guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease...
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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 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
Primary Panel
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 collaborationDisclosure of writers’ links to pharmaceutical
industryPartnered 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)•Moderate risk defined as FRS 10-19% ten-year risk •Family history part of risk stratification •hsCRP part of risk stratification in moderate 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 Disease
CVD causes 1:3 deaths 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 favour 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
Genest J et al. Can J Cardiol 2009 Oct;[in press].
Screening
• Men over 40 and postmenopausal women• Anyone with atherosclerosis regardless of age• Anyone with diabetes regardless of age• Family history of premature CVD (<60 yrs)• 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
• 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 (or more)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
Target Adults for Screening(unless compelling reason)
Determine Cardiovascular Risk
Institute Lifestyle Changes
Treat according to Level of Risk
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 Moderate 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 if hsCRP > 2.0 mg/L (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 (LDL-C > 5.0 mmol/L) Use clinical judgment, proper timing Careful family history for added risk factors RRS can re-classify low-risk patients
C
Guiding Principles
Target Adults for Screening(unless compelling reason)
Determine Cardiovascular Risk
Institute Lifestyle Changes
Treat according to Level of Risk
Health Behaviours
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
Target Adults for Screening(unless compelling reason)
Determine Cardiovascular Risk
Institute Lifestyle Changes
Treat according to Level of Risk
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
In high- and moderate-risk subjects
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
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
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
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 HPS2-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