25/02/2018

Dov Gavish MD

Wolfson hospital

Tel Aviv University

ISRAEL

Patient oriented treatment for

prevention of CVD : New targets

,Individual goals

Multiple factors contribute to increased CV risk

CRP, C-reactive protein; CV, cardiovascular; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglyceride.

1. World Heart Federation. Cardiovascular disease risk factors. www.world-heart-federation.org/cardiovascular-

health/cardiovascular-disease-risk-factors. [Accessed 17 July 2015].

2. Dekker JM, et al. Circulation 2005;112:666–73.

3. Bhatt DL, et al. JAMA 2010;304:1350–7.

4. Lagrand WK, et al. Circulation 1999;100:96–102.

5. Go AS. N Engl J Med 2004;351:1296–305.

Increased CV risk

Prior CV event/manifest

atherosclerosis3

Smoking, physical

inactivity1

Obesity1

Lipid disorders1

(LDL, HDL, TG)

Type 2 diabetes1

Hypertension1

High CRP,4

chronic kidney disease5

Metabolic syndrome2

Age, ethnicity, gender, family history/genetic

variations1

Focus on Critical Steps

• Deposition of cholesterol in the artery wall by LDL

• Oxidation of LDL

• Inflammation

• Attraction of monocytes and/or macrophages and plaque development

Elevated LDL-C: central in the pathogenesis of CVD, increasing risk for a CV event

ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; CETP, cholesteryl ester transfer protein; CRP,

C-reactive protein; CV, cardiovascular; CVD, cardiovascular disease; HDL, high-density lipoprotein; IL-6,

interleukin-6; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); OxPL, oxidized phospholipids.

Jensen MK, et al. Nat Revs Endocrinol 2014;10:659–72.

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Current Guidelines: LDL-C Targets

J Clin Lipidol 2015;9:129-69; EHJ 2016;37:2999-3058; JACC 2016;68:92-105

• Patients whose LDL-C cannot be controlled with

intensive statin therapy ± other current therapies

– High-risk patients (e.g., secondary prevention, diabetic) in

whom we cannot get LDL-C low enough

– Most patients with HeFH

– Almost all patients with HoFH

• Patients who cannot take a statin, or an effective dose

– Statin-intolerant, or for whom a statin is contraindicated

Which patients’ needs are not being met by current therapies?

HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia;

LDL-C, low-density lipoprotein cholesterol.

FDA Briefing Document (EMDAC) June 10 2015.

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Endocrinologicand

MetabolicDrugsAdvisoryCommittee/UCM452354.pdf. [Accessed 9 July 2015].

From: Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic,

epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society

Consensus Panel

Eur Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144 Main approach for LDL reduction

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

PCSK9 inhibitor CV outcomes trial

design comparison

*Non-haemorrhagic stroke.1.Sabatine MS, et al. Am Heart J 2016;173:94–101.2.Schwartz GG, et al. Am Heart J 2014;168:682–9.

History of MIn = 22,356

PADn = 3640

History of stroke*n = 5330

ODYSSEY OUTCOMES2

N ~ 18,000FOURIER1

N = 27,564

Recent MI< 1 year

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Summary of

FOURIER

• LDL-C by 59% (from 2.4 -> 0.8 [0.5, 1.2] mM)

• CV outcomes in patients already on statin therapy

• Evolocumab was safe and well-tolerated

0.0

0.5

1.0

1.5

2.0

2.5

0 4 12 24 48 72 96 120 144 168

LD

L-C

(m

M)

Weeks after randomization

EvolocumabMedian 0.78 mM

IQR [0.49-1.27]

Placebo

59% mean

decline P<0.00001

Absolute↓1.45 mM

(1.42-1.47)

14.6

9.9

12.6

7.9

0

5

10

15

CV death, MI, stroke,UA, cor revasc

CV death, MI, stroke

KM

Rate

(%

) at

3 Y

ears

Placebo

HR 0.80

(0.73-0.88)

P<0.00001

HR 0.85 (0.79-

0.92)

P<0.0001

Sabatine MS et al. New Engl J Med 2017;376:1713-22

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

CV Death, MI, Stroke, UA, or Coronary Revasc

Giugliano RP, ESC Congress 2017, Barcelona

8/28/2017

LDL-C (mM)

Adj HR

(95% CI)

<0.5 0.76 (0.64-

0.90)

0.5-1.3 0.85 (0.76-

0.96)

1.3-1.8 0.94 (0.82-

1.09)

1.8-2.6 0.97 (0.86-

1.09)

> 2.6 referent

P =

0.0012

LDL-C (mM) at 4

weeks

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

FOURIER – Sub Analysis

Lessons concerning individuals at an

extreme risk for whom LDL target

should be even lower

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

27,564

Patients with

Atherosclerosis

Randomized

3,642

Patients with

Symptomatic Lower

Extremity Peripheral

Artery Disease

1,505

Patients with

Symptomatic Lower

Extremity Peripheral

Artery Disease and no

prior MI or Stroke

Patients with Peripheral

Artery Disease57%

Peripheral Revascularization

(Median 3.7 years prior)

26%

955

27%

1,044

42%

1517

27

4%Amputation for

Ischemia

39

4119

69%Intermittent Claudication &

ABI < 0.85 at Baseline

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Peripheral Artery Disease and Risk in

Placebo Patients

Days from Randomization

CV

D /

MI / S

tro

ke

adjusted age, sex, race, BMI, diabetes, hypertension, smoking, eGFR, CHF, prior MI,

CABG/PCI, and history of stroke or TIA.

0%

2%

4%

6%

8%

10%

12%

14%

16%

0 180 360 540 720 900Days from Randomization

0%

2%

4%

6%

8%

10%

12%

14%

16%

0 180 360 540 720 900

P=0.0028

7.6%

10.3%

14.9%

P=0.0001

CV

D /

MI / S

tro

ke

7.6%

13.0%Adjusted HR

1.81(1.53 – 2.14)

P<0.001

PAD N=1784

MI or Stroke and no PAD N=11996 MI or Stroke and no PAD N=11996

PAD with MI/Stroke N=1036

PAD no MI/Stroke N=748

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

CV

De

ath

, M

I o

r S

tro

ke

Placebo

Evolocumab

13.0%

7.6%

9.5%

6.2%

PAD

3.5% ARR

NNT2.5y 29

No PAD

1.4% ARR

NNT2.5y 72

PADN=3,642

27% RRR

HR 0.73

(0.59 – 0.91)

P=0.0040

p-interaction = 0.41

No PAD

N=23,922

HR 0.81

95% CI (0.73 – 0.90)

P<0.001

Days from Randomization

CV Death, MI or Stroke in Patients with

and without Peripheral Artery Disease

0%

2%

4%

6%

8%

10%

12%

14%

0 90 180 270 360 450 540 630 720 810 900

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

0%

2%

4%

6%

8%

10%

12%

0 90 180 270 360 450 540 630 720 810 900

CV

De

ath

, M

I o

r S

tro

ke

Days from Randomization

Placebo

Evolocumab

10.3%

5.5%

PAD

4.8% ARR

NNT2.5y 21

PAD

(no MI/stroke, N=1505)

43% RRR

HR 0.57

(0.38 – 0.88)

P=0.0095

CV Death, MI or Stroke in Patients with

PAD and no MI or Stroke

Outcome HR 95% CI

MACE 0.57 (0.38–0.88)

CV Death 0.78 (0.39–1.57)

MI 0.66 (0.38–1.14)

Stroke 0.30 (0.11–0.82)

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Conclusion

LDL-C reduction to very low levels should be

considered in patients with PAD, regardless of

history of MI or stroke, to reduce the risk of

MACE and MALE

For more information see simultaneous publication in:

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Background & Objective

Patients at higher CV risk may derive greater benefit

from PCSK9 inhibition

Within the broad subgroup of patients w/ prior MI in

FOURIER, we investigated if readily ascertainable clinical

features of the CAD history identified patients:

1) At higher CV risk

2) Who derived greater benefit from PCSK9 inhibition

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Risk of CV Death, MI or Stroke

with Each Risk Factor

10.8%

9.3%

0%

2%

4%

6%

8%

10%

12%

14%

16%

<2 yrs ≥2 yrs

CV

D, M

I o

r S

tro

ke

(3-y

r K

M)

in P

bo

Years from Qualifying MI

HR 1.19

(1.04-1.37)

P=0.01 15.0%

8.2%

0%

2%

4%

6%

8%

10%

12%

14%

16%

≥2 1

# of Prior MIs

HR 2.04

(1.78-2.35)

P<0.001

12.6%

8.9%

0%

2%

4%

6%

8%

10%

12%

14%

16%

Yes No

Multivessel Disease

HR 1.47

(1.27-1.70)

P<0.001

Analyses in placebo arm

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

De

ath

, 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

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

De

ath

, 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

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

De

ath

, 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

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

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Benefit of EvoMab Based on

# of High-Risk MI Features

Months after Randomization

CV

De

ath

, 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

N=13,973 (63% of prior MI trial population)

High-risk feature: <2 yrs from qualifying MI, ≥2 prior MIs, or residual multivessel disease

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Summary

• Patients (1) closer to their most recent MI,

(2) with multiple prior MIs, or

(3) with multivessel disease

are at 34-90% risk for major vascular events

• These patients experience substantial:

- relative risk reductions (21-30%) and

- absolute risk reductions (2.6-3.4% over 3 yrs)

with intensive LDL-C lowering w/ the PCSK9i evolocumab

These readily ascertainable clinical features offer one

approach to tailoring therapy

26

RESULTSFigure 1: Risk Stratification for MACE with Placebo

# RI 0/1 2 3 4 ≥5

At Risk 747 3015 4468 3444 2106

% Pts 5 22 32 25 15

Events 32 154 278 257 292

Risk Indicators Points

CHF 1

HTN 1

Age ≥ 75 1

DM 1

Prior Stroke 1

Prior CABG 1

PAD 1

eGFR < 60 1

Current Smoking 1

Prior MI 1

Max Possible 10

5.0%

7.8% 8.2%9.8%

19.1%

0%

5%

10%

15%

20%

25%

3Y

r K

M M

AC

E

Low

Risk

Intermediate

Risk

High

Risk

P-trend<0.0001

• The integer-based scheme showed a strong, graded relationship with the rate of CV

death, MI or CVA and the components at 3 yrs in both treatment arms (Fig 1; p-trend

< 0.0001 for all endpoints; c-statistic = 0.61 [0.67 in prior validation set]).

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

RESULTSFigure 3: MACE by Risk Category & Randomized Treatment

• Low-risk pts had a 1.2% ARR, intermediate-risk a 1.9% ARR and high-risk a 3.6% ARR

in MACE at 3 years with EvoMab vs Pbo, translating to a NNT3Yr of 83, 53 and 28,

respectively (Fig 3).

Risk (Score) Low (0/1) Intermediate (2-4) High (≥5)

5.0%

8.6%

19.1%

3.8%

6.7%

15.5%

0%

5%

10%

15%

20%

25%

3Y

r K

M R

ate

of

MA

CE

Pbo EvoMab

P-trend < 0.001 for both treatments

P-interaction = 0.94

HR 0.73 (0.43, 1.23)

ARR 1.2%

HR 0.79 (0.71, 0.89)

ARR 1.9%

HR 0.80 (0.67, 0.95)

ARR 3.6%

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

CONCLUSIONS

• In FOURIER, the TIMI Risk Score for Secondary Prevention

(TRS 2ºP):

– Predicted a gradient of risk for major adverse CV events

– Identified high-risk pts w/ ASCVD who demonstrate a pattern of greater

ARR in major CV events with EvoMab, with an NNT3Yr ~ 25 in the

highest risk.

• This strategy may prove useful to personalize the

intensification of secondary preventative therapies.

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Cardiovascular Efficacy & Safety of

Evolocumab in Diabetes,

and Risk of Development of Diabetes:

An Analysis from the FOURIER Trial

MS Sabatine, LA Leiter, SD Wiviott, RP Giugliano, P Deedwania, GM De

Ferrari, SA Murphy, JF Kuder, AC Keech, PS Sever, and TR Pedersen,

for the FOURIER Steering Committee & Investigators

European Association for the Study of Diabetes – 53rd Annual Meeting

Clinical Trial Update

September 15, 2017SC-EU-AMG145-00708

Approved September 2017

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Risk of Primary Endpoint

with Diabetes

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

No diabetes at baseline

Diabetes at baseline

Months after Randomization

CV

Dea

th, M

I, S

tro

ke

,

Ho

sp

fo

r U

A,

or

Co

rR

eva

sc

0 6 12 18 24 30 36

Adj Hazard Ratio 1.26

(95% CI 1.13-1.40)

P<0.0001 13.0%

17.1%

Analyses in placebo arm and adj for age, sex, BMI, race, region,

history of MI, stroke, PAD, HTN, smoking, HF, eGFR, lipids,

statin.

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Effect of Evolocumab

on Primary Endpoint

Patients w/o Diabetes at BaselinePatients w/ Diabetes at Baseline

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Months after Randomization

CV

Dea

th, M

I, S

tro

ke

,

Ho

sp

fo

r U

A,

or

Co

rR

eva

sc

0 6 12 18 24 30 360%

2%

4%

6%

8%

10%

12%

14%

16%

18%

Hazard Ratio 0.83

(95% CI 0.75-0.93)

P=0.0008

14.4%

17.1%

0 6 12 18 24 30 36

Hazard Ratio 0.87

(95% CI 0.79-0.96)

P=0.0052

11.4%

13.0%

Pinteraction=0.60

D 2.7%

NNT 37

D 1.6%

NNT 62

Evolocumab

Placebo

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

Conclusion

Use of evolocumab is particularly clinically efficacious

in ASCVD patients with diabetes,

and evolocumab does not cause diabetes

or worsen glycemia in patients with or without diabetes

in the timeframe we studied.

An Academic Research Organization of

Brigham and Women’s Hospital and Harvard Medical School

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

Patients with

Baseline LDL-C <70 mg/dL

Evolocumab

Placebo

Months from Randomization

CV

Death

, M

I, S

tro

ke

0 6 12 18 24 30

N=2034

Hazard ratio 0.70

(95% CI, 0.48-1.01)

5.2%

7.7%

Use Ileo femoralis Aorta and Carotids plus CAC

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For primary prevention Not all candidates are the same: For better prediction we need tools

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כולסטרול גורם לדלקת

The best way to reduce inflammation

From: Anti-inflammatory therapies for cardiovascular diseaseEur Heart J. 2014;35(27):1782-1791. doi:10.1093/eurheartj/ehu203

Eur Heart J | Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions

please email: Journals.permissions@oup.com

Rational for CANTOS

Colchicine as treatment ?

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Ongoing studies of colchicine in CAD

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New and old targets

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Treat To the optimal LDLC and add Rx for inflammatin and thrombosis ?

New Targets

• Lp(a) :ongoing program with antisense to Apo(a)

• Angiopoietin like 3,4 : on going program with Evinocumab

• Apo protein C3 :Low expressors have reduced CVD BY 43% Rx : antisense to ApoC3

• TM6SF2 : Future Target

• Furin (pcsk3) : Future Target

ANGPTL3

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Furin affects cardio metabolic risk