# esccongress www.escardio.org/esc2014 Preventive Cardiology Geneviève DERUMEAUX (Créteil, Fr) Conflicts of Interest Speaker/advisor/research grant for Actelion, Sanofi, Servier, Toshiba
# 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
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
PREVENTIVE CARDIOLOGY
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
Coronary heart disease*5452 events, 18 studies
Ischaemic stroke*2265 events, 6 studies
All vascular death3273 events, 15 studies
Non-vascular death3694 events, 15 studies
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
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 (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
Coronary heart disease*5452 events, 18 studies
Ischaemic stroke*2265 events, 6 studies
All vascular death3273 events, 15 studies
Non-vascular death3694 events, 15 studies
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
PREVENTIVE CARDIOLOGY
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
1.3 mmol/L 48.3 mg/dL
3.2 mmol/L 123.0 mg/dL
1.4 mmol/L 53.1 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
PREVENTIVE CARDIOLOGY
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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