Beyond Framingham: Risk Assessment & Treatment for Primary Prevention

Transcription

1 Beyond Framingham: Risk Assessment & Treatment for Primary Prevention Ronald M. Goldenberg, MD, FRCPC, FACE Consultant Endocrinologist, North York General Hospital Medical Co-Director, LMC Endocrinology Centres, Thornhill

2 Disclosures Dr. Goldenberg has received honoraria, consultants fees, or research fees from: Astra Zeneca Merck Pfizer Abbott

3 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

4 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?

5 Case Presentation: Question What is his calculated 10 year risk of CVD?

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7 Estimate 10-Year Risk for Men 1. Age 2. Total Cholesterol (mmol/l) Age Points Total Cholesterol <4.1 Points > year old; BMI 27;Nonsmoker TC 4.4 mmol/l; HDL-C 1.04 mmol/l BP 135/85 FPG 5.4 mmol/l

8 Estimate 10-Year Risk for Men 3. Smoking Smoker Points No 0 Yes 4 4. HDL-C 5. Blood Pressure HDL-C > <0.9 Points Sys BP < Untreated Treated 58 year old; BMI 27;Nonsmoker TC 4.4 mmol/l; HDL-C 1.04 mmol/l BP 135/85 FPG 5.4 mmol/l

9 Global CVD 10-Year Risk for Men Points 10-year Risk, % -3 or less < > 30 Moderate Risk

10 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?

11 Canadian Cardiovascular Society Guidelines on Dyslipidemia 2009 Risk categories and treatment recommendations Level of Risk (definition) Initiate treatment if: Primary target LDL-C High CAD, PVD, atherosclerosis Most with diabetes FRS 20% Consider treatment in all patients < 2.0 mmol/l or 50% LDL-C Moderate FRS 10% - 19% LDL-C > 3.5 mmol/l TC/HDL-C > 5.0 < 2.0 mmol/l or 50% LDL-C Low FRS < 10% Genest J et al. Can J Cardiol 2009; 25: LDL-C 5.0 mmol/l 50% LDL-C 58 year old; BMI 27 LDL-C 2.8 mmol/l TC/HDL-C ratio 4.3 mmol/l BP 135/85 Nonsmoker

12 Case Presentation: Question What other factors or investigations should be considered to improve risk assessment and decide re: intervention?

13 Caveats of Framingham Risk Calculation 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

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15 Additional Investigations of Potential Use in Risk Assessment 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

16 Noninvasive Screening: Ankle-Brachial Index (ABI) Ratio of ankle to arm systolic blood pressure (SBP) ABI 0.90 indicates peripheral artery disease randomly selected older adults (55 to 74 years) 3 ABI 0.90 at baseline added predictive value for fatal MI ABI is useful to refine the assessment of intermediaterisk patients 50 years old 1,2 Measuring ABI. 1. Greenland P, et al. Circulation. 2001;104: Smith SC, et al. Circulation. 2000;101: Lee AJ, et al. Circulation. 2004;110:

17 Noninvasive Screening: Carotid Intima-Media Thickness (CIMT) CIMT measured by carotid artery ultrasound 1 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 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 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 therapy 3 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: Genest J et al. Can J Cardiol 2009; 25:

18 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* 25 CACS: Hazard Ratio Framingham Risk Score, % EBCT image showing extensive triple-vessel coronary calcification Greenland P, et al. JAMA. 2004;291:

19 Apolipoprotein B (ApoB) 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 Genest J et al. Can J Cardiol 2009; 25:

20 Lipoprotein (a) -- Lp(a) 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. The Emerging Risk Factors Collaboration. JAMA 2009; 302: McPherson R et al. Can J Cardiol. 2006;22:

21 Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) 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 Davidson MH et al. Am J Cardiol (supp); 51F-57F. The LP-PLA2 Studies Collaboration. Lancet :

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23 hs-crp as a Risk Factor For Future CVD : Primary Prevention Cohorts 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 Ridker PM. Circulation 2003;107:363-9 Relative Risk (upper vs lower quartile)

24 Event-Free Survival With CRP, LDL-C Levels Above or Below the Median* Low CRP low LDL-C Low CRP high LDL-C Probability 0.98 High CRP low LDL-C (25-30 million US adults) 0.97 N=27,939 High CRP high LDL-C Years *Median values: CRP=1.52 mg/l, LDL-C=3.22 mmol/l. Ridker PM et al. N Engl J Med. 2002;347:

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27 Reynolds Risk Score ( or 45% of women 1 and 20 % of men 2 at intermediate risk by Framingham are reclassified to higher or lower-risk groups using the Reynolds Score Accessed Nov. 11, Ridker P et al. JAMA 2007;297: ; 2 Ridker P et al. Circulation 2008;118.

28 JUPITER Trial Design JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hscrp No Prior CVD or DM Men >50, Women >60 LDL <3.4 mmol/l (median 2.8) hscrp >2 mg/l (median 4.3) Rosuvastatin 20 mg (N=8901) Placebo (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA 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 Ridker et al, Circulation 2003;108:

29 JUPITER Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hscrp Ridker et al NEJM 2008 hscrp (mg/l) LDL (mg/dl) LDL decrease 50 percent at 12 months hscrp decrease 37 percent at 12 months Months TG (mg/dl) HDL (mg/dl) HDL increase 4 percent at 12 months 1.33 TG decrease 17 percent at 12 months Months

30 JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Ridker et al NEJM 2008 Cumulative Incidence HR 0.56, 95% CI P < Number Needed to Treat (NNT5) = Placebo 251 / % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1,

31 JUPITER Individual Components of the Primary Endpoint Ridker et al NEJM 2008 Endpoint Rosuvastatin Placebo HR 95%CI P Primary Endpoint* < Non-fatal MI < Any MI < Non-fatal Stroke Any Stroke Revascularization or Unstable Angina < MI, Stroke, CV Death < *Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death

32 JUPITER Primary Endpoint Subgroup Analysis I Men Women Age < 65 Age > 65 Smoker Non-Smoker Caucasian Non-Caucasian USA/Canada Rest of World Hypertension No Hypertension All Participants N P for Interaction 11, ,801 8, ,261 2, ,975 12, ,117 6, ,761 10, ,586 17,802 Ridker et al NEJM Rosuvastatin Superior Rosuvastatin Inferior

33 Ridker P et al. Circ: CV Quality & Outcomes JUPITER Primary Endpoint Subgroup Analysis by FRS and RRS 5-y NNT: FRS 5-10%=40 FRS 11-20%=18

34 JUPITER Secondary Endpoint All Cause Mortality Ridker et al NEJM 2008 Cumulative Incidence HR 0.80, 95%CI P= Placebo 247 / % Rosuvastatin 198 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,847 8,787 6,999 4,312 2,268 1,602 1, ,901 8,852 8,775 6,987 4,319 2,295 1,614 1,

35 JUPITER Dual Target Analysis: LDLC<1.8mmol/L, hscrp<2 mg/l Ridker et al Lancet 2009 Cumulative Incidence Placebo HR 1.0 (referent) LDL > 1.8 mmol/l and / or hscrp > 2 mg/l HR 0.64 ( ) LDL < 1.8 mmol/l and hscrp < 2 mg/l HR 0.35 ( ) Number at Risk Rosuvastatin Placebo Follow-up (years) 7,716 7,699 7,678 6,040 3,608 1,812 1, ,832 7,806 7,777 6,114 3,656 1,863 1, P <

36 hs-crp:recommendations for use in Clinical Practice 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) Genest J et al. Can J Cardiol 2009; 25:

37 hs-crp:recommendations for use in Clinical Practice 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 Genest J et al. Can J Cardiol 2009; 25:

38 Canadian Cardiovascular Society Guidelines on Dyslipidemia 2009 Risk categories and treatment recommendations Level of Risk (definition) Initiate treatment if: Primary target LDL-C 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% Consider treatment in all patients LDL-C > 3.5 mmol/l TC/HDL-C > 5.0 hs-crp > 2 mg/l (men > 50y; women > 60y) LDL-C 5.0 mmol/l < 2.0 mmol/l or 50% LDL-C < 2.0 mmol/l or 50% LDL-C 50% LDL-C Genest J et al. Can J Cardiol 2009; 25:

39 Statins and Primary Prevention: Meta-analysis of 10 Trials All cause mortality: OR = 0.88 ( ) Major coronary events: OR = 0.70 ( ) Major cerebrovascular events: OR = 0.81 ( ) Cancer: OR = 0.97 ( ) Brugts, J J et al. BMJ 2009;338:b2376

40 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?

41 Case Presentation (cont d) Interventions: - Therapeutic Lifestyle Changes - Statin (based on JUPITER)

42 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 <3.5 mmol/l and treatment with statin if hs-crp is > 2mg/L

43 The unknown moderate risk patient His LDL-C was normal, but hs-crp high