Extending the Evidence:
What did the FOURIER trial teach us on
managing high risk patients?
Marc S. Sabatine, MD, MPH
Chairman, TIMI Study Group
Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine, BWH
Professor of Medicine, HMS
PCSK9i, Changing Practice in Cardiology:
The Emerging Story
ESC Satellite Symposium – August 31, 2019
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Trial Design
Evolocumab SC 140 mg Q2W or 420 mg QM
Placebo SCQ2W or QM
LDL-C ≥70 mg/dL (1.8 mmol/L) or
non-HDL-C ≥100 mg/dL (2.6 mmol/L)
Follow-up Q 12 weeks
Median f/up 2.2 yrs
Screening, Lipid Stabilization, and Placebo Run-in
High or moderate intensity statin therapy (± ezetimibe)
27,564 high-risk, stable patients with established CV disease
(prior MI, prior stroke, or symptomatic PAD)
RANDOMIZED
DOUBLE BLIND
Sabatine MS et al. Am Heart J 2016;173:94-101
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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
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 death, MI,
stroke, UA,
cor revasc
CVD death, 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
Key Subgroups
Subgroup Patients
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
1° Endpoint HR (95% CI) Key 2° Endpoint HR (95% CI)
1.0
EvoMab better Pbo better
0.4 2.5 1.0
EvoMab better Pbo better0.4 2.5
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Brigham and Women’s Hospital and Harvard Medical School
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120 132 144
LDL
Ch
ole
ste
rol (
mg
/dl)
Weeks
LDL Cholesterol2034 patients w/ baseline LDL-C<70 mg/dL
Evolocumab
(median 21 mg/dl, IQR 11.5-37 mg/dl)
Placebo
(median 66 mg/dl, IQR 56-78 mg/dl)
66% mean reduction (95%CI 62-69), P<0.00001
Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91
(median 0.5 mmol/L, IQR 0.3-1.0 mmol/L)
(median 1.7 mmol/L, IQR 1.4-2.0 mmol/L)
An Academic Research Organization of
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CVD, MI, stroke, UA, or cor revasc HR (95% CI) Pinteraction
All Patients 0.85 (0.79-0.92)
Baseline LDL-C <70 mg/dL 0.80 (0.60-1.07)
Baseline LDL-C ≥70 mg/dL 0.86 (0.79-0.92)
Clinical Outcomesby Baseline LDL-C
0.65
1.0
EvoMab better Pbo better
0.4 2.5
CVD, MI, or stroke
All Patients 0.80 (0.73-0.88)
Baseline LDL-C <70 mg/dL 0.70 (0.48-1.01)
Baseline LDL-C ≥70 mg/dL 0.81 (0.73-0.89)
1.00.4 2.5
0.44
Giugliano RP et al. and Sabatine MS. JAMA Cardiol 2017;2:1385-91
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Efficacy of LDL-C Lowering Even
When LDL-C ≤70 mg/dL (1.8 mM)
Sabatine MS et al. JAMA Cardiol 2018;3:823-8
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)
OVERALL SUMMARY 5514 5978 0.79 (0.71-0.87)
P=0.00005
P=0.000001
0.2 0.5 1 2 5
LDL-C Lowering Better LDL-C Lowering Worse
EventsStarting Major Vascular Events
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Efficacy by Diabetes Status
13,0
17,1
11,4
14,4
0
5
10
15
20
No Diabetes Diabetes
CV
De
ath
, M
I o
r S
tro
ke
, U
A o
r C
or
Re
va
sc
(KM
Ra
te a
t 3
yrs
)
Sabatine MS et al. Lancet Diab Endocrin 2017;5:941-50
RRR 13% 17%
ARR 1.6% 2.7%
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Efficacy by Baseline CKD Stage
7,17,7
12,8
5,46,2
10,3
0
5
10
15
≥90 60 to <90 <60
CV
De
ath
, M
I o
r S
tro
ke
KM
Ra
te (
%)
at
30
Mo
nth
s
eGFR (ml/min/1.73 m2)
Charytan et al. JACC 2019;73:2961-70
RRR 25% 18% 21%
ARR 1.7% 1.5% 2.5%
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
Months after Randomization
CV
Death
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
24% RRR
HR 0.76
(95% CI 0.64-0.89)
P<0.001 7.9%
10.8%
Pinteraction=0.18
D 2.9%
NNT 35
Evolocumab
Placebo
8.3%
9.3%
D 1.0%
NNT 101
Qualifying MI ≥2 yrs ago
13% RRR
HR 0.87
(95% CI 0.76-0.99)
P=0.04
0 6 12 18 24 30 36
Sabatine et al. Circ 2018;138:756-66
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Benefit of EvoMab Based on
# of Prior MIs ≥2 Prior MIs
Months after Randomization
CV
Death
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
21% RRR
HR 0.79
(95% CI 0.67-0.94)
P=0.006
12.4%
15.0%
Pinteraction=0.57
D 2.6%
NNT 38
Evolocumab
Placebo
6.6%
8.2%
D 1.7%
NNT 60
1 Prior MI
16% RRR
HR 0.84
(95% CI 0.74-0.96)
P=0.008
0 6 12 18 24 30 36
Sabatine et al. Circ 2018;138:756-66
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Benefit of EvoMab Based on
Multivessel DiseaseMultivessel Disease
Months after Randomization
CV
Death
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
30% RRR
HR 0.70
(95% CI 0.58-0.84)
P<0.001 9.2%
12.6%
Pinteraction=0.03
D 3.4%
NNT 29
Evolocumab
Placebo7.6%
8.9%
D 1.3%
NNT 78
No Multivessel Disease
11% RRR
HR 0.89
(95% CI 0.79-1.00)
P=0.055
0 6 12 18 24 30 36
Sabatine et al. Circ 2018;138:756-66
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Overlap Between Factors
22,351 patients
w/ prior MI
8402 Pts
<2 y from MI
5618 Pts
w/ MVD
5285 Pts
≥2 MIs
63% of the population
w/ at least 1 risk factor
37% of the population
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Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
10%
12%
Benefit of EvoMab Based on
# of High-Risk MI Features
Months after Randomization
CV
Death
, M
I, o
r S
tro
ke
0 6 12 18 24 30 36
Pinteraction=0.11
Evolocumab
Placebo≥1 Feature
22% RRR
2.5% ARR
High-risk feature: <2 yrs from qualifying MI, ≥2 prior MIs, or residual multivessel disease
Sabatine et al. Circulation 2018;138:756-66
0 Features
6% RRR
0.5% ARR
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
0%
2%
4%
6%
8%
Landmark Analyses in Pts
w/ a High-Risk MI Feature
Evolocumab
Placebo
Months from Randomization
CV
Death
, M
I, S
tro
ke
0 3 9 12 24 30 366 12 18
19% RRR
HR 0.81 (95%CI 0.68-0.95)
P=0.01
27% RRR
HR 0.73 (95%CI 0.62-0.86)
P<0.001
High-risk feature: <2 yrs from qualifying MI, ≥2 prior MIs, or multivessel disease
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Landmark Analyses in Pts
w/ a High-Risk MI Feature
Months from Randomization
CV
Death
, M
I, S
tro
ke
0 3 9 126
19% RRR
HR 0.81 (95%CI 0.68-0.95)
P=0.01
24 30 3612 18
27% RRR
HR 0.73 (95%CI 0.62-0.86)
P<0.001
Evolocumab
Placebo
2% absolute risk reduction
over 2 years
If same pattern continues,
would extrapolate to 5% ARR
over 5 years
NNT5y of ~20
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
Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Major Adverse Limb Events
Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
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