SStudy assesstudy assessIInnGG the morbidity-mortality the morbidity-mortality
bebeNNefits of the efits of the II ff inhibitor ivabradine inhibitor ivabradine
in patients with coronar in patients with coronarYY artery d artery disease isease
without heart failurewithout heart failure
SStudy assesstudy assessIInnGG the morbidity-mortality the morbidity-mortality
bebeNNefits of the efits of the II ff inhibitor ivabradine inhibitor ivabradine
in patients with coronar in patients with coronarYY artery d artery disease isease
without heart failurewithout heart failureConflict of interest
Kim Fox receives honoraria, fees, travel expenses from Servier
Conflict of interest
Kim Fox receives honoraria, fees, travel expenses from Servier
Study organisationStudy organisation
Executive CommitteeExecutive CommitteeK Fox (Chair, UK), R Ferrari (Co-chair, Italy), I Ford (K Fox (Chair, UK), R Ferrari (Co-chair, Italy), I Ford (UK), UK),
PG Steg (France), J-C Tardif (Canada), M Tendera (Poland)PG Steg (France), J-C Tardif (Canada), M Tendera (Poland)
Executive CommitteeExecutive CommitteeK Fox (Chair, UK), R Ferrari (Co-chair, Italy), I Ford (K Fox (Chair, UK), R Ferrari (Co-chair, Italy), I Ford (UK), UK),
PG Steg (France), J-C Tardif (Canada), M Tendera (Poland)PG Steg (France), J-C Tardif (Canada), M Tendera (Poland)
Endpoint Validation CommitteeEndpoint Validation Committee
K Thygesen (Chair, Denmark), K Thygesen (Chair, Denmark),
M Frenneaux (UK), M Frenneaux (UK),
G Jondeau G Jondeau (France), (France),
A Mosterd (The Netherlands)A Mosterd (The Netherlands)
Data Monitoring CommitteeData Monitoring Committee
J Camm (Chair, UK), J Camm (Chair, UK),
G Murray (UK), G Murray (UK),
H Dargie (UK), H Dargie (UK),
J Kjekshus (Norway), J Kjekshus (Norway),
AP Maggioni (Italy)AP Maggioni (Italy)
Study organisationStudy organisation
Steering committeeSteering committee
Argentina: Argentina: R Iglesias Armenia:Armenia: PA Zelveian Australia:Australia: B Freedman Austria: Austria: K Huber Belgium:Belgium: JL Vanoverschelde Brazil:Brazil: LA Machado Cesar Bulgaria:Bulgaria: N GotchevaCanada:Canada: P L’Allier China:China: DY Hu Croatia:Croatia: M Bergovec Czech Republic:Czech Republic: J Hradec Denmark:Denmark: P Clemmensen,
and P Hildebrandt Estonia:Estonia: J Eha Finland:Finland: M Laine France:France: N Danchin FYROM:FYROM: S Kedev Germany:Germany: T Münzel Georgia:Georgia: V Chumburidze
Argentina: Argentina: R Iglesias Armenia:Armenia: PA Zelveian Australia:Australia: B Freedman Austria: Austria: K Huber Belgium:Belgium: JL Vanoverschelde Brazil:Brazil: LA Machado Cesar Bulgaria:Bulgaria: N GotchevaCanada:Canada: P L’Allier China:China: DY Hu Croatia:Croatia: M Bergovec Czech Republic:Czech Republic: J Hradec Denmark:Denmark: P Clemmensen,
and P Hildebrandt Estonia:Estonia: J Eha Finland:Finland: M Laine France:France: N Danchin FYROM:FYROM: S Kedev Germany:Germany: T Münzel Georgia:Georgia: V Chumburidze
Greece:Greece: P Vardas Hong-Kong:Hong-Kong: CP Lau Hungary:Hungary: J Borbola India:India: R Kasliwal Ireland:Ireland: P Crean Italy:Italy: R Ferrari Kazakhstan:Kazakhstan: TZ Seisembekov Korea:Korea: KB Seung Latvia: Latvia: A Erglis Lithuania:Lithuania: A Laucevicius Malaysia:Malaysia: R Ali Mexico:Mexico: E Alexanderson The Netherlands:The Netherlands: WH van Gilst and JW JukemaNorway: Norway: D AtarD AtarPhilippines: Philippines: R SyR SyPoland: Poland: A RynkiewiczA RynkiewiczPortugal: Portugal: R Seabra GomesR Seabra Gomes
Greece:Greece: P Vardas Hong-Kong:Hong-Kong: CP Lau Hungary:Hungary: J Borbola India:India: R Kasliwal Ireland:Ireland: P Crean Italy:Italy: R Ferrari Kazakhstan:Kazakhstan: TZ Seisembekov Korea:Korea: KB Seung Latvia: Latvia: A Erglis Lithuania:Lithuania: A Laucevicius Malaysia:Malaysia: R Ali Mexico:Mexico: E Alexanderson The Netherlands:The Netherlands: WH van Gilst and JW JukemaNorway: Norway: D AtarD AtarPhilippines: Philippines: R SyR SyPoland: Poland: A RynkiewiczA RynkiewiczPortugal: Portugal: R Seabra GomesR Seabra Gomes
Romania:Romania: C Macarie Russia: Russia: VY Mareev
and YA Karpov Serbia:Serbia: MC Ostojic Singapore:Singapore: TH Koh Slovakia:Slovakia: J MurinSlovenia: Slovenia: P Rakovec South Africa:South Africa: P Sareli Spain:Spain: C Macaya de Miguel Sweden:Sweden: M Dellborg Switzerland:Switzerland: T Lüscher Taiwan:Taiwan: CE Chiang Thailand:Thailand: P Sritara Turkey:Turkey: O Ergene United Kingdom:United Kingdom: A HallUkraine:Ukraine: A ParkhomenkoUruguay: F Kuster Vietnam:Vietnam: NV Pham
Romania:Romania: C Macarie Russia: Russia: VY Mareev
and YA Karpov Serbia:Serbia: MC Ostojic Singapore:Singapore: TH Koh Slovakia:Slovakia: J MurinSlovenia: Slovenia: P Rakovec South Africa:South Africa: P Sareli Spain:Spain: C Macaya de Miguel Sweden:Sweden: M Dellborg Switzerland:Switzerland: T Lüscher Taiwan:Taiwan: CE Chiang Thailand:Thailand: P Sritara Turkey:Turkey: O Ergene United Kingdom:United Kingdom: A HallUkraine:Ukraine: A ParkhomenkoUruguay: F Kuster Vietnam:Vietnam: NV Pham
Patients with heart rate ≥70 bpm (n= 5392)Patients with heart rate ≥70 bpm (n= 5392)
Placebo
IvabradineIvabradine
HR (95% CI), 0.64 (0.49–0.84)P=0.001
Years0.5 1 1.5 20
0
8
4
6
2
Effect of ivabradine on hospitalization for fatal/nonfatal MI in patients with
stable CAD and LVSD
Overall placebo population (n=5438)Overall placebo population (n=5438)
Fox K et al. Lancet. 2008;372:807-816.
HR (95% CI), 1.46 (1.11–1.91)
P=0.0066
Years0 0.5 1 1.5 2
0
Heart rate <70 bpm
Heart rate ≥70 bpm
8
4
6
2
Fox K et al. Lancet. 2008;372:817-821.
Event rate (%) Event rate (%) Event rate (%) Event rate (%)
Study outcomes• Events: 2.8% PY placebo, N=19 102 • Median follow-up: 27.8 months• 51 countries - 1139 centres
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-in14 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
Study designStudy design
Fox K et al. Am Heart J. 2013;166:654-661.
Patients and follow-up
19 102 patients randomized
Ivabradine (n=9550) Placebo (n=9552)
9552 analyzed9550 analyzed
235 had incomplete follow-up231 withdrew consent3 lost to follow-up1 medical reason
200 had incomplete follow-up199 withdrew consent1 lost to follow-up
6037 with angina 3513 with no angina
6012 with angina 3540 with no angina
Baseline characteristics
Ivabradine Ivabradine n=9550n=9550
Placebo Placebo n=9552n=9552
Age, yearsAge, years 6565 6565
Male, %Male, % 7373 7272
Resting heart rate, bpmResting heart rate, bpm 7777 7777
LV ejection fraction, %LV ejection fraction, % 5656 5656
Previous MI, %Previous MI, % 7373 7373
Previous coronary revasc, %Previous coronary revasc, % 6868 6868
Dyslipidemia, %Dyslipidemia, % 7272 7272
Diabetes mellitus, %Diabetes mellitus, % 4343 4343
Peripheral artery disease, %Peripheral artery disease, % 2121 2121
Current smoker, %Current smoker, % 2424 2424
Hypertension, %Hypertension, % 8787 8686
Baseline cardiovascular medications
Ivabradine Ivabradine n=9550n=9550
Placebo Placebo n=9552n=9552
Antiplatelet or anticoagulants, % Antiplatelet or anticoagulants, % 9898 9898
Statins, %Statins, % 9292 9292
ACE inhibitors or ARB, % ACE inhibitors or ARB, % 8282 8181
Beta-blockers, %Beta-blockers, % 8383 8383
Dihydropyridine CCB, %Dihydropyridine CCB, % 2727 2727
Diltiazem or verapamil, %Diltiazem or verapamil, % 55 44
Organic nitrates, %Organic nitrates, % 4141 3939
Mean heart rate reduction Mean heart rate reduction
Time (months)
Hea
rt r
ate
(bp
m)
Placebo
IvabradineIvabradine
Mean reduction = 9.7 bpm
95% CI [-10.0 ; -9.5]
Ivabradine n=654 (3.03% PY) Placebo n=611 (2.82% PY)
HR = 1.08 [[95% CI 0.96-1.200.96-1.20] P=0.20
Primary composite end pointPrimary composite end point
95509550 92979297 90779077 86118611
95529552 93119311 91309130 86568656
Time from randomization (months)Time from randomization (months)IvabradineIvabradine 55705570
56495649
37763776
37493749
18321832
18361836
349349
365365
Numbers at risk Numbers at risk
Placebo
PlaceboIvabradine
Cardiovascular deathCardiovascular death
9550 9382 9240 8828
9552 9405 9284 885157555822
39263882
19141910
366
386
Time from randomization (months)
Ivabradine Placebo
Numbers at risk
Ivabradine n=329 (1.49% PY) Placebo n=301 (1.36% PY)
HR = 1.10 [[95% CI 0.94-1.280.94-1.28] P=0.25
PlaceboIvabradine
Nonfatal myocardial infarctionNonfatal myocardial infarction
9550 9297 9078 8611
9552 9311 9130 8656
5570
5649
3776
3749
1832
1836
349
365
Time from randomization (months)
Ivabradine n=351 (1.63% PY) Placebo n=339 (1.56% PY)
HR = 1.04 [[95% CI 0.90-1.210.90-1.21] P=0.60
Numbers at risk
Ivabradine
Placebo
PlaceboIvabradine
Incidence of selected adverse events Incidence of selected adverse events (n=19 083)(n=19 083)
Ivabradine (n=9539)Ivabradine (n=9539)% (n)% (n)
Placebo (n=9544)Placebo (n=9544)% (n)% (n)
Symptomatic bradycardiaSymptomatic bradycardia 7.9 (757)7.9 (757) 1.2 (110)1.2 (110)
Asymptomatic bradycardiaAsymptomatic bradycardia 11.0 (1047)11.0 (1047) 1.3 (126)1.3 (126)
Atrial fibrillationAtrial fibrillation 5.3 (508)5.3 (508) 3.8 (362)3.8 (362)
PhosphenesPhosphenes 5.4 (512)5.4 (512) 0.5 (52)0.5 (52)
Incidence of selected adverse events Incidence of selected adverse events (n=19 083)(n=19 083)
Ivabradine (n=9539)Ivabradine (n=9539)% (n)% (n)
Placebo (n=9544)Placebo (n=9544)% (n)% (n)
Ventricular tachycardiaVentricular tachycardia 0.6 (54)0.6 (54) 0.4 (41)0.4 (41)
Ventricular fibrillationVentricular fibrillation 0.3 (27)0.3 (27) 0.3 (26)0.3 (26)
Torsades de pointesTorsades de pointes 0 (1)0 (1) 0 (3)0 (3)
Primary composite end pointPrimary composite end point(angina population: CCS class (angina population: CCS class ≥≥II, n=12 049)II, n=12 049)
Ivabradine n=459 (3.37% PY) Placebo n=390 (2.86% PY)
HR = 1.18 [[95% CI 1.03-1.351.03-1.35] P=0.018
6037 5869 5712 54286012 5859 5747 5463
34833502
23872350
11971178
227232
Time from randomization (months)
PlaceboIvabradine
IvabradinePlacebo
Numbers at risk
Components of primary composite end Components of primary composite end point point (angina population: CCS class ≥II, n=12 049)(angina population: CCS class ≥II, n=12 049)
6037 5930 5823 55746012 5919 5844 5583
36043605
24832434
12491224
238247
Time from randomization (months)Ivabradine
Placebo
Numbers at risk6037 5869 5713 54286012 5859 5747 5463
34833502
23872350
11971178
227232
Time from randomization (months)
PlaceboIvabradine
Ivabradine n=235 (1.72% PY)
Placebo n=200 (1.47% PY)
HR = 1.18 [[95% CI 0.97-1.420.97-1.42] P=0.09
Ivabradine n=245 (1.76% PY)
Placebo n=210 (1.51% PY)
HR = 1.16 [[95% CI 0.97-1.400.97-1.40] P=0.11
Cardiovascular death Nonfatal myocardial infarction
Effect of ivabradine on symptomsEffect of ivabradine on symptoms(angina population: CCS class≥ II, n=12 049)(angina population: CCS class≥ II, n=12 049)
Patients (%)
24.8
19.4
0.31 0.55
P<0.01
Elective revascularization
Ivabradine 2.8% Placebo 3.5% HR 0.82
Elective revascularization
Ivabradine 2.8% Placebo 3.5% HR 0.82
ConclusionConclusion
Lowering heart rate with ivabradine in CAD patients without clinical heart failure does not reduce the risk of CV death or nonfatal MI
In the subgroup of patients with angina (CCS class ≥II), there appeared to be an increase in CV death or nonfatal MI
In the same subgroup there appeared to be improvement in symptoms and need for elective coronary revascularization
AcknowledgementsAcknowledgements
19 102 19 102 patients from patients from 5151 countries countries
11391139 centers centers
More than More than 5400 5400 investigatorsinvestigators
Study supported byStudy supported by
Fox K et al. N Engl J Med. Published online 31 August 2014.
Now available online from Now available online from NEJMNEJMNow available online from Now available online from NEJMNEJM