extending the evidence: what did the fourier trial teach ... · brigham and women’s hospital and...

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



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



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



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)



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



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



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%



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%



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




# of Prior MIs ≥2 Prior MIs


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





Multivessel DiseaseMultivessel Disease


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




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



0%

2%

4%

6%

8%

10%

12%


# of High-Risk MI Features


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



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



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



CV Death, MI or Stroke in Patients

w/ & w/o Peripheral Artery Disease

Bonaca MP et al. & Sabatine MS. Circulation 2018;137:338-50



Major Adverse Limb Events

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

extending the evidence: what did the fourier trial teach ... · brigham and women’s hospital and...

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