lipoprotein(a), pcsk9 inhibition and cardiovascular risk: insights … · 2019. 11. 15. · 2019....

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Lipoprotein(a), PCSK9 Inhibition and

Cardiovascular Risk:

Insights from the FOURIER Trial

Michelle L. O’Donoghue, Robert P. Giugliano, Anthony

C. Keech, Estella Kanevsky, KyungAh Im, Peter S.

Sever, Terje R. Pedersen, Marc S. Sabatine

European Atherosclerosis Society

May 7, 2018



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

Rate

(%

) at

3 Y

ears

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



Lp(a) and Risk of MI

• Mendelian randomization data support

a causal role for Lp(a) in risk of

coronary heart disease

Kamstrup et al, JAMA. 2009;301(22):2331-2339

Risk of MI for Doubling in Lp(a) concentration



Methods

• Lp(a) was measured at baseline and weeks 12 and 48 at Medpace Reference

Laboratories (Medpace Inc. Cincinnati, OH) using an isoform-independent

immunoturbidometric assay (Polymedco, Cortlandt Manor, New York)

• Association between Lp(a) and CV risk

– Examined in placebo arm

– Unadjusted, and then adjusting for age, sex, race, weight, region, prior MI,

history of stroke, PAD, HTN, DM, current smoking, baseline LDL-C

• Effect of evolocumab

– On Lp(a) and LDL-C

– CV outcomes by baseline Lp(a) concentration

• Association of achieved Lp(a), achieved LDL and CV risk

• Kaplan-Meier rates are reported at 3 years



Baseline Distribution of Lp(a)

0

5

10

15

20

25

30

35

40

45

Perc

ent

0 50 100 150 200 250 300 350 400 450 500 550 600

Baseline lp(a) in nmol/L

Min, max: 5, 1451

Median (IQR): 37 (13, 165)

Mean ± Std: 94.1 ± 112.7

N = 25,096

Descriptive Statistics

Pe

rce

nt

Baseline Lp(a) (nmol/L)


N=25096

Median (IQR) = 37 (13-165) nmol/L



Baseline Characteristics

Q1(<14nM)

Q2(14-37nM)

Q3(38-165nM)

Q4(>165nM)

P value

Age, y, mean (SD) 62 (9.0) 63 (9.1) 62 (9.1) 63 (8.8) 0.08

Male sex 80% 76% 76% 68% <0.001

Type of CV disease

Myocardial infarction 79% 79% 81% 83% <0.001

Ischemic stroke 21% 21% 20% 17% <0.001

PAD 13% 13% 13% 15% <0.001

CV Risk Factor

Hypertension 81% 81% 79% 80% 0.055

Diabetes Mellitus 41% 36% 36% 34% <0.001

Current tobacco 30% 30% 29% 25% <0.001

Baseline LDL-C, mean (SD) 93 (25) 96 (27) 98 (31) 101 (27) <0.001

Quartiles of baseline Lp(a)



Baseline Lp(a) and CV Risk

6.8

9.5

6.0

7.88.1

11.7

8.4

10.3

0.0

2.0

4.0

6.0

8.0

10.0

12.0

CHD death or MI CV death, MI or stroke

Q1 Q2 Q3 Q4

Adjusted HR Q4:Q1 = 1.26 (95% CI 1.02-1.56)

Adjusted HR Q4:Q1 = 1.12 (95% CI 0.93-1.34)

MV model: Age, sex, race, weight, region, prior MI, history of stroke, PAD, HTN, DM, current

smoking, baseline LDL-C

Restricted to placebo arm

KM

ra

tes a

t 3

ye

ars

(%

)



5.5

2.4

1.6

5.5

2.1

1.3

7.0

3.3

1.5

6.8

2.4

2.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

Myocardial infarction Stroke Coronary death

Q1 Q2 Q3 Q4Adj HR Q4:Q1 = 1.31 (95% CI 1.04-1.66)

Adj HR Q4:Q1 =0.92 (95% CI 0.63-1.33)

Adj HR Q4:Q1 =1.23 (95% CI 0.81-1.89)

Baseline Lp(a) and CV RiskK

M r

ate

s a

t 3

ye

ars

(%

)

MV model: Age, sex, race, weight, region, prior MI, history of stroke, PAD, HTN, DM, current

smoking, baseline LDL-C

Restricted to placebo arm



Change in Lp(a) from

Baseline to Week 48 with Evolocumab

-12

-10

-8

-6

-4

-2

0

2

-30

-25

-20

-15

-10

-5

0

5

-26.9%

nm

ol/L

Median % change in Lp(a)Median absolute change in Lp(a)

%

Placebo-controlled values

-11 nmol/L



Absolute change in Lp(a) for patients

on evolocumab

0

5

10

15

20

25

30

35

40

Perc

ent

-200 -180 -160 -140 -120 -100 -80 -60 -40 -20 0 20 40 60 80 100

Lp(a) Change from Baseline to 48 Weeks

Min, max: -603, 425

Median (IQR): -11.0 (-32.0, -1.0)

Mean ± Std: -22.4 ± 40.4

N = 11,864



N=11864

Median (IQR) = -11 (-32, -1) nmol/L

Absolute change from baseline to 48 weeks

Perc

ent

nmol/L



0

2

4

6

8

10

12

14

16

18

20

Perc

ent

-100 -80 -60 -40 -20 0 20 40 60 80 100 120 140 160 180 200

Lp(a) Percent Change from Baseline to 48 Weeks

Min, max: -98.3, 6,071.4

Median (IQR): -26.9 (-46.7, -6.2)

Mean ± Std: -23.7 ± 88.7

N = 11,864

Descriptive Statistics% change in Lp(a) for

patients on evolocumab


N=11864

Median (IQR) = -26.9 (-46.7, -6.2) %

Lp(a) % change from baseline to 48 weeks

Perc

ent



Change in Lp(a) by Quartile of Baseline

Lp(a) with Evolocumab

-1

-9

-24

-36-40

-35

-30

-25

-20

-15

-10

-5

0

5Q1 Q2 Q3 Q4

nm

ol/L

*Reflects change from baseline to week 48

Placebo-controlled values

-9.1

-41.9

-32.5

-16

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

%

Median % change in Lp(a)Median absolute change in Lp(a)

Q1 Q2 Q3 Q4



-250

-200

-150

-100

-50

0

50

100

150

200

250

Change in

LD

L-C

, m

g/d

l

-250 -200 -150 -100 -50 0 50 100 150 200 250

Change in Lp(a), nmol/l)

Absolute change in Lp(a) versus LDL

for patients on evolocumabA

bso

lute

ch

an

ge

in

LD

L-C

(m

g/d

l)

Absolute change in Lp(a) (nmol/L)

r = 0.21

Change from baseline to week 48



-100

-80

-60

-40

-20

0

20

40

60

80

100P

erc

ent C

hange in

LD

L-C

-100 -80 -60 -40 -20 0 20 40 60 80 100

Percent Change in Lp(a)

% change in Lp(a) versus LDL

for patients on evolocumab

% c

ha

ng

e in

LD

L-C

% change in Lp(a)

r = 0.37

Change from baseline to week 48



Efficacy by Baseline Lp(a)

7.48

8.17

8.74

10.97

0

2

4

6

8

10

12

Lp(a) <=median Lp(a) >median

Evolocumab

PlaceboHR 0.85

(95% CI 0.73-0.97)

ARR=1.26%

NNT=79

HR 0.76

(95% CI 0.66-0.86)

ARR=2.8%

NNT=36

CV

dea

th,

MI

or

str

oke (

3y K

M r

ate

, %

)

P interaction=0.26



Achieved Lp(a), LDL and CV Risk

LDL-C <=median

LDL-C>median

0

1

2

3

4

5

6

7

8

9

10

Lp(a) >median Lp(a) <=median

CV

de

ath

, M

I o

r str

oke

be

yo

nd

we

ek 1

2 (

%)

6.57%

7.88%

8.45%

9.43%

P<0.001

KM rate at 3 years



Summary

• Evolocumab significantly reduces Lp(a)

concentration

• Patients starting with higher Lp(a) levels

appear to derive greater absolute benefit

from PCSK9 inhibition.

• Patients who achieve lower levels of both

LDL-C and Lp(a) have the lowest subsequent

risk of CV events.

lipoprotein(a), pcsk9 inhibition and cardiovascular risk: insights … · 2019. 11. 15. · 2019....

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