1. EUROECHO 2007 Lisbon, Portugal, December 5 – 8, 2007 Carotid scanning: an extension of the routine echocardiography study? Damiano Baldassarre Enrica Grossi Paoletti Centre Department of Pharmacological Sciences, University of Milan and Cardiologico Monzino Centre IRCCS INTIMA-MEDIA THICKNESS AND ATHEROSCLEROSIS

2. INTIMA MEDIA THICKNESS (IMT) Near wall Far wall COMMON CAROTID BULB ICA ECA Non-invasive marker of early arterial wall alteration. Easily assessed by B-mode ultrasound. IMT

3. Ultrasound Histology Echogenic lines { { Lumen Adventitia Intima Media Thickness (IMT) Media Adventitia interface Blood intima interface Intimal plus media thickness of the arterial wall: a direct measurement with ultrasound imaging. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Circulation 1986;74:1399-1406

4. Methodology for IMT measurement (widely used in clinical research) PUBMED KEYWORDS: “Carotid IMT” OR "intima media thickness" OR "intimal medial thickness" OR "intima-media thickness" OR "intimal plus medial complex“. Pubmed limits: Humans and English 1986-1990 1991 1992 1993 1994 1995 1996 19971998 1999 20002001 2002 2003 2004 Year of publication 2005 0 100 200 300 400 2006 N° of studies published per year (as an index of interest of the scientific community for this methodology) starting from 1986, when the study of Pignoli was published the interest increases exponentially with the time (about a 1000 papers published in the last 3 years )

5. What have we learned from this big amount of information?

6. CAROTID IMT is associated: with the same vascular risk factors known to affect atherosclerosis at coronary level with the extent of coronary disease as assessed by angiography with the presence of clinical signs of coronary disease (i.e. AMI, angina etc.) with the incidence of previous vascular events IMT is now widely used in clinical trials as a marker of atherosclerosis to evaluate the effects of pharmacological agents

7. Despite this big amount of information, little is known about the usefulness of IMT as an additive marker of cardiovascular risk to be used in clinical practice on an individual basis.

8. Carotid IMT, measured with an electronic caliper (a method feasible in routine clinical practice) provides suitable information to associate carotid IMT –with atherosclerosis in other vascular districts –with the risk profile of the patient.

9. In a first series of cross-sectional studies, mainly performed in patients attending our Lipid Clinic, we have shown that carotid IMT, as measured in clinical practice, correlates well with coronary VRFs CAROTID ARTERY INTIMA-MEDIA THICKNESS MEASURED BY ULTRASONOGRAPHY IN NORMAL CLINICAL PRACTICE CORRELATES WELL WITH ATHEROSCLEROSIS RISK FACTORS. Baldassarre D, Amato M, Bondioli A, Sirtori CR, Tremoli E. Stroke 2000;31: 2426-2430. INCREASED CAROTID ARTERY INTIMA-MEDIA THICKNESS IN SUBJECTS WITH PRIMARY HYPOALPHALIPOPROTEINEMIA. Baldassarre D, Amato M, Pustina L, Tremoli E, Sirtori CR, Calabresi L, Franceschini G. Arterioscler, Thromb Vasc Biol 2002;22:317-322. CORRELATION OF PARENTS’ LONGEVITY WITH CAROTID INTIMA-MEDIA THICKNESS IN PATIENTS ATTENDING A LIPID CLINIC. Baldassarre D, Amato M, Veglia F, Pustina L, Castelnuovo S, Sirtori CR, and Tremoli E. Atherosclerosis 2005;179:111-117.

10. Characteristics of subjects with and without Coronary Heart Disease (CHD) With CHD (n=133) Without CHD (n=266) p Men (%)76 match Age (years)57.5 match Smokers (%)22.629.7ns BMI (Kg/m2 )24.624.4ns SBP (mmHg)138.9138.8ns DBP (mmHg)82.884.1ns TC (mg/dl)258.8258.9match LDL-C (mg/dl)176.5179.6ns HDL-C (mg/dl)47.449.4ns TG (mg/dl)2.162.17ns Lp(a) (mg/dl)1.251.1ns Blood glucose (mg/dl)97.195.2ns Uric acid (mg/dl)5.115.09ns Max-IMT (mm)2.361.940.0001 MM-IMT (mm)1.080.940.005 Baldassarre et al., Stroke 2000;31: 2426-2430.

11. even when measured in the routine clinical practice, carotid IMT is a suitable marker: These results support very well the concept that: to investigate the effect of vascular risk factors to identify groups of patients with and without a history of vascular events they do not provide any information concerning the potential role of IMT as a test for predictive purposes on individual basis

12. Before a new test can be used for predictive purposes Essential to establish its performance in the recognition of those individuals who PREVENTIVE MEDICINE effectively had experienced the target end point. had not

13. Thus, we have performed a study aimed at investigating on an individual basis whether IMT measurements can be added to, or used instead of, vascular risk factors in the recognition of patients with and without a history of vascular events

14. RECOGNITION OF PATIENTS WITH AND WITHOUT VASCULAR EVENTS BY ARTIFICIAL NEURAL NETWORK ANALYSES Combining some ultrasonic variables with a set of clinical variables, it was possible to reach an accuracy of prediction of about 92%, with 95% of correct classification of patients with a history of vascular events 91% of correct classification of those without Patients without events (specificity) 91% Patients with events (sensitivity) 95% Weighted Mean (Prediction accuracy) 92% Thus, also the results of this study supported a potential role of carotid IMT to be used for predictive purposes Baldassarre et al., Ann Med. 2004;36(8):630-40.

15. 1.Is there a direct correlation between carotid and coronary atherosclerosis? Before trying to use carotid IMT for predictive purposes three further questions had to be answered: 2.In what kind of patients IMT measurement may actually have the highest clinical usefulness? 3.what threshold value has to be adopted to obtain the maximal IMT predictive capacity?

16. 1.Is there a direct correlation between carotid and coronary disease? 2.In what kind of patients IMT measurement may actually have the highest clinical usefulness? 3.what threshold value has to be adopted to obtain the maximal IMT predictive capacity? Before trying to use carotid IMT for predictive purposes three questions had to be answered:

17. AUTOPSY STUDIES Significant correlation between carotid and coronary atherosclerosis (correlation coefficient = 0.5-0.6) CAROTID AND CORONARY ATHEROSCLEROSIS Young et al., Am J Cardiol 1960;6:300-308. Holme et al. Arteriosclerosis 1981 Mitchell et al. BMJ 1962;5288:1293-301 CC Bif ICA ECA weaker correlations (r ≈ 0.3) VS (B-mode Ultrasound)(Quantitative angiography) Carotid Atherosclerosis Coronary Atherosclerosis IN VIVO STUDIES Adams Circulation 1995 - Balbarini Angiology 2000 - Holaj Can J Cardiovasc 2003

18. This lower correlation was just due to methodological problems HYPOTHESIS External carotid ultrasound (ECU) is focused on arterial wall Quantitative coronary angiography (QCA) provides information on arterial lumen diameter

19. INTRAVASCULAR ULTRASOUND (IVUS) The miniaturisation of high-frequency intravascular ultrasound transducers has allowed the direct examination, in living humans, of the thickening of vessel walls of coronary arteries

20. AIM OF THE STUDY To evaluate whether a correlation closer to the one obtained in autopsy studies can be obtained by measuring carotid and coronary atherosclerosis by using more homogeneous arterial wall parameters, i.e. IMT, in both vascular districts

21. APPROACH Carotid wall B-Mode ultrasound Coronary lumen Classical approach VS Angiography Coronary wall More homogeneous parameters from both vascular districts VS Intravascular ultrasound

22. Correlation coefficients between Carotid and Coronary atherosclerosis 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.51 Autopsy Studies (mean of 3 studies) Correlation coefficient (r) PRESENT STUDY DATA REPORTED IN LITERATURE 0.360.35 Carotid IMT Vs Angiography (mean of 6 studies) %DS 0.55 0.52 Carotid IMT Vs IVUS (Present study) C-IMT Mean C-IMT Max Thus, carotid IMT correlates very well with coronary atherosclerosis Correlation coefficients between carotid IMT and coronary lumen were much lower than those observed in autopsy studies those obtained evaluating IMT in both arterial districts were much higher and reach values very similar to the ones observed in studies post- mortem

23. 1.Is there a direct correlation between carotid and coronary disease? 2.In what kind of patients IMT measurement may actually have the highest clinical usefulness? 3.what threshold value has to be adopted to obtain the maximal IMT predictive capacity? Before trying to use carotid IMT for predictive purposes three questions had to be answered:

24. Patients at high risk (e.g. those with a Framingham Risk Score >20%) are already qualified for aggressive treatment Is the population with FRS≥20% (high risk) a good target for IMT measurements? Thus, in this kind of patients, no further risk stratification tools are needed.

25. Patients at intermediate-risk (FRS: 10-20%) represent for many clinicians a gray decision area In fact, although these patients do not currently qualify for aggressive treatment, epidemiological and clinical evidences show that cardiac events occur in many of these individuals The number of patients at intermediate-risk is high (for instance, they constitute 40% of the US population) Thus, tools to further stratify the risk in patients at intermediate- risk are actually needed

26. 1.Is there a direct correlation between carotid and coronary disease? 2.In what kind of patients IMT measurement may actually have the highest clinical usefulness? 3.what threshold value has to be adopted to obtain the maximal IMT predictive capacity? Before trying to use carotid IMT for predictive purposes three questions had to be answered:

27. 2,381,881,380,880,38 Frequency 400 300 200 100 0 MEAN MAX IMT IMT ≥ 1 mm LowHigh Epidemiologic data currently available indicate that a value of IMT equal or greater than 1 mm at any age is associated with a significantly increased risk of myocardial infarction or cerebrovascular disease. Folsom et al. Diabetes Care 2003;26:2777-84. Chambless et al. Clin Epidemiol 2003;56:880. Salonen et al. Arterioscler Thromb 1991;11:1245-9. Chambless et al. Am J Epidemiol 1997;146:483. Risk of CAD and CVD GENERAL POPULATION

28. A longitudinal observational study aimed at investigating whether the measurement, in clinical practice, of carotid Max-IMT could be combined with the FRS to improve the predictability of cardiovascular events in patients who are at low or intermediate risk AIM OF THE STUDY Baldassarre et al., Atherosclerosis 2006 May 6 [Epub ahed of print]

29. The addition to the FRS of the “plaque status”, expressed in terms of presence or absence of a Max-IMT value ≥1 mm (or even ≥ 1.3 mm), did not significantly improve the predictive power of the FRS. Thus, can we say that IMT has not predictive capacity? NO !

30. Age and sex known to have a major impact on IMT measurements have not been taken into account. Baldassarre et al., STROKE 2000;31: 2426-2430 0.5 1.0 1.5 2.0 WomenMen Age adjusted Max-IMT (mm) P<0.0001 Effect of gender on carotid IMT 0 2 4 6 8 020406080 r =0.43 p<0.0001 Age (years) Max-IMT (mm) Effect of age on carotid IMT

31. MEN 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th WOMEN 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th Deciles of Max-IMT distribution Deciles of Max-IMT distribution in men and women calculated in a group of about 2000 Italian dyslipidemic patients, plotted for 10- years age intervals. Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.

32. 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th Deciles of Max-IMT distribution In selected populations affected by major risk factors like patients with dyslipidemia, hypertension, or diabetes, an IMT greater than 1 mm is present in almost every patient above 50 years of age MENWOMEN Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.

33. 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th Deciles of Max-IMT distribution In addition, if age and sex are not taken into account, each patient with an IMT ≥1 mm is classified as having the same risk either if man or women, and either if young or old; MENWOMEN Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.

34. 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th Deciles of Max-IMT distribution In addition, if age and sex are not taken into account, each patient with an IMT ≥1 mm is classified as having the same risk either if man or women and either if young or old; MENWOMEN but, if we consider for example an IMT value of 1.3 mm, this may be the highest value within the IMT distribution of young patients but even the lowest one when the IMT distribution of patients older 50 are considered Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.

35. 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th Deciles of Max-IMT distribution In addition, by using this approach, each patient with an IMT value greater than 1 mm is classified as having the same risk either if he has an IMT of 1.1 mm or if he has an IMT of 2.5 mm or greater: this is out of any biological plausibility. MENWOMEN Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.

36. MEN 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th WOMEN 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th Deciles of Max-IMT distribution To overcome this problem in our study the “best threshold values” (BTVs), above which to consider Max-IMT as abnormally high, were calculated for each 10-years age interval in men and women. Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.

37. MEN 0.8 0.9 1.4 2.0 2.5 3.0 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th WOMEN 0.7 1.3 1.7 2.1 2.5 3.0 0.0 1.0 2.0 3.0 4.0 20-29 30-39 40-49 50-59 60-69 70-79 DECADES OF AGE (years) Max-IMT (mm) 90 th 80 th 70 th 60 th 50 th 40 th 30 th 20 th 10 th Deciles of Max-IMT distribution To overcome this problem in our study the “best threshold values” (BTVs), above which to consider Max-IMT as abnormally high, were calculated for each 10-years age interval in men and women. These were found to be the 60 th and 80 th percentiles of Max-IMT distribution for men and women, respectively, for each decade of age. Baldassarre et al., Atherosclerosis. 2007;191(2):403-408. By using these new IMT threshold values the results of the analyses completely changed

38. a FRS above 10% was associated with an HR of 2.60; p = 0.03 (95% CI 1.07 - 6.3) Baldassarre et al., Atherosclerosis. 2007;191(2):403-408. Repeating the Cox analysis, using these BTVs as stratification tools: FRS Max-IMT a Max-IMT above BTV gave a HR of 2.42; p = 0.04 (95% CI 1.04 - 5.66) independent predictors of new cardiovascular events.

39. Max-IMT < BTV Max-IMT ≥ BTV FRS < 10% 10<FRS<20% Max-IMT best threshold value (BTV): men = 60 th percentile women = 80 th percentile Stratifying the study population according to the presence of a FRS above or below 10% and Max-IMT above or below BTV Values are adjusted for pharmacological treatments 0 1 2 3 4 5 6 7 Hazard ratio Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.

40. Max-IMT < BTV Max-IMT ≥ BTV FRS < 10% 10<FRS<20% Max-IMT best threshold value (BTV): men = 60 th percentile women = 80 th percentile Values are adjusted for pharmacological treatments 0 1 2 3 4 5 6 7 4.1 P<0.05 4.2 P<0.05 6.7 (p=0.01) Hazard ratio Baldassarre et al., Atherosclerosis. 2007;191(2):403-408. the strength of the associations between Max-IMT and outcome was at least as strong as the associations seen with FRS the concomitant presence of FRS ≥10% and Max-IMT above the BTV yielded a marked increase in the HR. Stratifying the study population according to the presence of a FRS above or below 10% and Max-IMT above or below BTV

41. Log Hazard Ratio Values are adjusted for pharmacological treatments Max-IMT best threshold value (BTV): men = 60 th percentile women = 80 th percentile p=0.67 0 1 2 3 Baldassarre et al., Atherosclerosis. 2007;191(2):403-408. Max-MT<BTV Max-MT≥BTV Intermediate risk 10≤FRS<20% Low risk FRS<10% High risk 20<FRS<30% HR FOR HAVING A NEW CARDIOVASCULAR EVENT IN LOW, INTERMEDIATE AND HIGH RISK GROUPS In addition, compared to low-risk patients

42. Max-MT< BTVMax-MT ≥ BTVMax-MT< BTVMax-MT ≥ BTV Incidence of cardiovascular events (%) Low risk patients (FRS<10%) Intermediate risk patients (10%<FRS<20%) Threshold for drug therapy 0 10 20 30 40 50 Predicted incidence by the Framingham Risk Score Observed incidence incidence of new cardiovascular events predicted on the basis of FRS vs. incidence actually observed (estimated by the Kaplan-Meyer method) Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.

43. Predicted incidence by the Framingham Risk Score Incidence of cardiovascular events (%) Threshold for drug therapy 0 10 20 30 40 50 Observed incidence Max-MT< BTVMax-MT ≥ BTV Low risk patients (FRS<10%) incidence of new cardiovascular events predicted on the basis of FRS vs. actually observed incidence (estimated by the Kaplan-Meyer method) Max-MT< BTVMax-MT ≥ BTV Intermediate risk patients (10%<FRS<20%) Baldassarre et al., Atherosclerosis. 2007;191(2):403-408.

44. Predicted incidence by the Framingham Risk Score Incidence of cardiovascular events (%) Low risk patients (FRS<10%) Threshold for drug therapy 0 10 20 30 40 50 Observed incidence incidence of new cardiovascular events predicted on the basis of FRS vs. actually observed incidence (estimated by the Kaplan-Meyer method) Max-MT ≥ BTV Intermediate risk patients (10%<FRS<20%) Ratio = 3.11 Baldassarre et al., Atherosclerosis. 2007;191(2):403-408. On the basis of the two last histograms it can be calculated that the “actually observed incidence of new cardiovascular events” can be better predicted by FRS if this is multiplied for 3.11.

45. IMT as predictor of vascular events

46. O’Leary et al. New Eng J Med 1999 One American study provides convincing evidences that carotid artery IMT is a good predictor of new vascular events. about the 95% of the subjects with an IMT classifiable in the first quintile were free of vascular events. In contrast, the percentage of subjects free of vascular events in the group with the highest quintile of IMT was less than 75% 4500 patients 65 years or older Follow up: about 7 years Thus suggesting that carotid IMT may be effectively considered as a good marker of evolutive atherosclerotic disease.

47. THE IMPROVE STUDY Carotid Intima Media Thickness (IMT) and IMT-Progression as Predictors of Vascular Events in a High Risk European Population

48. The IMPROVE Study is a multicenter, longitudinal, observational study carried out in an Pan-European population of 3732 patients at high risk of cardiovascular disease for the presence of at least three vascular risk factors. DESIGN Vascular risk factors: Male or Female at least 5 years after menopause Hypercholesterolemia Hypertriglyceridemia Hypo-alpha-lipoproteinemia Hypertension Diabetes Smoking habits Family history of cardiovascular diseases SWEDEN n=533 FINLAND n=1050 (2 clinical centers) FRANCE n=501 THE NETHERLANDs n=553 ITALY n=1095 (2 clinical centers)

49. OBJECTIVE Cross-sectional carotid IMT To evaluate the association between the rate of subsequent vascular events Carotid IMT-progression within 15 months

50. Baseline carotid IMT Mean-Max as predictor of new cardiovascular events 1 st quintile 2 nd quintile 3 rd quintile 4 th quintile 5 th quintile 0.98 0 1 2 3 % event free 0.89 0.92 0.95 follow-up (years) 1.00 IMT Mean-Max < 1.04 >1.70 1.42 - 1.70 1.22 - 1.41 1.04 - 1.20 Thus, also in an European population carotid IMT is a very good predictor of new vascular events

51. Since carotid IMT: correlates well with atherosclerosis risk factors correlates well with coronary atherosclerosis can be used in clinical practice to enhance the predictability of cardiovascular events in patients who fall into the intermediate-risk category is a very good predictor of new vascular events Summary

52. Carotid IMT is an excellent marker of carotid and even coronary atherosclerosis CONCLUSION