An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Inflammatory and Cholesterol Risk in the

FOURIER Trial

Erin A Bohula, Robert P Giugliano, Lawrence A Leiter, Subodh

Verma, Jeong-Gun Park, Peter S Sever, Armando Lira Pineda,

Narimon Honarpour, Huei Wang, Sabina A Murphy, Anthony Keech,

Terje R Pederson, Marc S Sabatine

On behalf of the FOURIER Investigators

American College of Cardiology Scientific Sessions

March 12, 2018

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Background

LDL-C is a well-recognized risk factor for

atherosclerotic CV disease (ASCVD)

CV benefit of LDL-C, including w/ PCSK9i

evolocumab in the FOURIER trial

Inflammation also plays a role in ASCVD; hsCRP is a

marker of inflammation and increased CV risk

The CANTOS trial of the anti-IL-1β Ab, canakinumab,

demonstrated that inflammation was a modifiable risk

factor with a ↓ hsCRP and MACE

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Objectives

To explore the consistency of benefit of evolocumab

for prevention of CV events by baseline hsCRP

To investigate the importance of inflammatory and

residual cholesterol risk as defined by hsCRP and

LDL-C levels

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Summary of Effects of

PCSK9i Evolocumab

0

20

40

60

80

100

0 24 48 72 96 120 144 168

LD

L C

ho

les

tero

l (m

g/d

l)

Weeks after randomization

• 27,564 pts w/ stable ASCVD & LDL-C ≥70mg/dL on a statin

• LDL-C by 59% down to a median of 30 mg/dl

• CV outcomes in patients on statin

• Safe and well-tolerated

Evolocumab

(median 30 mg/dl, IQR 19-46 mg/dl)

Placebo

59% reduction

P<0.00001

Absolute 56 mg/dl

14.6

9.9

12.6

7.9

0

5

10

15

KM

Ra

te (

%)

at

3 Y

ea

rs

HR 0.85 (0.79-0.92)

P<0.0001

HR 0.80 (0.73-0.88)

P<0.0001

CVD, MI, stroke

UA, cor revasc

CVD, MI, stroke

Sabatine MS et al. NEJM 2017;376:1713-22

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Methods

• Effect of evolocumab on hsCRP levels

• In pts stratified by baseline hsCRP according to AHA/CDC

risk groups (hsCRP<1, 1-3, >3 mg/L) determine:

• Rate of CV outcomes by hsCRP levels

• Effect of evolocumab on CV outcomes stratified by hsCRP• PEP (CV death, MI, stroke, UA, cor revasc)

• Key SEP (CV death, MI, stroke)

• Prognostic value for CV outcomes of inflammatory &

cholesterol risk according to baseline hsCRP and 1 mo

achieved LDL-C, adjusted for variables independently

associated w/ hsCRP or LDL-C

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Baseline Characteristics

Baseline characteristics hsCRP<1

(N=7981, 29%)

hsCRP 1-3

(N=11,177, 41%)

hsCRP>3

(N=8337, 30%)

hsCRP, mg/L 0.6 1.7 5.4

Age, years 64 63 62

Female 21 33 39

Diabetes mellitus 31 36 43

Smoking 23 29 32

eGFR<60 15 19 23

Prior stroke 18 19 21

Prior myocardial infarction 84 82 78

Most recent MI, years 3.5 3.4 3.2

High-intensity statin 69 69 70

Baseline LDL-C, mg/dL 90 92 94

P-trend < 0.0001 for all except statin use

P-value > 0.05 by EvoMab vs Pbo w/in subgroups

% or median values shown

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

-2

0

2

4

6

8

Media

n h

sC

RP

(m

g/L

)

Effect of Evolocumab on hsCRP

Minimal change in hsCRP from baseline (-0.2mg/L)

&

No difference between treatment arms

p-value=0.34 p-value = 0.72

Placebo Evolocumab

p-value = 0.34

Baseline 48 Weeks Change from

Baseline

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Association Between hsCRP & CV

Outcomes in Placebo Arm

12.0

7.4

1.4

5.1

1.8

8.3

2.1 2.3

13.7

9.1

1.7

6.1

2.3

8.7

2.2

3.2

18.1

13.2

4.2

7.5

3.8

10.5

2.7

7.4

0

2

4

6

8

10

12

14

16

18

20

CV death,MI, stroke,

UA, correvasc

CV death,MI, stroke

CV death MI Stroke Cor Revasc UA All-causemortality

3 Y

ea

r K

M R

ate

(%

)

hsCRP<1hsCRP 1-3hsCRP>3

P < 0.0001

P < 0.0001

P < 0.0001

P < 0.0001

P < 0.0001

P < 0.0001 P = 0.50

P < 0.0001

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Clinical Benefit of Evolocumab

by Baseline hsCRP

7.4%

9.1%

13.2%

6.6%7.1%

10.2%

0%

5%

10%

15%

3Y

r K

M R

ate

of C

V d

ea

th, M

I, s

tro

ke

12.0%

13.7%

18.1%

10.4%

11.9%

15.5%

0%

5%

10%

15%

20%

3Y

r K

M R

ate

of C

V d

ea

th, M

I,str

oke

, U

A, co

r re

va

sc

hsCRP (mg/L) <1 1-3 >3

Primary End Point Secondary End Point

<1 1-3 >3

Placebo Evolocumab

P-interaction for HR >0.05 for both

0.82 0.93 0.80

(0.70-0.95) (0.83-1.05) (0.71-0.90)

HR

95% CI

1.6% 1.8% 2.6%ARR

0.81 0.87 0.73

(0.66-0.99) (0.75-1.02) (0.63-0.85)

0.8% 2.0% 3.0%

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

hsCRP Levels Risk Stratify for PEP

Even When LDL-C<20mg/dL

<1

1-3

>3

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

<20 20-49 50-69 70-99 ≥100

9.0%9.8%

10.4%10.9%

12.3%10.8%12.0%

12.6% 13.2%

14.9%13.1%

14.7%15.4%

16.4%

18.2%

Ad

jus

ted

* 3 Y

ear

Ra

te o

f P

EP

hsCRP

(mg/L)

LDL-C at 1 month (mg/dL)

*Adjusted for age, BMI, sex, race, region, prior MI, prior stroke, PAD, HTN, DM, CHF,

smoking, eGFR<60, high-intensity statin, ezetimibe, baseline LDL-C, HDL-C and log(TG)

N=2,707

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Inflammatory & Cholesterol Risk

for PEP

LDL-C (per doubling):

- Adj* HR 1.09 (1.05-1.14)

- p<0.0001

hsCRP (per doubling):

- Adj* HR 1.09 (1.07-1.12)

- p<0.0001

Adju

ste

d*

3Y

r R

ate

of

PE

P

*Adjusted for age, BMI, sex, race, region, prior MI, prior stroke, PAD,

HTN, DM, CHF, smoking, eGFR<60, high-intensity statin, ezetimibe,

baseline LDL-C, HDL-C and log(TG)

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Limitations

Analyses w/ on-treatment LDL-C values were not

randomized; multivariable adjustment used to limit

confounding due to differences in baseline

characteristics by achieved LDL-C

hsCRP was not measured at 1 month; simultaneous

assessment of achieved LDL-C & hsCRP not possible.

Stable ASCVD population

Minimal change in hsCRP over time

On statin at baseline baseline hsCRP reflects residual

inflammatory risk after standard LDL-C lowering Rx

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Summary

Relative benefit of evolocumab for risk of CV events

was consistent irrespective of baseline hsCRP

Pts w/ higher hsCRP had higher event rates;

tended to experience greater absolute CV risk

reduction with evolocumab

CV event rates were independently associated with

both LDL-C and hsCRP, even in pts with very low

achieved LDL-C levels (<20 mg/dL)

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Conclusions/Implications

In pts with stable ASCVD

LDL-C reduction with evolocumab is beneficial

across hsCRP strata with a trend towards greater

absolute benefit in pts with higher hsCRP

LDL-C and hsCRP were independently associated

with outcomes supporting the importance of both

inflammatory and residual cholesterol risk in

secondary prevention

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Additional Details Available

Inflammatory and Cholesterol Risk in the FOURIER Trial

Erin A Bohula, Robert P Giugliano, Lawrence A Leiter, Subodh Verma, Jeong-Gun Park, Peter S Sever, Armando Lira Pineda,

Narimon Honarpour, Huei Wang, Sabina A Murphy, Anthony Keech, Terje R Pederson, Marc S Sabatine