Introduction ESC CLINICAL TRIAL UPDATE

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1 European Heart Journal (2009) 30, doi: /eurheartj/ehp358 ESC CLINICAL TRIAL UPDATE Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial Kim Fox 1 *, Ian Ford 2, Ph. Gabriel Steg 3, Michal Tendera 4, Michele Robertson 2, and Roberto Ferrari 5 on behalf of the BEAUTIFUL Investigators 1 Royal Brompton Hospital, Sydney Street, London, UK; 2 Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK; 3 INSERM U-698, Hôpital Bichat-Claude Bernard, AP-HP, University Paris 7, Paris, France; 4 Medical University of Silesia, Katowice, Poland; and 5 Chair of Cardiology, University of Ferrara, S. Maugeri Foundation, Ferrara, Italy Received 18 June 2009; revised 11 August 2009; accepted 12 August 2009; online publish-ahead-of-print 31 August 2009 See page 2300 for the commentary on this article (doi: /eurheartj/ehp360) Aims BEAUTIFUL found no impact of ivabradine on outcomes in patients with stable coronary artery disease (CAD) and left ventricular systolic dysfunction (LVSD). We performed a post hoc analysis of the effect of ivabradine in BEAUTI- FUL patients whose limiting symptom at baseline was angina, particularly in terms of coronary outcomes.... Methods Of the BEAUTIFUL population, 13.8% had limiting angina at baseline (734 ivabradine, 773 placebo); of these, 712 and results patients had heart rate 70 b.p.m. Median duration of follow-up was 18 months. Ivabradine was associated with a 24% reduction in the primary endpoint (cardiovascular mortality or hospitalization for fatal and non-fatal myocardial infarction [MI] or heart failure) (HR, 0.76; 95% CI, ) and a 42% reduction in hospitalization for MI (HR, 0.58, 95% CI, ). In patients with heart rate 70 b.p.m., there was a 73% reduction in hospitalization for MI (HR, 0.27, 95% CI, ) and a 59% reduction in coronary revascularization (HR, 0.41, 95% CI, ). Ivabradine was safe and well tolerated.... Conclusion Our analyses raises the possibility that ivabradine may be helpful to reduce major cardiovascular events in patients with stable CAD and LVSD who present with limiting angina. However, a large-scale clinical trial is ongoing, which will formally test this hypothesis Keywords Coronary artery disease Heart rate I f inhibition Ivabradine Prognosis Stable angina pectoris Introduction The BEAUTIFUL (morbidity-mortality EvAlUaTion of the I f inhibitor ivabradine in patients with coronary disease and left ventricu- Lar dysfunction) study established resting heart rate 70 b.p.m. as a risk factor for cardiovascular outcomes in patients with stable coronary artery disease (CAD) and left ventricular systolic dysfunction (LVSD). 1 Elevated heart rate (70 b.p.m.) was associated with increased risk of cardiovascular death (34%), hospitalization for fatal and non-fatal myocardial infarction (MI) (46%), and coronary revascularization (38%). These observations confirmed previous retrospective data on the prognostic role of elevated heart rate in CAD patients. 2 4 Although there was no measurable impact of treatment with the I f inhibitor ivabradine on primary * Corresponding author. Tel: þ , Fax: þ , k.fox@rbht.nhs.uk Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oxfordjournals.org.

2 2338 K. Fox et al. endpoint, cardiovascular death, or heart failure (HF) outcomes in the whole population, the BEAUTIFUL trial suggested that reduction of heart rate in patients with an elevated heart rate (70 b.p.m.) with ivabradine has an impact on coronary outcomes 5 with 36 and 30% reductions in relative risk of hospitalization for fatal and non-fatal MI and coronary revascularization, respectively. These observations were attributed to possible differential effects of increased heart rate on cardiovascular outcomes, probably reflecting more complex compensatory haemodynamic responses in patients with HF, in contrast to a direct effect on coronary outcomes (i.e. ischaemia or MI). 1 Heart rate is one of the principal determinants of myocardial oxygen consumption, and elevated heart rate is a state where energy requirements and myocardial oxygen demand are increased. Elevated heart rate shortens the length of each cardiac cycle, thereby reducing diastolic perfusion time and oxygen supply. Heart rate also appears to have an impact on the development of atherosclerosis via an increase in the exposure of endothelium to low shear stress at higher values. 6 Acceleration of heart rate may increase the risk of acute coronary syndromes by excessive mechanical stress to atherosclerotic plaque. 7 Therefore, elevated heart rate potentially plays an important role in the development and progression of coronary atherosclerosis, triggering ischaemic events through an increase in myocardial oxygen demand and a reduction in diastolic perfusion. The anti-ischaemic efficacy of heart rate reduction with ivabradine has been demonstrated clinically in patients with stable angina pectoris, 8,9 and supported in patients with stable CAD and LV dysfunction in BEAUTIFUL in terms of a reduction in rates of coronary revascularization. 5 The most important clinical manifestation of myocardial ischaemia is anginal pain or discomfort. The presence of limiting angina can have a profound impact on the quality of life of patients with stable CAD, and may affect prognosis The increased risk of mortality in patients with limiting angina appears to be comparable to a decade of age difference, the presence of diabetes, or the presence of HF. 14 Limiting angina symptoms have been found to be independently predictive of adverse outcomes, 15 with a substantial increase in risk for every change in step on the Canadian Cardiovascular Society (CCS) classification. Ivabradine is currently indicated in the management of stable angina pectoris due to its heart rate lowering action. In view of its benefits in terms of coronary outcomes, we sought to explore the effects of ivabradine on cardiovascular outcomes in a subpopulation of BEAUTIFUL whose limiting symptom at baseline was angina. Methods Study design BEAUTIFUL was a randomized, double-blind, placebo-controlled, parallel-group trial recruiting male and female patients with stable CAD and LVSD. The study design has been described previously. 5,16 Briefly, patients eligible for inclusion were male or female, aged 55 years or over (18 years or over if diabetic), with stable CAD (documented by previous MI, previous coronary revascularization, or angiographic evidence of the narrowing of one or more coronary arteries), LV ejection fraction,40%, and end-diastolic short-axis internal dimension.56 mm by echocardiography. Patients had to be in sinus rhythm with resting heart rate 60 b.p.m. Angina and/or HF symptoms (if any) should have been stable for 3 months and patients should have received appropriate conventional cardiovascular medication at stable doses for at least 1 month. Patients with a history of MI or coronary revascularization in the previous 6 months were excluded from the study. Following a 2-week run-in period with no study treatment, patients were randomly allocated to receive either ivabradine 5 mg b.i.d. or matched placebo. After 2 weeks, patients with resting heart rate 60 b.p.m. had their treatment uptitrated to ivabradine 7.5 mg b.i.d. or matched placebo. The dosage could subsequently be reduced in patients with resting heart rate,50 b.p.m. or signs or symptoms of bradycardia. Study visits were programmed at 2 weeks, 1, 3, and 6 months, and then every 6 months. All BEAUTIFUL participants received optimal background therapy for stable CAD, including b-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, lipid-lowering agents, and antiplatelet agents. In this post hoc analysis, the BEAUTIFUL population was divided according to the presence of limiting angina symptoms at baseline using the New York Heart Association (NYHA) functional classification. Patients were questioned at the inclusion visit regarding the presence of symptoms limiting activity, and whether they were related to anginal pain or due to the presence of HF (fatigue, palpitations, or dyspnoea). Patients with limiting symptoms of angina were in NYHA classes II or III, which include slight and marked limitation of physical activity due to angina pectoris, respectively (equivalent to CCS classes II and III). NYHA class IV was an exclusion criterion. 5,16 This population was also subdivided according to heart rate at baseline with an analysis in a pre-specified subgroup with heart rate 70 b.p.m., in line with the analysis of the main study. 5 The primary endpoint in this analysis was the same as in the main study: a composite of cardiovascular death, hospitalization for fatal and non-fatal MI, and hospitalization for new-onset or worsening HF. Secondary endpoints included mortality (all-cause death; cardiovascular death; and cardiac death), HF (hospitalization for new-onset or worsening HF; and a composite of cardiovascular death and hospitalization for new-onset or worsening HF), and coronary outcomes (hospitalization for fatal and non-fatal MI; a composite of hospitalization for fatal and non-fatal MI and unstable angina pectoris; and coronary revascularization). 5 These outcomes were evaluated in the subpopulation with limiting angina, as well as in the subpopulation with limiting angina and heart rate 70 b.p.m. All pre-specified outcomes were adjudicated by an independent central endpoint validation committee. This analysis was performed to determine the effects of ivabradine, a recognized anti-anginal agent, on the outcome of patients with CAD and LV dysfunction whose limiting symptom at randomization was angina. Statistical methods Descriptive statistics are presented for the baseline characteristics for continuous variables (means [SD]) or categorical variables (n [%]). All analyses were carried out for the whole population with limiting angina and for the pre-specified subgroup with heart rate 70 b.p.m. For analyses where subjects did not have the event, they were censored at the time of the last follow-up (i.e. the end of study for subjects still alive or date of death for subjects who died) in the same way as for the main study analysis. The Kaplan Meier method was used to calculate time-to-event curves. The risk of cardiovascular outcomes was compared between randomized treatment groups using Cox proportional hazards models, adjusted for b-blocker treatment status at randomization. Hazard ratios (HR) for outcomes for ivabradine vs. placebo were

3 Relationship between ivabradine treatment and cardiovascular outcomes 2339 calculated with associated 95% CIs and P-values. It is appreciated that statistical significance has less meaning in subgroup analyses such as this and is presented in the results for indicative purposes only. None of the analyses was confirmatory, and there was no adjustment for multiple testing. All analyses were carried out by the independent trial statistical centre in the Robertson Centre for Biostatistics, University of Glasgow, UK, using SASw software for Windows version 9.1. Results Limiting angina symptoms were identified in 13.8% of the BEAUTI- FUL population at baseline (1507 out of patients). Of these, 734 were randomized to ivabradine treatment and 773 to placebo. A total of 712 patients had resting heart rate 70 b.p.m. at baseline: 47.2% of the population; of these, 349 were randomized to ivabradine treatment and 363 to placebo. The baseline characteristics of the subpopulations with and without limiting angina are presented in Tables 1 and 2, together with those for the subpopulations with resting heart rate 70 b.p.m. There were no relevant differences in baseline characteristics between the ivabradine and placebo groups for either of the subpopulations. There were no unexpected differences between patients with limiting angina and the total BEAUTIFUL population: 5 patients with limiting angina had higher rates of hypertension (80 vs. 71%), were less likely to have previously undergone coronary revascularization (35 vs. 52%), and had a considerably higher rate of intake of organic nitrates (73 vs. 43%). The rates of use of cardiovascular medication in the subpopulation with limiting angina were high (Table 1), notably for antithrombotic treatment (92%) and ACE inhibitor or angiotensin II receptor blockade (87%). The use of b-blockers was also high (90%), though not all patients achieved target dose. The Table 1 Baseline characteristics of the population with and without limiting angina symptoms at baseline Patients with limiting angina (n )... Patients without limiting angina (n )... Ivabradine (n 5 734) Placebo (n 5 773) Ivabradine (n ) Placebo (n ) Demographics Age (years) 64.8 (8.1) 64.1 (8.4) 65.4 (8.5) 65.1 (8.4) Sex (male) 594 (81%) 639 (83%) 3946 (83%) 3868 (83%) Smoking (current) 111 (15%) 123 (16%) 702 (15%) 711 (15%) BMI (kg/m 2 ) 28.4 (4.4) 28.4 (4.0) 28.5 (4.4) 28.5 (4.5) Medical history History of hypertension 581 (79%) 622 (80%) 3301 (70%) 3216 (69%) History of diabetes 234 (32%) 266 (34%) 1783 (38%) 1753 (38%) History of dyslipidaemia 566 (77%) 577 (75%) 3733 (79%) 3701 (79%) Previous MI 659 (90%) 716 (93%) 4169 (88%) 4101 (88%) Previous PCI/CABG 275 (37%) 258 (33%) 2544 (54%) 2566 (55%) Previous stroke 138 (19%) 138 (18%) 882 (19%) 834 (18%) Peripheral artery disease 78 (11%) 93 (12%) 614 (13%) 655 (14%) Cardiac parameters Heart rate (b.p.m.) 71.0 (9.4) 71.1 (9.3) 71.6 (9.9) 71.7 (10.0) SBP (mm Hg) (14.7) (14.7) (15.9) (15.6) DBP (mm Hg) 79.2 (9.1) 79.0 (8.8) 77.2 (9.4) 77.2 (9.3) LVEF (%) 33.1 (5.2) 33.6 (4.9) 32.3 (5.5) 32.1 (5.6) NYHA Class II 549 (75%) 574 (74%) 2797 (59%) 2785 (60%) NYHA Class III 185 (25%) 199 (26%) 1108 (23%) 1040 (22%) Medication at randomization Aspirin or antithrombotic agent 673 (92%) 713 (92%) 4493 (95%) 4390 (94%) Statin 491 (67%) 498 (64%) 3573 (75%) 3534 (76%) ACE inhibitor and/or ARB 643 (88%) 668 (86%) 4274 (90%) 4205 (90%) b-blocker 654 (89%) 697 (90%) 4095 (86%) 4041 (87%) Organic nitrates 529 (72%) 579 (75%) 1869 (39%) 1757 (38%) Diuretics (excluding antialdosterone) 367 (50%) 371 (48%) 2865 (60%) 2823 (61%) Antialdosterone agents 137 (19%) 140 (18%) 1350 (28%) 1326 (28%) Data are number (%) or mean (SD). BMI, body mass index; MI, myocardial infarction; PCI, primary coronary intervention; CABG, coronary artery bypass graft; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker.

4 2340 K. Fox et al. Table 2 Baseline characteristics of the population with and without limiting angina symptoms at baseline and heart rate 70 b.p.m. Patients with limiting angina and heart rate 70 b.p.m. (n 5 712)... Patients without limiting angina and heart rate 70 b.p.m. (n )... Ivabradine (n 5 349) Placebo (n 5 363) Ivabradine (n ) Placebo (n ) Demographics Age (years) 64.4 (7.8) 63.1 (8.4) 64.9 (8.7) 64.6 (8.6) Sex (male) 278 (80%) 298 (82%) 1928 (82%) 1911 (82%) Smoking (current) 69 (20%) 66 (18%) 363 (15%) 415 (18%) BMI (kg/m 2 ) 28.9 (4.2) 28.7 (4.3) 28.8 (4.6) 28.7 (4.7) Medical history History of hypertension 278 (80%) 297 (82%) 1669 (71%) 1630 (70%) History of diabetes 122 (35%) 138 (38%) 1010 (43%) 1017 (44%) History of dyslipidaemia 266 (76%) 261 (72%) 1853 (79%) 1862 (80%) Previous MI 312 (89%) 330 (91%) 2043 (87%) 2019 (87%) Previous PCI/CABG 122 (35%) 117 (32%) 1211 (52%) 1243 (53%) Previous stroke 60 (17%) 66 (18%) 441 (19%) 437 (19%) Peripheral artery disease 40 (11%) 43 (12%) 333 (14%) 359 (15%) Cardiac parameters Heart rate (b.p.m.) 78.6 (8.2) 78.8 (8.1) 79.2 (8.6) 79.3 (8.8) SBP (mm Hg) (14.5) (15.1) (16.0) (15.7) DBP (mm Hg) 79.9 (9.0) 80.1 (8.8) 78.1 (9.4) 78.0 (9.2) LVEF (%) 33.0 (5.1) 33.4 (4.9) 31.8 (5.7) 31.7 (5.8) NYHA Class II 251 (72%) 265 (73%) 1324 (56%) 1350 (58%) NYHA Class III 98 (28%) 98 (27%) 637 (27%) 607 (26%) Medication at randomization Aspirin or antithrombotic agent 319 (91%) 329 (91%) 2217 (94%) 2178 (93%) Statin 219 (63%) 226 (62%) 1722 (73%) 1719 (74%) ACE inhibitor and/or ARB 302 (87%) 320 (88%) 2109 (90%) 2101 (90%) b-blocker 306 (88%) 328 (90%) 1927 (82%) 1945 (83%) Organic nitrates 245 (70%) 265 (73%) 916 (39%) 937 (40%) Diuretics (excluding antialdosterone) 188 (54%) 187 (52%) 1503 (64%) 1517 (65%) Antialdosterone agents 67 (19%) 67 (18%) 725 (31%) 733 (31%) Data are number (%) or mean (SD). BMI, body mass index; MI, myocardial infarction; PCI, primary coronary intervention; CABG, coronary artery bypass graft; SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker. percentage of patients receiving at least half the target dose of the five most common b-blockers were as follows: 48% (121/254) of patients on carvedilol (target dose, 50 mg/day); 33% (58/175) of patients on metoprolol succinate (target dose, 200 mg/day); 66% (200/301) of patients on bisoprolol (target dose, 10 mg/day); 79% (26/33) of patients on nebivolol (target dose, 10 mg/day); and 36% (157/438) of patients on metoprolol tartrate (target dose, 150 mg/day). The reasons given for intake of a lower than recommended dosage of b-blocker were bradycardia (17% ivabradine and 13% placebo); fatigue (20 and 21%); hypotension (23 and 20%); cardiac decompensation (7 and 6%); dizziness and vertigo (6 and 6%); and sexual dysfunction (7 and 4%). The median duration of follow-up was 18 months. The rate of uptitration to ivabradine 7.5 mg b.i.d. after 15 days was 44% in the subpopulation with limiting angina, and 37% remained at higher dosage for the duration of the study. The mean dosage of ivabradine in the subpopulation with limiting angina was 6.11 mg b.i.d. and 6.46 mg b.i.d. when resting heart rate 70 b.p.m. The rates of compliance in the subpopulation with limiting angina were similar to the main BEAUTIFUL population with 97 and 98% of the ivabradine and placebo groups, respectively, having taken at least 70% of the planned dose of study drug. Figure 1 presents the mean change in resting heart rate throughout the study for the patients with limiting angina. Treatment with ivabradine in this subpopulation reduced resting heart rate by 10.6 b.p.m. (standard deviation [SD] 9.8) at 30 days vs. 3.2 b.p.m. (SD 9.0) with placebo. Heart rate remained stable thereafter, and the mean reduction from baseline was 8.1 b.p.m. (SD 11.6) at 18 months with ivabradine and 2.5 b.p.m. (SD 10.8) with placebo. For the subpopulation with limiting angina and resting heart rate

5 Relationship between ivabradine treatment and cardiovascular outcomes 2341 Figure 1 Resting heart rate during the study in patients with limiting angina at baseline (A) and in patients with limiting angina and resting heart rate 70 b.p.m. at baseline (B). Table 3 baseline Effect of ivabradine on cardiovascular outcomes in patients with and without limiting angina symptoms at Patients with limiting angina (n ) Patients without limiting angina (n ) Ivabradine Placebo HR (95% CI) P Ivabradine Placebo HR (95% CI) P (n 5 734) (n 5 773) (n ) (n ) Primary endpoint CV death or 88 (12.0%) 120 (15.5%) 0.76 ( ) (15.9%) 712 (15.3%) 1.04 ( ) 0.41 hospitalization for MI or HF Mortality endpoints All-cause death 64 (8.7%) 77 (10.0%) 0.87 ( ) (10.7%) 470 (10.1%) 1.06 ( ) 0.33 CV death 54 (7.4%) 64 (8.3%) 0.88 ( ) (8.7%) 371 (8.0%) 1.10 ( ) 0.18 Cardiac death 11 (1.5%) 16 (2.1%) 0.72 ( ) (2.6%) 135 (2.9%) 0.91 ( ) 0.45 HF endpoints Hospitalization for HF 33 (4.5%) 41 (5.3%) 0.84 ( ) (8.3%) 386 (8.3%) 1.00 ( ) 0.99 CV death or 73 (9.9%) 95 (12.3%) 0.80 ( ) (14.4%) 628 (13.5%) 1.07 ( ) 0.21 hospitalization for HF Coronary endpoints Hospitalization for MI 28 (3.8%) 50 (6.5%) 0.58 ( ) (3.6%) 176 (3.8%) 0.96 ( ) 0.67 Hospitalization for MI 56 (7.6%) 65 (8.4%) 0.90 ( ) (5.2%) 252 (5.4%) 0.96 ( ) 0.68 or unstable angina Coronary 23 (3.1%) 34 (4.4%) 0.70 ( ) (2.8%) 152 (3.3%) 0.70 ( ) 0.19 revascularization Data are numbers of events (%), hazard ratios (HR) and 95% CIs, and P-values. CV death, cardiac death, vascular procedure death, presumed arrhythmic death, stroke death, other vascular death, or sudden death of unknown cause; HF, new-onset or worsening heart failure; cardiac death, death from myocardial infarction (MI), HF, or cardiac procedures. Hospitalization for MI or HF includes fatal and non-fatal events.

6 2342 K. Fox et al. Table 4 Effect of ivabradine on cardiovascular outcomes in patients with and without limiting angina symptoms at baseline and heart rate 70 b.p.m. Patients with limiting angina and heart rate Patients without limiting angina and with heart rate 70 b.p.m. (n 5 712) b.p.m. (n )... Ivabradine Placebo HR (95% CI) P Ivabradine Placebo HR (95% CI) P (n 5 349) (n 5 363) (n ) (n ) Primary endpoint CV death or 43 (12.3%) 65 (17.9%) 0.69 ( ) (17.9%) 433 (18.6%) 0.95 ( ) 0.45 hospitalization for MI or HF Mortality endpoints All-cause death 37 (10.6%) 47 (12.9%) 0.83 ( ) (12.5%) 277 (11.9%) 1.05 ( ) 0.55 CV death 32 (9.2%) 38 (10.5%) 0.90 ( ) (10.1%) 225 (9.7%) 1.04 ( ) 0.65 Cardiac death 5 (1.4%) 9 (2.5%) 0.59 ( ) (3.3%) 88 (3.8%) 0.86 ( ) 0.34 HF endpoints Hospitalization for HF 18 (5.2%) 20 (5.5%) 0.96 ( ) (10.6%) 251 (10.8%) 0.97 ( ) 0.77 CV death or 41 (11.7%) 52 (14.3%) 0.84 ( ) (16.8%) 390 (16.7%) 0.99 ( ) 0.94 hospitalization for HF Coronary endpoints Hospitalization for MI 6 (1.7%) 23 (6.3%) 0.27 ( ) (3.4%) 108 (4.6%) 0.72 ( ) Hospitalization for MI 20 (5.7%) 31 (8.5%) 0.68 ( ) (5.2%) 151 (6.5%) 0.80 ( ) 0.07 or unstable angina Coronary 7 (2.0%) 18 (5.0%) 0.41 ( ) (2.9%) 90 (3.9%) 0.76 ( ) 0.08 revascularization Data are numbers of events (%), hazard ratios (HR) and 95% CIs, and P-values. CV death, cardiac death, vascular procedure death, presumed arrhythmic death, stroke death, other vascular death, or sudden death of unknown cause; HF, new-onset or worsening heart failure; cardiac death, death from myocardial infarction (MI), HF, or cardiac procedures. Hospitalization for MI or HF includes fatal and non-fatal events. Figure 2 Kaplan Meier time-to-event curves by treatment group for composite primary endpoint (cardiovascular death, hospitalization for fatal and non-fatal myocardial infarction and hospitalization for new-onset or worsening heart failure) in patients with limiting angina at baseline (A) and in patients with limiting angina and resting heart rate 70 b.p.m. at baseline (B). HR¼ hazard ratio; CI ¼ confidence interval. 70 b.p.m., ivabradine reduced resting heart rate by an average of 15.3 b.p.m. (SD 10.3) at 30 days vs. 6.0 b.p.m. (SD 10.0) with placebo; at 18 months, the reduction from baseline was 13.6 b.p.m. (SD 12.2) with ivabradine and 5.9 b.p.m. (SD 11.9) with placebo. The effects of treatment on cardiovascular outcomes in the subpopulations with and without limiting angina are presented in Tables 3 and 4. Primary endpoint was reached by 88 patients in the ivabradine group (12.0%) vs. 120 in the placebo group (15.5%)

7 Relationship between ivabradine treatment and cardiovascular outcomes 2343 Figure 3 Kaplan Meier time-to-event curves by treatment group for the secondary endpoint of hospitalization for fatal and non-fatal myocardial infarction (MI) in patients with limiting angina at baseline (A) and in patients with limiting angina and resting heart rate 70 b.p.m. at baseline (B). HR ¼ hazard ratio; CI ¼ confidence interval. (HR, 0.76; 95% CI, , P ¼ 0.05) (Figure 2A). In the subpopulation with limiting angina and heart rate 70 b.p.m., 43 patients reached primary endpoint with ivabradine (12.3%) vs. 65 with placebo (17.9%) (HR, 0.69, 95% CI, , P ¼ 0.06) (Figure 2B). There were also treatment-related reductions in the relative risk of all the mortality or HF endpoints (Tables 3 and 4), though none of these reached statistical significance. There was a reduction in hospitalization for fatal and non-fatal MI with ivabradine (HR, 0.58, 95% CI, , P ¼ 0.021) (Figure 3A). The effect on coronary outcomes was even stronger in the subpopulation with limiting angina and heart rate 70 b.p.m. with substantial treatment-related reductions in both hospitalization for fatal and non-fatal MI (HR, 0.27, 95% CI, , P ¼ 0.002) (Figure 3B) and coronary revascularization (HR, 0.41, 95% CI, , P ¼ 0.040). In the complementary subgroup of patients with limiting angina and resting heart rate,70 b.p.m., there was a trend also towards treatment-related reductions in the relative risk of the main cardiovascular events, though these were less marked and not significant (primary endpoint, HR, 0.85, 95% CI, , P ¼ 0.41; cardiovascular death, HR, 0.88, 95% CI, , P ¼ 0.65; hospitalization for fatal and non-fatal MI, HR, 0.86, 95% CI, , P ¼ 0.59; hospitalization for HF, HR, 0.73, 95% CI, , P ¼ 0.36). In contrast, in patients without limiting angina and heart rate,70 b.p.m. there may be a possible increase in the relative risk of the main cardiovascular events (primary endpoint, HR, 1.19, 95% CI, , P ¼ 0.033; cardiovascular death, HR, 1.19, 95% CI, , P ¼ 0.11; hospitalization for fatal and non-fatal MI, HR, 1.33, 95% CI, , P ¼ 0.07; hospitalization for HF, HR, 1.04, 95% CI, , P ¼ 0.73). The safety and tolerability of ivabradine was found to be similar to that in the main study. The rate of treatment discontinuation in patients in the subpopulation with limiting angina, who took at least one dose of the study drug, was 23% (170/734 patients) with ivabradine vs. 15% (115/772) with placebo. This difference can be explained by the difference in the rates of bradycardia, mainly protocol-driven withdrawal of patients with heart rate,50 b.p.m. independently of the presence of symptoms. Thus, 82 patients (11%) in the ivabradine group withdrew due to bradycardia, only 12 (15%, i.e. 12/82) of whom were symptomatic; 11 patients (1.4%) in the placebo group withdrew due to bradycardia, 5 (42%, i.e. 5/12) of whom were symptomatic. Four patients withdrew due to phosphenes (3 [0.4%] with ivabradine vs. 1 [0.1%] with placebo). Serious adverse events were experienced by 135 patients (18%) in the ivabradine group vs. 144 patients in the placebo group (19%), with no significant difference in any case. Discussion Treatment with ivabradine in the BEAUTIFUL subpopulation with limiting angina was associated with a 24% reduction in risk for primary endpoint and a 31% reduction in risk for primary endpoint in patients with limiting angina and heart rate 70 b.p.m. The primary endpoint appears to be driven by the coronary outcomes since there was a treatment-related 42% reduction in the risk for hospitalization for fatal and non-fatal MI in patients with limiting angina. There were consistent, smaller reductions in all other endpoints examined, with 13, 12, and 28% reductions in all-cause, cardiovascular, and cardiac death, respectively; a 16% reduction in new-onset or worsening HF; and a 30% reduction in the risk for coronary revascularization. The reduction in the risk of cardiovascular outcomes was even greater in patients with angina and heart rate 70 b.p.m., notably with a significant 73% ivabradine-related reduction in hospitalization for fatal and non-fatal MI and a 59% reduction in coronary revascularization. Our results should be compared with those from the main BEAUTIFUL study, 5 in which ivabradine failed to have an impact on the composite primary endpoint. This was attributed to the domination of HF events in the primary endpoint. In the anginal population described herein, the primary endpoint has proportionately more coronary events, notably MI. This reinforces the observation that heart rate reduction is most effective on coronary outcomes. Moreover, the incidence of admission to hospital for fatal and non-fatal MI was markedly higher in the anginal population receiving placebo than in the main study (whole population, 6.5 vs.

8 2344 K. Fox et al. 4.2%; population with heart rate 70 b.p.m., 6.3 vs. 4.9%), while the rates for admission to hospital for HF were lower in the anginal population (5.3 vs. 7.9%; and 5.5 vs. 10.1%, respectively). The anti-anginal and anti-ischaemic properties of the I f inhibitor ivabradine are well established, 8,9,17,18 and it is currently indicated in the symptomatic treatment of angina. Our results suggest that the beneficial effect of ivabradine on the outcome may be mediated through an effect on myocardial ischaemia and possibly a reduction in the incidence of MI. Our data are consistent with previous studies showing that the symptoms of angina are associated with higher rates of admission to hospital for coronary events. 19 Recent data from a community cohort study in Ireland indicate that patients with angina have a similar prognosis to those with a history of acute MI or revascularization. 20 This is in line with other reports that the presence of limiting angina symptoms places patients at increased cardiovascular risk This appears to be true for patients with stable angina pectoris 12,15 and for patients with stable CAD with and without LV dysfunction. 11,13,14 The mechanism of action by which limiting angina, i.e. ischaemic pain, is predictive of coronary events remains unclear, though it is most likely related to the obstructive nature of coronary atherosclerosis. 12,14 Ischaemic pain is usually indicative of an obstructive lesion, 12 while disease progression and the occurrence of an acute coronary event may be related to overall plaque burden and plaque vulnerability. Ivabradine s anti-ischaemic effect has been traced to its selective heart rate reduction via inhibition of the pacemaker current in the sinoatrial node. 21 This has been 8,9,22 24 clearly demonstrated in experimental and clinical studies. Furthermore, recent experimental data suggest that ivabradine can improve endothelial function and attenuate the progression of atherosclerosis. 25,26 These mechanisms require further investigation in clinical settings. The heart rate reductions observed with treatment with ivabradine in patients included in the BEAUTIFUL study, who presented with limiting angina, were between 8 and 10 b.p.m., with greater reductions in patients with heart rate 70 b.p.m. These reductions were similar to those observed in the main BEAUTIFUL study population. 5 Our analysis also confirmed the good safety and tolerability of ivabradine in patients with limiting angina, as observed in the BEAUTIFUL study 5 and in other clinical trials in anginal populations. 8,9 The patients in the BEAUTIFUL population were treated according to current guidelines, 5 and the baseline characteristics presented here indicate that this is also true of the subpopulation with limiting angina. The rates of use of b-blocker are particularly high (90% of the patients with limiting angina). However, nearly half of these patients failed to reach target dose of b-blocker, for reasons including bradycardia, hypotension, and sexual dysfunction. Similar suboptimal b-blocker therapy, in terms of uptitration to target dose, has been reported in surveys in patients with HF, post-mi, and stable angina, which found low rates of uptitration after initiation of treatment. In this context, a recent study has demonstrated that ivabradine is safe in combination with the b-blocker atenolol, and indeed can further improve exercise capacity. 22 To our knowledge, cardiovascular outcomes have not been shown to improve with an anti-anginal treatment in patients with stable angina pectoris. The effects of calcium channel blockade on cardiovascular mortality and morbidity were tested in CAMELOT (Comparison of AMlodipine vs. Enalapril to Limit the Occurrence of Thrombosis) and ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine), 30,31 but neither trial demonstrated a significant reduction in major cardiovascular events. Although there were lower event rates for the composite primary endpoint of CAD mortality, non-fatal MI, or unplanned hospitalization for cardiac chest pain and for the composite endpoint of CAD mortality, non-fatal MI, or unstable angina with nicorandil vs. placebo in IONA (Impact Of Nicorandil in Angina), this trial was not powered to show a benefit on CAD mortality or non-fatal MI, and all-cause mortality and therefore we are unable to draw conclusions regarding effects on these endponts. 32 On the other hand, the benefits of b-blockade in terms of reduction of mortality are well known, but are limited to post-mi and HF. Moreover, most of these post-mi trials with b-blockers were performed before the era of extensive use of ACE inhibitors and statins, 10 which leaves uncertainty regarding their efficacy on top of more recent management strategies. From these results in high-risk patients, it has been extrapolated that b-blockade may have an effect on prognosis in angina pectoris, but this has never been evaluated in randomized controlled trials. 10 There are a number of limitations to our study. First, this is a post hoc analysis, and therefore the results should be considered as hypothesis-generating, and will be tested in the SIGNIFY study. Despite the exploratory nature of this analysis, we have observed consistent reductions in all outcomes. In addition, the sample size is relevant, and the results are plausible and in line with previous data for ivabradine in a pure anginal population. 9,22 Another limitation to our study is that anginal symptoms were measured only at baseline, and there may have been changes in symptoms during the study. Finally, the constraints of the design of the BEAUTIFUL study 16 meant that limiting angina symptoms were measured using the NYHA classification, which depends on disability due to a number of factors other than angina, such as LV dysfunction and HF. For this reason, we also included the patient report of anginal pain as a criterion for inclusion in the subpopulation with limiting angina. This method of identification may well have excluded patients with angina pectoris who were controlled by anti-anginal medication or patients with limiting anginal symptoms who also had symptoms associated with HF that were more significant. In conclusion, this post hoc analysis proposes that the anti-anginal agent ivabradine may reduce major cardiovascular events in patients with stable CAD and LVSD who present with limiting angina. Also, our results suggest that there is no indication for treating patients with a heart rate less than 70 b.p.m. with ivabradine if they have significant LV dysfunction (EF,40%) and do not have symptoms of limiting angina. At this stage these findings can only be considered as hypothesis-generating and the benefits of ivabradine in patients with limiting angina will be tested in the SIGNIFY study.

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