Design and baseline characteristics. Trial hypothesis Fox K et al. Am Heart J. 2013;166(4):654-661. SIGNIFY is assessing whether heart rate reduction

Design and baseline characteristicsDesign and baseline characteristics

Trial hypothesisTrial hypothesis

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

SIGNIFY is assessing whether heart SIGNIFY is assessing whether heart

rate reduction using ivabradine rate reduction using ivabradine

improves cardiovascular mortality and improves cardiovascular mortality and

morbidity in patients with stable CAD, morbidity in patients with stable CAD,

without clinical heart failurewithout clinical heart failure

SIGNIFY is assessing whether heart SIGNIFY is assessing whether heart

rate reduction using ivabradine rate reduction using ivabradine

improves cardiovascular mortality and improves cardiovascular mortality and

morbidity in patients with stable CAD, morbidity in patients with stable CAD,

without clinical heart failurewithout clinical heart failure

• 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 populationTarget population


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 Additional cardiovascular risk factors (1)risk factors (1)


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 Additional cardiovascular risk factors (2)risk factors (2)



Multinational studyMultinational study

19 102 patients, 51 19 102 patients, 51 countriescountries, 1139 , 1139 centerscenters

Steering CommitteeSteering Committee

Executive CommitteeExecutive Committee

K. Fox chair, R. Ferrari co-chairK. Fox chair, R. Ferrari co-chair

I. Ford, P.G. Steg, J-C Tardif, M. Tendera I. Ford, P.G. Steg, J-C Tardif, M. Tendera

Executive CommitteeExecutive Committee

K. Fox chair, R. Ferrari co-chairK. Fox chair, R. Ferrari co-chair

I. Ford, P.G. Steg, J-C Tardif, M. Tendera 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)

Study designStudy 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


Study end pointsStudy end points

Cardiovascular death

Nonfatal myocardial infarction

Primary composite end pointPrimary composite end point

Secondary end pointsSecondary end points All-cause death

CV death

Coronary death

Nonfatal MI

Coronary revascularization

Elective coronary revascularization

New-onset or worsening heart failure


Baseline characteristicsBaseline characteristics

n=19 102n=19 102

Age, yearAge, year 6565

<70, %<70, % 7272

≥≥70, %70, % 2828

≥≥75, %75, % 1212

Male, %Male, % 7272

Heart rate, bpmHeart rate, bpm 77.277.2

Systolic BP, mm HgSystolic BP, mm Hg 130.5130.5

Diastolic BP, mm HgDiastolic BP, mm Hg 78.278.2

LVEF, %LVEF, % 56.556.5


Baseline characteristicsBaseline characteristics

n= 19 102n= 19 102

CCS class II to IV, %CCS class II to IV, % 6363

CAD duration, yearCAD duration, year 6.26.2

Previous MI, %Previous MI, % 7373

Previous coronary revascularization, %Previous coronary revascularization, % 6868

Dyslipidemia, %Dyslipidemia, % 7171

Diabetes mellitus, %Diabetes mellitus, % 4343

Peripheral artery disease, %Peripheral artery disease, % 2121

Current smoker, %Current smoker, % 2424


0

10

20

30

40

50

60

70

80

90

100

Background therapiesBackground therapies


Use of background preventive therapies Use of background preventive therapies in clinical trials and registriesin clinical trials and registries

SubstudiesSubstudies


n Measurements

Quality of life substudy

4500 Seattle Angina Questionnaire in patients with angina pectoris at baseline (CCS class II or higher)

Biomarkers substudy

380 Circulating 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

5000 Genetic variations in candidate genes and in the whole genome vs clinical outcomes

ConclusionConclusion


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

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

Documents

Design and baseline characteristics. Trial hypothesis Fox K et al. Am Heart J. 2013;166(4):654-661. SIGNIFY is assessing whether heart rate reduction