S tudy assess I n G the morbidity-mortality S tudy assess I n G the morbidity-mortality N efits of the I be N efits of the I inhibitor ivabradine be f inhibitor ivabradine f Y artery d in patients with coronar Y artery disease isease in patients with coronar without heart failure without heart failure Conflict of interest Kim Fox receives honoraria, fees, travel expenses from Servier
Study organisation Study organisation Executive Committee Executive Committee K Fox (Chair, UK), R Ferrari (Co-chair, Italy), I Ford (UK), UK), K Fox (Chair, UK), R Ferrari (Co-chair, Italy), I Ford ( PG Steg (France), J-C Tardif (Canada), M Tendera (Poland) PG Steg (France), J-C Tardif (Canada), M Tendera (Poland) Endpoint Validation Committee Data Monitoring Committee Endpoint Validation Committee Data Monitoring Committee K Thygesen (Chair, Denmark), K Thygesen (Chair, Denmark), J Camm (Chair, UK), J Camm (Chair, UK), M Frenneaux (UK), M Frenneaux (UK), G Murray (UK), G Murray (UK), G Jondeau G Jondeau (France), (France), H Dargie (UK), H Dargie (UK), A Mosterd (The Netherlands) A Mosterd (The Netherlands) J Kjekshus (Norway), J Kjekshus (Norway), AP Maggioni (Italy) AP Maggioni (Italy)
Study organisation Study organisation Steering committee Steering committee Argentina: R Iglesias Argentina: Greece: P Vardas Greece: Romania: C Macarie Romania: Armenia: PA Zelveian Armenia: Hong-Kong: CP Lau Hong-Kong: Russia: VY Mareev Russia: Australia: B Freedman Australia: Hungary: J Borbola Hungary: and YA Karpov Austria: K Huber Austria: India: R Kasliwal India: Serbia: MC Ostojic Serbia: Belgium: JL Vanoverschelde Belgium: Ireland: P Crean Ireland: Singapore: TH Koh Singapore: Brazil: LA Machado Cesar Brazil: Italy: L Tavazzi Italy: Slovakia: J Murin Slovakia: Bulgaria: N Gotcheva Bulgaria: Kazakhstan: TZ Seisembekov Kazakhstan: Slovenia: P Rakovec Slovenia: Canada: P L’Allier Canada: Korea: KB Seung Korea: South Africa: P Sareli South Africa: China: DY Hu China: Latvia: A Erglis Latvia: Spain: C Macaya de Miguel Spain: Croatia: M Bergovec Croatia: Lithuania: A Laucevicius Lithuania: Sweden: M Dellborg Sweden: Czech Republic: J Hradec Czech Republic: Malaysia: R Ali Malaysia: Switzerland: T Lüscher Switzerland: Denmark: P Clemmensen, Denmark: Mexico: E Alexanderson Mexico: Taiwan: CE Chiang Taiwan: and P Hildebrandt The Netherlands: WH van Gilst The Netherlands: Thailand: P Sritara Thailand: Estonia: J Eha Estonia: and JW Jukema Turkey: O Ergene Turkey: Finland: M Laine Finland: Norway: D Atar Norway: D Atar United Kingdom: A Hall United Kingdom: France: N Danchin France: Philippines: R Sy R Sy Philippines: Ukraine: A Parkhomenko Ukraine: FYROM: S Kedev FYROM: Poland: A Rynkiewicz A Rynkiewicz Poland: Uruguay: F Kuster Germany: T Münzel Germany: Portugal: R Seabra Gomes R Seabra Gomes Portugal: Vietnam: NV Pham Vietnam: Georgia: V Chumburidze Georgia:
Effect of ivabradine on hospitalization for fatal/nonfatal MI in patients with stable CAD and LVSD HR (95% CI), 0.64 (0.49–0.84) HR (95% CI), 1.46 (1.11–1.91) P =0.001 P =0.0066 Event rate (%) Event rate (%) 8 8 Placebo Heart rate ≥70 bpm 6 6 4 4 2 2 Ivabradine Heart rate <70 bpm 0 0 0 0.5 1 1.5 2 0 0.5 1 1.5 2 Years Years Patients with heart rate ≥70 bpm (n= 5392) Patients with heart rate ≥70 bpm (n= 5392) Overall placebo population (n=5438) Overall placebo population (n=5438) Fox K et al. Lancet. 2008;372:817-821. Fox K et al. Lancet. 2008;372:807-816.
Study design Study design Study outcomes Population • 55 years, stable CAD • Events: 2.8% PY placebo, N=19 102 • Median follow-up: 27.8 months • With at least one other CV risk factor (including • 51 countries - 1139 centres angina CCS class II) • Without clinical heart failure (LVEF >40%) • HR 70 bpm Ivabradine Ivabradine 5, 7.5, or 10 mg bid according to heart 7.5 mg bid rate (target 55-60 bpm) and tolerability Run-in 14 to 30 days Matching placebo, bid M6 Every 6 D0 M1 M2 M3 months 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) 235 had incomplete follow-up 200 had incomplete follow-up 199 withdrew consent ü 231 withdrew consent ü ü 3 lost to follow-up ü 1 lost to follow-up ü 1 medical reason 9550 analyzed 9552 analyzed ü 6037 with angina ü 6012 with angina ü 3513 with no angina ü 3540 with no angina
Baseline characteristics Ivabradine Placebo Ivabradine Placebo n=9550 n=9550 n=9552 n=9552 65 65 65 65 Age, years Age, years 73 72 73 72 Male, % Male, % 77 77 77 77 Resting heart rate, bpm Resting heart rate, bpm 56 56 56 56 LV ejection fraction, % LV ejection fraction, % Previous MI, % 73 73 Previous MI, % 73 73 Previous coronary revasc, % 68 68 Previous coronary revasc, % 68 68 Dyslipidemia, % 72 72 Dyslipidemia, % 72 72 Diabetes mellitus, % 43 43 Diabetes mellitus, % 43 43 Peripheral artery disease, % 21 21 Peripheral artery disease, % 21 21 Current smoker, % 24 24 Current smoker, % 24 24 Hypertension, % 87 86 Hypertension, % 87 86
Baseline cardiovascular medications Ivabradine Placebo Ivabradine Placebo n=9550 n=9550 n=9552 n=9552 Antiplatelet or anticoagulants, % 98 98 Antiplatelet or anticoagulants, % 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
Mean heart rate reduction Mean heart rate reduction Mean reduction = 9.7 bpm 95% CI [-10.0 ; -9.5] Placebo Heart rate (bpm) Ivabradine Time (months)
Primary composite end point end point Primary composite 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 Ivabradine Placebo Time from randomization (months) Numbers at risk Ivabradine 9550 9297 9077 8611 5570 3776 1832 349 365 1836 5649 3749 9130 8656 Placebo 9552 9311
Cardiovascular death Cardiovascular death 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 Ivabradine Placebo Time from randomization (months) Numbers at risk 366 9550 1914 Ivabradine 9382 8828 3926 9240 5755 1910 386 Placebo 9552 9405 9284 8851 3882 5822
Nonfatal myocardial infarction Nonfatal myocardial infarction 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 Ivabradine Placebo Time from randomization (months) Numbers at risk 8611 5570 3776 Ivabradine 1832 349 9297 9078 9550 Placebo 1836 9552 9311 9130 8656 5649 3749 365
Incidence of selected adverse events Incidence of selected adverse events (n=19 083) (n=19 083) Ivabradine (n=9539) Ivabradine (n=9539) Placebo (n=9544) Placebo (n=9544) % (n) % (n) % (n) % (n) Symptomatic bradycardia 7.9 (757) 1.2 (110) Symptomatic bradycardia 7.9 (757) 1.2 (110) Asymptomatic bradycardia 11.0 (1047) 1.3 (126) Asymptomatic bradycardia 11.0 (1047) 1.3 (126) Atrial fibrillation 5.3 (508) 3.8 (362) Atrial fibrillation 5.3 (508) 3.8 (362) Phosphenes 5.4 (512) 0.5 (52) Phosphenes 5.4 (512) 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) Placebo (n=9544) Placebo (n=9544) % (n) % (n) % (n) % (n) Ventricular tachycardia 0.6 (54) 0.4 (41) Ventricular tachycardia 0.6 (54) 0.4 (41) Ventricular fibrillation 0.3 (27) 0.3 (26) Ventricular fibrillation 0.3 (27) 0.3 (26) Torsades de pointes 0 (1) 0 (3) Torsades de pointes 0 (1) 0 (3)
Primary composite end point Primary composite end point ≥ II, n=12 049) (angina population: CCS class ≥ II, n=12 049) (angina population: CCS class 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 Ivabradine Placebo Time from randomization (months) Numbers at risk Ivabradine 6037 5869 5712 5428 3483 2387 1197 227 6012 Placebo 5859 5747 5463 3502 2350 1178 232
Components of primary composite end primary composite end Components of point (angina population: CCS class point (angina population: CCS class ≥ ≥II, n=12 049) II, n=12 049) Cardiovascular death Nonfatal myocardial infarction Ivabradine n=235 (1.72% PY) Ivabradine n=245 (1.76% PY) Placebo n=200 (1.47% PY) Placebo n=210 (1.51% PY) HR = 1.18 [ 0.97-1.42 ] P =0.09 HR = 1.16 [ 0.97-1.40 ] P =0.11 [95% CI 0.97-1.40 [95% CI 0.97-1.42 Time from randomization (months) Time from randomization (months) Numbers at risk Ivabradine 6037 5869 5713 5428 3483 2387 1197 227 6037 5930 5823 5574 3604 2483 1249 238 6012 6012 5859 5747 5463 Placebo 5919 5844 5583 3605 2434 1224 247 3502 2350 1178 232 Ivabradine Placebo
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 (%) P <0.01 Elective revascularization 24.8 Ivabradine 2.8% Placebo 3.5% HR 0.82 (p=0.058) 19.4 0.31 0.55
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