1. Design and baseline characteristics

2. Trial hypothesis Fox K et al. Am Heart J. 2013;166(4):654-661. SIGNIFY is assessing whether heart rate reduction using ivabradine improves cardiovascular mortality and morbidity in patients with stable CAD, without clinical heart failure

3. Proven stable CAD Age >55 years Without LVSD (EF >40%, no clinical signs of HF) In sinus rhythm, with a resting heart rate >70 bpm Receiving appropriate and stable doses of conventional cardiovascular medication With one or more other cardiovascular risk factors Target population Fox K et al. Am Heart J. 2013;166(4):654-661.

4. At least ONE major risk factor:  Angina pectoris in CCS class II or higher (≥1 mo); or  Objective evidence of myocardial ischemia with moderate to large deficit induced by noninvasive stress testing (≤12 mo) without subsequent revascularization; or  Hospital discharge after coronary event ≤12 mo (AMI >3 mo or UA >1 mo) Additional cardiovascular risk factors (1) Fox K et al. Am Heart J. 2013;166(4):654-661.

5. OR at least TWO minor risk factors:  Low HDL-C (<40 mg/dL) and/or high LDL-C (<160 mg/dL) despite lipid-lowering treatment; or  Type 1 or 2 diabetes mellitus; or  Peripheral artery disease; or  Current smoker (≥10 cigarettes/d); or  Age ≥70 years Additional cardiovascular risk factors (2) Fox K et al. Am Heart J. 2013;166(4):654-661.

6. Multinational study 19 102 patients, 51 countries, 1139 centers

7. Steering Committee Executive Committee K. Fox chair, R. Ferrari co-chair I. Ford, P.G. Steg, J-C Tardif, M. Tendera R. Ferrari (Chair, Ferrara, Italy) R. Iglesias (Argentina) P.A. Zelveian (Armenia) B. Freedman (Australia) K. Huber (Austria) J-L.Vanoverschelde (Belgium) L.A. Machado Cesar (Brazil) N. Gotcheva (Bulgaria) P. L’Allier (Canada) D.Y. Hu (China) C.P. Lau (Hong Kong) M. Bergovec (Croatia) J. Hradec (Czech Republic) P. Clemmensen and P. Hildebrandt (Denmark) J. Eha (Estonia) M. Laine (Finland) N. Danchin (France) S. Kedev (FYROM) V. Chumburidze (Georgia) T. Münzel (Germany) P. Vardas (Greece) J. Borbola (Hungary) R. Kasliwal (India) P. Crean (Ireland) L. Tavazzi (Italy) T.Z. Seisembekov (Kazakhstan) K.B. Seung (Korea) A.Erglis (Latvia) A. Laucevicius (Lithuania) R. Ali (Malaysia) E. Alexanderson (Mexico) D. Atar (Norway) R. Sy (Philippines) A. Rynkiewicz (Poland) R. Seabra-Gomes (Portugal) C. Macarie (Romania) V.Y. Mareev and Y.A. Karpov (Russia) M.C. Ostojic (Serbia) T.H. Koh (Singapore) J. Murin (Slovakia) P. Rakovec (Slovenia) P. Sareli (South Africa) C. Macaya (Spain) M. Dellborg( Sweden) T. Lüscher (Switzerland) C.E. Chiang (Taiwan) P. Sritara (Thailand) W.H. Van Gilst and J.W. Jukema (The Netherlands) O. Ergene (Turkey) A. Parkhomenko (Ukraine) A. Hall (UK) F. Kuster (Uruguay) N.V. Pham (Vietnam)

8. Study design Ivabradine: starting dose of 7.5 mg bid, then 5, 7.5, 10 mg bid to reach target heart rate of 60 bpm Matching placebo, bid Follow-up visit every 6 months M0 Inclusion Mean follow-up of 2.75 years Placebo run-in 2 - 4 weeks M1 M2 M3 M6 M48 or study end 19 102 patients randomized Selection A randomized, double-blind, placebo-controlled trial Fox K et al. Am Heart J. 2013;166(4):654-661.

9. Study end points  Cardiovascular death  Nonfatal myocardial infarction Primary composite end point Secondary end points  All-cause death  CV death  Coronary death  Nonfatal MI  Coronary revascularization  Elective coronary revascularization  New-onset or worsening heart failure Fox K et al. Am Heart J. 2013;166(4):654-661.

10. Baseline characteristics n=19 102 Age, year 65 <70, % 72 ≥70, % 28 ≥75, % 12 Male, % 72 Heart rate, bpm 77.2 Systolic BP, mm Hg 130.5 Diastolic BP, mm Hg 78.2 LVEF, % 56.5 Fox K et al. Am Heart J. 2013;166(4):654-661.

11. Baseline characteristics n= 19 102 CCS class II to IV, % 63 CAD duration, year 6.2 Previous MI, % 73 Previous coronary revascularization, % 68 Dyslipidemia, % 71 Diabetes mellitus, % 43 Peripheral artery disease, % 21 Current smoker, % 24 Fox K et al. Am Heart J. 2013;166(4):654-661.

12. Background therapies Fox K et al. Am Heart J. 2013;166(4):654-661.

13. Use of background preventive therapies in clinical trials and registries

14. Substudies Fox K et al. Am Heart J. 2013;166(4):654-661. nMeasurements Quality of life substudy 4500Seattle Angina Questionnaire in patients with angina pectoris at baseline (CCS class II or higher) Biomarkers substudy 380Circulating von Willebrand factor, high-sensitivity troponin T, and other biomarkers of CAD progression and endothelial function, at baseline, and 3 and 12 months Pharmaco- genomics substudy 5000Genetic variations in candidate genes and in the whole genome vs clinical outcomes

15. Conclusion Fox K et al. Am Heart J. 2013;166(4):654-661.  Elevated resting heart rate is an important correlate of outcomes in patients with CAD  Heart rate lowering may therefore be expected to reduce mortality and cardiovascular event rates in patients with stable CAD  SIGNIFY will shed further light on the role of heart rate lowering with ivabradine in patients with stable CAD without clinical heart failure  The study is expected to end in 2014