S tudy assess I n G the morbidity-mortality be N efits of the I f inhibitor ivabradine in patients with coronar Y artery disease without heart failure Conflict of interest Kim Fox receives honoraria, fees, travel expenses from Servier

Study organisation Executive Committee K Fox (Chair, UK), R Ferrari (Co-chair, Italy), I Ford (UK), PG Steg (France), J-C Tardif (Canada), M Tendera (Poland) Endpoint Validation Committee K Thygesen (Chair, Denmark), M Frenneaux (UK), G Jondeau (France), A Mosterd (The Netherlands) Data Monitoring Committee J Camm (Chair, UK), G Murray (UK), H Dargie (UK), J Kjekshus (Norway), AP Maggioni (Italy)

Study organisation 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: 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 Jukema Norway: D Atar Philippines: R Sy Poland: A Rynkiewicz Portugal: 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

Patients with heart rate ≥70 bpm (n= 5392) Placebo Ivabradine HR (95% CI), 0.64 (0.49–0.84) P=0.001 Years Effect of ivabradine on hospitalization for fatal/nonfatal MI in patients with stable CAD and LVSD Overall placebo population (n=5438) Fox K et al. Lancet. 2008;372: HR (95% CI), 1.46 (1.11–1.91) P= Years Heart rate <70 bpm Heart rate ≥70 bpm Fox K et al. Lancet. 2008;372: Event rate (%)

Study outcomes Events: 2.8% PY placebo, N= Median follow-up: 27.8 months 51 countries 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 Primary composite end point: cardiovascular death or nonfatal myocardial infarction Primary analysis: ivabradine versus placebo on primary end point Prespecified analysis: in patients with angina CCS class ≥II on primary end point Ivabradine 7.5 mg bid Matching placebo, bid Run-in 14 to 30 days M1M2 Every 6 months D0M3 Ivabradine 5, 7.5, or 10 mg bid according to heart rate (target bpm) and tolerability M6 Study design Fox K et al. Am Heart J. 2013;166:

Patients and follow-up patients randomized Ivabradine (n=9550) Placebo (n=9552) 9552 analyzed 9550 analyzed 235 had incomplete follow-up 231 withdrew consent 3 lost to follow-up 1 medical reason 200 had incomplete follow-up 199 withdrew consent 1 lost to follow-up 6037 with angina 3513 with no angina 6012 with angina 3540 with no angina

Baseline characteristics Ivabradine n=9550 Placebo n=9552 Age, years 6565 Male, % 7372 Resting heart rate, bpm 7777 LV ejection fraction, % 5656 Previous MI, % 7373 Previous coronary revasc, % 6868 Dyslipidemia, % 7272 Diabetes mellitus, % 4343 Peripheral artery disease, % 2121 Current smoker, % 2424 Hypertension, % 8786

Baseline cardiovascular medications Ivabradine n=9550 Placebo n=9552 Antiplatelet or anticoagulants, % 9898 Statins, % 9292 ACE inhibitors or ARB, % 8281 Beta-blockers, % 8383 Dihydropyridine CCB, % 2727 Diltiazem or verapamil, % 54 Organic nitrates, % 4139

Mean heart rate reduction Time (months) Heart rate (bpm) Placebo Ivabradine 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 ] P=0.20 Primary composite end point Time from randomization (months) Ivabradine Numbers at risk Patients with event (%) Placebo Ivabradine

Cardiovascular death Time from randomization (months) Patients with event (%) Ivabradine Placebo Numbers at risk Ivabradine n=329 (1.49% PY) Placebo n=301 (1.36% PY) [ HR = 1.10 [95% CI ] P=0.25 Placebo Ivabradine

Nonfatal myocardial infarction Patients with event (%) Time from randomization (months) Ivabradine n=351 (1.63% PY) Placebo n=339 (1.56% PY) [ HR = 1.04 [95% CI ] P=0.60 Numbers at risk Ivabradine Placebo Ivabradine

Incidence of selected adverse events (n=19 083) Ivabradine (n=9539) % (n) Placebo (n=9544) % (n) Symptomatic bradycardia Symptomatic bradycardia 7.9 (757) 1.2 (110) Asymptomatic bradycardia Asymptomatic bradycardia 11.0 (1047) 1.3 (126) Atrial fibrillation 5.3 (508) 3.8 (362) Phosphenes Phosphenes 5.4 (512) 0.5 (52)

Incidence of selected adverse events (n=19 083) Ivabradine (n=9539) % (n) Placebo (n=9544) % (n) Ventricular tachycardia Ventricular tachycardia 0.6 (54) 0.4 (41) Ventricular fibrillation Ventricular fibrillation 0.3 (27) 0.3 (26) Torsades de pointes Torsades de pointes 0 (1) 0 (3)

Primary composite end point (angina population: CCS class ≥ II, n=12 049) Ivabradine n=459 (3.37% PY) Placebo n=390 (2.86% PY) [ HR = 1.18 [95% CI ] P= Time from randomization (months) Placebo Ivabradine Patients with event (%) Ivabradine Placebo Numbers at risk

Components of primary composite end point (angina population: CCS class ≥II, n=12 049) Time from randomization (months) Patients with event (%) Ivabradine Placebo Numbers at risk Time from randomization (months) Patients with event (%) Placebo Ivabradine Ivabradine n=235 (1.72% PY) Placebo n=200 (1.47% PY) [ HR = 1.18 [95% CI ] P=0.09 Ivabradine n=245 (1.76% PY) Placebo n=210 (1.51% PY) [ HR = 1.16 [95% CI ] P=0.11 Cardiovascular death Nonfatal myocardial infarction

Effect of ivabradine on symptoms (angina population: CCS class≥ II, n=12 049) Patients (%) P<0.01 Elective revascularization Ivabradine 2.8% Placebo 3.5% HR 0.82

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

Acknowledgements patients from 51 countries patients from 51 countries 1139 centers 1139 centers More than 5400 investigators More than 5400 investigators Study supported by Study supported by

Fox K et al. N Engl J Med. Published online 31 August Now available online from NEJM