CIMT: a Useful Surrogate for Assessing the Efficacy of new Cardiovascular Drugs? Daniel H. O’Leary, M.D.

Daniel H. O'Leary, MD DISCLOSURES Consulting Fees Genzyme, Pfizer, Inc. Ownership Interest (Stocks, Stock Options or Other Ownership Interest) Medpace, Inc.

Ultrasound measurement of CIMT probe carotid bulb internal carotid artery common carotid artery blood flow Early detection and treatment of subclinical atherosclerosis is highly valuable in CHD prevention. Techniques to image vascular changes are important to assess disease development and response to treatment. Measuring carotid IMT using B-mode ultrasound has been found to be a reliable marker of atherosclerotic burden and predicts future events. Several studies have shown that increased carotid IMT is associated with an increased risk of CHD (reviewed in Bots & Grobbee 2002). Indeed, the value of B-mode ultrasound has been recognised by the American Heart Association Prevention Conference V Writing Group III which indicated that carotid ultrasound examination with IMT measurement is useful to assess plaque progression or regression during patient follow-up (Greenland et al 2000). References Bots ML, Grobbee DE. Intima media thickness as a surrogate marker for generalised atherosclerosis. Cardiovasc Drugs Ther 2002; 16: 341–351. Greenland P et al. Prevention Conference V: Beyond secondary prevention: identifying the high-risk patient for primary prevention: noninvasive tests of atherosclerotic burden: Writing Group III. Circulation 2000; 101: E16–E22. carotid dilatation carotid flow divider external carotid artery

Change over time in CIMT trials CIMT varies with age, gender, ethnicity, location of measurement, ultrasound equipment used, and off line reading system Average CIMT in healthy middle age adult = 0.6 – 0.7 mm Annual CIMT progression rates average 0.005 – 0.01 mm/yr Axial resolution of ultrasound device is between 0.1 – 0.3 mm Measurement error is 5 %-10% baseline CIMT Above data determines appropriate study design

Ultrasound Measurement of Atheroma Volume (IVUS) Courtesy S. Nissen 1 mm spacing Cross-section 48 Cross-section 26 Cross-section 10

Ultrasound Determination of Atheroma Area Precise Planimetry of EEM and Lumen Borders with Calculation of Atheroma Cross-sectional Area Courtesy S. Nissen EEM Area Lumen Area Atheroma Area

Concurrence between CIMT and IVUS ASAP (atorvastatin 80 mg) METEOR (rosuvastatin 40 vs. placebo) CHICAGO (pioglitazone) CAPTIVATE (pactimibe) RADIANCE 1 and 2 (torcetrapib + atorvastatin) AUDITOR (rimonabant 20) REVERSAL (vs. simvast 40)* ASTEROID (rosuvastatin only) PERISCOPE (vs. glimepiride) ACTIVATE (vs. placebo) ILLUSTRATE(atorvastatin)* STRADIVARIUS (placebo)* * = hard outcomes study

Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolemia (ASAP) Smilde TJ, Kastelein JJP, et al. Lancet 2001;577- 325 patients with familial hypercholesterolemia (average age = 48 years; baseline CIMT = 0.93 mm) atorvastatin 80 mg (n=160) simvastatin 40 mg (n=165) At 2 yrs atovastatin IMT decreased (-0.031 mm; p=.0017) At 2 yrs simvastatin IMT increased (0.036 mm; p=0.0005) Conclusion: aggressive LDL-cholesterol reduction by atorvastatin was accompanied by a regression of IMT in patients with heterozygous familial hypercholesterolemia, whereas conventional LDL lowering was not

Changes in intima media thickness (mm) in the different segments of the carotid artery after 1 and 2 years of treatment with simvastatin (S) or atorvastatin (A) Data are combined measurements of posterior and anterior wall on both right and left side in CCA, bulb, and ICA. Overall IMT=mean of all segments. Vertical bars=SD. Smilde et al. Lancet 2001

*Wilcoxon signed rank test †ANCOVA of rank transformed results REVERSAL: IVUS Study (prava 40 vs atorva 80) Nissen et al. JAMA 2004;291:1071 Progression (p=0.001*) Percent Change In Atheroma Volume p = 0.02† The primary prespecifed endpoint, the percent change in atheroma volume showed 2.7% progression in the pravastatin arm, shown in blue, p = 0.001 compared to baseline. In contrast, the INTENSIVE atorvastatin arm, shown in orange, showed a reduction in atheroma volume, minus 0.4%, which represented no change from baseline, p = 0.98. Unpaired comparison of the two treatment cohorts revealed a significant difference in progression rate, p = 0.02, favoring atorvastatin. These data demonstrate that MODERATE treatment of lipids with pravastatin was associated with significant progression, whereas, INTENSIVE treatment with atorvastatin halted progression. No change (p=0.98*) *Wilcoxon signed rank test †ANCOVA of rank transformed results Pravastatin Atorvastatin

Conclusion of ASAP (2001) and REVERSAL(2004) LDL: lower is better hard outcome studies Supported by PROVE-IT TIMI-22 (2005) (2006) TNT IDEAL

METEOR: CIMT Study Patients (n=984) Asymptomatic for CHD Maximum IMT ≥1.2–<3.5 mm Modest hypercholesterolaemia Men (aged 45-70) Women (aged 55-70) rosuvastatin 40 mg (n =702) placebo (n=282) Visit: Week: 1 –6 2 –4 3 –2 4 5 6 6 13 7 26 8 39 9 52 10 65 11 78 12 91 13 104 METEOR is a randomised, double-blind, placebo-controlled, parallel-group, multicentre phase III study of rosuvastatin 40 mg in the prevention of atherosclerosis among asymptomatic patients assessed as being at low risk of CHD. Patients are asymptomatic for atherosclerosis and are considered at low risk of CHD according to conventional risk factors; 10-year CHD risk is assessed using the Framingham Risk Index. 984 patients were recruited from approximately 30 US and European centres and randomised to receive rosuvastatin or placebo in a 5:2 ratio. The 5:2 randomisation ratio in METEOR is due to the primary endpoint consisting of a two-stage test. See the following slide. Reference Crouse III JR et al. Measuring Effects on Intima Media Thickness: an Evaluation of Rosuvastatin in Subclinical Atherosclerosis – The Rationale and Methodology of the METEOR Study. Cardiovasc Drugs Ther 2004; 18: 231–238. Adapted from Cardiovasc Drugs Ther 2004; 18: 231–238, with permission from Springer. Run in / eligibility Lipids Safety Lipids Safety CIMT Safety CIMT Safety Lipids Safety CIMT Safety CIMT Lipids Safety CIMT= carotid intima media thickness Adapted from Crouse JR et al. Cardiovasc Drugs Ther 2004; 18: 231–238

METEOR primary endpoint: Rate of change of maximum IMT at 12 carotid sites Left Right Internal Bulb Common Time Maximum IMT For each segment The maximum IMT at each of the 12 carotid sites is measured over 2 years. The rate of change is calculated. Primary end point was rate of change (mm/yr) in maximum CIMT, based on all 12 carotid artery segments (pre-defined segments of the anterior (near) and posterior (far) walls of the right and left common carotid artery (CCA), carotid bifurcation and internal carotid artery (ICA) combined). This measure is superior to the MeanMax IMT in that it minimises bias whilst maximising the utilised data. Briefly, Each participant is scanned 7 times over the period of the trial For each participant, the best scanning angle was determined At each scan, the images were recorded and analysed semi automatically in a random order to prevent reader drift At each scan, 12 measurements are taken of the maxima at each of the segments of the carotid artery (right/left, near/far, CCA/IMT/bifurcation). Each of the 12 boxes in the following slide represents one of the 12 carotid segments The rate of change at each segment is calculated and, as shown in the graph, a line of best fit is plotted against the points. The following slide shows how each segment is analysed individually. The slopes for each individual segment are combined to generate the mean slope for each individual patient. Crouse JR et al. Cardiovasc Drugs Ther 2004; 18: 231–238

(Rosuvastatin vs. placebo) METEOR primary endpoint: Rate of change of maximum IMT at 12 carotid sites Rosuvastatin vs placebo +0.03 Placebo +0.0131 mm/yr (n=252) P<0.0001 (Rosuvastatin vs. placebo) +0.02 Progression Change in IMT of 12 carotid sites (mm) +0.01 Time (years) 1 2 0.00 This graph displays the results of the two-stage primary endpoint. It’s important when assessing the results from METEOR, to remember that the primary endpoint had 2 stages. These were (i) to examine the difference in CMT between placebo and rosuvastatin, where a significant difference would confirm a slowing of progression with rosuvastatin compared to placebo and (ii) to examine the difference between rosuvastatin and baseline, where a significant difference would confirm regression with rosuvastatin. The two-stage test accounts for the 5:2 randomisation ratio in METEOR. Looking the first stage, it is apparent that for all carotid sites, the rate of progression was significantly reduced compared with placebo For the second objective, the rate of change for CRESTOR was negative but the difference compared to baseline was not statistically significant. Reference Crouse J et al. Effect of Rosuvastatin on Progression of Carotid Intima-Media Thickness in Low-Risk Individuals With Subclinical Atherosclerosis. The METEOR Trial. JAMA 2007;297:(doi:10.1001/jama.297.12.joc70024) P=NS (Rosuvastatin vs. zero slope Regression Rosuvastatin 40 mg -0.0014 mm/yr (n=624) -0.01 Placebo; Change in CIMT (95% CI) Rosuvastatin 40 mg; Change in CIMT (95% CI) Crouse JR, et al. JAMA 2007;297:(doi:10.1001/jama.297.12.joc70024)

ASTEROID: IVUS Study (Rosuvastatin) Nissen et al ASTEROID: IVUS Study (Rosuvastatin) Nissen et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis JAMA 2006, 295:1556 Objective: To evaluate whether 24 months treatment with rosuvastatin 40 mg will result in regression of coronary atherosclerosis as measured by IVUS (no control group) Primary hypothesis: Very Intensive lipid lowering with 40 mg rosuvastatin will reduce coronary atheroma burden using two separate IVUS measures Null hypothesis: Treatment will result in either progression or no change in disease burden

Dual Primary IVUS Efficacy Parameters Median Change in Percent Atheroma Volume Median Change in Most Diseased Subsegment Change In Percent Atheroma Volume (%) Change In Atheroma Volume (mm3) Regression p<0.001* Regression p<0.001* *Wilcoxon signed rank test for comparison with baseline Courtesy S. Nissen (from JAMA 2006)

RADIANCE 1 Conclusion: Use of torcetrapib in patients with FH did not result in regression of atherosclerosis, as assessed by CIMT, and even caused progression of disease in the common carotid segment. These effects occurred despite an unparalleled increase in HDL-C (52%) and substantial decrease in LDL-C (21%).

ILLUSTRATE: IVUS Study (Torcetrapib) 910 subjects with symptomatic CAD Change in percent atheroma volume, the primary efficacy parameter, was nearly identical in patients randomized to torcetrapib vs. atorvastatin (0.12 vs 0.19%, P=0.72) Nissen et al. Effect of torcetrapib on progression of coronary atherosclerosis. N Engl J Med 2007, 356:1304

ILLUMINATE: Outcomes Study (Torcetrapib) 15,067 subjects with CHD or CHD risk equivalent At termination, the torcetrapib group showed a 25% increased risk over the groups that received atorvastatin alone (hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.09-1.44; P = .001) A total of 464 events occurred in the torcetrapib group vs 373 in the atorvastatin-only group Barter et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007, 357:2109

Summary: CIMT Noninvasive; repeatable Best validated of the noninvasive imaging technologies Methodology becoming standardized; moderate cost Continuous measure; all subjects have a measureable wall Valid measurements; normative values vary with age, gender, and race; intervention affects CIMT progression within 12 to 18 months Currently most widely used surrogate both as a risk equivalent and outcome measure Consistent concurrence among CIMT, IVUS, and outcome studies