The 2009 Canadian Lipid Guidelines

Milan Gupta, MD

Department of Medicine, McMaster UniversityDivision of Cardiology, William Osler Health Centre

Division of Cardiology / CV Surgery, University of Toronto

Disclosures

HonorariaAbbott, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, IMI, Merck, Merck Schering, Novartis, Pfizer, Roche, sanofi-aventis, Servier, Solvay

ResearchAstraZeneca, Bristol Myers Squibb, GSK, IMI, Pfizer, sanofi-aventis

EquityNone

2009 Lipid Guidelines

Care Gap

Secondary Prevention

Primary Prevention and Risk Assessment

A 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a…

Pro

port

ion

al re

du

cti

on

in

even

t ra

te (

%

SE)

Pro

port

ion

al re

du

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on

in

even

t ra

te (

%

SE)

Adapted from Baigent C, et al, Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2005;366:1267–1278.

50

40

30

20

10

0

0.5(19)

1.0(38)

1.5(58)

2.0(77)

-10Reduction in

LDL-C mmol/L (mg/dL)

50

40

30

20

10

-10

0

0.5(19)

1.0(38)

1.5(58)

2.0(77)

Reduction in LDL-C mmol/L (mg/dL)

A prospective meta-analysis of data from 90,056 individuals from 14 trials of statins1

23% reduction in major coronary events

21% reduction in major vascular events

Relationship Between Proportional Reduction in Relationship Between Proportional Reduction in Events and Optimal LDL-C Reduction at 1 YearEvents and Optimal LDL-C Reduction at 1 Year

2006 CCS Dyslipidemia Guidelines

*McPherson 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.

Risk level 

10-year CAD risk

and

and

and

High* >20%

Moderateठ10%-19%

Lowठ<10%

Recommendations

Treatment targets†:Primary: LDL-C <2.0 mmol/LSecondary: TC:HDL-C <4.0

Treat when:

LDL-C ≥3.5 mmol/L orTC:HDL-C ≥5.0

Treat when:

LDL-C ≥5.0 mmol/L orTC: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.

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

CHRC High-Risk Registries: VP and GOALL

Patients are Not Reaching LDL Targets

Statin therapy associated with low risk

Kashani A et al. Circulation. 2006;114:2788-97.

Review of placebo-controlled statin monotherapy* trials; N = 74,102

*Atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatinCK = creatine kinaseAE = adverse events

OutcomeStatin

(%)Placebo

(%) RD P value

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 0.80

Statin better Placebo better

-30 -15 0 15 30Risk difference per 1000 patients (RD)

(95% CI)

2009 Lipid Guidelines

Care Gap

Secondary Prevention

Primary Prevention and Risk Assessment

Primary EndpointCV Death or Non-fatal MI or Non-fatal Stroke

10

5

0

Pe

r cen

t 20

35

15

25

30

Pe

r cen

t

Placebon = 732 (29.3%)

Rosuvastatinn = 692 (27.5%)

No. at riskPlacebo 2497 2315 2156 2003 1851 1431 811Rosuvastatin 2514 2345 2207 2068 1932 1484 855

Hazard ratio = 0.9295% CI 0.83 to 1.02

p = 0.12

Kjekshus J et al,N Engl J Med 2007;357

Months of follow-up0 36302418126

HR – Hazard Ratio; CI – Confidence Interval*adjusted HR

0.90

0.94

p value

[99% CI 0.91-1.11]

[95.5% CI 0.90-1.12]

CI

1.01

1.00

HR*

1283 (56)1305 (57)All-cause mortality or CV hospitalisations

644 (28)657 (29)All-cause mortality

Primary Endpoints

Placebo(n=2289)

n (%)

Rosuvastatin(n=2285)

n (%)

(i) All cause mortality and (ii) All cause mortality or hospitalizations for cardiovascular reasons

GISSI-HF – Co-Primary Endpoints

GISSI-HF Investigators. Lancet 2008; doi:10.1016/S01.40-6736(08)61240-4

p=0.37

4D study in diabetic hemodialysis 4D study in diabetic hemodialysis patients: no benefit of statin therapypatients: no benefit of statin therapy

4D=Die Deutsche Diabetes Dialyse Studie

No. at risk:

Placebo 636 532 383 252 136 51 19

Atorvastatin 619 515 378 252 136 58 29

Wanner C et al. N Engl J Med 2005; 353: 238–248

Cumulative incidence of primary endpoint (%)

Time (years)

Atorvastatin

Placebo60

50

40

30

20

10

060 1 2 3 4 5

Placebo

AURORA: primary endpointAURORA: primary endpointKaplan-Meier estimate of time to Kaplan-Meier estimate of time to

first major CV eventfirst major CV event

No. at risk:

Rosuvastatin 1390 1152 962 826 551 148

Placebo 1384 1163 952 809 534 153

Cumulative incidence of primary endpoint (%)

Years from randomization

Rosuvastatin

HR=0.96 (95% CI 0.84–1.11)P=0.59

0

5

10

15

20

25

30

35

40

0 1 2 3 4 5

2009 Lipid Guidelines

Care Gap

Secondary Prevention

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 resistance-related 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. fathypertension and intracerebral

haemorrhage

May overestimate

Lifetime Risk

70

60

50

40

30

20

10

050 60 70 80 90

69

5046

36

5

60

50

40

30

20

10

0

Men(n = 3564)

Women

(n = 4362)

Adjusted cumulative incidence of CVD (%)

50 60 70 80 90

≥2 Major RFs1 Major RF

≥1 Elevated RF≥1 Not optimal RF

All optimal RFs

70

50

39

27

8

Attained age (years)

Lloyd-Jones DM et al. Circulation. 2006;113:791-8.

*Optimal RF defined as total cholesterol <4.65 mmol/LBP <120/80 mmHg, nonsmoker, nondiabetic

< 1 mg/L 1 to 3 mg/L > 3 mg/L

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

PHS 1997 WHS 2000 UK 2000 MONICA 2004 ARIC 2004 Iceland 2004

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

0

1

2

3

NHS 2004

HPFUS 2004 EPIC-N 2005 Strong 2005 Kuopio 2005 FHS 2008

0

1

2

3

0

1

2

3

0

1

2

3

CHS 2005 PIMA 2005

Fu

lly A

dju

ste

d R

ela

tive

Ris

k

0

1

2

3

hsCRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated

Ridker PM et al. Circulation 2003;108:2292-7.

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 hsCRP

Rosuvastatin 20 mg (n=8,901) MIStrokeUnstable anginaCVD DeathCABG/PTCA

4-week run-in

No prior CVD or DMMen ≥50, Women ≥ 60

LDL <130 mg/dL(3.36 mmol/L)

hsCRP ≥2 mg/L

Placebo (n=8,901)

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

JUPITER -1° Composite Endpoint of Non-Fatal MI, Non-Fatal Stroke, UA/Revascularization and CV Death

0 1 2 3 4Follow-up (Years)Number at Risk

Rosuvastatin

Placebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157

8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Placebo251/8,901

Rosuvastatin142/8,901

HR 0.56, 95% CI 0.46-0.69p<0.00001

- 44%

Cu

mu

lati

ve In

cid

ence

0.00

0.02

0.04

0.06

0.08

Number Needed to Treat (NNT5) = 25

Ridker PM et al. N Engl J Med 2008;359:2195-207.

JUPITERSecondary Endpoint – All Cause Mortality

Placebo 247 / 8901

Rosuvastatin 198 / 8901

HR 0.80, 95%CI 0.67-0.97

P= 0.02

- 20 %

0 1 2 3 4

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cu

mu

lati

ve I

nci

den

ce

Number at Risk Follow-up (years)

RosuvastatinPlacebo

8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 2278,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246

Ridker et al NEJM 2008

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 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, MDDominic Ng, MD, PhD Glen J. Pearson, Pharm DAllan Sniderman, MD James M. Stone, MD, PhDEhud Ur, MD

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

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

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

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

C

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 hsCRP– Web-based version www.reynoldsriskscore.org

We now recommend cardiovascular risk (total CVD) assessment, not only CAD, as CHEP and CDA do.

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

• “ 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”

C

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

• 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

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 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

•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 hsCRP

•If hsCRP > 2, consider treatment (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 be used.

Which Moderate Risk Patients Warrant Treatment?

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

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

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

<2 mmol/L Or ↓50% LDL-C ApoB<0.80

Class IIA Level A Class IIA Level A

Target Levels

A A

A A

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

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

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

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

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