Design and baseline characteristics
Trial hypothesis
SIGNIFY is assessing whether heart
rate
reduction
using
ivabradine
improves cardiovascular mortality and
morbidity in patients with stable CAD,
without clinical heart failure
Fox K et al. Am Heart J. 2013;166(4):654-661.
Target population
•
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
Fox K et al. Am Heart J. 2013;166(4):654-661.
Additional cardiovascular
risk factors (1)
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)
Fox K et al. Am Heart J. 2013;166(4):654-661.
Additional cardiovascular
risk factors (2)
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
Fox K et al. Am Heart J. 2013;166(4):654-661.
Multinational study
19 102 patients, 51 countries, 1139 centers
Fox K et al. Am Heart J. 2013;166(4):654-661.
Executive Committee
K. Fox chair, R. Ferrari co-chair
I. Ford, P.G. Steg, J-C Tardif, M. Tendera
Steering Committee
V. Chumburidze (Georgia)
R. Ferrari (Chair, Ferrara, Italy)
T. Münzel (Germany)
R. Iglesias (Argentina)
P. Vardas (Greece)
P.A. Zelveian (Armenia)
J. Borbola (Hungary)
B. Freedman (Australia)
R. Kasliwal (India)
K. Huber (Austria)
P. Crean (Ireland)
J-L.Vanoverschelde (Belgium)
L. Tavazzi (Italy)
L.A. Machado Cesar (Brazil)
T.Z. Seisembekov (Kazakhstan)
N. Gotcheva (Bulgaria)
K.B. Seung (Korea)
P. L’Allier (Canada)
A.Erglis (Latvia)
D.Y. Hu (China)
A. Laucevicius (Lithuania)
C.P. Lau (Hong Kong)
R. Ali (Malaysia)
M. Bergovec (Croatia)
E. Alexanderson (Mexico)
J. Hradec (Czech Republic)
D. Atar (Norway)
P. Clemmensen and P. Hildebrandt
R. Sy (Philippines)
(Denmark)
A. Rynkiewicz (Poland)
J. Eha (Estonia)
R. Seabra-Gomes (Portugal)
M. Laine (Finland)
C. Macarie (Romania)
N. Danchin (France)
V.Y. Mareev and Y.A. Karpov (Russia)
S. Kedev (FYROM)
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 design
A randomized, double-blind, placebo-controlled trial
Ivabradine: starting dose of 7.5 mg bid,
then 5, 7.5, 10 mg bid to reach target heart rate of 60 bpm
Placebo
run-in
2 - 4 weeks
19 102 patients randomized
Matching placebo, bid
M0
Selection
M1
M2
Inclusion
M3
M6
Follow-up visit
every 6 months
Mean follow-up of 2.75 years
Fox K et al. Am Heart J. 2013;166(4):654-661.
M48 or
study
end
Study end points
Primary composite end point
 Cardiovascular death
 Nonfatal myocardial infarction
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.
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.
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.
Background therapies
100
90
80
70
60
50
40
30
20
10
0
Fox K et al. Am Heart J. 2013;166(4):654-661.
Use of background preventive therapies
in clinical trials and registries
Substudies
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
Pharmacogenomics
substudy
5000
Genetic variations in candidate genes and in the
whole genome vs clinical outcomes
Fox K et al. Am Heart J. 2013;166(4):654-661.
Conclusion
 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
Fox K et al. Am Heart J. 2013;166(4):654-661.