Extending the Evidence: What did the FOURIER trial teach us on managing high risk patients? PCSK9i, Changing Practice in Cardiology: The Emerging Story ESC Satellite Symposium – August 31, 2019 Marc S. Sabatine, MD, MPH Chairman, TIMI Study Group Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine, BWH Professor of Medicine, HMS
Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-C ≥70 mg/ dL (1.8 mmol/L) or non-HDL-C ≥100 mg/ dL (2.6 mmol/L) RANDOMIZED DOUBLE BLIND Evolocumab SC Placebo SC 140 mg Q2W or 420 mg QM Q2W or QM Follow-up Q 12 weeks Median f/up 2.2 yrs An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Sabatine MS et al. Am Heart J 2016;173:94-101
Summary of Effects of PCSK9i Evolocumab 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 Placebo 14,6 15 HR 0.80 (0.73-0.88) 12,6 59% reduction P<0.0001 KM Rate (%) at 3 Years P<0.00001 9,9 10 7,9 Absolute 56 mg/dl 5 Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) 0 CVD death, MI, CVD death, MI, stroke stroke, UA, cor revasc An Academic Research Organization of Sabatine MS et al. NEJM 2017;376:1713-22 Brigham and Women’s Hospital and Harvard Medical School
Key Subgroups Subgroup Patients 1° Endpoint HR (95% CI) Key 2° Endpoint HR (95% CI) Overall 27564 Type of disease MI alone 19113 Stroke alone 3366 PAD alone 1505 Polyvascular disease 3563 Baseline LDL-C Q1 (<80 mg/dl) 6961 Q2 (80-<92 mg/dl) 6886 Q3 (92-109 mg/dl) 6887 Q4 (>109 mg/dl) 6829 Baseline statin intensity High 19103 Not high 8461 Ezetimibe Yes 1440 No 26124 Initial Dosing Regimen Every 2 weeks 24774 Monthly 2790 0.4 1.0 2.5 0.4 1.0 2.5 An Academic Research Organization of EvoMab better Pbo better EvoMab better Pbo better Brigham and Women’s Hospital and Harvard Medical School
LDL Cholesterol 2034 patients w/ baseline LDL-C<70 mg/dL 100 90 Placebo 80 (median 66 mg/dl, IQR 56-78 mg/dl) (median 1.7 mmol/L, IQR 1.4-2.0 mmol/L) LDL Cholesterol (mg/dl) 70 60 50 66% mean reduction (95%CI 62-69), P<0.00001 40 30 20 Evolocumab 10 (median 21 mg/dl, IQR 11.5-37 mg/dl) (median 0.5 mmol/L, IQR 0.3-1.0 mmol/L) 0 0 12 24 36 48 60 72 84 96 108 120 132 144 Weeks An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91
Clinical Outcomes by Baseline LDL-C CVD, MI, stroke, UA, or cor revasc HR (95% CI) P interaction All Patients 0.85 (0.79-0.92) Baseline LDL-C <70 mg/dL 0.80 (0.60-1.07) 0.65 Baseline LDL- C ≥70 mg/ dL 0.86 (0.79-0.92) 0.4 1.0 2.5 CVD, MI, or stroke 0.80 (0.73-0.88) All Patients Baseline LDL-C <70 mg/dL 0.70 (0.48-1.01) 0.44 Baseline LDL- C ≥70 mg/ dL 0.81 (0.73-0.89) 0.4 1.0 2.5 EvoMab better Pbo better An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91
Efficacy of LDL-C Lowering Even When LDL- C ≤70 mg/ dL (1.8 mM) Starting Events Major Vascular Events Trial LDL-C (mg/dl) Expt Arm Ctrl Arm RR (95% CI) per 1 mM in LDL-C Statins CTTC <2 mmol/L subgp 66 910 1012 0.78 (0.65-0.94) Non-statin LDL-C Lowering IMPROVE-IT 70 2455 2649 0.79 (0.67-0.93) FOURIER <1.8 mmol/L subgp 66 81 103 0.80 (0.61-1.04) REVEAL 63 2068 2214 0.77 (0.63-0.96) Summary 4604 4966 0.79 (0.70-0.88) P=0.00005 OVERALL SUMMARY 5514 5978 0.79 (0.71-0.87) P=0.000001 0.2 0.5 1 2 5 LDL-C Lowering Better LDL-C Lowering Worse An Academic Research Organization of Sabatine MS et al. JAMA Cardiol 2018;3:823-8 Brigham and Women’s Hospital and Harvard Medical School
Efficacy by Diabetes Status RRR 13% 17% ARR 1.6% 2.7% 20 17,1 CV Death, MI or Stroke, UA or Cor 14,4 Revasc (KM Rate at 3 yrs) 15 13,0 11,4 10 5 0 No Diabetes Diabetes An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Sabatine MS et al. Lancet Diab Endocrin 2017;5:941-50
Efficacy by Baseline CKD Stage RRR 25% 18% 21% ARR 1.7% 1.5% 2.5% 15 12,8 KM Rate (%) at 30 Months CV Death, MI or Stroke 10,3 10 7,7 7,1 6,2 5,4 5 0 ≥90 60 to <90 <60 eGFR (ml/min/1.73 m 2 ) Charytan et al. JACC 2019;73:2961-70 An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
Benefit of EvoMab Based on Time from Qualifying MI Qualifying MI ≥2 yrs ago Qualifying MI <2 yrs ago 13% RRR 24% RRR 10.8% D 2.9% 9.3% HR 0.87 HR 0.76 NNT 35 CV Death, MI, or Stroke (95% CI 0.64-0.89) (95% CI 0.76-0.99) 8.3% P=0.04 P<0.001 7.9% D 1.0% NNT 101 Placebo Evolocumab P interaction =0.18 0 6 12 18 24 30 36 0 6 12 18 24 30 36 An Academic Research Organization of Months after Randomization Sabatine et al. Circ 2018;138:756-66 Brigham and Women’s Hospital and Harvard Medical School
Benefit of EvoMab Based on # of Prior MIs ≥2 Prior MIs 1 Prior MI 15.0% 16% RRR 21% RRR D 2.6% NNT 38 HR 0.84 HR 0.79 12.4% CV Death, MI, or Stroke (95% CI 0.67-0.94) (95% CI 0.74-0.96) P=0.008 P=0.006 Placebo 8.2% 6.6% D 1.7% Evolocumab NNT 60 P interaction =0.57 0 6 12 18 24 30 36 0 6 12 18 24 30 36 An Academic Research Organization of Months after Randomization Sabatine et al. Circ 2018;138:756-66 Brigham and Women’s Hospital and Harvard Medical School
Benefit of EvoMab Based on Multivessel Disease Multivessel Disease No Multivessel Disease 11% RRR 30% RRR 12.6% D 3.4% HR 0.89 HR 0.70 NNT 29 CV Death, MI, or Stroke (95% CI 0.58-0.84) (95% CI 0.79-1.00) P=0.055 P<0.001 9.2% 8.9% 7.6% Placebo D 1.3% NNT 78 Evolocumab P interaction =0.03 0 6 12 18 24 30 36 0 6 12 18 24 30 36 An Academic Research Organization of Months after Randomization Sabatine et al. Circ 2018;138:756-66 Brigham and Women’s Hospital and Harvard Medical School
Overlap Between Factors 22,351 patients w/ prior MI 37% of the population 8402 Pts 5285 Pts <2 y from MI ≥2 MIs 63% of the population w/ at least 1 risk factor 5618 Pts w/ MVD An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
Benefit of EvoMab Based on # of High-Risk MI Features 12% High-risk feature: <2 yrs from qualifying MI, ≥2 prior MIs, or residual multivessel disease ≥1 Feature Placebo 10% 22% RRR Evolocumab 2.5% ARR CV Death, MI, or Stroke 8% 0 Features 6% RRR 0.5% ARR 6% P interaction =0.11 4% 2% 0% 0 6 12 18 24 30 36 An Academic Research Organization of Sabatine et al. Circulation 2018;138:756-66 Months after Randomization Brigham and Women’s Hospital and Harvard Medical School
Landmark Analyses in Pts w/ a High-Risk MI Feature 8% 8% 19% RRR 27% RRR HR 0.81 (95%CI 0.68-0.95) HR 0.73 (95%CI 0.62-0.86) P=0.01 P<0.001 6% 6% CV Death, MI, Stroke 4% 4% Placebo 2% 2% Evolocumab 0% 0% 0 3 6 9 12 12 18 24 30 36 Months from Randomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School High-risk feature: <2 yrs from qualifying MI, ≥2 prior MIs, or multivessel disease
Landmark Analyses in Pts w/ a High-Risk MI Feature 19% RRR 27% RRR 2% absolute risk reduction HR 0.81 (95%CI 0.68-0.95) HR 0.73 (95%CI 0.62-0.86) over 2 years P=0.01 P<0.001 CV Death, MI, Stroke If same pattern continues, would extrapolate to 5% ARR over 5 years NNT 5y of ~20 Placebo Evolocumab 0 3 6 9 12 12 18 24 30 36 Months from Randomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
CV Death, MI or Stroke in Patients w/ & w/o Peripheral Artery Disease An Academic Research Organization of Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50 Brigham and Women’s Hospital and Harvard Medical School
Major Adverse Limb Events An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50
Conclusions 1. Evolocumab reliably reduces LDL-C by ~60% 2. Reduces risk of major vascular events in Pts w/ ASCVD already on statin • Confirms benefit from lowering LDL-C to <1 mM • Benefit grows over time 3. Largest absolute risk reductions in Pts w/ highest baseline risk & largest amount of athero • Diabetes, CKD • Closer to MI, multiple prior MIs, multivessel CAD • PAD An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
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