Presentation on theme: "Treating arteries instead of treating risk factors"— Presentation transcript:
1Treating arteries instead of treating risk factors J. David SpenceStroke Prevention & Atherosclerosis Research CentreRobarts Research InstituteLondon, Canada
2Disclosures Grants for research from HSF, NIH, CIHR Grants for research from Pfizer, Merck, Pan American LabsLecture fees from Pfizer, AstraZeneca, Merck, Novartis, Boehringer-IngelheimConsulting fees from Novartis, Boehringer-IngelheimInterest in
3Post-prandial oxidative stress and inflammation* * ROS, inflammatory mediators, oxidized LDL: not fasting Chol/Trig/HDL
4Composite drawing of all plaques in extracranial carotids Large artery strokesNot just stenosis: also high plaque burdenPlaque measurement very useful79 yo woman72 yo manComposite drawing of all plaques in extracranial carotidsBogiatzi C…Spence JD SPARKLE classification Neuroepidemiology 2014;42:243–251.
5Ischemic stroke subtypes are changing Better BP controlMore statinsBogiatzi C ….Spence JD. Stroke Sep 11
6Ischemic stroke subtypes are changing Before 2005After 2009Cardioembolic strokes more common, large artery strokes less commonBogiatzi C ….Spence JD. Stroke. 2014;45:
7Measurement of subclinical atherosclerosis There are 2 distinct kinds of IMTIMT isn’t atherosclerosisPlaque predicts events better than IMTPlaque measurement can be used for treatmentPlaque measurement is more sensitive to effects of therapyPlaque measurement is superior to IMTSpence JD. Atherosclerosis. 2012;220:34-5.
8Ultrasound measurement of “Atherosclerosis” It is important to recognize biological differences amongIntima-media thickness- with and without plaque thicknessPlaqueStenosis
9Carotid Intima-Media Thickness (IMT) Mannheim consensus conferenceSite : common carotid artery , far wall ,Quality Index > 0.50Cerebrovascular Diseases 2007;23:75-80
10Phenotypes of atherosclerosis Traditional coronary risk factors as predictors of ultrasound phenotype:In multivariable regression:IMT R2 is 0.15 for internal, 0.17 for common carotid1Plaque area R2 is (similar to R2 for coronary events)Stenosis (Doppler velocity) R2 is 0.1321. O’Leary DH, et al Stroke 1996; 27:2. Spence JD, Hegele RA Stroke 2004; 35:
11Measurement of IMT, plaque area and volume Al-Shali et al. Atherosclerosis 2005; 178: 319–325
12Phenotypes of atherosclerosis Thus Intima-media thickness (IMT), plaque and stenosis must be regarded as distinct phenotypes, with distinct biologies and determinants. Therapies would also be expected to differentially affect these distinct manifestations of atherosclerosis.Biologies of IMT, plaque and stenosis are distinctIMT: mainly hypertensive medial hypertrophyPlaque: reflects endothelial dysfunction, oxidative stress, lipidsStenosis: consequence of plaque rupture and thrombosis– reflects plaque instability, inflammation, MMP, thrombosis, impaired fibrinolysisSpence JD, Hegele RA Noninvasive Phenotypes of Atherosclerosis: Similar Windows but Different Views Stroke 2004; 35:Spence JD, Hegele RA. Noninvasive phenotypes of atherosclerosis. Arterioscler Thromb Vasc Biol Nov;24(11):e188
13Plaque is more closely related to coronary artery disease than IMT Ebrahim S, et al. Stroke 1999; 30:Chan SY et al. J Am Coll Cardiol. 2003;42: Brook R et. al. ATVB 2006;26:Johnsen, SH et al. Stroke 2007;38;Inaba Y, et al. Atherosclerosis. 2011;220:
14IMT isn’t atherosclerosis Correlation Between Carotid Intimal/Medial Thickness (IMT) and Atherosclerosis: A Point of View from Pathology Finn AV, Kolodgie FD, Virmani R. ATVB 2009 online
15Measurement of 2-D Plaque area* * Invented in our lab in 1990 by Maria DiCicco, R.V.T.
16Carotid Plaque Area as predictor of events 1,686 patients in our Atherosclerosis Prevention Clinic followed up to 5yearsDuring mean followup of years:94 MI, 45 strokes, 44 deaths (27 vascular).Spence JD, Eliasziw M, DiCicco M et al. Carotid Plaque Area: A Tool for Targeting and Evaluating Vascular Preventive Therapy. Stroke. 2002;33:
17Baseline Carotid plaque area as a predictor of events Baseline Carotid plaque area as a predictor of events Stroke, MI, Death (after adjustment for risk factors*)*Age, sex, SBP, tChol, pack-yrs, tHcy, diabetes, Rx lipids and BPStroke 2002; 33:
18Prediction of outcomes Plaque measurement is a stronger predictor of outcomes than EBCT, presence of plaque, and somewhat more predictive than IMT, particularly for myocardial infarction
19TPA increases AUC in ROC Romanens M, Spence JD et al. Cardiovasc. Med. 2011;14:53–57
20Tromsø Study 6226 men and women aged 25 to 84 6 year followup: MI in 6.6% of men and 3.0% of women.TPA: RR (95% CI) 1.56 (1.04 to 2.36) in men3.95 (2.16 to 7.19) in womenIMT RR (95% CI) 1.73 (0.98 to 3.06) in men2.86 (1.07 to 7.65) in womenWhen bulb IMT was excluded from analyses, IMT did not predict MI in either sex.Johnsen, SH et al. Stroke 2007;38;
215-year MI risk by Total Plaque Area Tertile MenWomenIMT in the CCA was not predictiveJohnsen, SH et al. Stroke 2007;38;
2210-year stroke risk more strongly predicted by plaque area in Tromsø Study Hazard ratio 1.73 for men(p=0.004), for women (p=0.03)No differences for quartiles of IMTTotal plaque areaMathiesen ES et al. Stroke online Feb 10
23Distribution of carotid plaque area by age groups and sex Spence JD. Nature Clinical Practice Neurology 2006;2:
24Plaque progression despite therapy doubles the risk* Medical treatment was failing in half the cases, and they were at double the risk: we needed to do better!*Adjusted for Age, sex, SBP, tChol, pack-yrs, tHcy, diabetes, Rx lipids and BPStroke 2002; 33:
25Paradigm change: Treating arteries, not risk factors Instead of treating risk factors to target, since 2003 we treat patients more intensively if their plaque is progressing , regardless of their level of LDL or other risk factorsi.e. – since 2003our target is now plaque regression
26Treating arteries without measuring plaque is like treating hypertension without measuring blood pressure
27Benefit of carotid endarterectomy Symptomatic severe stenosis:2-yr reduction of stroke death from 26% to 9%Asymptomatic: 5-yr risk reduction 10% to 5%NNT to prevent 1 stroke in 2 years1:NNTSymptomatic severe >70% age<75 6Symptomatic severe >70% age>75 3Symptomatic moderate 50-69% 15Asymptomatic * Predicated on 3% surgical risk, and historical medical therapy1.Barnett HJM. CMAJ 2004;171: 473-4The high number needed to treat is entirely predicated on a low (3%) surgical risk in clinical trials; there would be no benefit expected with real-world surgical risk (see next slide)
28TCD microembolus detection 319 ACS patientsbetween 2000 and 200410% had microemboli1-year Stroke RiskNo Emboli Emboli1% 15.6%95% CI ( ) (4.1-79)p<0.0001Spence JD et al. Stroke 2005; 36:
29Stroke risk over 2 years by baseline microembolic status Spence JD et al. Stroke 2005;36:
30Decline of microemboli with more intensive medical therapy < 5% of ACS patients can now benefit from carotid endarterectomyor stentingSpence JD et al. Arch Neurol. 2010;67:180-6P<0.00111%2.2%
31Annual rate of plaque progression in ACS patients before and since 2003 Spence JD et al. Arch Neurol. 2010;67:180-6
32Kaplan-Meier Survival free of stroke, death, MI logrank test p<0.0001logrank test p<0.0001Spence JD et al. Arch Neurol. 2010;67:180-6
33Plaque area by age group and clinic pop. age by year Spence JD, Hackam DG. Stroke 2010 Jun;41(6):1193-9
34Average rate of plaque progression by year among all patients in clinic
35Effects of more intensive therapy on plasma lipids in clinic population n=4,328
36Rates of progression and LDL by year Spence JD, Hackam DG. Stroke 2010 Jun;41(6):1193-9
37Decline in events in ACS with more intensive medical therapy No embolin=431Microembolin=37pBefore2003n=199Sincen=269p*Stroke in year 11.4%10.3%0.0163.3%1%0.155Stroke in year 21.8%18.5%0.0015.5%0%0.006MI in year 12.2%6.9%0.1654.9%0.5%0.007MI in year 23.2%0.3942.7%0.104Death in year 12.8%0.0694.4%%2.4%0.386Death in year 22.1%3.7%0.4773.8%0.044CEA year 112.9%0.0031.9%0.739CEA year 20.3%0.1461.1%0.499Stroke, death or CEA 1st 2 years6.5%32.4%<0.000114.1%4.5%Stroke, death, MI or CEA 1st 2 years8.6%17.6%5.2%Events declined markedly among patients with asymptomatic carotid stenosis after the paradigm change in 2003, though microemboli on transcranial Doppler remained strong predictors of risk.Spence JD et al. Arch Neurol. 2010;67:180-6
38Carotid plaque measurement SummaryPlaque measurement is useful for:Managing patientsStratifying riskManaging resourcesEncouraging patients to follow regimenMonitoring success of therapyGenetic researchQuantitative traits for linkage studiesStudying effects of new therapiesMuch smaller sample size x durationProof of concept studies in human subjectsDose-finding studies
39Plaque measurement to study effects of new therapies New therapies being developed for atherosclerosis- effective in animal models- no effect on blood pressure or lipidsIt will be necessary to measure plaque- for dose finding studies- to demonstrate efficacy before committing to very expensive events –based studiesEg: inhibitors ACAT CETP, Leukotriene B4, etc.
40Sample size x duration required To show a 30% reduction in rate of progressionPower 80%, p<0.05IMT: 468 patients/group x 2 years1(less with automated edge detection)Plaque area: patients /group x 2 years23-D plaque volume: ?Bots M et al, Stroke 2003;34:Hackam DG et al Am J Hypertens 2000;13:
41Disk segmentation for measurement of plaque volume
46Plaque volume fixed at bifurcation Stroke 2005; 35:
473-D ultrasound carotid plaque volume: a tool for quickly measuring effects of treatment on atherosclerosis38 patients with carotid stenosis >60% age 68 ± 6.6 years, 15 female, randomly assigned to atorvastatin 80mg daily (n=17) vs placebo (n=21)Stroke 2005; 35:
48Rate of plaque volume progression on placebo vs Atorvastatin 80mg In 3 months: Placebo Atorvastatin mm mm3 (p<0.0001)Stroke 2005; 35:
493-month progression of carotid plaque volume with placebo vs 3-month progression of carotid plaque volume with placebo vs. atorvastatin 80mgP<0.0001Stroke 2005; 35:
50Sample size for change in progression of plaque volume To show treatment effect in 3 monthsplacebo progression mm3
51Sample size for change in progression of plaque volume To show treatment effect in 6 monthsassuming linear progression on placebo and regression on active treatment; placebo progression mm3Stroke 2005; 35:
52Vessel Wall VolumeEgger M, Spence JD, Fenster A, Parraga G. Validation of 3D Ultrasound Vessel Wall Volume: An Imaging Phenotype of Carotid Atherosclerosis. Ultrasound Med Biol Jun;33(6):
53Atorvastatin 80 vs placebo on VWV VWV PlaceboAtorvastatinp+70 ± 140 mm3-30 ± 110 mm3<0.05(14.9 ± 10.3%)(-1.4 ± 7.7%)Krasinski A, Chiu B, Spence JD, Fenster A, Parraga G. Ultrasound Med Biol Jul 31.
54DIRECT 3D Ultrasound Study Atherosclerosis regression on all 3 diets, proportional to BP reduction and weight lossShai I, Spence JD, Parraga A, Mallette C, Fenster JD et al. Circ 2010;121:
55Annual change cannot be measured within patients by IMT Resolution of carotid ultrasound is ~ 0.3mmMean rate of change of IMT is only for mean and for maximum IMT1Large groups required to show changes for groups, not individualsMean change in TPA is 11mm2; can easily be measured.mm2Bots ML, et a. Stroke 2003 Dec;34(12):Spence JD. Can J Cardiol 2008; 24 (Suppl C): 61C-64C.
56Plaque measurement is superior to IMT Greater dynamic range (~ 100-fold)More predictive of stroke and MIMore sensitive to effects of therapySpence JD. Plaque measurement is superior to IMT. Atherosclerosis 2011.
57Treating arteries without measuring plaque is like treating hypertension without measuring blood pressure
583D Volume AnalysisEnable Imaging Technologies BeijingMeasurement of plaque volume at baseline, and change over time
59Acknowledgements 3-D Ultrasound technology Genetics Drs. Aaron Fenster, Grace Parraga Dr. Rob HegeleMeasurements Lab Manager2-D : Maria DiCicco RVT Tisha Mabb3-D: Craig Ainsworth, FundingAnthony Landry, Chris Blake, NINDSMicaela Egger, Christiane Mallet, Silvia Riccio HSF OntarioBernard Chiu, Shayna McKay, Adam Krasinsky CHRIUlcers Dr. Vadim Beletsky, Jeremy MasonPlaque composition Jeremy Mason, Dr. Joseph AwadTCD StudyDr. Arturo Tamayo MRIDr. Claudio Munoz Dr. Brian RuttScanning PET/CTMaria DiCicco RVT Dr. Jean-Luc UrbainJanine Desroches RVT Dr. Ting Lee
60Acknowledgements Maria DiCicco R.V.T. Plaque area Aaron Fenster Ph.D. Plaque volumePlaque roughness, texture3D U/SGrace ParragaPh.D.Vessel wall volume