Beyond Framingham: Risk Assessment & Treatment for .../media/...Objectives •Understand our current guidelines for risk assessment and treatment of dyslipidemia in primary prevention

Ronald M. Goldenberg, MD, FRCPC, FACEConsultant Endocrinologist, North York General Hospital

Medical Co-Director, LMC Endocrinology Centres, Thornhill

Beyond Framingham: Risk Assessment & Treatment for Primary Prevention

Disclosures

Dr. Goldenberg has received honoraria, consultants fees, or research fees from:

• Astra Zeneca• Merck• Pfizer• Abbott

Objectives

• Understand our current guidelines for risk assessment and treatment of dyslipidemia in primary prevention patients

• Review the role of additional investigations, beyond traditional risk factors, and their potential use in risk assessment

• Discuss the role of hs-CRP in determining CV risk and influencing treatment decisions

Case Presentation

• 58 year-old male, europid, BMI 27, waist 92 cm

• Non smoker

• BP 135/85

• Father died of MI at 62

• Fasting laboratory values: Total C: 4.4 mmol/L TG: 1.3 mmol/L HDL-C: 1.04 mmol/L LDL-C: 2.8 mmol/L TC/HDL-C ratio: 4.3 FPG: 5.4 mmol/L

Would you treat him with a statin?

Case Presentation: Question

• What is his calculated 10 year risk of CVD?

www.cvdriskcheck.ca

Estimate 10-Year Risk for Men

1470-74

65-69

1160-64

1055-59

850-54

1575+

745-49

540-44

235-39

030-34

PointsAge

4>7.2

36.2 - 7.2

25.2 – 6.2

14.1 – 5.2

0

0No

4Yes

Points

3. Smoking

2 1.6

4. HDL-C

42140 - 159

3

1

0

-2

Untreated

5160+

3130 - 139

2120 - 129

0

1.911.601.4-11.1-2

6.785.67

4.763.953.342.832.32

21.61518.41415.61313.31211.2119.4107.99

Moderate Risk

Global CVD 10-Year Risk for MenPoints 10-year Risk, %

-3 or less

1617

18+

< 1

25.329.4> 30

• Framingham Risk Calculation: 15.6%

• Moderate Risk

Case Presentation: Question

• What is his calculated 10 year risk of CVD?

• What are guideline recommendations regarding statin based on lipids?

HighCAD, PVD, atherosclerosisMost with diabetesFRS ≥ 20%

ModerateFRS 10% - 19%

LowFRS < 10%

Level of Risk (definition)

Risk categories and treatment recommendations

Canadian Cardiovascular Society Guidelines on Dyslipidemia

2009

Initiate treatment if: LDL-C

Consider treatment < 2.0 mmol/L or

in all patients ≥ 50% LDL-C

LDL-C > 3.5 mmol/L < 2.0 mmol/L or

TC/HDL-C > 5.0 ≥ 50% LDL-C

LDL-C ≥ 5.0 mmol/L ≥ 50% LDL-C

Genest J et al. Can J Cardiol 2009; 25: 567-579.

Primary target

58 year old; BMI 27LDL-C 2.8 mmol/L

TC/HDL-C ratio 4.3 mmol/L BP 135/85

Nonsmoker

Case Presentation: Question • What other factors or investigations should be considered

to improve risk assessment and decide re: intervention?

• Framingham data underestimate CVD risk for patients with very high cholesterol levels. Hence, most patients with an LDL-C ≥ 5.0 mmol/L require drug treatment.

• Framingham data may underestimate the importance of family history. A positive family history of premature CVD (< 60y) increases risk by 1.7-fold in women and 2-fold in men.

• Only conventional risk factors are considered.

• Only 10 year risk is calculated. Longer term risk is underestimated.

• Underestimates risk in metabolic syndrome.

Use clinical judgement

Caveats of Framingham Risk Calculation

• Assess exercise capacity: graded exercise stress testing

• Noninvasive assessment of atherosclerosis:

• ankle-brachial index (ABI)

• carotid imaging (CIMT)

• coronary calcium score: EB-CT or MD-CT

• Laboratory: apo B; Lp (a); Lp-PLA2; hs-CRP

• Individuals in the intermediate-risk category (FRS between 10% to 19%) may be moved to a higher or lower risk category based on additional investigations

Additional Investigations of Potential Use in Risk Assessment

Noninvasive Screening: Ankle-Brachial Index (ABI)

• Ratio of ankle to arm systolic blood pressure (SBP)– ABI ≤0.90 indicates

peripheral artery disease1-3

• 1592 randomly selected older adults (55 to 74 years)3

– ABI ≤0.90 at baseline addedpredictive value for fatal MI

• ABI is useful to refine the assessment of intermediate-risk patients ≥50 years old1,2

1. Greenland P, et al. Circulation. 2001;104:1863-1867.2. Smith SC, et al. Circulation. 2000;101:111-116.3. Lee AJ, et al. Circulation. 2004;110:3075-3080.

Measuring ABI.

Noninvasive Screening: Carotid Intima-Media Thickness (CIMT)

• CIMT measured by carotid artery ultrasound1– SHAPE Task Force: Warranted for screening asymptomatic men

45 to 75 years old and women 55 to 75 years old who are not in the category of very low cardiovascular risk

– Although CIMT quantification is not yet a standard measure, evidence of early carotid atherosclerosis (visible plaques or IMT ≥ 1.5 mm) by routine ultrasonography places patient in high-risk category and is probably an indication for statin therapy3

1. Naghavi M, et al. Am J Cardiol. 2006;98[suppl]:2H-15H. 2. Adapted from Sethi KS, et al. Ind J Radiol Imag. 2005;15:91-98. 3. Genest J et al. Can J Cardiol 2009; 25:567-579.

Profiled view of the normal carotid bifurcation; an area of normal flow reversal (blue) is noted at the carotid bulb.2

Significant internal carotid stenosis in the region of an echogenic plaque indicated by color flow Doppler aliasing, with lighter shades of color indicating turbulence with increased velocity of flow.2

Noninvasive Screening : Coronary Artery Calcium Score (CACS)

Relationship between CACS and the baseline Framingham risk score in the prediction of

coronary death or nonfatal MI*

CACS:

Greenland P, et al. JAMA. 2004;291:210-215.

0

5

10

15

20

25

0-9 10-15 16-20 ≥21Framingham Risk Score, %

Haz

ard

Rat

io

0 1-100 101-300 ≥301

EBCT image showing extensive triple-vessel coronary calcification

• Measure of total atherogenic particle number (>90% are LDL particles)

• May be better marker for risk of vascular disease than LDL-C

• Can be substituted for LDL-C in practice and is primary alternate target to LDL-C in new lipid guidelines

• Target < 0.80 g/L in high and moderate-risk patients

• Not measured in most laboratories and poor provincial coverage

Apolipoprotein B (ApoB)

Genest J et al. Can J Cardiol 2009; 25: 567-579.

• LDL particle with apo B attached to apo (a) protein

• Potent predictor of premature atherosclerosis

• Meta-analysis of 36 studies indicates RR for CHD events of 1.27 for those in upper vs. lower tertile of Lp(a)

• No longer a predictor once LDL-C markedly reduced

• May be useful for risk assessment in moderate-risk patients or those with family history of early CAD

• Lp(a)> 30 mg/dl (300 mg/L) in an individual with a TC/HDL-C ratio > 5.0 or other major risk factors may indicate a need for more intensive LDL-C lowering.

Lipoprotein (a) -- Lp(a)

The Emerging Risk Factors Collaboration. JAMA 2009; 302:412-423.McPherson R et al. Can J Cardiol. 2006;22:913-927.

• Lipoprotein-associated, macrophage-secreted enzyme

• Highly specific biomarker for vascular inflammation

• Elevated LP-PLA2 activity (1 SD) predicts an 8 to 16% increased risk for MI, stroke, or CV mortality

• Cleaves oxidized fatty acids from lipids; in plasma, mainly carried by LDL-C

• Some recommend testing in moderate and high-risk patients

• Ongoing hard outcome trial assessing role of Lp-PLA2 inhibitor (darapladib) in reducing CV events

Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)

Davidson MH et al. Am J Cardiol 2008. 101 (supp); 51F-57F.The LP-PLA2 Studies Collaboration. Lancet 2010. 375:1536-1544.

hs-CRP as a Risk Factor For Future CVD : Primary Prevention Cohorts

0 1.0 2.0 3.0 4.0 5.0 6.0

Kuller MRFIT 1996 CHD Death

Ridker PHS 1997 MI

Ridker PHS 1997 Stroke

Tracy CHS/RHPP 1997 CHD

Ridker PHS 1998,2001 PAD

Ridker WHS 1998,2000,2002 CVD

Koenig MONICA 1999 CHD

Roivainen HELSINKI 2000 CHD

Mendall CAERPHILLY 2000 CHD

Danesh BRHS 2000 CHD

Gussekloo LEIDEN 2001 Fatal Stroke

Lowe SPEEDWELL 2001 CHD

Packard WOSCOPS 2001 CV Events*

Ridker AFCAPS 2001 CV Events*

Rost FHS 2001 Stroke

Pradhan WHI 2002 MI,CVD death

Albert PHS 2002 Sudden Death

Sakkinen HHS 2002 MI

Relative Risk (upper vs lower quartile)Ridker PM. Circulation 2003;107:363-9

Event-Free Survival With CRP, LDL-C Levels Above or Below the Median*

Ridker PM et al. N Engl J Med. 2002;347:1557-1565.*Median values: CRP=1.52 mg/L, LDL-C=3.22 mmol/L.

1.00

0.99

0.98

0.97

0.96

0.000 2 4 6 8

Years

Probability

N=27,939

Low CRP–low LDL-C

Low CRP–high LDL-C

High CRP–low LDL-C (25-30 million US adults)

High CRP–high LDL-C

Reynolds Risk Score(www.reynoldsriskscore.org

or www.cvdriskcheck.ca)

www.reynoldsriskscore.org; Accessed Nov. 11, 20081Ridker P et al. JAMA 2007;297:611-619; 2Ridker P et al. Circulation 2008;118.

45% of women1 and 20 % of men2 at intermediate risk by Framingham are reclassified to higher or lower-risk groups using the Reynolds Score

http://www.reynoldsriskscore.org�http://www.reynoldsriskscore.org�

Rosuvastatin 20 mg (N=8901) MIStrokeUnstableAngina

CVD DeathCABG/PTCA

JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of

Rosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRP

Ridker et al, Circulation 2003;108:2292-2297.

No Prior CVD or DMMen >50, Women >60

LDL 2 mg/L (median 4.3)

JUPITERTrial Design

Placebo (N=8901)

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

0

1

2

3

4

5

hsC

RP

(mg/

L)

0

20

40

60

80

100

120

140

LD

L (m

g/dL

)

Months0 12 24 36 48

0

10

20

30

40

50

60

0

20

40

60

80

100

120

140

0 12 24 36 48

TG

(m

g/dL

)H

DL

(mg/

dL)

Months

JUPITEREffects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP

LDL decrease 50 percent at 12 months

hsCRP decrease 37 percent at 12 months

HDL increase 4 percent at 12 months

TG decrease 17 percent at 12 months

Ridker et al NEJM 2008

2.8

1.4

4.3

1.27

1.33

2.2

3.5

JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Placebo 251 / 8901

Rosuvastatin 142 / 8901

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

Number Needed to Treat (NNT5) = 25

- 44 %

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulat

ive

Inci

denc

e

Number at Risk Follow-up (years)

RosuvastatinPlacebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

Ridker et al NEJM 2008

JUPITERIndividual Components of the Primary Endpoint

*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death

Endpoint Rosuvastatin Placebo HR 95%CI P

Primary Endpoint* 142 251 0.56 0.46-0.69

JUPITERPrimary Endpoint – Subgroup Analysis I

0.25 0.5 1.0 2.0 4.0

Rosuvastatin Superior Rosuvastatin Inferior

MenWomen

Age < 65Age > 65

SmokerNon-Smoker

CaucasianNon-Caucasian

USA/CanadaRest of World

HypertensionNo Hypertension

All Participants

N P for Interaction

11,001 0.806,801

8,541 0.329,261

2,820 0.6314,975

12,683 0.575,117

6,041 0.5111,761

10,208 0.537,586

17,802

Ridker et al NEJM 2008

JUPITERPrimary Endpoint – Subgroup Analysis by FRS and RRS

Ridker P et al. Circ: CV Quality & Outcomes 2010.

5-y NNT: FRS 5-10%=40FRS 11-20%=18

JUPITERSecondary Endpoint – All Cause Mortality

Placebo 247 / 8901

Rosuvastatin 198 / 8901

HR 0.80, 95%CI 0.67-0.97P= 0.02

- 20 %

0 1 2 3 4

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cum

ulat

ive

Inci

denc

e

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

JUPITERDual Target Analysis: LDLC 2 mg/LHR 0.64 (0.49-0.84)

LDL < 1.8 mmol/Land

hsCRP < 2 mg/L HR 0.35 (0.23-0.54)

Placebo HR 1.0 (referent)

P < 0.0001

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulat

ive

Inci

denc

e

Number at Risk Follow-up (years)

RosuvastatinPlacebo

7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 1457,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168

Ridker et al Lancet 2009

♦hs-CRP measurement is independent marker of CVD risk

♦ In men >50y and women > 60y at intermediate risk (10%–19% risk of CVD per 10 years) and LDL-C < 3.5 mmol/L:

-hs-CRP may help further risk stratification (RRS)

-statin therapy beneficial in those with hs-CRP > 2 mg/L (JUPITER)

hs-CRP:Recommendations for use in Clinical Practice

Genest J et al. Can J Cardiol 2009; 25: 567-579.

♦Measurements of hs-CRP:♦should be performed twice ( at least 2 weeks apart)♦should be free of acute illness♦ lower of the 2 values constitutes the baseline value♦ fasting or nonfasting♦ if level >10 mg/L, test should be repeated, patient

examined for sources of infection or inflammation

hs-CRP:Recommendations for use in Clinical Practice

Genest J et al. Can J Cardiol 2009; 25: 567-579.

High

CAD, PVD, atherosclerosis

Most with diabetes

FRS ≥ 20%RRS ≥ 20%

Moderate

FRS 10% - 19%

Family history and

hs-CRP modulates risk (RRS)

Low

FRS < 10%

Level of Risk (definition)

Risk categories and treatment recommendations

Canadian Cardiovascular Society Guidelines on Dyslipidemia

2009

Initiate treatment if: LDL-C

Consider treatment < 2.0 mmol/L or

in all patients ≥ 50% LDL-C

LDL-C > 3.5 mmol/L < 2.0 mmol/L or

TC/HDL-C > 5.0 ≥ 50% LDL-C

hs-CRP > 2 mg/L

(men > 50y; women > 60y)

LDL-C ≥ 5.0 mmol/L ≥ 50% LDL-C

Genest J et al. Can J Cardiol 2009; 25: 567-579.

Primary target

Brugts, J J et al. BMJ 2009;338:b2376

Statins and Primary Prevention: Meta-analysis of 10 Trials

All cause mortality: OR = 0.88 (0.81-0.96)

Major coronary events: OR = 0.70 (0.61-0.81)

Major cerebrovascular events: OR = 0.81 (0.71-0.93)

Cancer: OR = 0.97 (0.89-1.05)

Case Presentation

• 58 yo male at moderate risk (Framingham)

• LDL-C = 2.8 mmol/L; TC/HDL ratio 4.3

• hs-CRP = 4.3 mg/L

• Question: Would you treat him with a statin?

• Interventions:

- Therapeutic Lifestyle Changes

- Statin (based on JUPITER)

Case Presentation (cont’d)

Conclusions

• Additional investigations can be used to enhance risk by FRS (e.g., hs-CRP; Lp (a); Lp-PLA2; ABI; CIMT; CCS)

• Adding hs-CRP and family history to risk calculation (e.g., Reynolds Risk Score) may improve risk assessment

• Primary prevention patients (men >50y and women >60y) with hs-CRP > 2mg/L and LDL-C< 3.5 mmol/L benefit from statin therapy (JUPITER)

• Canadian Lipid Guidelines for primary prevention now recommend hs-CRP testing for moderate-risk men >50y and women >60y with LDL-C 2mg/L

His LDL-C was normal, but hs-CRP high

1943-2010

The unknown moderate risk patient

Slide Number 1DisclosuresObjectivesCase Presentation Case Presentation: Question Slide Number 6Estimate 10-Year Risk for MenSlide Number 10Global CVD 10-Year Risk for MenCase Presentation: Question Canadian Cardiovascular Society Guidelines on Dyslipidemia 2009Slide Number 14Slide Number 15Slide Number 16Slide Number 17Noninvasive Screening: Ankle-Brachial Index (ABI)Noninvasive Screening: �Carotid Intima-Media Thickness (CIMT)Noninvasive Screening : Coronary Artery Calcium Score (CACS)Slide Number 21Slide Number 22Slide Number 23Slide Number 24hs-CRP as a Risk Factor For Future CVD : Primary Prevention Cohorts�Event-Free Survival With CRP, LDL-C �Levels Above or Below the Median*Slide Number 27Slide Number 28Reynolds Risk Score�(www.reynoldsriskscore.org �or www.cvdriskcheck.ca)Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 37Slide Number 38Slide Number 39hs-CRP:Recommendations �for use in Clinical PracticeSlide Number 43Canadian Cardiovascular Society Guidelines on Dyslipidemia 2009Slide Number 45Case Presentation Slide Number 47ConclusionsSlide Number 49