preventive cardiology - european society of cardiology affairs... · preventive cardiology 19 102...

# esccongress www.escardio.org/esc2014

Preventive Cardiology

Geneviève DERUMEAUX (Créteil, Fr)

Conflicts of Interest Speaker/advisor/research grant for Actelion, Sanofi, Servier, Toshiba

TOPIC 1 SIGNIFY

TOPIC 2

TOPIC 3 ODYSSEY FH I / FHII / COMBO II / LONG TERM

PREVENTIVE CARDIOLOGY

SOLID-TIMI 52

/f inhibition

Lp-PLA2

PCSK9

Study design Population

≥ 55 years, stable CAD (With at least one other CV risk factor (including angina CCS class ≥ II))

Without clinical heart failure (LVEF >40%)

HR ≥ 70 bpm

Ivabradine 7.5 mg bid

Matching placebo, bid

Run-in 14 to 30 days

Every 6 months

Ivabradine 5, 7.5, or 10 mg bid according to heart rate (target 55-60 bpm) and tolerability

Fox K et al. Am Heart J. 2013;166:654-661.

Primary composite end point:

Cardiovascular death or nonfatal myocardial infarction

Primary analysis: Ivabradine versus placebo on primary end point

Prespecified analysis: in patients with angina CCS class ≥II on primary end point

Study design Population

≥ 55 years, stable CAD (With at least one other CV risk factor (including angina CCS class ≥ II))

Without clinical heart failure (LVEF >40%)

HR ≥ 70 bpm

Ivabradine 7.5 mg bid

Matching placebo, bid

Run-in 14 to 30 days

M1 M2

Every 6 months

D0 M3

Ivabradine 5, 7.5, or 10 mg bid according to heart rate (target 55-60 bpm) and tolerability

M6

Fox K et al. Am Heart J. 2013;166:654-661.

Patients and follow-up Preventive Cardiology

19 102 patients randomized

Ivabradine (n=9550) Placebo (n=9552)

9552 analyzed 9550 analyzed

235 had incomplete follow-up 231 withdrew consent 3 lost to follow-up 1 medical reason

6037 with angina 3513 with no angina

6012 with angina 3540 with no angina

230 had incomplete follow-up 199 withdrew consent 1 lost to follow-up

50

55

60

65

70

75

80

0 1 2 3 6 12 18 24 30 36 42

Time (months)

He

art

rate

(b

pm

)

Placebo

Ivabradine

Mean reduction = 9.7 bpm 95% CI [-10.0 ; -9.5]

Mean heart rate reduction

0

20

40

60

80

100

0 6 12 18 24 30 36 42

Placebo

Primary composite end point

9550 9297 9077 8611

9552 9311 9130 8656

Time from randomization (months)

Ivabradine 5570

5649

3776

3749

1832

1836

349

365

Numbers at risk

Pat

ien

ts w

ith

eve

nt

(%)

0

3

6

9

12

15

0 6 12 18 24 30 36 42

Placebo

Placebo

Ivabradine

Ivabradine n=654 (3.03% PY) Placebo n=611 (2.82% PY) HR = 1.08 [95% CI 0.96-1.20] P=0.20

Ivabradine (n=9539)

% (n)

Placebo (n=9544)

% (n)

Symptomatic bradycardia 7.9 (757) 1.2 (110)

Asymptomatic bradycardia 11.0 (1047) 1.3 (126)

Atrial fibrillation 5.3 (508) 3.8 (362)

Phosphenes 5.4 (512) 0.5 (52)

Incidence of selected adverse events (n=19 083)

Effect of Ivabradine on symptoms (angina population: CCS class≥ II, n=12 049)

0

5

10

15

20

25

30

Improvement in CCS class at M3

Worsening in CCS class at M3

Ivabradine

Placebo

Pat

ien

ts (

%)

24.8

19.4

0.31 0.55

P<0.01

Elective revascularization Ivabradine 2.8% Placebo 3.5% HR 0.82 (p=0.058)

Primary composite end point (angina population: CCS class ≥II, n=12 049)

0

20

40

60

80

100

0 6 12 18 24 30 36 42

6037 5869 5712 5428

6012 5859 5747 5463

3483

3502

2387

2350

1197

1178

227

232

Time from randomization (months)

Pat

ien

ts w

ith

eve

nt

(%)

Ivabradine Placebo

Numbers at risk

0

3

6

9

12

15

0 6 12 18 24 30 36 42

Ivabradine n=459 (3.37% PY) Placebo n=390 (2.86% PY) HR = 1.18 [95% CI 1.03-1.35] P=0.018

Placebo

Ivabradine

TOPIC 1 SIGNIFY

TOPIC 2

TOPIC 3 ODYSSEY FH I / FHII / COMBO II / LONG TERM


SOLID-TIMI 52

/f inhibition

Lp-PLA2

PCSK9

Lipoprotein- associated Phospholipase A2 (Lp-PLA2): Background

Lumen

Intima

native LDL carrier of Lp-

PLA2

Leukocyte

Atheroma

Lp-PLA2

Oxidized LDL substrate for Lp-PLA2

Lp-PLA2

Sustained Inflammation

Necrotic Core Expansion

Macphee, Biochem J 1999; Zalewski and Macphee, ATVB 2005; Shi Atherosclerosis 2007; Kolodgie, ATVB 2006

Adjusted for age, sex, diabetes and baseline history of vascular disease

Lp-PLA2 Studies Collaboration. Lancet 2010;375:1536-44

79,036 participants, 32 prospective studies

Lp-PLA2 activity and risk of CV outcomes

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

-1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5

Coronary heart disease*5221 events, 17 studies

Ischaemic stroke*1400 events, 7 studies

All vascular death2965 events, 13 studies

Non-vascular death3317 events, 12 studies

Ris

k ra

tio (

95%

CI)

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

-1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5





Ris

k ra

tio (

95%

CI)

Standardized Lp-PLA2 activity Standardized Lp-PLA2 activity Standardized Lp-PLA2 activity Standardized Lp-PLA2 activity

Standardized Lp-PLA2 mass Standardized Lp-PLA2 mass Standardized Lp-PLA2 mass Standardized Lp-PLA2 mass

(a) Lp-PLA2 activity

(b) Lp-PLA2 mass

Coronary Heart Disease

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

-1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5





Ris

k ra

tio (9

5% C

I)

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

1.0

1.5

2.0

2.5

-1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5 -1.5 -1 -.5 0 .5 1 1.5





Ris

k ra

tio (9

5% C

I)

Standardized Lp-PLA2 activity Standardized Lp-PLA2 activity Standardized Lp-PLA2 activity Standardized Lp-PLA2 activity

Standardized Lp-PLA2 mass Standardized Lp-PLA2 mass Standardized Lp-PLA2 mass Standardized Lp-PLA2 mass

(a) Lp-PLA2 activity

(b) Lp-PLA2 mass

Vascular Death

* High-risk criteria (≥1 of the following): age ≥60 years, diabetes mellitus requiring Rx, eGFR 30-59 ml/min/1.73 m2, polyvascular disease, HDL <40 mg/dl (STABILITY only), tobacco use (STABILITY only), or prior MI (SOLID-TIMI 52 only)

Randomization to Darapladib or Placebo

n= 13,026 (2.5 year median follow-up)

ACS patients (NSTE- or STE-ACS) with high-risk features*

Randomization ≤30 days from hospitalization with ACS

Darapladib Phase III Clinical Programme

Primary Endpoint: CHD Death, Non-fatal MI, or Urgent Coronary Revascularization for Myocardial Ischemia

High-risk* patients ≤30 days post-ACS: UA, NSTEMI or STEMI

Double-blind Randomized 1:1

Median f/u 2.5y

Total N 13,026 * Must have met ≥1 enrichment criteria

Guideline-recommended background Rx, including statins and antiplatelet drugs

SOLID TIMI 52: Lp-PLA2 inhibition in ACS

Darapladib (160mg daily)

Placebo (daily)

No. at risk Placebo 6522 6219 6060 5945 5825 5726 5638 5544 5046 3942 2684 1550 669 Darapladib 6504 6201 6038 5902 5787 5708 5636 5534 5061 3955 2673 1558 634

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

0 3 6 9 12 15 18 21 24 27 30 33 36

Eve

nt r

ate

Months

Placebo Darapladib

HR 1.00 (95% CI 0.91-1.09) P=0.93

Primary endpoint: CHD death, MI or urgent coronary revascularization

TOPIC 1 SIGNIFY

TOPIC 2

TOPIC 3 ODYSSEY FH I / FH II / COMBO II / LONG TERM


SOLID-TIMI 52

/f inhibition

Lp-PLA2

PCSK9

PCSK9 – A novel target to lower LDL

Monoclonal AB

Investigational Product Company Stage of Development

Monoclonal antibodies

Alirocumab (SAR236553, REGN727)

Sanofi (Regeneron) Phase III

AMG 145 Amgen Phase III

PF-0490615 (RN316) Pfizer (Rinat) Phase IIb

LY3015014 Lilly Phase I

PCSK9 synthesis inhibitor/siRNA

Alnylam ALN-PCS02 Phase I

Bristols Myers Squibb/Adnexus BMS-962476 (Adnectin) Phase I

Small molecule

Serometrix SX-PCK9 Preclinical

PCSK9 Inhibitors in development

Modified from Stein et al Curr Atheroscler Rep 2013; 15: 310

Overview of studies presented at ESC-2014 from the ODYSSEY Phase 3 Programme

22

ODYSSEY LONG TERM (NCT01507831; LTS11717)

LDL-C ≥70 mg/dL n=2,341; 18 months

ODYSSEY FH II (NCT01709500; CL1112)

LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=249; 18 months

HeFH population HC in high CV-risk population

ODYSSEY FH I (NCT01623115; EFC12492) LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=486; 18 months

Add-on to max tolerated statin (± other LLT)

Add-on to max tolerated statin (± other LLT)

*ODYSSEY COMBO II (NCT01644188; EFC11569)

LDL-C ≥70 mg/dL OR LDL-C ≥100 mg/dL n=720; 24 months

ODYSSEY LONG TERM Study Design

23

HeFH or High CV-risk patients

On max-tolerated statin other lipid-lowering

therapy

LDL-C ≥1.81 mmol/L [70 mg/dL]

Double-blind treatment (18 months)

n=1553

n=788

Follow-up (8 weeks)

Alirocumab 150 mg Q2W SC

(single 1-mL injection using prefilled syringe for self-administration)

Placebo Q2W SC

Assessments W0

W4

W8

W12

W16

W24

W36

W52 W64 W78

86% (2011/2341) completed 52 weeks (both treatment arms) 26.1% (405/1553 alirocumab) and 25.6% (202/788 placebo) had completed 78 weeks by time of

this analysis Mean treatment duration: 65 weeks (both treatment arms)

R

ClinicalTrials.gov identifier: NCT01507831.

Primary efficacy

endpoint

Pre-specified analysis Efficacy: All Patients To W52

Safety: Baseline-W78 (all patients at least W52)

Alirocumab maintained consistent LDL-C reductions over 52 weeks

24

39

53

67

81

95

109

123

137

151

1

1,5

2

2,5

3

3,5

4

0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week

3.1 mmol/L 118.9 mg/dL




mg/

dL

Placebo

Alirocumab

LDL-

C, L

S m

ean

(SE

), m

mo

l/L

Achieved LDL-C Over Time All patients on background of maximally-tolerated statin

±other lipid-lowering therapy

Intent-to-treat (ITT) analysis

Post-hoc adjudicated cardiovascular TEAEs† safety analysis (at least 52 weeks for all patients in ongoing study)

25

Kaplan-Meier Estimates for Time to First Adjudicated Major CV Event Safety Analysis (at least 52 weeks for all patients continuing treatment,

including 607 patients who completed W78 visit)

Intent-to-treat (ITT) analysis

No. at Risk Placebo Alirocumab

Weeks

Mean treatment duration: 65 weeks

Placebo + max-tolerated statin ± other LLT

Cu

mu

lati

ve p

rob

abili

ty o

f ev

en

t

Alirocumab + max-tolerated statin ± other LLT

Cox model analysis: HR=0.46 (95% CI: 0.26 to 0.82) Nominal p-value = <0.01

84 72 60 48 36 24 12 0

0.06

0.05

0.04

0.02

0.01

0.00

0.03

788

1550

776

1534

731

1446

703

1393

682

1352

667

1335

321

642

127

252

TAKE HOME MESSAGES


SIGNIFY: Lowering heart rate by /f inhibition with Ivabradine in stable CAD patients without clinical heart failure does not reduce risk of CV death or nonfatal MI

SOLID-TIMI 52: Lp-PLA2 inhibition by Darapladip failed to reduce cardiovascular events in patients after ACS

ODYSSEY: PCSK9 inhibition by alirocumab efficiently reduces LDL-C in addition to maximally tolerated statin therapy. A post-hoc safety analysis showed a lower rate of adjudicated major CV events.

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preventive cardiology - european society of cardiology affairs... · preventive cardiology 19 102...

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