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