plough (significant) and Resverlogix (significant)• Dr. Ruth McPherson reports receiving honoraria (speaker’s fess, advisory boards) and grants in aid for research from AstraZeneca, Merck Frosst, Pfizer, Oryx and Schering-Plough.• Dr. Jiri Frohlich received honoraria (speaker’s fees, advisory board and consultants meetings) and grants in-aid for research from Merck Frosst, Astra-Zeneca, Schering-Plough, Pfizer, Oryx and Glaxo-Smith-Kline.• Dr. Todd Anderson Honorarium and research grants, advisory boards for Pfizer, Astra-Zeneca, Merck, Schering, GSK and Eli Lilly. • Dr. Norm Campbell has given talks sponsored by Bayer, Sanofi Aventis, Biovail, Bristol Myers Squibb, Pfizer, Novartis and Merck Frosst and also has been on advisory boards for Novartis, Pfizer, Servier, Boehringer

Ingelheim and Schering Plough.• Dr. André Carpentier reports receiving honoraria (speaker’s fees, advisory boards, consultant meetings) from Astra-Zeneca, Glaxo-Smith-Kline, Merck-Frosst, Pfizer and Schering-Plough; research support from Aventis,

Astra-Zeneca, Glaxo-Smith-Kline (significant), Merck-Frosst-Schering Plough, Novartis, Pfizer, Philips, and Amsterdam Molecular Therapeutics. • Dr. Patrick Couture received honoraria (speaker fees and advisory boards) from AstraZeneca, Merck-Frosst, Merck-Schering, Pfizer and Solvay; research support from Merck-Frosst, Merck-Schering and Pfizer.• Dr. Robert Dufour received honoraria (speaker’s fees, advisory boards and consultant meetings) and grants in aid for research from Astra-Zeneca, Bristol Myers Squibb, Pfizer (significant), Genzyme, Isis and Merck-Frosst.• Dr. George Fodor• Dr. Gordon A Francis reports receiving honoraria (speaker’s fees, advisory boards) from AstraZeneca, Merck Frosst, Merck Frosst/Schering, Oryx, and Solvay Pharma and an unrestricted research grant from Pfizer Canada.• Dr. Steven Grover• Dr. Milan Gupta. Research Grants - AZ, Pfizer, Merck Schering. Honoraria: AZ, Pfizer, BMS, Novartis, Merck Frosst, Oryx, Solvay, Schering-Plough, Abbott• Dr. Robert Hegele received honoraria (speaker fees and advisory boards) from AstraZeneca, Merck-Frosst, Pfizer, Solvay, Sepracor, Kowa, Roche, Schering and Merck-Schering; research support (significant) from

AstraZeneca, Merck-Schering and Pfizer• Dr. David C Lau• Dr. L.A. Leiter reports receiving honoraria (speaker’s fees, advisory boards) and grants in aid for research from AstraZeneca, Merck Frosst, Merck Schering Plough, Pfizer, Roche, and Solvay.• Dr. Gary F Lewis reports receiving honoraria (speaker’s fees, advisory boards, consultant meetings) from Astra-Zeneca, Merck-Frosst, Pfizer, Solvay Pharma, Eli Lilly and Merck-Schering; research support from Amylin

Pharmaceuticals, Pfizer• Dr. Eva Lonn - Research support and/or speaking or consulting honoraria: Merck, Shering Plough, Pfizer, Abbott, Astra Zeneca, GSK• Dr. G. B. John Mancini. Grant-in-aid Merck-Frosst; honoraria: Merck Frosst, Astra Zeneca, GSK, Pfizer, sanofi-aventis, Schering-Plough, Abbott/Solvay• Dr. Dominic Ng received honoraria (speaker’s fees, advisory boards, consultant meetings) and travel grants from Astra Zeneca, Merck Frosst, Schering Plough, Sanofi-Aventis, GlaxoSmithKline and Pfizer.• Dr. Glen J. Pearson reports receiving (minor) honoraria (speaker’s fees, advisory boards, consultant meetings) from Astellas, AstraZeneca, Merck Frosst, Pfizer, Novartis, Roche, Sanofi-Aventis, and Schering Plough and

(minor) research support from Fujisawa, Merck Frosst, and Novartis• Dr. A.D. Sniderman received research support (significant) from Astra Zeneca and speakers fees from Merck Schering.• Dr. James Stone. reports receiving honoraria (speaker’s fees, advisory boards, consultant meetings) from Astra-Zeneca, Brsitol Myers Squibb, Merck Frosst, Novartis, Pfizer, Sanofi-Aventis, Servier, and Schering Plough.• Dr. Ehud Ur –Received honoraria (speaker’s fees, advisory board and consultant meetings) and grants-in-aid for research from Merck Frosst, AstraZeneca, Schering-Plough and Pfizer.• Acknowledgments.• The Authors wish to thank the external reviews by Dr. Philip Barter, Sydney Heart Institute, Sydney, Australia and Dr. David Waters, Professor Emeritus, University of California in San Francisco for their comments.

Process:Transparency and Cooperation

Address stakeholder concernsRetain 2006 principles but more collaborationTransparent disclosure of potential biasDisclosure of writers’ links to pharmaceutical

industryTeamed with Canadian Cardiovascular SocietyTeamed with CIHRUsed primary and secondary review panels

Involvement of the Canadian Vascular Coalition and CIHR Secondary and High-Risk prevention:

•Strategy better defined •Clinical studies on end-stage disease (advanced heart failure and hemodialysis)

Primary prevention•Cardiovascular risk evaluation tools•Framingham risk score includes cardiovascular diseases (CVD)•Intermediate risk defined as FRS 10-19% ten-year risk •Family history part of risk stratification •hsCRP part of risk stratification in intermediate risk subjects whose LDL-C does not already suggest treatment (men >50 and women >60 years)

Targets•Simplified target levels•Apo B role defined•Secondary targets evaluated according to available evidence

Changes Since 2006

Genest J et al. Can J Cardiol 2009 Oct;[in press].

Introduction: Burden of Health

CVD causes 1:3 death in Canada

StatsCan/Canada

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)

Stakeholders in the Elaboration of Canadian Lipid Guidelines

Guiding Principles

Target adults for screening (unless compelling reason)

Determine cardiovascular risk

Institute lifestyle changes

Treat according to level of risk

Criteria Used for Evaluation of Evidence

Recommendation GradeClass IEvidence and/or general agreement that a given diagnostic procedure/treatment is beneficial, useful and effective

Class IIConflicting 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 Class IIIEvidence that the treatment is not useful and in some cases may be harmful

Level of Evidence Level AData derived from multiple randomized clinical trials (RCT) or meta-analysis

Level BData derived from a single RCT or large non-randomized studies

Level CConsensus of opinion by experts and/or small studies, retrospective studies, registries

I IIb IIIIIa

A

CC

Guiding Principles

Target Adults for Screening(unless compelling reason)

Determine Cardiovascular Risk

Institute Lifestyle Changes

Treat according to Level of Risk


Screening

• 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)

C

Screening

• Children of patients with severe dyslipidemia• HIV infection with HAART therapy• Clinical hyperlipidemias (xanthomas,

xanthelasmas, premature arcus corneus)• Erectile dysfunction• Chronic renal disease

C

Metabolic Syndrome

• Association of several metabolic abnormalities• Uniform classification remains elusive• International Diabetes Federation classification• Higher long-term risk than FRS estimates• Measuring hsCRP may help stratify risk

C

Metabolic Syndrome: Meta-analysis of Cardiovascular Risk

Motillo S, Eisenberg M. 2009 Unpublished

• Central obesity: Europids Men 94 cm Women 80 cm South Asians Men 90 cm Women 80 cm Chinese Men 90 cm Women 80 cm Japanese Men 90 cm Women 80 cm Ethnic south and central Americans: Use South Asian recommendations First Nations: Use South Asian recommendations until more specific data are available. Sub-Saharan African: Use European data until more specific data are available Eastern Mediterranean and middle east (Arab) populations: Use European data

• Plus 2 of these factors: Plasma triglycerides >1.7 mmol/l HDL cholesterol Men <1.03 mmol/l Women <1.3 mmol/l Blood pressure >130/85 mm Hg (or treatment for hypertension) Fasting plasma glucose >5.6 mmol/l

Classification of the Metabolic Syndrome (International Diabetes Federation)

Guiding Principles






Risk Assessment

CV risk assessment remains imperfect

• Framingham Risk Score (CVD) [FRS may underestimate risk in some patients]

• Reynolds Risk Score (CVD) [RRS web-based, includes family history and hsCRP]

We now recommend Cardiovascular Risk (Total CVD) assessment, not only CAD. As CHEP and CDA do.

Short-term versus Long-term Risk

FRS estimates 10-year risk Family history increases risk 1.7- 2.0 fold Risk levels can change over time CVD risk needs reassessment every 3-5 years

Ankle brachial indexExercise stress testCarotid B mode ultrasonographyCardiac Computed tomography (Electron beam

Computed Tomography -EBCT); Multi-Detector Computed Tomography Coronary Angiography (MDCT-CA)

Surrogate End-points of Atherosclerosis - Testing for Atherosclerosis

The presence of atherosclerosis places the individual in the high-risk category

C

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

Moderate Risk Levels

Major health concern among midlife Canadians• FRS 10-19% at 10 years

o Family history and high hsCRP modulate risko Reynolds Risk Score potentially useful

• Requires lifestyle changes• May require pharmacological therapy

Moderate Risk Level

Pharmacological therapy indicated if: LDL-C > 3.5 mmol/L (apoB > 1.00 g/L) TC/HDL-C ratio > 5.0 hsCRP > 2mg/L in men over 50, women over 60

– hsCRP should be performed selectively

Consider cost/benefit of preventative therapyDiscuss and weigh patient’s desire

C

A

B

Treatment for the Moderate Risk Supported by Primary Prevention Data

The indications for pharmacological interventions are based on the statin primary prevention studies including:

AFCAPS/TexCAPS WOSCOP ASCOT HPS JUPITER


0

1

2

3

4

5

6

7

8

9

0 1 2 3 4 5 Years

Placebo

Rosuvastatin 20 mg

hsCRP Identifies a Group of Intermediate Risk Subjects Who Benefit From Statin Therapy

Perc

ent o

f pati

ents

with

prim

ary

endp

oint

Number at risk RSV 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174

Hazard Ratio 0.56 (95% CI 0.46-0.69)P<0.00001

Ridker P et al. N Eng J Med 2008;359: 2195-2207

CV death, non-fatal stroke, non-fatalMI, unstable angina or arterial revascularization

The measurement of high-sensitivity C-reactive protein (hsCRP) should not be performed on everyone.

Men >50 years and women >60 years who are at Moderate risk for CVD (by FRS) and whose level of LDL-C is <3.5 mmol/L are candidates, since such individuals have been shown to benefit from statin therapy (Class IIA, Level B).

Subjects should be free of acute illness and the lower of 2 hsCRP values, taken at least 2 weeks apart, should constitute the baseline value.

When to Screen for hsCRP?


Low Risk Level

Framingham Risk Score < 10% Pharmacological treatment for severe

genetic dyslipidemia Use clinical judgment, proper timing Careful family history for added risk factors RRS can re-classify low-risk patients

C

Guiding Principles






Health Behaviors

Lifestyle is cornerstone of CAD prevention and should be universally applied

• Prevent chronic diseases Type 2 diabetes, hypertension, dyslipidemia Atherosclerosis Cancer Neuro-degenerative diseases

Recommended Lifestyle Changes:

Smoking cessation Diet: fruit, vegetables, decreased saturated

fats, decreased salt intake Calorie restriction for ideal body weight Daily exercise (30-60 min) Stress management

Guiding Principles






Targets for LDL-C (or apoB):

Nearly all clinical trials measure LDL-C as index of therapy. Recommendations:

Primary target is LDL-C decrease to < 2.0 mmol/L or 50% relative reduction

We recommend apoB < 0.80 g/L as primary alternate target

A

A

Treatment Targets

Each 1.0 mmol/L reduction in LDL-C, is associated with a corresponding 20-25% reduction in CVD mortality and non-fatal myocardial infarction. (Cholesterol Treatment Trialists meta-analysis of 14 statin trials)

Data from the PROVE-IT, TNT, A to Z, IDEAL and SEARCH trials have confirmed that lowering LDL-C to a mean of 2.0 mmol/L or less is associated with the lowest risk of recurrent CVD events in secondary prevention patient populations.

A 50% relative reduction in LDL-C confers close to optimal benefit.


Risk Level Initiate treatment if:

Primary PrimaryLDL-C Alternate

High Consider treatment in all patientsCAD,PVDAtherosclerosisMost Pts with DiabetesFRS>20%RRS>20%

<2 mmol/L Or ↓50% LDL-C ApoB<0.80

Class I Level A Class I Level A

Target Levels

A A






Moderate (strive towards )FRS 10-19% LDL-C>3.5 mmol/L TC/HDL >5.0 hsCRP >2 men 50+, women 60+Family history and hsCRP modulate risk


Class IIA Level A Class IIA Level A

Target Levels

A A

A A






Moderate (strive towards )FRS 10-19% LDL-C>3.5 mmol/L TC/HDL >5.0 hsCRP >2 men 50+, women 60+Family history and hsCRP modulate risk


Class IIA Level A Class IIA Level A

LowFRS<10% LDL-C>5.0mmol/L

↓50% LDL-C

Target Levels

A A

A A

A

Residual Risk (When LDL-C at target)OPTIONAL Secondary Targets

Test Cut-point Intervention

TC/HDL-C >4.0• Niacin• Fibrate

Non HDL-C >3.5 mmol/L• Niacin• Fibrate

Apo B/AI >0.8•Niacin•Ezetimibe

Triglycerides >1.7 mmol/L• Fibrate• Niacin

hsCRP >2.0 mg/L• Statin• Ezetimibe


Targets other than LDL-C (or apoB)

After reaching primary targets (LDL-C or apoB)• High HDL-C predicts atherosclerosis regression• Low HDL-C predicts mortality even when

LDL-C < 1.8 mmol/L• No specific target HDL-C or triglyceride levels

Secondary optional targets unproven to reduce riskConsider them for high-risk patients

Residual Risk

Clinical study data suggest that patients achieving secondary targets have better outcomes.

Therapeutic options include: Fibrates to lower triglycerides, Niacin to raise HDL-C and increasing Statins and/or adding Ezetimibe to further lower LDL-C, apo B and

hsCRP

These therapies must be tested clinically with CV outcome data

• New studies on statins and heart failure• Statins may not reduce risk in advanced heart

failure (CORONA, GISSI HF)

• Similar results for hemodialysis patients (AURORA, 4D trials): no effect on CVD

Use clinical judgment

End-stage renal disease or congestive heart failure due

to systolic dysfunction:

A

A

Pharmacotherapy (LDL Cholesterol):

Immediate treatment for high-risk patients Concomitant diet and lifestyle changes Statin monotherapy decreases LDL-C level A minority will need combination therapy Ezetimibe, Cholestyramine, Niacin, Fibrates Clinical trials ongoing (combination versus

monotherapy)

Pharmacotherapy (Triglycerides)

Levels for high-risk subjects not established Studies show Gemfibrozil reduces CVD Gemfibrozil with statins contraindicated Diet/lifestyle first-line therapies for

hypertriglyceridemia Fibrates prevent pancreatitis (with extreme

hypertriglyceridemia) Impact of fibrates on CVD mortality unproven

Fibrates and Non-Fatal MI

Abourbih S and Eisenberg M. 2009 Am J Med (2009 Aug 19. [Epub ahead of print])

Fibrates and Mortality

Abourbih S and Eisenberg M. 2009 Am J Med (2009 Aug 19. [Epub ahead of print])

Pharmacotherapy (HDL-Cholesterol)

Healthy lifestyle measures increase HDL-C Controversy surrounds low HDL-C treatment Genetic low HDL-C often poses no risk Current medications not effective Statins and fibrates have little effect New clinical trials ongoing

The metabolic pathway of HDL particles: Potential Novel Therapeutic Approaches..

Nissen, S.E. et al.

TorcetrapibDalcetrapib (RO4607381/JTT-705)Anacetrapib

LxR agonists

Apo AI Prod

Statin + niacin helps dyslipidemia with low HDL-C Niacin raises HDL-C better than fibrates Crystalline niacin side-effects Follow serum transaminase levels (hepatoxicity) Awaiting AIM-High and HPS-THRIVE trial results Fibrates effectiveness/safety under study Omega 3 fatty acids + statins

Pharmacotherapy (Combination therapy)

Safety and laboratory monitoring

Measure baseline lipoproteins, CK, ALT before pharmacological therapy

Follow-up measurements semiannually or with therapy changes

Statin side-effects: myalgias, myositis, rhabdomyolysis

Niacin can elevate glucose and ALT Monitor parameters and adjust/withdraw doses Fibrates can raise plasma creatinine: avoid in renal

insuffiency Re-evaluate renal functions and lipid parameters

Risk Assessment and Treatment Targets

Risk Assessment

Initiate/consider treatmentif any of the following:

Primary TargetLDL-C

Primary Alternate ApoB

HIGHFRS > 20%RRS > 20%

• CAD• PVD• Atherosclerosis• Most Diabetic Patients

(consider treatment in all patients)

< 2 mmol/L or ↓ LDL-C 50% ApoB < 0.80

ModerateFRS 10-19%

• LDL-C > 3.5 mmol/L• TC/HDL-C > 5.0• hsCRP > 2 mg/L *• Family history

(strive towards )

LOWFRS < 10%

• LDL-C > 5.0mmol/L ↓ LDL-C 50%

* Only screen for hsCRP in men ≥ 50 and women ≥ 60 if they do NOT already have CVD, diabetes, multiple risk factors, family history or hyperlipidemia


A

A A

Harmonization of CVD Prevention Guidelines Across Canada

2009 ccs can lipid guidelines slide kit

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