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Guidelines for the diagnosis

and Treatment of Dyslipidemia


and Prevention of
Cardiovascular Disease 2009
2009 Canadian Lipid Guidelines

Jacques Genest MD Milan Gupta MD


Ruth McPherson MD PhD Robert A. Hegele MD
Jiri Frohlich MD David C. Lau MD
 Lawrence Leiter MD
Todd Anderson MD Gary F. Lewis MD
Norm Campbell MD
Eva Lonn MD
André Carpentier MD
G.B. John Mancini MD
Patrick Couture MD
Dominic Ng MD PhD
Robert Dufour MD
Glen J. Pearson Pharm D
George Fodor MD
Allan Sniderman MD
Gordon Francis MD
James M. Stone MD, PhD
Ehud Ur MD
Steven Grover 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,
Process:
Transparency and Cooperation
Æ Address stakeholder concerns
Æ Retain 2006 principles but more
collaboration
Æ Transparent disclosure of potential
bias
Æ Disclosure of writers’ links to
pharmaceutical industry
Æ Teamed with Canadian Cardiovascular
Society
Æ Teamed with CIHR
Æ Used primary and secondary review
Changes Since 2006

èInvolvement of the Canadian Vascular Coalition and CIHR


èSecondary and High - Risk prevention :
•Strategy better defined
•Clinical studies on end-stage disease (advanced heart failure
and hemodialysis)
èPrimary 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)
èTargets
•Simplified target levels
•Apo B role defined
•Secondary targets evaluated according to available evidence

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


Introduction: Burden of
Health
CVD causes 1:3 death in Canada

StatsCan/Canada
Stakeholders in the
Elaboration
of Canadian Lipid Guidelines
Æ C-Change: Canadian Cardiovascular Harmonization
of National Guidelines Endeavor.

Æ Canadian Association of Cardiac Rehabilitation


Æ Canadian Cardiovascular Society
Æ Canadian College of Family Physicians
Æ Canadian Council for Tobacco Control
Æ Canadian Council of Cardiovascular Nurses
Æ Canadian Diabetes Association
Æ Canadian Hypertension Society
Æ Canadian Medical Association
Æ Canadian Obesity Network
Æ Canadian Pharmacist Association
Æ Canadian Society for Exercise Physiology
Æ Canadian Stroke Network
Æ Canadian Working Group on Dyslipidemias
Æ Obesity Canada
Æ Public Health Agency of Canada
Æ Royal College of Physicians and Surgeons of Canada
Æ Canadian Institutes of Health Research (CIHR)
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 Grade
 Class I
 Evidence and/or general agreement that a given diagnostic procedure/treatment is beneficial,
useful and effective
I IIa IIb III

 

 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
A

 Class II b Usefulness/efficacy less well established


 

 Class III
 Evidence that the treatment is not useful and in some cases may be harmful
 

C

 Level of Evidence
 Level

A
 Data derived from multiple randomized clinical trials (RCT) or meta-analysis
Guiding Principles

Target Adults for


Screening
( unless compelling reason )

Determine Cardiovascular
Risk

Institute Lifestyle
Changes

Treat according to Level


of Risk

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


C
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)
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

Metabolic Syndrome C

• 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

Metabolic Syndrome:
Meta-analysis of Cardiovascular
Risk

Motillo S, Eisenberg M. 2009 Unpublished


Classification of the Metabolic Syndrome
(International Diabetes Federation)

• Central obesity:
Æ 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)
Guiding Principles

Target Adults for


Screening
( unless compelling reason )

Determine Cardiovascular
Risk

Institute Lifestyle
Changes

Treat according to Level


of Risk

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


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

v FRS estimates 10-year risk


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

S u rro g a te E n d - p o in ts o f
A th e ro scle ro sis - Te stin g fo r
A th e ro scle ro sis
v Ankle brachial index
v Exercise stress test
v Carotid B mode ultrasonography
v Cardiac Computed tomography
(Electron beam Computed
Tomography -EBCT); Multi-Detector
Computed Tomography Coronary
Angiography (MDCT-CA)
The presence of atherosclerosis C
• places the individual in the high -
risk category
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 risk
o 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
A g/L)
§ TC/HDL-C ratio > C5.0
§ hsCRP > 2mg/L in men over 50, B

women over 60
– hsCRP should be performed selectively

Consider cost/benefit of preventative

therapy
Discuss and weigh patient’s desire


Treatment for the Moderate Risk
Supported by Primary Prevention
Data
 The indications for pharmacological
interventions are based on the statin
primary prevention studies including:

è AFCAPS/TexCAPS
è WOSCOP
è ASCOT
è HPS
è JUPITER

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


hsCRP Identifies a Group of
Intermediate Risk Subjects Who
Benefit From Statin Therapy
CV death , non - fatal stroke , non -
9 fatalMI , unstable angina or arterial
revascularization
8
7 Placebo
Percent of patients with

6
Hazard Ratio 0 . 56
5 ( 95 % CI 0 . 46 - 0 . 69 )
P < 0 . 00001 Rosuvastatin 20 mg
primary endpoint

4
3
2
1
0
0 1 2 3 4 5 Years
Number at risk
RSV 8901 8412 3893
1353 538 157
Placebo 8901 8353 3872
1333 531 174

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


When to Screen for hsCRP?

èThe measurement of high-sensitivity C-reactive


protein (hsCRP) should not be performed on
everyone.
èMen >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).
èSubjects should be free of acute illness and the
lower of 2 hsCRP values, taken at least 2 weeks apart,
should constitute the baseline value.

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


Low Risk Level

§ Framingham Risk Score < 10%


§ Pharmacological treatment for severe
C

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

Guiding Principles

Target Adults for


Screening
( unless compelling reason )

Determine Cardiovascular
Risk

Institute Lifestyle
Changes

Treat according to Level


of Risk

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


Health Behaviors
 Lifestyle is cornerstone of CAD
prevention and should be
universally applied
• Prevent chronic diseases
ÆType 2 diabetes, hypertension,
dyslipidemia
ÆAtherosclerosis
ÆCancer
ÆNeuro-degenerative diseases

Recommended Lifestyle
Changes:

ÆSmoking cessation
ÆDiet: fruit, vegetables,
decreased saturated fats,
decreased salt intake
ÆCalorie restriction for ideal body
weight
ÆDaily exercise (30-60 min)
ÆStress management

Guiding Principles

Target Adults for


Screening
( unless compelling reason )

Determine Cardiovascular
Risk

Institute Lifestyle
Changes

Treat according to Level


of Risk

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


Targets for LDL-C (or apoB):

 Nearly all clinical trials measure LDL-


C as index of therapy.
Recommendations:

ÆPrimary target is LDL-C


A decrease to <
2.0 mmol/L or 50% relative
reduction
Æ
A
ÆWe recommend apoB < 0.80 g/L as
primary alternate target

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


Genest J et al. Can J Cardiol 2009 Oct;[in press].
Target Levels
Risk Level Primary
Initiate treatment if : Primary
High Consider treatment in < 2 mmol
LDL - C /L
all patients Or Alternate
↓50% LDL-C
CAD,PVD ApoB<0.80
Atherosclerosis
Most Pts with Diabetes
FRS>20% Class I Level A
RRS>20% Class I Level A
A A
Target Levels
Risk Level Primary
Initiate treatment if : Primary
High Consider treatment in < 2 mmol
LDL - C /L
all patients Or Alternate
↓50% LDL-C
Moderate
CAD,PVD (strive towards ) ApoBmmol
< 2 /L
<0.80
FRS 10-19% LDL-C>3.5 mmol/L
Atherosclerosis Or ↓50% LDL-C
Most Pts with Diabetes TC/HDL >5.0 ApoB<0.80
FRS>20% hsCRP >2 Class I Level A
RRS>20% men Class I Level A
50+, women 60+ A A
Family history and hsCRP modulate
risk Class IIA Level A
Class IIA Level A

A A
Target Levels
Risk Level Primary
Initiate treatment if : Primary
High Consider treatment in < 2 mmol
LDL - C /L
all patients Or Alternate
↓50% LDL-C
Moderate
CAD,PVD (strive towards ) ApoBmmol
< 2 /L
<0.80
FRS 10-19% LDL-C>3.5 mmol/L
Atherosclerosis Or ↓50% LDL-C
Most Pts with Diabetes TC/HDL >5.0 ApoB<0.80
FRS>20% hsCRP >2 Class I Level A
RRS>20% men Class I Level A
50+, women 60+ A A
Family history and hsCRP modulate
risk Class IIA Level A
Class IIA Level A
Low ↓50% LDL-C
FRS<10% LDL-C>5.0mmol/L

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].


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
Residual Risk

v Clinical study data suggest that patients


achieving secondary targets have better
outcomes.
v
v Therapeutic options include:
v Fibrates to lower triglycerides,
v Niacin to raise HDL-C and
v increasing Statins and/or
v adding Ezetimibe to further lower LDL-C, apo B
and hsCRP
v
v These therapies must be tested clinically
with CV outcome data
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 A
advanced heart failure (CORONA,
GISSI HF)

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

Pharmacotherapy (LDL
Cholesterol):

v Immediate treatment for high-risk


patients
v Concomitant diet and lifestyle
changes
v Statin monotherapy decreases LDL-C
level
v A minority will need combination
therapy
v Ezetimibe, Cholestyramine, Niacin,
Fibrates
v Clinical trials ongoing (combination
Pharmacotherapy
(Triglycerides)

v Levels for high-risk subjects not


established
v Studies show Gemfibrozil reduces
CVD
v Gemfibrozil with statins
contraindicated
v Diet/lifestyle first-line therapies for
hypertriglyceridemia
v Fibrates prevent pancreatitis (with
extreme hypertriglyceridemia)
v 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)

v Healthy lifestyle measures increase


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

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

Apo AI Prod

LxR agonists

Torcetrapib
Dalcetrapib (RO4607381/JTT-705)
Anacetrapib

Nissen, S.E. et al.


Pharmacotherapy
( Combination therapy )
v Statin + niacin helps dyslipidemia
with low HDL-C
v Niacin raises HDL-C better than
fibrates
v Crystalline niacin side-effects
v Follow serum transaminase levels
(hepatoxicity)
v Awaiting AIM-High and HPS-THRIVE
trial results
v Fibrates effectiveness/safety under
study
Safety and laboratory
monitoring

v Measure baseline lipoproteins, CK,


ALT before pharmacological therapy
v Follow-up measurements
semiannually or with therapy
changes
v Statin side-effects: myalgias,
myositis, rhabdomyolysis
v Niacin can elevate glucose and ALT
v Monitor parameters and
adjust/withdraw doses
v Fibrates can raise plasma creatinine:
avoid in renal insuffiency
v Re-evaluate renal functions and lipid
parameters
Risk Assessment and
Treatment Targets
Risk Initiate/consider treatment Primary Target Primary Alternate
Assessment if any of the following: LDL-C ApoB

HIGH CAD
FRS > 20% PVD
RRS > 20% Atherosclerosis

Most Diabetic Patients < 2 mmol/L or


 ↓ LDL-C 50% ApoB < 0.80
(consider treatment in all patients)

Moderate LDL-C > 3.5 mmol/L A A


FRS 10-19% TC/HDL-C > 5.0
hsCRP > 2 mg/L *

Family history

(strive towards )
LOW LDL-C > 5.0mmol/L ↓ LDL-C 50%
FRS < 10% 

A
* 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].


Harmonization of CVD
Prevention Guidelines Across
Canada