15th Annual Heart CongressDurban, SA, October 19th 2014

Thomas F. Lüscher, FESC, FRCPProfessor and Chairman Cardiology University Hospital and Director

Center for Molecular Cardiology, University of Zürich

Stable Coronary Artery Disease

CoronaryArtery Disease

1. Definition2. Epidemiology3. Natural history and prognosis4. Diagnosis and assesssement5. Lifestyle and pharmacological

management6. Revascularization7. Special groups or considerations

CoronaryArtery Disease

1. Definition2. Epidemiology3. Natural history and prognosis4. Diagnosis and assesssement5. Lifestyle and pharmacological

management6. Revascularization7. Special groups or considerations

Main Features of Stable CAD

Group A:No Angina

Group B:History ofAngina

Group C:CurrentAngina

Diagnosing Stable Coronary Disease

Non-Invasive Testing in Patients with SuspectedStable CAD

Coronary CT - Anatomical Information

CoronaryArtery Disease

1. Definition2. Epidemiology3. Natural history and prognosis4. Diagnosis and assesssement5. Lifestyle and pharmacological

management6. Revascularization7. Special groups or considerations

Treatment of Stable Coronary Artery Disease

Optimal Medical Therapy(OMT)

Percutaneous CoronaryIntervention (PCI)

Aorto-CoronaryBypass (ACBP)

Drugs to Treat Coronary Artery Disease

Long-term safety, tolerability and efficacy of alirocumab versus placebo in high cardiovascular risk patients: first results from

the ODYSSEY LONG TERM study in 2,341 patients

Jennifer G. Robinson,1 Michel Farnier,2 Michel Krempf,3

Jean Bergeron,4 Gérald Luc,5 Maurizio Averna,6 Erik Stroes,7

Gisle Langslet,8 Frederick J. Raal,9 Mahfouz El Shahawy,10

Michael J. Koren,11 Norman Lepor,12 Christelle Lorenzato,13

Robert Pordy,14 Umesh Chaudhari,15 John J.P. Kastelein7

1University of Iowa, Iowa City, IA, USA; 2Point Médical, Dijon, France; 3CHU de Nantes - Hôpital Nord Laennec, Saint-Herblain, France; 4Clinique des Maladies Lipidiques de Quebec Inc., Quebec, Canada; 5University Hospital of Lille, Lille, France; 6Università di Palermo – Policlinico “P.Giaccone”, Palermo, Italy; 7Department of Vascular Medicine, Academic

Medical Center, Amsterdam, The Netherlands; 8Lipid Clinic, Oslo University Hospital, Oslo, Norway; 9University of Witwatersrand, Johannesburg, South Africa; 10Cardiovascular Center of Sarasota, Sarasota, FL, USA; 11Jacksonville Center

For Clinical Research, Jacksonville, FL, USA; 12Westside Medical Associates of Los Angeles, Beverly Hills, CA, USA; 13Sanofi, Chilly-Mazarin, France; 14Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 15Sanofi, Bridgewater, NJ, USA

16

ODYSSEY LONG TERM Study Design

ClinicalTrials.gov identifier: NCT01507831.

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

R

Follow-up(8 weeks)

Alirocumab 150 mg Q2W SC(single 1-mL injection using prefilled syringe for self-administration)

Placebo Q2W SC

AssessmentsW0

W4

W8

W12

W16

W24

W36

W52

Primaryefficacy endpoint

Pre-specified analysisEfficacy: All Patients To W52Safety: Baseline-W78

(all patients at least 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 analysisMean treatment duration: 65 weeks (both treatment arms)

J.G. Robinson et a. ESC 2014

Alirocumab Maintained Consistent LDL-C Reductions over 52 Weeks

17

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 52Week

3.1 mmol/L118.9 mg/dL

1.3 mmol/L48.3 mg/dL

3.2 mmol/L123.0 mg/dL

1.4 mmol/L53.1 mg/dL

mg

/dL

PlaceboAlirocumab

LD

L-C

, LS

mea

n (

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 J.G. Robinson et a. ESC 2014

81% 79%

9% 8%

0

10

20

30

40

50

60

70

80

90 P<0.0001

% p

atie

nts

Very high-risk: LDL-C <1.8 mmol/L (70 mg/dL) High-risk: <2.6 mmol/L (100 mg/dL)

<1.8 mmol/L (70 mg/dL) regardless of risk

P<0.0001

Most Patients Receiving Alirocumab on Background Statin ± Other LLT Achieved LDL-C Goals

Placebo

Alirocumab

Proportion of patients reaching LDL-C goal at Week 24

Intent-to-treat (ITT) analysis; LLT = lipid-lowering therapy J.G. Robinson et a. ESC 2014

7881550

7761534

7311446

7031393

6821352

6671335

321642

127252

00

No. at RiskPlaceboAlirocumab

Weeks

Mean treatment duration: 65 weeks

Placebo + max-tolerated statin ± other LLT0.10

0.08

0.06

0.04

0.02

0.0096847260483624120

Est

imat

ed p

rob

abili

ty o

f ev

ent

Alirocumab + max-tolerated statin ± other LLT

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

†Primary endpoint for the ODYSSEY OUTCOMES trial: CHD death, Non-fatal MI, Fatal and non-fatal ischemic stroke, Unstable angina requiring hospitalisation. LLT, lipid-lowering therapy

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)

Post-hoc Adjudicated Cardiovascular TEAEs (Same as primary endpoint of ongoing ODYSSEY OUTCOMES trial†)

J.G. Robinson et a. ESC 2014

Fox et al. NEJM 2014

Ivabradine in Coronary Artery DiseaseWith Normal LVEF: Signify

Ivabradine in Coronary Artery DiseaseWith Normal LVEF: Signify

Fox et al. NEJM 2014

Fox et al. NEJM 2014

Ivabradine in Coronary Artery DiseaseWith Normal LVEF: Signify

Ivabradine in Coronary Artery DiseaseWith normal LVEF: Signify

Fox et al. NEJM 2014

Recommendations for Optimal Medical Therapy

Management during Follow-up of CAD

CoronaryArtery Disease

1. Definition2. Epidemiology3. Natural history and prognosis4. Diagnosis and assesssement5. Lifestyle and pharmacological

management6. Revascularization7. Special groups or considerations

Treatment of Stable Coronary Artery Disease

Optimal Medical Therapy(OMT)

Percutaneous CoronaryIntervention (PCI)

Aorto-CoronaryBypass (ACBP)

Restenosis and Otcome:(assessed at Control Angiograph (6-8 months after PCI)

Entire Cohort Subgroups

Asymptomatic Patients

Treatment of Stable Coronary Artery Disease

Optimal Medical Therapy(OMT)

Percutaneous CoronaryIntervention (PCI)

Aorto-CoronaryBypass (ACBP)

SYNTAX Score:Sum of points assigned to lesionidentified in the coro-nary tree with>50% diameter narro-wing in ves-sels >1.5mm diameter. The coronary tree is divided into 16 segments (AHA). Each segment isgiven a score of 1 or 2 based on thepresence of disease and this score is then weighted based on a chart, with values ranging from 3.5 for theproximal LAD to 5.0 for left main, and 0.5 for smaller branches.

Network Analysis of Randomized Revascularization Trial

Windecker et al. Brit. Med. J. 2014

Network Analysis of Randomized Revascularization Trial

Windecker et al. Brit. Med. J. 2014

Network Analysis of Randomized Revascularization Trial

Win

deck

er e

t al.

Brit

. Med

. J. 2

014

Indications for Revascularization of Stable CAD in Patients with OMT

Deciding for PCI or CABG in Stable CAD:The HeartTeam Approach

Stable Coronary Artery Disease

Optomal Medical Therapy(OMT)

Perkutane CoronareIntervention (PCI)

Aorto-CoronareBypasserkrankung (PCI)