Effect of the PCSK9 Inhibitor, - PowerPoint Presentation

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Effect of the PCSK9 Inhibitor, Evolocumab, on the Composition of Coronary Atherosclerosis: Insights from the GLAGOV Trial

SJ Nicholls, H Kassahun, DM Brennan, K Wolski, J Yang, R Somaratne, SM Wasserman and SE Nissen

Disclosures

Research support: AstraZeneca, Amgen,

Anthera

, Eli Lilly, Esperion, Novartis,

Cerenis

, The Medicines Company,

Resverlogix

,

InfraReDx

, Roche, Sanofi-Regeneron and

LipoScience

Consulting and honoraria: AstraZeneca, Eli Lilly,

Anthera

,

Omthera

, Merck, Takeda,

Resverlogix

,

Sanofi-Regeneron

, CSL Behring,

Esperion

,

Boehringer

Ingelheim

Background

The

PCSK9 inhibitor,

evolocumab

, lowers LDL-C, induces plaque regression on IVUS and reduces CV events in statin-treated ASCVD patients

The impact of PCSK9 inhibition on the composition of coronary atheroma has not been investigated.

Virtual histology is an experimental technique which characterizes plaque composition and may have utility in assessing effects of anti-atherosclerotic therapies.

Placebo SC monthly

Evolocumab

420 mg SC monthly

Randomization

End of Study IVUS

Up to 4 week lipid stabilization period

Screening, placebo run-in period

Coronary Angiogram

Baseline IVUS

2-4 weeks

Max. 6 weeks

0

4

12

24

36

52

64

70

76

80

Week

968 patients with angiographic CAD, stable statin dose and LDL-C

≥80 mg/

dL

OR 60-80 mg/

dL

and 1 major or 3 minor risk factors

GLAGOV Trial Schematic

GLAGOV VH Substudy

Determine if

evolocumab

produced changes in VH-derived plaque components (dense calcium, fibrous,

fibrofatty

, necrotic core) compared with placebo in 331 patients with evaluable VH imaging.

The

prespecified

statistical plan sought to compare changes in volumetric measures, adjusting for baseline values and multiple comparisons.

The primary endpoint was the absolute change in dense calcium volume

from baseline to week 78.

Baseline Demographics and Statin Usage

Characteristic

Placebo (n=167)

Evolocumab

(n=164)

Age

59.7

59.3

Male Gender

76.0%

70.7%

BMI (kg/m

2)

29.5

29.7

Diabetes

16.2%

18.9%

Smoking

22.2%

29.9%

Baseline statin use

99.4%

98.8%

High intensity

57.5%

59.8%

Moderate intensity

41.3%

37.8%

Baseline LDL-C (

mg/

dL

)

92.0

90.9

Baseline CRP (mg/L)

1.5

1.7

Percent Change in Biochemical Parameters

CharacteristicPlacebo (n=167)Evolocumab (n=164)P ValueLDL Cholesterol+0.6%-62.8%***<0.0001HDL Cholesterol+7.5%***+11.6%***0.02Triglycerides+2.7%*-11.5%**0.0002CRP-21.4%-6.7%**0.11Lp(a)-2.5%-22.7%***<0.0001

* P<0.05, ** P<0.01 and *** P<0.0001 compared with baseline

Change in Measures of Plaque Burden

CharacteristicPlacebo(n=167)Evolocumab (n=164)P ValuePAV (%)+0.17-1.20*<0.0001TAV (mm3)-0.8-3.6*0.04PAV regressors (%)46.168.3<0.0001TAV regressors (%)53.364.60.04

PAV: percent atheroma volume; TAV: total atheroma volume. * P<0.0001 compared with baseline

Primary Endpoint: Change in Normalized Dense Calcium Volume

0.6*

1.0**

P=0.49***

Statin Monotherapy

Statin +

Evolocumab

* P<0.05 and ** P<0.001 compared with baseline (exploratory analysis). *** Hochberg adjusted p value

Secondary Endpoint: Change in Volume of Other VH Parameters

* P<0.01 and ** P<0.001 compared with baseline (exploratory analysis). *** Hochberg adjusted p value

-3.0*

P=0.49***

P=0.49***

P=0.49***

-5.0**

-2.4**

-3.0**

-0.6

-0.1

Statin Monotherapy

Statin +

Evolocumab

Fibrofatty

Necrotic Core

Fibrous

Secondary Endpoint: Absolute Change in VH-Derived Percentage Plaque Measures

CharacteristicPlacebo (n=167)Evolocumab (n=164)P Value**Dense calcium (%)+1.00.4*+2.20.4*0.10Fibrofatty (%)-0.91.1-1.61.10.67Fibrous (%)-0.60.8-1.40.80.67Necrotic core (%)+0.40.5+0.90.60.67

* P<0.01 compared with baseline (exploratory analysis) **Hochberg adjusted

Correlation Between Change in VH Measures and Biochemical Parameters

Characteristic

Change LDL-C

Change CRP

Dense calcium

r =

-0.15

r =

0.07

Fibrofatty

r =

0.03

r =

-0.04

Fibrous

r =

0.06

r =

-0.01

Necrotic core

r =

-0.01

r =

0.07

Exploratory Analysis: Change in VH-Derived Plaque Measures and Regression

CharacteristicTertiles of Change PAV (%)P Value<-1.57-1.57 – 0.57>0.57Dense calcium (mm3)0.50.30.90.3**1.00.3**0.65Fibrofatty (mm3)-6.31.2**-3.71.2**-2.01.20.03Fibrous (mm3)-6.30.7**-2.30.7**0.50.8<0.001Necrotic core (mm3)-2.60.6**0.10.61.30.6*<0.001

* P<0.05 and ** P<0.01 compared with baseline

Exploratory Analysis: Baseline LDL-C <70 mg/dL

CharacteristicPlacebo (n=26)Evolocumab (n=35)P ValueDense calcium (mm3)+0.40.8-0.31.70.54Fibrofatty (mm3)-6.03.1-6.72.6**0.87Fibrous (mm3)-0.82.0-3.41.7*0.32Necrotic core (mm3)+0.41.4-2.91.2*0.08

* P<0.05 and ** P<0.01 compared with baseline

Conclusion

Evolocumab

on a background of optimal statin therapy produced robust lowering of LDL cholesterol and plaque regression by conventional IVUS.

However, VH imaging failed to detect any difference between treatment groups for individual plaque components.

These findings further fuel uncertainty regarding the utility of VH imaging in drug development to assess the effect of anti-atherosclerotic therapies.

Final Thoughts

The inverse correlation between changes in LDL cholesterol and plaque calcium supports prior reports in studies of high intensity statins.

While the underlying mechanism remains uncertain, it questions the use of serial calcium scoring to monitor responses to lipid lowering interventions.

VH yields predictable, but not incremental information, in the setting of plaque regression. It will be of interest to see if other modalities can provide better insights.