I S IVUS R EGRESSION R ELEVANT ? Todd Anderson Mar 2017 - PowerPoint PPT Presentation

I S IVUS R EGRESSION R ELEVANT ? Todd Anderson Mar 2017

Disclosures • Todd Anderson – Advisory board: Merck – Clinical Trials: Amgen, Merck, Pfizer, Dalcor – Speakers Bureau: Sanofi, Amgen, Pfizer

The Case for Lower is Better • Biological plausibility – Apo B lipoproteins linked to atherogenesis • Epidemiology data – Mendelian randomization • On Rx LDL-C related to events • CTT meta-analysis – 22% reduction per 1 mmol/L ↓ • Emerging randomized trial data with new meds • IVUS trials • Guidelines

Vulnerable plaque Rupture not seen but was present Thin-cap large lipid core with cholesterol crystals Fuster et al. JACC 2005;46:937

IVUS with radiofrequency analysis • Spectral analysis of radiofrequency backscatter of ultrasound images • Color coding (virtual histology) allows for classification into: fibrous, fibrofatty, necrotic and calcified • Recent data suggests relationship between necrotic plaque and cardiac events but most TCFA do not go on to rupture • Volcano system – 20MHz Puri et al. Nature CV reviews 2011;8:131-139

Vulnerable Plaque Detection-OCT Fibrous atheroma Thick walled plaque TFCA Suh et al. Circ CV Imag 2011;4:169-

CHD Reduction from Earlier LDL-C Lowering: Lifetime low LDL Lifetime lower LDL-C due to genetics resulted in a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life Association between 1mmol/L lower LDL-C and risk of CHD Ferrence BA, et al. J Am Coll Cardiol. 2012;60(25):2631-9.

Achieving Very Low LDL-C Levels Results in Lower Risk for Major CV Events than Achieving Moderately Low Levels On-Statin LDL-C Levels and Risk for Major Cardiovascular Events Meta-Analysis of 8 40 1.00 HR for Major CV Events statin trials (n=38,153): Percent of Patients 30 • >40% did not reach 0.75 LDL-C target (<1.8 0.50 20 mmol/L) on high dose statin 0.25 10 0 1.3 2.6 3.9 5.2 6.5 Achieved On-statin LDL Levels CV = cardiovascular; CVD = cardiovascular disease; HR = hazard ratio Boekholdt et al. J Am Coll Cardio. 2014;64(5):485-495.

Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction, by baseline LDL-C No. of events (% pa) Relative risk (CI) per mmol/L LDL-C reduction Statin/more Control/less More vs less statin < 2.0 704 (17.9%) 795 (20.2%) 0.71 (0.52 - 0.98)  2,<2.5 1189 (18.4%) 1317 (20.8%) 0.77 (0.64 - 0.94)  2.5,<3.0 1065 (20.1%) 1203 (22.2%) 0.81 (0.67 - 0.97)  3,<3.5 517 (20.4%) 633 (25.8%) 0.61 (0.46 - 0.81)  3.5 303 (23.9%) 398 (31.2%) 0.64 (0.47 - 0.86) 3837 (19.4%) 4416 (22.3%) 0.72 (0.66 - 0.78) Total Statin vs control < 2.0 206 (9.0%) 217 (9.7%) 0.87 (0.60 - 1.28)  2,<2.5 339 (7.7%) 412 (9.1%) 0.77 (0.62 - 0.97)  2.5,<3.0 801 (8.2%) 1022 (10.5%) 0.76 (0.67 - 0.86)  3,<3.5 1490 (10.8%) 1821 (13.3%) 0.77 (0.71 - 0.84)  3.5 4205 (12.6%) 5338 (15.9%) 0.80 (0.77 - 0.84) 7136 (11.0%) 8934 (13.8%) 0.79 (0.77 - 0.81) Total All trials < 2.0 910 (14.7%) 1012 (16.4%) 0.78 (0.61 - 0.99)  2,<2.5 1528 (14.0%) 1729 (15.9%) 0.77 (0.67 - 0.89)  2.5,<3.0 1866 (12.4%) 2225 (14.7%) 0.77 (0.70 - 0.85)  3,<3.5 2007 (12.3%) 2454 (15.2%) 0.76 (0.70 - 0.82)  3.5 4508 (13.0%) 5736 (16.5%) 0.80 (0.76 - 0.83) 10973 (13.0%) 13350 (15.8%) 0.78 (0.76 - 0.80) Total 99% or 95% CI 0.5 0.75 1 1.25 1.5 Statin/more better Control/less better

IVUS Regression Trials 349 subjects with CAD 40 mg of rosuvastatin LDL 1.5 mmol/L HDL 1.2 53% ↓ LDL 14% ↑ HDL 24 month follow-up Open label, no control 6.8% ↓ TAV Negative remodeling as well Nissen et al. JAMA 2006;295:1561

GLAGOV: Objective Objective • To test the hypothesis that LDL-C lowering with a monthly subcutaneous injection of evolocumab 420 mg for 78 weeks will result in a significantly greater change from baseline in percentage atheroma volume (PAV) compared with placebo in subjects taking background statin therapy Design • A 78-week, randomized, double-blind, placebo-controlled, multicenter, phase 3 study. Nicholls SJ, et al. JAMA . [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951. Puri R, et al. Am Heart J . 2016;176:83-92.

GLAGOV: Key Inclusion Criteria • Men or women aged ˃ 18 years • Clinically indicated coronary angiogram, evidence of coronary disease • LDL-C criteria met within 4 weeks of screening visit or, if applicable, at the end of lipid-stabilization period: – LDL- C ≥ 2.07 mmol/L, OR – LDL- C ≥ 1.56 but < 2.07 mmol/L in the presence of risk factors as shown in the table below: • Non-coronary atherosclerotic vascular disease Major Risk Factors (One Required) • Documented myocardial infarction or hospitalization for unstable angina within the last 2 years • Documented type 2 diabetes mellitus OR • Age (men ≥ 50 years; women ≥ 55 years) Minor Risk Factors (Three Required) • Hypertension (BP ≥ 140/90 mmHg or current use of antihypertensive medications) • Low HDL-C (men: < 1.04 mmol/L; women < 1.30 mmol/L) • Family history of premature coronary heart disease (first-degree male relative < 55 years of age or first-degree female relative < 65 years of age) • hs- CRP ≥ 19.0 nmol/L • Cigarette smoking (current) Nicholls SJ, et al. JAMA . [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951. Puri R, et al. Am Heart J . 2016;176:83-92.

GLAGOV: Study Design Screening and placebo run-in period Placebo SC Up to • Clinically indicated every month 4-week lipid Randomization 1:1 End Of Study coronary angiogram stabilization to study drug period • IVUS based on coronary angiogram results Assigned to Evolocumab background • SC injection of 3 mL statin therapy 420 mg SC placebo every month 2 – 4 weeks Maximum 6 weeks D1 W4 W12 W24 W36 W52 W64 W76 W78 W80 EOS Study visits: Study drug was administered monthly at home or in the clinic Last Last dose of IVUS study procedure drug *Nominal change refers to the actual number, as opposed to percent change D = day; IVUS = intravascular ultrasound; SC = subcutaneously; W = week. Puri R, et al. Am Heart J . 2016;176:83-92.

GLAGOV: Analysis of IVUS Imaging • Plaque area is calculated as the area between the two leading edges • Two measures of atheroma burden will be calculated for each patient − PAV is calculated as the proportion of the EEM volume occupied by atherosclerotic plaque Σ (EEM area – lumen area ) PAV = X 100 Σ (EEM area ) − TAV is calculated as the summation of plaque areas in each measured cross- sectional image within the segment and subsequently normalized by the median number of images analyzed in the entire cohort to account for heterogeneity in segment length between subjects Leading edge of Leading edge of Σ (EEM area – lumen area ) TAV normalized = X Median number of images in cohort the EEM the lumen Number of images in pullback IVUS = intravascular ultrasound; EEM = external elastic membrane; PAV = percentage atheroma volume; TAV = total atheroma volume. Puri R, et al. Am Heart J . 2016;176:83-92. Nicholls SJ, et al. JAMA . [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951

GLAGOV: Disposition of Patients During the Study 2628 screened 1382 did not meet eligibility criteria 276 enrolled but not randomized 1246 enrolled 235 did not meet inclusion/ exclusion criteria 32 withdrew informed consent 9 other 970 Patients randomized 486 assigned to receive placebo 484 assigned to receive 2 never received study drug evolocumab 423 included in primary analysis 423 included in primary analysis 61 did not complete endpoint assessment 61 did not complete endpoint assessment 484 included in safety analysis 484 included in safety analysis (received placebo as randomized) (received evolocumab as randomized) Adapted from: Nicholls SJ, et al. JAMA . [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.

GLAGOV: Baseline Characteristics of Randomized Patients Placebo Evolocumab Parameter* (N = 484) (N = 484) Age, years 59.8±8.8 59.8±9.6 Men, n (%) 350 (72.3) 349 (72.1) White, n (%) 452 (93.4) 456 (94.2) BMI 29.5±5.0 29.4±5.0 Hypertension, n (%) 405 (83.7) 398 (82.2) Previous PCI, n (%) 188 (38.8) 189 (39.0) Previous MI, n (%) 171 (35.3) 169 (34.9) Smoking, n (%) 113 (23.3) 124 (25.6) Diabetes, n (%) 104 (21.5) 98 (20.2) Baseline statin use,* n (%) 476 (98.3) 478 (98.8) 290 (59.9) 280 (57.9) Moderate intensity, n (%) 185 (38.2) 196 (40.5) Low intensity, n (%) 1 (0.2) 2 (0.4) Baseline ezetimibe use,* n (%) 9 (2.1) 9 (2.1) Baseline medications Anti-platelet therapy, n (%) 465 (96.1) 454 (93.8) Beta-blocker, n (%) 370 (76.4) 362 (74.8) ACE inhibitor, n (%) 264 (54.5) 260 (53.7) ARB, n (%) 92 (19.0) 87 (18.0) Age and BMI expressed as mean ± standard deviation. *Baseline statin and ezetimibe use is defined as subject treated with statin or ezetimibe therapy at the end of the lipid stabilization period at randomization. † High intensity statin as defined by ACC/AHA criteria Nicholls SJ, et al. JAMA . [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.