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

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-1 β 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 • 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 HR 0.85 (0.79-0.92) P<0.0001 100 Placebo 14.6 15 59% reduction HR 0.80 (0.73-0.88) 12.6 80 LDL Cholesterol (mg/dl) P<0.00001 P<0.0001 KM Rate (%) at 3 Years 9.9 60 10 Absolute  56 mg/dl 7.9 40 5 Evolocumab 20 (median 30 mg/dl, IQR 19-46 mg/dl) 0 0 CVD, MI, stroke CVD, MI, stroke 0 24 48 72 96 120 144 168 UA, cor revasc Weeks after randomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Sabatine MS et al. NEJM 2017;376:1713-22

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 hsCRP 1-3 hsCRP>3 (N=7981, 29%) (N=11,177, 41%) (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 % or median values shown P-trend < 0.0001 for all except statin use P-value > 0.05 by EvoMab vs Pbo w/in subgroups An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Effect of Evolocumab on hsCRP Placebo Evolocumab 8 p-value=0.34 p-value = 0.72 p-value = 0.34 Median hsCRP (mg/L) 6 4 2 0 Baseline 48 Weeks Change from -2 Baseline Minimal change in hsCRP from baseline (-0.2mg/L) & No difference between treatment arms An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Association Between hsCRP & CV Outcomes in Placebo Arm P < 0.0001 20 hsCRP<1 18.1 hsCRP 1-3 18 hsCRP>3 16 P < 0.0001 13.7 3 Year KM Rate (%) 14 13.2 P < 0.0001 12.0 12 10.5 P < 0.0001 10 9.1 P < 0.0001 8.7 8.3 7.4 7.5 7.4 8 P < 0.0001 6.1 P < 0.0001 6 P = 0.50 5.1 4.2 3.8 4 3.2 2.7 2.3 2.3 2.2 2.1 1.7 1.8 1.4 2 0 CV death, CV death, CV death MI Stroke Cor Revasc UA All-cause MI, stroke, MI, stroke mortality UA, cor revasc An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Clinical Benefit of Evolocumab by Baseline hsCRP Placebo Evolocumab Secondary End Point Primary End Point HR 0.82 0.93 0.80 0.81 0.87 0.73 95% CI (0.70-0.95) (0.83-1.05) (0.71-0.90) (0.66-0.99) (0.75-1.02) (0.63-0.85) ARR 1.6% 1.8% 2.6% 0.8% 2.0% 3.0% 20% 15% 3Yr KM Rate of CV death, MI, stroke 18.1% 13.2% 3Yr KM Rate of CV death, MI, 15.5% stroke, UA, cor revasc 15% 13.7% 10.2% 10% 12.0% 9.1% 11.9% 10.4% 7.4% 7.1% 10% 6.6% 5% 5% 0% 0% hsCRP (mg/L) <1 1-3 >3 <1 1-3 >3 An Academic Research Organization of P-interaction for HR >0.05 for both Brigham and Women’s Hospital and Harvard Medical School

hsCRP Levels Risk Stratify for PEP Even When LDL-C<20mg/dL 18.2% N=2,707 16.4% 15.4% 14.7% 20% 13.1% 14.9% 18% Adjusted* 3 Year Rate of PEP 13.2% 12.6% 16% 12.0% 10.8% 12.3% 14% 10.9% 10.4% 12% 9.8% 9.0% 10% 8% 6% >3 4% 1-3 2% <1 hsCRP 0% ≥100 (mg/L) <20 20-49 50-69 70-99 LDL-C at 1 month (mg/dL) *Adjusted for age, BMI, sex, race, region, prior MI, prior stroke, PAD, HTN, DM, CHF, An Academic Research Organization of smoking, eGFR<60, high-intensity statin, ezetimibe, baseline LDL-C, HDL-C and log(TG) Brigham and Women’s Hospital and Harvard Medical School

Inflammatory & Cholesterol Risk for PEP Adjusted* 3Yr Rate of 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 for age, BMI, sex, race, region, prior MI, prior stroke, PAD, HTN, DM, CHF, smoking, eGFR<60, high-intensity statin, ezetimibe, An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School baseline LDL-C, HDL-C and log(TG)

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 An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School