SLIDE 1 S Study assess tudy assessI In nG G the morbidity-mortality the morbidity-mortality be beN Nefits of the efits of the I I
f
f inhibitor ivabradine
inhibitor ivabradine in patients with coronar in patients with coronarY Y artery d artery disease isease without heart failure without heart failure
Conflict of interest Kim Fox receives honoraria, fees, travel expenses from Servier
SLIDE 2
Study organisation Study organisation
Executive Committee Executive Committee
K 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 Committee Endpoint 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 Committee Data 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)
SLIDE 3 Study organisation Study organisation
Steering committee Steering 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 Gotcheva Canada: 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: L Tavazzi 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 Jukema Norway: Norway: D Atar D Atar Philippines: Philippines: R Sy R Sy Poland: Poland: A Rynkiewicz A Rynkiewicz Portugal: Portugal: R Seabra Gomes R Seabra Gomes Romania: Romania: C Macarie Russia: Russia: VY Mareev and YA Karpov Serbia: Serbia: MC Ostojic Singapore: Singapore: TH Koh Slovakia: Slovakia: J Murin Slovenia: 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 Hall Ukraine: Ukraine: A Parkhomenko Uruguay: F Kuster Vietnam: Vietnam: NV Pham
SLIDE 4 Patients with heart rate ≥70 bpm (n= 5392) Patients with heart rate ≥70 bpm (n= 5392)
Placebo Ivabradine
HR (95% CI), 0.64 (0.49–0.84) P=0.001
Years
0.5 1 1.5 2 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
Years
0.5 1 1.5 2
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 (%)
SLIDE 5 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-in 14 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 design Study design
Fox K et al. Am Heart J. 2013;166:654-661.
SLIDE 6 Patients and follow-up
19 102 patients randomized Ivabradine (n=9550) Placebo (n=9552) 9552 analyzed 9550 analyzed
235 had incomplete follow-up ü 231 withdrew consent ü 3 lost to follow-up ü 1 medical reason 200 had incomplete follow-up ü 199 withdrew consent ü 1 lost to follow-up
ü 6037 with angina ü 3513 with no angina ü 6012 with angina ü 3540 with no angina
SLIDE 7
Baseline characteristics
Ivabradine Ivabradine
n=9550 n=9550
Placebo Placebo
n=9552 n=9552
Age, years Age, years 65 65 65 65 Male, % Male, % 73 73 72 72 Resting heart rate, bpm Resting heart rate, bpm 77 77 77 77 LV ejection fraction, % LV ejection fraction, % 56 56 56 56 Previous MI, % Previous MI, % 73 73 73 73 Previous coronary revasc, % Previous coronary revasc, % 68 68 68 68 Dyslipidemia, % Dyslipidemia, % 72 72 72 72 Diabetes mellitus, % Diabetes mellitus, % 43 43 43 43 Peripheral artery disease, % Peripheral artery disease, % 21 21 21 21 Current smoker, % Current smoker, % 24 24 24 24 Hypertension, % Hypertension, % 87 87 86 86
SLIDE 8
Baseline cardiovascular medications
Ivabradine Ivabradine
n=9550 n=9550
Placebo Placebo
n=9552 n=9552
Antiplatelet or anticoagulants, % Antiplatelet or anticoagulants, % 98 98 98 98 Statins, % Statins, % 92 92 92 92 ACE inhibitors or ARB, % ACE inhibitors or ARB, % 82 82 81 81 Beta-blockers, % Beta-blockers, % 83 83 83 83 Dihydropyridine CCB, % Dihydropyridine CCB, % 27 27 27 27 Diltiazem or verapamil, % Diltiazem or verapamil, % 5 5 4 4 Organic nitrates, % Organic nitrates, % 41 41 39 39
SLIDE 9 Mean heart rate reduction Mean heart rate reduction
Time (months) Heart rate (bpm)
Placebo Ivabradine
Mean reduction = 9.7 bpm 95% CI [-10.0 ; -9.5]
SLIDE 10 Ivabradine n=654 (3.03% PY) Placebo n=611 (2.82% PY) HR = 1.08 [ [95% CI 0.96-1.20 0.96-1.20] P=0.20
Primary composite Primary composite end point end point
9550 9297 9077 8611 9552 9311 9130 8656
Time from randomization (months)
Ivabradine 5570 5649 3776 3749 1832 1836 349 365
Numbers at risk
Placebo
Placebo Ivabradine
SLIDE 11 Cardiovascular death Cardiovascular death
9550 9382 9240 8828 9552 9405 9284 8851 5755 5822 3926 3882 1914 1910 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 0.94-1.28 0.94-1.28] P=0.25
Placebo Ivabradine
SLIDE 12 Nonfatal myocardial infarction Nonfatal 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 0.90-1.21 0.90-1.21] P=0.60
Numbers at risk Ivabradine Placebo
Placebo Ivabradine
SLIDE 13 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 bradycardia Symptomatic bradycardia 7.9 (757) 7.9 (757) 1.2 (110) 1.2 (110) Asymptomatic bradycardia Asymptomatic bradycardia 11.0 (1047) 11.0 (1047) 1.3 (126) 1.3 (126) Atrial fibrillation Atrial fibrillation 5.3 (508) 5.3 (508) 3.8 (362) 3.8 (362) Phosphenes Phosphenes 5.4 (512) 5.4 (512) 0.5 (52) 0.5 (52)
SLIDE 14 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 tachycardia Ventricular tachycardia 0.6 (54) 0.6 (54) 0.4 (41) 0.4 (41) Ventricular fibrillation Ventricular fibrillation 0.3 (27) 0.3 (27) 0.3 (26) 0.3 (26) Torsades de pointes Torsades de pointes 0 (1) 0 (1) 0 (3) 0 (3)
SLIDE 15 Primary composite end point Primary 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 1.03-1.35 1.03-1.35] P=0.018
6037 5869 5712 5428 6012 5859 5747 5463 3483 3502 2387 2350 1197 1178 227 232
Time from randomization (months) Placebo Ivabradine
Ivabradine Placebo Numbers at risk
SLIDE 16 Components of Components of primary composite end primary composite end point point (angina population: CCS class
(angina population: CCS class ≥ ≥II, n=12 049) II, n=12 049)
6037 5930 5823 5574 6012 5919 5844 5583 3604 3605 2483 2434 1249 1224 238 247
Time from randomization (months)
Ivabradine Placebo Numbers at risk 6037 5869 5713 5428 6012 5859 5747 5463 3483 3502 2387 2350 1197 1178 227 232
Time from randomization (months)
Placebo Ivabradine
Ivabradine n=235 (1.72% PY) Placebo n=200 (1.47% PY)
HR = 1.18 [
[95% CI 0.97-1.42
0.97-1.42] P=0.09
Ivabradine n=245 (1.76% PY) Placebo n=210 (1.51% PY)
HR = 1.16 [
[95% CI 0.97-1.40
0.97-1.40] P=0.11
Cardiovascular death Nonfatal myocardial infarction
SLIDE 17 Effect of ivabradine on symptoms Effect 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 (p=0.058)
SLIDE 18
Conclusion Conclusion § 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
SLIDE 19
Acknowledgements Acknowledgements
¢ ¢
19 102
19 102 patients from
patients from 51
51 countries
countries
¢ ¢
1139
1139 centers
centers
¢ ¢
More than More than 5400
5400 investigators
investigators
¢ ¢
Study supported by Study supported by
SLIDE 20 Available now online from Available now online from NEJM NEJM
Fox K et al. N Engl J Med. Published online 31 August 2014.
