Inflammatory and Cholesterol Risk in the FOURIER Trial Erin A Bohula - - PowerPoint PPT Presentation

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

20 40 60 80 100

24 48 72 96 120 144 168

LDL Cholesterol (mg/dl) 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

5 10 15 KM Rate (%) at 3 Years

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

2 4 6 8 Median hsCRP (mg/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

2 4 6 8 10 12 14 16 18 20 CV death, MI, stroke, UA, cor revasc CV death, MI, stroke CV death MI Stroke Cor Revasc UA All-cause mortality 3 Year KM Rate (%)

hsCRP<1 hsCRP 1-3 hsCRP>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%

3Yr KM Rate of CV death, MI, stroke

12.0% 13.7% 18.1% 10.4% 11.9% 15.5% 0% 5% 10% 15% 20%

3Yr KM Rate of CV death, MI, stroke, UA, cor revasc 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% Adjusted* 3 Year Rate of PEP

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

Adjusted* 3Yr Rate of PEP

*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