speaker_slides_2012

1、PLAC® Test for Lp-PLA2Lipoprotein-Associated Phospholipase A2(PLAC Test ELISA Kit),A Risk Marker for Heart Attack and Stroke,Copyright 2012 diaDexus. All rights reserved.,Cardiovascular Disease Background,Copyr

2、ight 2012 diaDexus. All rights reserved.,PLAC® Test for Lp-PLA2,Cardiovascular Disease (CVD) BackgroundAtherosclerotic Disease Progression and Lp-PLA2 Clinical EvidenceTesting Scenarios for the PLAC® Test fo

3、r Lp-PLA2 -Primary and Secondary Events Guidelines and Clinical UtilityCase Study Ongoing Patient Management,Copyright 2012 diaDexus. All rights reserved.,1 Heart Disease and Stroke Statistics – 2012 Update, American

4、 Heart Association* 87% of all strokes are ischemic (Circulation 2012, 125:e2-e220.),PLAC ® Test,Uncover Hidden Risk,Copyright 2012 diaDexus. All rights reserved.,Cardiovascular Disease Remains the Number One Heal

5、th Concern in the US,Myerburg RJ et al. Circulation. 2012;125:1043-1052,Copyright 2012 diaDexus. All rights reserved.,Sudden Cardiac Death:Frequently the First Presentation for Heart Disease,,,Sachdeva et al. Am Heart J

6、 2009; 157:111-7.e2,< 130,LDL-C Levels in Coronary Artery Disease Admissions: 72% Had LDL-C Less Than 130 mg/dL,,,,,,,,,,,LDL-C (mg/dL),LDL-C (mg/dL),> 130,LDL-C Levels in 136,905 Patients Hospitalized With CAD: 2

7、000-2006,Get With the Guidelines database, levels at admission;,Copyright 2012 diaDexus. All rights reserved.,,Total Cholesterol and LDLLimitations in Predicting Coronary Heart Disease,Framingham Heart Study - 26 year f

8、ollow-up data35% of persons who develop CHD have total cholesterol < 200 mg/dL180% of myocardial infarction (MI) patients had similar cholesterol levels as those who did not have an MI1The median LDL level in CHD i

9、s 150 mg/dL1As little as 25% of premature CHD is attributable to elevated low density lipoprotein-cholesterol (LDL-C) values2,1Castelli W, Atherosclerosis 19962Genest J Jr, et al. J Am Coll Cardiol 1992,Copyright 2012

10、diaDexus. All rights reserved.,Ballantyne CM, et al. AHA 2004Berger K, et al. Stroke 1998Tanne D, et al. Circ.2001,4. Bowman TS, et al. Stroke 1998Oei HH, et al. Circ. 2005Wannamethee SG, et al. Stroke 2000,P >

11、 0.05,LDL Cholesterol,Total Cholesterol,PROCAM 2,ARIC 1,BIP REGISTRY 3,PHS 4,ROTTERDAM 5,BRHS 6,P = 0.20,P = NS,P > 0.05,P = 0.44,No Stroke Stroke,P = NS,Cholesterol is Not a Reliable Predictor for Stroke,Copyrig

12、ht 2012 diaDexus. All rights reserved.,Prevalence of Conventional Risk Factors in 87,869 Patients* with Established CHD,Khot UM, et al. JAMA 2003.,,,,,,,,,,,4 Conventional Risk Factors Analyzed: Hypertension, Smoking,

13、Hypercholesterolemia and Diabetes,N=87,869,0 Risk Factors19.4%,1 Risk Factor43%,2 Risk Factors27.8%,3 Risk Factors8.9%%,4 Risk Factors0.9%,62.4% have 0-1Conventional Risk Factors,Copyright 2012 diaDexus. All right

14、s reserved.,*Numbers shown are for male segment of study,Adapted from Kolodgie F, et al. ATVB 2006 and Virmani R,et al. ATVB 2000,More than 2/3 of all CV Events are Subsequent to Plaque Rupture,Lesion % stenosis,Type o

15、f culprit lesion,Acute Myocardial Infarction,Sudden Cardiac Death,Copyright 2012 diaDexus. All rights reserved.,Atherosclerotic Disease Progression and Lp-PLA2,Copyright 2012 diaDexus. All rights reserved.,,Vasoconstrict

16、ion Thrombosis Superoxide,,? NO Synthesis,,,? COX Activity,Thromboxane A2Prostaglandin H2Prostacyclin,,,? Inflammation,Leukocyte adhesion Endothelial permeabilityFoam cell formationT-cell activation,,,? Endothel

17、in,VasoconstrictionCalcium mobilization,,,,,,,,NO = nitric oxide; COX = oxygenase. Liao JK. Clin Chem. 1998;44:1799-1808. Libby P. J Intern Med. 2000;247:349-3586(l 3):11-17.,Integrated Cellular Mechanisms of CVD,Hy

18、pertension,Dyslipidemia,Diabetes,,Endothelial Dysfunction,,Endothelial dysfunction is associated with inflammation, leading to leukocyte adhesion, increased endothelial permeability,Copyright 2012 diaDexus. All rights re

19、served.,Contrasting Histopathological Characteristics of a Stable Versus Ruptured Plaque,Stable PlaqueLess Lp-PLA2 accumulation (dark staining)Thick fibrous cap with high collagen contentMinimal necrotic lipid poolL

20、ess inflammation,Ruptured PlaqueHigh Lp-PLA2 accumulation (dark staining)Thin fibrous cap with low collagen contentLarge necrotic lipid poolMore inflammation,Minimal NecroticLipid Pool,Large Necrotic Lipid Pool,,,C

21、opyright 2012 diaDexus. All rights reserved.,Corson MA et al, Am J Card Suppl 2008:101 (41F-50F),Thrombus,Atherosclerosis Progression,Early Lesion,Fatty Streak,Intermediate Lesion,Atheroma,Fibroatheroma,Complex lesion,(F

22、irst decade),(Third decade),(Fourth Decade),Early lesions characterized by intracellular lipid accumulation,Smooth muscle cell proliferation and collagen deposition characterizes advanced lesions,Thrombosis,Lesion Growth

23、,Principal Lesion Histology,Copyright 2012 diaDexus. All rights reserved.,Adapted from Libby et al, Circulation. 2002 and Virmani R et al. ATVB 2000,Presence of Lp-PLA2 in Normal and Atherosclerotic Carotid Arteries,Vic

24、kers: J.Lipid Res. 2009,,Lp-PLA 2 presence in normal (n = 16) and atheroscleroticCEA tissues ( n = 15). Concentration normalized to total protein content. * P<0.05,Digital images of normal and atherosclerotic caroti

25、d endarterectomy (CEA) tissues.,Copyright 2012 diaDexus. All rights reserved.,,Ruptured plaquewith thrombus in lumen,Kolodgie F, et al. Arterioscler Thromb Vasc Biol 2006,Lp-PLA2 Stains Reddish Brown,Disease Progressio

26、n,,Plaque Vulnerability is Proportionate to Lp-PLA2 Accumulation in Atheroma,Copyright 2012 diaDexus. All rights reserved.,Lp-PLA2 Concentration in Plaque,Increasing Lp-PLA2 concentration is found in atherosclerotic pla

27、que progression,Kolodgie F, et al. Arterioscler Thromb Vasc Biol 2006,Copyright 2012 diaDexus. All rights reserved.,Legend X axis,,,LUMEN,MEDIA,INTIMA,Oxidized LDL,The Role of Lp-PLA2 in the Formationof Vulnerable Plaqu

28、e,Copyright 2011 diaDexus, Inc. All rights reserved.,MEDIA,INTIMA,Oxidized LDL,Adhesion molecules,Lp-PLA2,,LUMEN,The Role of Lp-PLA2 in the Formationof Vulnerable Plaque,Copyright 2011 diaDexus, Inc. All rights reser

29、ved.,Lyso-PCOxFA,The Role of Lp-PLA2 in the Formationof Vulnerable Plaque,Copyright 2011 diaDexus, Inc. All rights reserved.,20,Macrophage,Cytokines,Plaque formation,Foam cell,Monocytes,MEDIA,INTIMA,Oxidized LDL,Adhe

30、sion molecules,Lp-PLA2,,LUMEN,Lyso-PCOxFA,Copyright 2011 diaDexus, Inc. All rights reserved.,The Role of Lp-PLA2 in the Formationof Vulnerable Plaque,Copyright 2011 diaDexus, Inc. All rights reserved.,21,Cytokines,P

31、laque formation,Foam cell,Monocytes,MEDIA,INTIMA,Oxidized LDL,Adhesion molecules,Lp-PLA2,,,Lyso-PCOxFA,LUMEN,Macrophage,Copyright 2011 diaDexus, Inc. All rights reserved.,Clinical Evidence,Copyright 2012 diaDexus. Al

32、l rights reserved.,Lp-PLA2 is Vascular Specific and Independent of Systemic Inflammation,Adapted from: Rader D. N Engl J Med. 2000,,Copyright 2012 diaDexus. All rights reserved.,Lp-PLA2: Specific for Vascular Inflammati

33、on with Lower Biovariability vs. Other Inflammatory Markers,Lp-PLA2 is not typically elevated in healthy individuals,Lp-PLA2 has minimal biovariability,Lerman A, McConnell JP. Am J Card Supplement 2008.,Blood from 90 he

34、althy heart disease free individuals,Blood from 43 healthy adults each drawn 7 times over 4 weeks,Copyright 2012 diaDexus. All rights reserved.,,,Hazard Ratio,1st,2nd,3rd,1.0,1.8,2.1,Lp-PLA2 Tertile,*,Low,(<113MM H

35、g),Medium,(113 -130MM Hg),High,(>130MM Hg),Below Mean,Above Mean,Blood Pressure,RiskRatio,Individuals who suffered a stroke (median)LDL = 136 mg/dLIndividuals who did NOT suffer a stroke (median)LDL = 132 mg/dL,1B

36、allantyne CM et al. Circulation. 2004; 109: 837-842,30% of ARIC Study coronary events occurred in individuals with LDL-C<130 mg/dL,2 Gorelick AJC 2008;101[suppl]:34F-40F adapted from Ballantyne CM et al. Arch Int Med

37、 2005; 165:2479-2484,Lp-PLA2 Level,Increased Lp-PLA2 Presence Indicates Increased Risk Even with “Normal” LDL,Copyright 2012 diaDexus. All rights reserved.,,ARIC- Additive Risk for Incident CHD and Stroke by Lp-PLA2 W

38、hen Added to hs-CRP,,Adjusted for demographics, current smoking status, blood pressure, diabetes and HDL- ARIC Study data,1 Ballantyne et al, Circulation. 2004,4.2,1.2,1.4,1.0,Risk Ratio,Heart Attack1,Stroke2,11.4,5.8,5

39、.5,1.0,Risk Ratio,2 Ballantyne et al, Arch Intern Med. 2005,,Lp-PLA2 top tertile,Lp-PLA2 bottom tertile,Lp-PLA2 top tertile,Lp-PLA2 bottom tertile,hs-CRP top,hs-CRP bottom,hs-CRP top,hs-CRP bottom,(n>12,000, 6-8 yr f/

40、u, 194 ischemic strokes),(n>12,000, 6-8 yr f/u, 203 coronary events, LDL < 130 mg/dL),Lp-PLA2, in combination with hs-CRP, demonstrates increased clinical utility,p=0.001, 95% CI 1.7-10.3,p<0.001, 95% CI 3.1-4

41、1.4,Copyright 2012 diaDexus. All rights reserved.,tertile,tertile,tertile,tertile,Copyright 2011 diaDexus, Inc. All rights reserved.,27,,>25 Published Studies Show Elevated Lp-PLA2 Is Associated with a Doubling of Ri

42、sk,Packard (WOSCOPS), N Engl J Med 2000 – CHDBlake (WHS), J Am Coll Cardiol 2001 – CHDBlankenberg (AtheroGENE), J Lipid Res 2003 - CADBallantyne (ARIC), Circulation 2004 - CHD LDL < 130Winkler, J Clin Endocrinolo

43、gy and Metabolism 2004 – CHDOei (Rotterdam), Circulation 2005 – CHDBrilakis (Mayo Heart), Eur Heart J 2005 – CHDBallantyne (ARIC), Arch Intern Med 2005 – StrokeOei (Rotterdam), Circulation 2005 – StrokeWinkler (LUR

44、IC), Circulation 2005 – CHDKhuseyinova (HELICOR), Atherosclerosis 2005 – CHDKoenig (KAROLA), Arterioscler Thromb Vasc Biol 2005 – CVDMay (Intermountain Heart), Am Heart J - CHDJenny (CHS), AHA-EPI Abstract 2006 – M

45、IElkind (NOMAS), Arch Intern Med 2006 – StrokeO’Donoghue (PROVE IT), Circulation 2006 – CVDCorsetti (THROMBO), Clinical Chemistry 2006 - CHDGerber (Olmsted County), ATVB 2006 - Death S/P MIOldgren (GUSTO / FRISC),

46、Eur Heart J 2007 - Acute ACSSabatine (PEACE), AHA-Scientific Sessions 2006 - CVDPersson (Malmo), Arterioscler Thromb Vasc Biol 2007 - CVDMockel (NOBIS-II), Clin Res Cardiol 2007 – CVDHatoum (Nurse’s Health Study), Ci

47、rc Suppl 2007 – MIDaniels (Rancho Bernardo), JACC 2008 – CHD,,Corson MA et al, Am J Card Suppl 2008:101 (41F-50F),Copyright 2012 diaDexus. All rights reserved.,The Lp-PLA2 Studies Collaboration, Lancet 2010; 375: 1536–

48、44.,,,The coronary heart disease Risk Ratio increases per each standard deviation elevation of Lp-PLA2 (and other markers) over baseline levels,Lp-PLA2 Studies CollaborationLancet 2010,Copyright 2012 diaDexus. All right

49、s reserved.,Lp-PLA2 levels are significantly related to CVD risk in a continuous association.Lp-PLA2 levels above 200 ng/mL warrant more aggressive patient management due to the elevated CVD risk.,Key PointsLp-PLA2 lev

50、els (mass and activity) found to be associated with each other and with other biomarkers,Lp-PLA2 Studies CollaborationLancet 2010,The Lp-PLA2 Studies Collaboration, Lancet 2010; 375: 1536–44.,Copyright 2012 diaDexus. A

51、ll rights reserved.,Key Points – continuedThe CVD risk due to elevated Lp-PLA2 is comparable to the elevated CVD risk associated with two other well established risk markers: non-HDL-C and blood pressure.Lp-PLA2 levels

52、 provide independent CVD risk assessment from other biomarkers — providing distinct insight into the relationship between inflammation, atherosclerosis and cardiovascular outcomes.,Lp-PLA2 Studies CollaborationLancet

53、2010,The Lp-PLA2 Studies Collaboration: Lancet 2010; 375: 1536–44.,Copyright 2012 diaDexus. All rights reserved.,Testing Scenarios for Lp-PLA2,Primary and Secondary Prevention,Copyright 2012 diaDexus. All rights reserv

54、ed.,ARIC Study: Initial Classification of Individuals (% distribution) Based on Traditional Risk Factor (TRF) Assessment,Baseline Risk Category Assigned by TRF*NO BIOMARKERS USED,Percent ofARIC study population in ea

55、ch category,5-year stroke risk cut pointsLow Risk 5%,Nambi V, et al. Stroke 2009.,Copyright 2012 diaDexus. All rights reserved.,*Age, sex, race, current smoking status, systolic blood pressure, LDL-C, HDL-C, diabetes

56、, antihypertensive medication use, and body mass index, no biomarkers used,,Re-classification of Stroke Risk with Biomarkers** 39% of Moderate Risk Group Reclassified to Other Risk Groups,Low Stroke Risk< 2% 5-yea

57、r risk,High Stroke Risk> 5% 5-year risk,,Baseline Risk by TRF* Only,BIOMARKERS USED**,*Age, sex, race, current smoking status, systolic blood pressure, LDL-C, HDL-C, diabetes, antihypertensive medication use, and

58、body mass index; no biomarkers used. **Added Lp-PLA2, hs-CRP to TRF,,Moderate Risk by TRF*,28%,11%,Nambi V, et al. Stroke 2009.,Maintain current patient management,Consider more aggressive patient management,Copy

59、right 2012 diaDexus. All rights reserved.,ReclassifiedStroke RiskLevel,,Mayo Study: Utility of Lp-PLA2 In Predicting Survival,* p < 0.001 after multivariate adjustment for age, sex, hypertension, BMI, diabetes, smo

60、king, LDL-C,*,,,,,,,,,,,,,1.0,2.2,5.4,0.0,1.0,2.0,3.0,4.0,5.0,6.0,≤ 166 ng/mL,167-218 ng/mL,≥219 ng/mL,Hazard Ratio,Gerber Y, et al. Arterioscler Thromb Vasc Biol 2006,Copyright 2012 diaDexus. All rights reserved.,,,L

61、p-PLA2 Predicts Major CV Events in CHD Patients: Mayo Heart Study,Brilakis ES et al. Mayo Heart Study. Euro Heart J 2005,95% of patients with Lp-PLA2 < 200 ng/ml were Event Free at 4 years,Copyright 2012 diaDexus. Al

62、l rights reserved.,Elevated Lp-PLA2 Doubles Risk of Recurrent Stroke Northern Manhattan Stroke Study (NOMAS),Elkind MS, et al. Arch Int Med 2006.,? Lp-PLA2 Utility in Secondary Stroke Prevention,Recurrent Stroke Events

63、 N=80, All CV Events N=122Adjusted for demographics, traditional risk factors, stroke severity, and both markers,Copyright 2012 diaDexus. All rights reserved.,3 6 9 12 15 18

64、 21 24 27 30,Follow-up (months),30,25,20,15,10,5,0,,,,,,,,,,P =0.005,Recurrent MI, Cardiac Death, Revasc or UA Hospitalization,,,16% RRR,,,,,,,,,,Atorvastatin 80 mg/dPravastatin 40 mg/d,Cannon CP et

65、al. NEJM 2004;350:1495-1504,Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study,4,162 patients with an ACS randomized to atorvastatin 80mg or pravastatin 40mg for 2 yrs.,Copyright 2012 d

66、iaDexus. All rights reserved.,Baseline -LDL 106 -HDL 38-39,Guidelines and Clinical Utility,The only blood test cleared by the FDA to assess the risk for both heart attack and ischemic strokeThe PLAC Test measures Lp-P

67、LA2, a vascular specific-inflammatory marker implicated in the progression to rupture-prone plaque*Simple blood test, no fasting required prior to drawReadily available through advanced cardiovascular panel (ACVD) test

68、ing laboratoriesLp-PLA2 CPT Code: 83698; the PLAC Test is reimbursed by Medicare, and many insurance providers. There are more than 150 million covered lives in the US.,The PLAC Test for Lp-PLA2,Copyright 2012 diaDexu