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

IS IVUS REGRESSION RELEVANT?

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

Fuster et al. JACC 2005;46:937

Rupture not seen but was present Thin-cap large lipid core with cholesterol crystals

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

Suh et al. Circ CV Imag 2011;4:169-

Fibrous atheroma Thick walled plaque TFCA

CHD Reduction from Earlier LDL-C Lowering: Lifetime low LDL

Ferrence BA, et al. J Am Coll Cardiol. 2012;60(25):2631-9.

Association between 1mmol/L lower LDL-C and risk of CHD

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

Achieving Very Low LDL-C Levels Results in Lower Risk for Major CV Events than Achieving Moderately Low Levels

CV = cardiovascular; CVD = cardiovascular disease; HR = hazard ratio Boekholdt et al. J Am Coll Cardio. 2014;64(5):485-495.

Meta-Analysis of 8 statin trials (n=38,153):

• >40% did not reach

LDL-C target (<1.8 mmol/L) on high dose statin

1.00 0.75 0.50 0.25 10 20 30 40 1.3 2.6 3.9 5.2 6.5 HR for Major CV Events Percent of Patients

Achieved On-statin LDL Levels

On-Statin LDL-C Levels and Risk for Major Cardiovascular Events

0.5 0.75 1 1.25 1.5

Statin/more better Control/less better <2.0 2,<2.5 2.5,<3.0 3,<3.5 3.5 Total 910 (14.7%) 1528 (14.0%) 1866 (12.4%) 2007 (12.3%) 4508 (13.0%) 10973 (13.0%) 1012 (16.4%) 1729 (15.9%) 2225 (14.7%) 2454 (15.2%) 5736 (16.5%) 13350 (15.8%) 0.78 (0.61 - 0.99) 0.77 (0.67 - 0.89) 0.77 (0.70 - 0.85) 0.76 (0.70 - 0.82) 0.80 (0.76 - 0.83) 0.78 (0.76 - 0.80)

• No. of events (% pa)

Statin/more Control/less

<2.0 2,<2.5 2.5,<3.0 3,<3.5 3.5 Total 704 (17.9%) 1189 (18.4%) 1065 (20.1%) 517 (20.4%) 303 (23.9%) 3837 (19.4%) 795 (20.2%) 1317 (20.8%) 1203 (22.2%) 633 (25.8%) 398 (31.2%) 4416 (22.3%) 0.71 (0.52 - 0.98) 0.77 (0.64 - 0.94) 0.81 (0.67 - 0.97) 0.61 (0.46 - 0.81) 0.64 (0.47 - 0.86) 0.72 (0.66 - 0.78) <2.0 2,<2.5 2.5,<3.0 3,<3.5 3.5 Total 206 (9.0%) 339 (7.7%) 801 (8.2%) 1490 (10.8%) 4205 (12.6%) 7136 (11.0%) 217 (9.7%) 412 (9.1%) 1022 (10.5%) 1821 (13.3%) 5338 (15.9%) 8934 (13.8%) 0.87 (0.60 - 1.28) 0.77 (0.62 - 0.97) 0.76 (0.67 - 0.86) 0.77 (0.71 - 0.84) 0.80 (0.77 - 0.84) 0.79 (0.77 - 0.81)

More vs less statin Statin vs control All trials

Relative risk (CI) per mmol/L LDL-C reduction

99% or 95% CI

Proportional effects on MAJOR VASCULAR EVENTS per mmol/L LDL-C reduction, by baseline LDL-C

Nissen et al. JAMA 2006;295:1561

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

IVUS Regression Trials

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:

Major Risk Factors (One Required)

• Non-coronary atherosclerotic vascular disease
• Documented myocardial infarction or hospitalization for unstable angina within the last

2 years

• Documented type 2 diabetes mellitus

Minor Risk Factors (Three Required)

• Age (men ≥ 50 years; women ≥ 55 years)
• 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
• r first-degree female relative < 65 years of age)
• hs-CRP ≥ 19.0 nmol/L
• Cigarette smoking (current)

OR

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

*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.

Up to 4-week lipid stabilization period Assigned to background statin therapy

Placebo SC every month

Randomization 1:1 to study drug

End Of Study

Maximum 6 weeks

D1 W4 W12 W24 W36 W52 W64 W76 W78 W80 EOS

Study drug was administered monthly at home or in the clinic

Study visits:

Screening and placebo run-in period

• Clinically indicated

coronary angiogram

• IVUS based on

coronary angiogram results

• SC injection of 3 mL

placebo 2–4 weeks

Last dose of study drug Last IVUS procedure

Evolocumab 420 mg SC every month

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 − 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

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

Leading edge of the EEM Leading edge of the lumen

PAV = Σ(EEMarea – lumenarea) Σ(EEMarea) 100 X

= Σ(EEMarea – lumenarea)

Number of images in pullback Median number of images in cohort

X TAVnormalized

GLAGOV: Disposition of Patients During the Study

2628 screened

1382 did not meet eligibility criteria 1246 enrolled

970 Patients randomized

276 enrolled but not randomized 235 did not meet inclusion/ exclusion criteria 32 withdrew informed consent 9 other

484 assigned to receive evolocumab 486 assigned to receive placebo

2 never received study drug

Adapted from: Nicholls SJ, et al. JAMA. [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.

423 included in primary analysis

61 did not complete endpoint assessment

484 included in safety analysis (received placebo as randomized) 423 included in primary analysis

61 did not complete endpoint assessment

484 included in safety analysis (received evolocumab as randomized)

GLAGOV: Baseline Characteristics of Randomized Patients

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

Parameter* Placebo (N = 484) Evolocumab (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)

Nicholls SJ, et al. JAMA. [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.

Mean Absolute Change in LDL-C

Absolute change for evolocumab-statin group: -1.46 (-1.54 to -1.38); P < 0.001

Statin monotherapy Statin + evolocumab

80

LDL-C Absolute Change From Baseline, mmol/L

4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 76

484 484 418 434

Study Week

• No. of patients

Placebo Evolocumab 446 456 441 452 447 444 441 449 425 426

72 68

Mean LDL-C 2.41 mmol/L* Mean LDL-C 0.95 mmol/L* Change from baseline 3.9% Change from baseline -59.8%

0.2 –1.8 –0.2 –0.4 –0.6 –0.8 –1.0 –1.2 –1.4 –1.6

Data shown are Mean (95% CI) *Time-weighted LDL-C; LDL-C = low-density lipoprotein cholesterol Nicholls SJ, et al. JAMA. [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951. Nissen SE, et al. American Heart Association Scientific Sessions, Nov 12 - 16, 2016, New Orleans, Louisiana. Oral Presentation.

Primary Endpoint: Nominal Change in PAV From Baseline to Week 78

Difference between groups: -1.0% (-1.8 to -0.64); P < 0.001

Data shown are least-squares mean (95% CI). PAV = Percent Atheroma Volume *Comparison versus baseline Nicholls SJ, et al. JAMA. [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.

Change in % atheroma volume (%)

P = NS* P < 0.001*

Exploratory Analysis: Achieved LDL-C and Change in PAV in All Patients

• 1.5
• 1.0
• 0.5

0.5 1.0 0.4

Change Percent Atheroma Volume (%) On-Treatment LDL-C (mmol/L)

0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0

Local regression (LOESS) curve illustrating the association (with 95% CI) between achieved LDL-C levels and change in PAV in all patients undergoing serial IVUS evaluation. PAV = percentage atheroma volume; LDL-C = low-density lipoprotein cholesterol Nicholls SJ, et al. JAMA. [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.

Exploratory Subgroup: LDL-C Change from Baseline in Patients with LDL-C < 1.81 mmol/L at Baseline

Nissen SE, et al. American Heart Association Scientific Sessions, Nov 12 - 16, 2016, New Orleans, Louisiana. Oral Presentation

Mean LDL-C 1.83 mmol/L Mean LDL-C 0.62 mmol/L Change from baseline 16.4% Change from baseline -58.3% 0.39 mmol/L 1.70 mmol/L Statin monotherapy Statin + evolocumab

Patients with LDL-C < 1.81 mmol/L at Baseline (n = 144)

*Between-treatment group comparison PAV = percentage atheroma volume Nicholls SJ, et al. JAMA. [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.

Percent Atheroma Volume Fraction Showing Regression

Change in PAV (%) P < 0.001* % of Patients with Regression in PAV P < 0.001*

Patients with LDL-C < 1.81 mmol/L at Baseline (n = 144)

Exploratory Subgroup: Change in PAV & Regression in Patients with LDL-C < 1.81 mmol/L at Baseline

Clinical and Biochemical Adverse Events in the Safety Population*

Parameter Placebo (N = 484) Evolocumab (N = 484) Clinically important adverse events, n (%) Injection site reactions 0 (0) 2 (0.4) Myalgia 28 (5.8) 34 (7.0) Neurocognitive eventsa 6 (1.2) 7 (1.4) New diagnosis of diabetes mellitus† 18 (3.7) 17 (3.6) Abnormality in laboratory value, n (%)‡ Aspartate or alanine aminotransferase >3xULN 2 (0.5) 2 (0.5) Total bilirubin >2xULN 2 (0.5) 1 (0.3) Creatine phosphokinase >5xULN 3 (0.7) 3 (0.7) Creatinine >ULN 5 (1.0) 3 (0.6) Anti-Evolocumab binding antibody NA 1 (0.2) Anti-Evolocumab neutralizing antibody NA 0 (0)

*All patients who received at least one dose of study drug were included in the safety analyses (n = 968)

†Neurocognitive events and new diagnosis diabetes mellitus as reported by investigators as adverse events. ‡The denominator for both

placebo and evolocumab with normal value at baseline in 958. There were a total of 10 patients with missing safety laboratory data, clinical and laboratory adverse events, and reasons for discontinuation in the safety population. NA = Not Available; ULN = Upper Limit of Normal Nicholls SJ, et al. JAMA. [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.

GLAGOV Summary

• In statin-treated patients with symptomatic coronary disease,

addition of evolocumab, 420 mg monthly for 18 months: – Achieved LDL-C levels averaging 0.95 mmol/L compared with 2.41 mmol/L for a statin alone. – Produced regression, mean change in PAV of -0.95% for evolocumab-statin treated group, compared with statin only patients, whose mean change in PAV was +0.05% (P < 0.001). – Produced regression (change in PAV <0) in a greater percentage of patients; 64% for evolocumab-statin treated patients vs. 47% in statin only patients (P < 0.001).

• No new safety signals were observed
• Further studies assessing the effects of PCSK9 inhibition on clinical
• utcomes are pending.

PAV = percentage atheroma volume; LDL-C = low-density lipoprotein cholesterol Nicholls SJ, et al. JAMA. [published online ahead of print November 15, 2016]. doi: 10.1001/jama.2016.16951.

Achieved LDL-C and Plaque Progression

50 100 150

• 1.2
• 0.8
• 0.4

0.0 0.4 0.8 1.2

Achieved LDL-C (mg/dL) Annual Change PAV (%)

REV - prava REV - atorva ACT - placebo GLAGOV - placebo ILL - placebo AST - rosuva GLAGOV Evolocumab SAT - rosuva SAT - atorva

Ongoing Outcome Trials with PCSK9 Inhibitors

ACS: acute coronary syndrome; CAD: coronary artery disease; CHD: coronary heart disease; CVD: coronary vascular disease; EZE: ezetimibe; FH:Familial Hypercholesterolemia; HeFH: Heterozygous Familial Hypercholesterolemia; PAD: peripheral-artery disease; T2DM: type 2 diabetes mellitus. clinicaltrials.gov accessed August 25, 2015.

Study

FOURIER ODYSSEY OUTCOMES SPIRE-1/ SPIRE-2

Treatment Evolocumab: 420 mg QM or 140 mg Q2W Background: optimal lipid lowering therapy Alirocumab: 75 mg Q2W (up titrated to 150 mg Q2W if LDL >1.3 mmol/L; down titrated if LDL <0.65 mmol/L) Background: optimized lipid lowering therapy Bococizumab: 150 mg Q2W Background: lipid lowering therapy Population MI or stroke (≥ last 4 weeks) OR PAD (plus Risk factors for CVD) Patients hospitalized for ACS (<12 months before randomization) Patients at high risk of a CV event # patients 27,500 18,000 SPIRE-1: 17,000 SPIRE-2: 9,000 LDL-C for eligibility LDL-C ≥ 1.8 mmol/L (or non- HDL-C ≥ 2.6 mmol/L) after 4 week stabilization with optimal lipid lowering therapy ≥ 1.8 mol/L or non-HDL-C ≥ 2.6 mmol/L SPIRE-1: LDL-C ≥1.8 and <2.6 mmol/L SPIRE-2: LDL-C ≥2.6 mmol/L or non-HDL-C ≥3.4 mmol/L Estimated study completion 2017 December 2017 SPIRE-1:June 2018 SPIRE-2: March 2018

The Case for IVUS

• Well established and reproducible
• Quantifies plaque volume
• Drugs that decrease events have been shown to have

great regression or less progression than placebo

• Not clear that we can predict vulnerable plaque
• Correlation between change in PAV and outcomes not

established