Introduction. CLINICAL RESEARCH Heart failure/cardiomyopathy

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1 European Heart Journal (2013) 34, doi: /eurheartj/eht101 CLINICAL RESEARCH Heart failure/cardiomyopathy Effect of ivabradine in patients with left-ventricular systolic dysfunction: a pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials Kim Fox 1 *, Michel Komajda 2, Ian Ford 3, Michele Robertson 3, Michael Böhm 4, Jeffrey S. Borer 5, Philippe Gabriel Steg 6,7, Luigi Tavazzi 8, Michal Tendera 9, Roberto Ferrari 10, and Karl Swedberg 11 1 NHLI Imperial College and ICMS, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK; 2 Department of Cardiology, University Pierre et Marie Curie Paris VI, La Pitié-Salpétrière Hospital, Paris, France; 3 Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK; 4 Universitätskliniken des Saarlandes, Klinik für Innere Medizin III, Homburg/Saar, Germany; 5 Division of Cardiovascular Medicine and the Howard Gilman Institute for Heart Valve Disease, State University of New York Downstate Medical Center, Brooklyn and New York, NY, USA; 6 Assistance Publique Hôpitaux de Paris, Université Paris-Diderot, Paris, France; 7 INSERM U-698, Paris, France; 8 Maria Cecilia Hospital GVM Care and Research, Ettore Sansavini Health Science Foundation, Cotignola, Italy; 9 Medical University of Silesia, Katowice, Poland; 10 Department of Cardiology, University of Ferrara, and Salvatore Maugeri Foundation, IRCCS, Lumezzane, Italy; and 11 Department of Emergency and Cardiovascular Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden Received 19 December 2012; revised 22 February 2013; accepted 4 March 2013; online publish-ahead-of-print 26 March 2013 Aims To test the effect of ivabradine on the outcomes in a broad population with left-ventricular (LV) systolic dysfunction with coronary artery disease (CAD) and/or heart failure (HF).... Methods Individual trial data from BEAUTIFUL and SHIFT were pooled to evaluate the effect of ivabradine on the outcomes in and results patients with LV dysfunction and heart rate 70 b.p.m. The pooled population (n ¼ ; baseline age years, heart rate b.p.m., and LV ejection fraction %) was well treated according to current recommendations (87% beta-blockers, 90% renin angiotensin system inhibitors). Median follow-up was 21 months. Treatment with ivabradine was associated with a 13% relative risk reduction for the composite of cardiovascular mortality or HF hospitalization (P, vs. placebo); this was driven by HF hospitalizations (19%, P, 0.001). There were also significant relative risk reductions for the composite of cardiovascular mortality, HF hospitalizations, or myocardial infarction (MI) hospitalization (15%, P, 0.001); cardiovascular mortality and non-fatal MI (10%, P ¼ 0.023); and MI hospitalization (23%, P ¼ 0.009). Similar results were found in patients with differing clinical profiles. Ivabradine was well tolerated.... Conclusion Ivabradine may be important for the improvement of clinical outcomes in patients with LV systolic dysfunction and heart rate 70 b.p.m., whatever the primary clinical presentation (CAD or HF) or clinical status (NYHA class) Keywords BEAUTIFUL SHIFT Ivabradine Heart rate LV function Prognosis Introduction Elevated heart rate is an important determinant of ischaemia and is an established risk factor in cardiovascular disease. 1,2 Epidemiological and observational studies indicate that patients with lower heart rate have better outcomes. However, until recently, this had never been tested in randomized controlled trials, partly due to the multiple effects of beta-blockers and calcium channel blockers beyond the reduction of heart rate, making it difficult to disentangle the effects of the heart rate component. Ivabradine specifically inhibits the I f current in the sinoatrial node, thereby lowering heart rate without affecting other aspects of cardiac function. 3 It has proven anti-ischaemic and antianginal efficacy in patients with stable chronic angina pectoris. 4,5 * Corresponding author. Tel: , Fax: , k.fox@rbht.nhs.uk Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com

2 2264 K. Fox et al. Two large randomized trials have recently tested the impact of ivabradine on cardiovascular outcomes: BEAUTIFUL (morbiditymortality EvAlUaTion of the I f inhibitor ivabradine in patients with coronary disease and left-ventricular dysfunction) in patients with stable coronary artery disease (CAD) and left-ventricular (LV) dysfunction, and SHIFT (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial) in patients with heart failure. 6,7 The results of BEAUTIFUL suggested that ivabradine reduces the incidence of coronary outcomes in such populations (notably, admission to hospital for myocardial infarction), provided that heart rate was 70 b.p.m. or higher. 6 SHIFT was performed in patients with heart failure, LV dysfunction, and heart rate 70 b.p.m., and reported significant ivabradine-associated reductions in the incidence of heart failure outcomes (notably, hospital admission due to worsening heart failure and death due to heart failure). 7 The BEAUTIFUL and SHIFT populations clearly differ in their primary diagnosis, particularly with regard to the presence of heart failure. Indeed, all of the patients in SHIFT had a history of heart failure and a recent hospital admission for the condition, while many of the patients in BEAUTIFUL had no symptoms of heart failure. On the other hand, all of the patients in the two studies had impaired LV function (Table 1), which is associated with increased mortality in patients with CAD, as well as in those with heart failure. 8 Therefore, it seems valuable to explore the consistency of these findings across the two trials. In this article, we describe a pooled analysis of individual trial data from BEAUTIFUL and SHIFT to evaluate the effect of heart rate reduction with ivabradine on outcomes in a broad population of patients with LV dysfunction, whatever their background condition (CAD or heart failure). Table 1 Main features of the SHIFT population and the BEAUTIFUL population with heart rate 70 b.p.m. 6,7 BEAUTIFUL with heart rate SHIFT (n ) 70 b.p.m. (n ) Main inclusion criteria Age (years) Primary diagnosis CAD Symptomatic HF Heart rate (b.p.m.) Left-ventricular dysfunction Yes (LVEF,40%) Yes (LVEF 35%) Characteristics at randomization a Age (years) 64.6 (8.6) 60.4 (11.4) Heart rate (b.p.m.) 79.2 (8.6) 79.9 (9.6) LVEF (%) 32.0 (5.6) 29.0 (5.1) History of CAD 5392 (100%) 4732 (73%) NYHA class Class I 762 (14%) 0 Class II 3190 (59%) 3169 (49%) Class III 1440 (27%) 3223 (50%) Class IV (2%) Dosage of study treatment Ivabradine mg bid Ivabradine mg bid Main outcomes Primary endpoint Composite of CV mortality, hospital Composite of CV mortality or hospital admission for HF admission for HF, or hospital admission for MI Secondary outcomes Individual components of the primary Individual components of the primary endpoint; all-cause mortality; endpoint, all-cause mortality HF mortality; composite of CV mortality, hospital admission for HF, or hospital admission for non-fatal MI Recruitment Recruitment period January 2005 to December 2006 October 2006 to June 2009 Median duration of follow-up 19 months (IQR 15 24) 23 months (IQR 18 28) Follow-up Mean dosage ivabradine 6.6 mg bid at 1 month 6.4 mg bid at 1 month Heart rate reduction at 1 year (placebo-corrected) 10 b.p.m b.p.m. CAD, coronary artery disease; CV, cardiovascular; HF, heart failure; LVEF, left-ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association. a Values are number of patients (%) or mean (SD).

3 BEAUTIFUL and SHIFT 2265 Methods Patients The study designs of the BEAUTIFUL and SHIFT trials have been described at length elsewhere and the principal characteristics of the two trials are summarized in Table 1. 6,7 Our pooled analysis of individual trial data included all the patients in SHIFT (6505 patients) and the patients in BEAUTIFUL who had baseline heart rate 70 b.p.m. [5392 patients (49%) out of patients in the whole BEAUTIFUL trial]. The main features of these two populations are compared in Table 1. This pooled population comprised patients, all of whom had resting heart rate 70 b.p.m. at baseline. A heart rate 70 b.p.m. was selected to identify a high-risk subgroup a priori in the BEAUTI- FUL study; 6 70 b.p.m. was the heart rate required for entry to the SHIFT study. 7 Subsequent analyses of both trials did indeed confirm the suitability of this heart rate to define a population most likely to benefit from heart rate lowering. 9,10 Outcomes In this analysis, we assessed the SHIFT primary endpoint (a composite of cardiovascular mortality or hospital admission for worsening heart failure), as well as the individual components separately. We also explored the BEAUTIFUL primary endpoint [a composite of cardiovascular mortality, hospital admission for new or worsening heart failure (fatal or non-fatal), or hospital admission for myocardial infarction (fatal or non-fatal)], as well as its individual components separately. The definitions of the endpoints across the trials were carefully checked, and were not essentially different between the trials. Analyses were also performed in the population divided according to clinical profile at baseline [heart rate 75 or,75 b.p.m.; beta-blocker dosage; LV ejection fraction 35 or 40%; and New York Heart Association (NYHA) class I or II, class I IV, or class II IV]. Statistical methods Baseline characteristics are presented as means (SD) for continuous variables, and counts (percentages) for categorical variables for patients in the pool by treatment group. Survival analysis was done on a time-to-first event basis with the intention-to-treat principle. Treatment effect was estimated using a Cox s proportional hazards model adjusted for baseline beta-blocker intake and study to reflect differences between the trials. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented, and P-values calculated from the Wald Statistic. A P-value of 0.05 was considered as significant. A Cox s proportional hazards model adjusted for prognostic factors at baseline (beta-blocker intake, heart rate, NYHA class, LV ejection fraction, ischaemic cause, age, and systolic blood pressure) was also investigated and confirmed the results. Lack of proportionality of hazards was assessed in the Cox models for the effect of ivabradine vs. placebo by adding and testing an interaction term between the logarithm of time and the treatment effect. Time-to-event curves were estimated using the Kaplan Meier method. Adverse events are reported as descriptive statistics (numbers of events and percentages) with a P-value for the between-group differences (Fishers Exact test stratified by beta-blocker use at baseline and trial). SAS (version 9.1) was used for all analyses. Role of the funding source The BEAUTIFUL and SHIFT executive committees were responsible for the study design, the interpretation of the results, the development and writing of the report, and the decision to submit for publication; they had full access to all data. Members of the medical and scientific departments of the sponsor supported the work of the executive committees, but did not make any scientific or research decisions independent of these committee. The sponsor was responsible for data management and final data analyses, in collaboration with independent statistical centre at Robertson Centre for Biostatistics, University of Glasgow, UK. Results The baseline characteristics are presented in Table 2. The population was aged and was predominantly male (9385, Table 2 Baseline characteristics of the population with LV dysfunction and heart rate 70 b.p.m. (n ) Ivabradine Placebo group group (n ) (n ) Demographic parameters Age (years) 62.6 (10.3) 62.0 (10.5) Sex (male) 4668 (79%) 4717 (79%) Current smoker 973 (16%) 1058 (18%) BMI (kg/m 2 ) 28.4 (4.9) 28.3 (4.9) Cardiac parameters Heart rate (b.p.m.) 79.4 (9.1) 79.7 (9.3) Sitting SBP (mmhg) (16.3) (16.2) Sitting DBP (mmhg) 76.9 (9.6) 76.8 (9.4) LVEF (%) 30.4 (5.6) 30.3 (5.6) NYHA class I 390 (7%) 374 (6%) NYHA class II 3160 (53%) 3199 (54%) NYHA class III 2340 (39%) 2323 (39%) NYHA class IV 50 (0.8%) 61 (1%) Medical history Coronary artery disease 5060 (85%) 5064 (85%) Myocardial infarction 4184 (70%) 4186 (70%) Hypertension 4109 (69%) 4079 (69%) Diabetes 2105 (35%) 2161 (36%) Dyslipidaemia 2716 (46%) 2747 (46%) Previous stroke 729 (12%) 798 (13%) Treatment at randomization Beta-blocker 5130 (86%) 5196 (87%) ACE inhibitor 4734 (80%) 4697 (79%) ARB 729 (12%) 787 (13%) ARB/ACE inhibitor 5374 (91%) 5381 (90%) Lipid-modifying agent 3851 (65%) 3829 (64%) Diuretic (excluding anti-aldosterone) 4410 (74%) 4399 (74%) Anti-aldosterone agent 2773 (47%) 2741 (46%) Values are number of patients (%) or mean (SD). ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BMI, body mass index; DBP, diastolic blood pressure; LVEF, left-ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; SBP, systolic blood pressure.

4 2266 K. Fox et al. 79%); heart rate at baseline was b.p.m. and LV ejection fraction %. The pooled population was well treated in terms of beta-blockers (10 326, 87%) and angiotensin-convertingenzyme inhibitor or angiotensin II receptor blockers (10 755, 90%), and the majority were receiving diuretics (8809, 74%). Coronary disease was frequent, notably a history of CAD (10 124, 85%) or myocardial infarction (8370, 70%). There were no important differences between the treatment groups. After 1 month (i.e. after titration), treatment with ivabradine reduced heart rate to vs. to b.p.m. with placebo. Mean dosage of ivabradine at 1 month in the treatment group was mg twice daily. The median follow-up was 21 (IQR 16 26) months. There was significant reduction vs. placebo in the composite endpoint of cardiovascular mortality or hospitalization for heart failure (13% reduction in relative risk, P, 0.001) (Table 3). The survival curves for this composite endpoint separated after just 3 months of treatment (Figure 1A). This reduction in risk was mainly driven by hospitalization for heart failure, for which there was 19% reduction in relative risk in the ivabradine group (P, 0.001). Cardiovascular deaths were not significantly reduced in the ivabradine group (P ¼ 0.272). Also in this population with LV dysfunction, treatment with ivabradine was associated with significant reductions vs. placebo in the composite endpoint of cardiovascular mortality, hospitalization for heart failure, or hospitalization for myocardial infarction (15% relative risk reduction, P, 0.001) (Figure 1B), as well as hospitalization for myocardial infarction (23%, P ¼ 0.009) and the composite endpoint of cardiovascular death or non-fatal myocardial infarction (10%, P ¼ 0.023) (Table 3). There was no evidence for non-proportionality of hazards for the effect of ivabradine vs. placebo for the two composite endpoints shown in Figure 1A (P-value for interaction of treatment group and time: P ¼ 0.18, adjusted for beta-blocker and study; P ¼ 0.16, unadjusted) or Figure 1B (P ¼ 0.41, adjusted for beta-blocker and study; P ¼ 0.37 unadjusted). Nearly two-thirds of the population had heart rate 75 b.p.m. (n ¼ 7632). In this population, treatment with ivabradine was associated with significant reduction in heart failure outcomes (Table 4) including the composite of cardiovascular mortality and heart failure hospitalization (P, ), cardiovascular mortality (P ¼ 0.049), hospitalization for heart failure (P, ), and all-cause mortality (P ¼ 0.048). In the smaller complementary subgroup of patients with heart rate between 70 and 75 b.p.m. (n ¼ 4265), the risk was lower with an 18% incidence of primary composite endpoint in placebo patients vs. 26% in placebo patients 75 b.p.m. In patients with heart rate between 70 and 75 b.p.m., there was no significant impact of ivabradine on the composite of cardiovascular mortality and heart-failure hospitalization (P ¼ 0.83), cardiovascular mortality (P ¼ 0.31), or hospitalization for heart failure (P ¼ 0.22). We also tested the effect of background beta-blocker dosage on the results in the pooled population. There was no significant impact of beta-blocker dosage on the effect of treatment on outcomes (Supplementary material online, Tables S1 and S2). Within the population, there were 9236 patients (4604 ivabradine, 4632 placebo) with a more severe clinical profile of LV dysfunction (LV ejection fraction 35% and NYHA class II IV, as well as heart rate 70 b.p.m.). Analysis of the heart failure outcomes in these patients showed a significant relative risk reduction in the ivabradine group for the composite of cardiovascular mortality or hospitalization for heart failure (13%, P, 0.001) and for hospitalization for heart failure (20%, P, 0.001) (Table 5). Cardiovascular mortality was not significantly reduced in the ivabradine group. A similar analysis of the 2731 BEAUTIFUL patients in this population (1363 patients on ivabradine, 1368 on placebo), showed no significant impact of ivabradine on the composite endpoint of cardiovascular mortality or heart failure hospitalization (P ¼ 0.86) or its components cardiovascular mortality (P ¼ 0.47) and hospitalization for heart failure (P ¼ 0.89). Analyses in the complementary population of 2651 patients with LVEF between 35 and 40% and/ or NYHA class I, and heart rate 70 b.p.m. (patients from the BEAUTIFUL trial) showed no significant treatment effect on any endpoint, and there was no significant interaction between the two complementary populations (interaction P ¼ 0.64 for composite of cardiovascular mortality and hospitalization for heart Table 3 Cardiovascular outcomes in patients with left-ventricular dysfunction and heart rate 70 b.p.m. (n ; 5940 ivabradine, 5957 placebo) Event rates, n (%)... HR (95% CI) P-value Ivabradine group (n ) Placebo group (n ). CV mortality or hospitalization for HF 1229 (21%) 1379 (23%) 0.87 ( ),0.001 CV mortality 718 (12%) 754 (13%) 0.94 ( ) Hospitalization for HF 782 (13%) 943 (16%) 0.81 ( ),0.001 Total mortality 834 (14%) 876 (15%) 0.96 ( ) CV mortality, hospitalization for HF, 1288 (22%) 1477 (25%) 0.85 ( ),0.001 or hospitalization for MI Hospitalization for MI 169 (3%) 218 (4%) 0.77 ( ) CV death or non-fatal MI 816 (14%) 900 (15%) 0.90 ( ) Adjusted for beta-blocker intake at baseline and study. CV, cardiovascular; HF, heart failure; MI, myocardial infarction.

5 BEAUTIFUL and SHIFT 2267 Figure 1 Kaplan Meier cumulative event curves for (A) the composite endpoint of cardiovascular mortality or hospital admission for heart failure and (B) the cardiovascular mortality, hospital admission for heart failure, or hospital admission for myocardial infarction in patients with all-cause left-ventricular dysfunction. Table 4 Heart failure outcomes in patients with left-ventricular dysfunction and heart rate 75 b.p.m. (n ; 3812 ivabradine, 3820 placebo) Event rates, n (%)... HR (95% CI) P-value Ivabradine group (n ) Placebo group (n ). CV mortality or hospitalization for HF 858 (23%) 1003 (26%) 0.82 ( ), CV mortality 492 (13%) 548 (14%) 0.88 ( ) Hospitalization for HF 568 (15%) 704 (18%) 0.78 ( ), Total mortality 577 (15%) 636 (17%) 0.89 ( ) Adjusted for beta-blocker intake at baseline and study. CV, cardiovascular; HF, heart failure; MI, myocardial infarction.

6 2268 K. Fox et al. Table 5 Heart failure outcomes in patients with left-ventricular dysfunction (ejection fraction 35%), New York Heart Association (NYHA) class II IV, and heart rate 70 b.p.m. (n ; 4604 ivabradine, 4632 placebo) Event rates, n (%)... HR (95% CI) P-value Ivabradine group (n ) Placebo group (n ). CV mortality or hospitalization for HF 1077 (23%) 1217 (26%) 0.87 ( ),0.01 CV mortality 621 (13%) 652 (14%) 0.96 ( ) Hospitalization for HF 701 (15%) 856 (18%) 0.80 ( ),0.001 Total mortality 714 (16%) 748 (16%) 0.96 ( ) Adjusted for beta-blocker intake at baseline and study. CV, cardiovascular; HF, heart failure; MI, myocardial infarction. Table 6 Effect of treatment with ivabradine on the composite endpoint of cardiovascular mortality or hospitalization for heart failure in patients with heart rate 70 b.p.m. and differing clinical profiles according to left-ventricular ejection fraction (LVEF) and New York Heart Association (NYHA) class for heart failure Clinical profile Placebo event n HR (95% CI) P-value rate (%) (per year). LVEF 40% NYHA class I (pooled analysis) ( ),0.001 LVEF 35% NYHA class I ( ) LVEF 35% NYHA class II ( ),0.001 failure). Moreover, this improvement in heart failure outcomes with ivabradine was not confined to the most severe, symptomatic patients with the worst outcome, but was also observed in patients with less severe profiles (e.g. LV ejection fraction 40% and NYHA class I) (Table 6). Ivabradine was well tolerated with rates of adverse events similar to those reported in the original studies. There were no relevant differences from placebo in the incidence of serious adverse events by system organ class. There were more cases of symptomatic or asymptomatic bradycardia in the ivabradine group (P, vs. placebo), which led to withdrawal of study drug in,1% of cases (P, vs. placebo) (Table 7). Phosphenes, i.e. transient enhanced brightness in the visual field, were more frequent in patients receiving ivabradine (3 vs.,1%, P, vs. placebo), but rarely led to treatment withdrawal (0.3% of the ivabradine group). Discussion The SHIFT study 7 clearly demonstrated the benefits of pure heart rate lowering with ivabradine in patients with heart failure and markedly impaired LV function (ejection fraction 35%) and heart rate 70 b.p.m. The SHIFT patients were at high risk (placebo event rate for cardiovascular death or heart failure hospitalization, 17.68% annually); all had been admitted to hospital for heart failure within 12 months and had symptomatic disease in spite of maximal medical therapy (NYHA class II). The important question for the clinician is whether the benefits of pure heart rate reduction are confined only to the sickest patients with heart Table 7 Incidence of specific adverse events during the study and those leading to drug withdrawal in patients who had taken at least one dose of study treatment Ivabradine Placebo P-value (n ) (n ) Patients with adverse event All 4236 (71%) 4187 (70%) Heart failure 1226 (21%) 1365 (23%) Symptomatic 211 (4%) 49 (0.8%),0.001 bradycardia Asymptomatic 237 (4%) 66 (1%),0.001 bradycardia Atrial fibrillation 501 (8%) 400 (7%),0.001 Phosphenes 189 (3%) 42 (0.7%),0.001 Blurred vision 46 (0.8%) 25 (0.4%) Patients with adverse event leading to drug withdrawal All 794 (13%) 645 (11%),0.001 Heart failure 102 (2%) 106 (2%) Symptomatic bradycardia 54 (0.9%) 14 (0.2%),0.001 Asymptomatic bradycardia 55 (0.9%) 13 (0.2%),0.001 Atrial fibrillation 204 (3%) 164 (3%) Phosphenes 18 (0.3%) 4 (0.1%) Blurred vision 3 (0.1%) 4 (0.1%) Data are numbers (%) of patients.

7 BEAUTIFUL and SHIFT 2269 failure or may be seen in a broader population of patients with LV dysfunction. The BEAUTIFUL study 6 included patients very different from SHIFT, in that LV dysfunction was defined as ejection fraction,40% and neither admission to hospital for heart failure within 12 months nor limiting symptoms of heart failure was required. All the patients had coronary disease, in contrast to SHIFT in which coronary disease represented 60% of the population. Consequently, the BEAUTIFUL patients were at lower risk (placebo event rate for cardiovascular death or heart failure hospitalization, 8.48% annually). Our pooled analysis of individual patient data from BEAUTIFUL and SHIFT demonstrates that heart rate reduction with ivabradine does reduce the risk for major outcomes in a broad population of patients with LV systolic dysfunction and heart rate 70 b.p.m., and provides useful benefits in terms of heart failure outcomes although less evident than the more severe SHIFT population. Heart rate reduction with ivabradine was associated with significant reductions in the relative risk for the composite of cardiovascular mortality or hospitalization for heart failure, driven by hospitalizations for heart failure (relative reduction in risk, 13%). Furthermore, there was also a significant reduction in the composite of cardiovascular mortality, hospitalization for heart failure, or hospitalization for myocardial infarction (relative reduction in risk, 15%), and its components, notably of both cardiovascular death and admission for myocardial infarction (relative reduction in risk, 10%). Our data also provide robust evidence of the safety of ivabradine in a large population of patients with LV dysfunction, notably with low rates of bradycardia. Analysis of various subgroups presented as well as the whole pooled analysis suggest that patients with LV dysfunction may benefit from heart rate reduction with ivabradine, even if they are asymptomatic or have only mild symptoms of heart failure. Our analyses also confirm that the effect of ivabradine is greatest in patients with highest heart rates at baseline ( 75 b.p.m.) 11 and is not affected by the background dosage of beta-blocker. 12 The population of patients with LV dysfunction is growing and is fuelling the dramatic growth in the number of patients with heart failure in recent years. 13 LV systolic dysfunction is associated with higher risk of mortality. 8 Elevated heart rate is believed to contribute to the development and progression of LV dysfunction, and is associated with higher risk of cardiovascular events. 9,10 It is also a major determinant of myocardial ischaemia and the development and progression of LV remodelling. 1,2 Elevated heart rate may also be partly responsible for the development of atherogenesis and plaque rupture. 14,15 The Sibutramine Cardiovascular Outcomes (SCOUT) trial study appeared to confirm this association. 16 Sibutramine, a dopamine analogue known to increase heart rate, was shown to significantly increase the frequency of non-fatal myocardial infarction in a diabetic and coronary disease population, in spite of substantial weight loss and a trivial effect on blood pressure. Heart rate reduction is known to have a beneficial effect on energy expenditure and blood supply, 1,2 endothelial function, and LV remodelling. 17 BEAUTIFUL was the first large study to indicate that elevated heart rate was associated with an increased frequency of hospitalization for myocardial infarction and that lowering heart rate with ivabradine in patients with values 70 b.p.m. was associated with a reduction in the number of patients admitted with myocardial infarction. 6,9 This pooled analysis was limited to patients with elevated heart rate 70 b.p.m. This cut-off was selected prospectively in both BEAUTIFUL and SHIFT. 6,7 Indeed, analyses in the BEAUTIFUL placebo group indicated that risk rises steeply above 70 b.p.m. in patients with CAD and LV dysfunction. 9 This cut-off is also consistent with the results of an analysis of the effect of resting heart rate on major cardiovascular events in a population with stable coronary heart disease in the TNT (Treating to New Targets) trial. In that analysis, a heart rate 70 b.p.m. was associated with substantial increases in risk for all-cause mortality and hospitalization for heart failure, but not stroke or myocardial infarction. 18 Preliminary results from ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global endpoint trial) in patients with stable cardiovascular disease confirmed that a heart rate.70 b.p.m. was associated with a poorer prognosis. 19 Finally, this target makes sense clinically, being approximately the median heart rate in most contemporary observational registries. The limitations of our study are those of a pooled post hoc analysis. The conclusions are therefore less strong than those from a pre-specified analysis and have problems related to the multiplicity of testing; however, the observed effects on cardiovascular outcomes are clear and robust. Moreover, the use of the cut-off of 70 b.p.m. limited the analysis to half of BEAUTIFUL population. Another limitation is between-trial differences in inclusion criteria and patient selection, but these are minimal (consistency in terms of dosage, measurement of heart rate, and endpoint adjudication). There are also between-trial differences in the patient characteristics, in that SHIFT included a selected heart failure population (NYHA classes II, III, and IV), while BEAUTIFUL included patients with mild heart failure (NYHA classes I, II, or III, and with relatively higher LV ejection fraction). Testing the effect of the drug in a population with extended range of clinical severity of cardiac dysfunction was one of the reasons to perform this analysis. These differences were taken into account in the results since the model was adjusted by study factor. Moreover, the results were also confirmed using a model adjusted on prognostic factors. In conclusion, heart rate remains elevated in many patients with LV systolic dysfunction despite treatment with guidelinesrecommended therapies, and reducing it selectively with ivabradine seems to be an alternative in the management strategy of these patients. Our results support the importance of ivabradine for improvement of clinical outcomes in patients with LV dysfunction and heart rate 70 b.p.m., whatever the primary clinical presentation (CAD or heart failure) or clinical profile (ejection fraction or NYHA class). Supplementary material Supplementary material is available at European Heart Journal online. Acknowledgement KF is an NIHR Senior Investigator supported by the NIHR Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital.

8 2270 K. Fox et al. Funding This work was supported by Servier, France. Conflict of interest: KF, MK, IF, MB, JSB, PGS, LT, MT, RF and KS have received fees and/or honoraria and/or travel expenses from Servier. References 1. Fox K, Borer JS, Camm AJ, Danchin N, Ferrari R, Lopez Sendon JL, Steg PG, Tardif JC, Tavazzi L, Tendera M. Resting heart rate in cardiovascular disease. J Am Coll Cardiol 2007;50: Fox KM, Ferrari R. Heart rate: a forgotten link in coronary artery disease? Nat Rev Cardiol 2011;8: DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective blockers. Pharmacol Res 2006;53: Borer JS, Fox K, Jaillon P, Lerebours G. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003;107: Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005;26: Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372: Swedberg K, Komajda M, Böhm M, Borer J, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled trial. Lancet 2010;376: Wang TJ, Evans JC, Benjamin EJ, Levy D, LeRoy EC, Vasan RS. Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation 2003;108: Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008;372: Bohm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L. Heart rate as a risk factor in chronic heart failure (SHIFT) : the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 2010;376: Böhm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil JC, Swedberg K, Tavazzi L. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure. Analysis from the SHIFT study. Clin Res Cardiol 2012;10: Swedberg K, Komajda M, Bohm M, Borer J, Robertson M, Tavazzi L, Ford I. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose? J Am Coll Cardiol 2012; 59: Gheorghiade M, Sopko G, De LL, Velazquez EJ, Parker JD, Binkley PF, Sadowski Z, Golba KS, Prior DL, Rouleau JL, Bonow RO. Navigating the crossroads of coronary artery disease and heart failure. Circulation 2006;114: Beere PA, Glagov S, Zarins CK. Experimental atherosclerosis at the carotid bifurcation of the cynomolgus monkey. Localization, compensatory enlargement, and the sparing effect of lowered heart rate. Arterioscler Thromb 1992;12: Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation 2001;104: James WP, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Maggioni AP, Torp-Pedersen C, Sharma AM, Shepherd GM, Rode RA, Renz CL. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med 2010;363: Custodis F, Schirmer SH, Baumhakel M, Heusch G, Bohm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol 2010;56: Ho JE, Bittner V, Demicco DA, Breazna A, Deedwania PC, Waters DD. Usefulness of heart rate at rest as a predictor of mortality, hospitalization for heart failure, myocardial infarction, and stroke in patients with stable coronary heart disease (Data from the Treating to New Targets [TNT] trial). Am J Cardiol 2010;105: Rambiha S, Gao P, Teo K, Bohm M, Yusuf S, Lonn EM. Heart rate is associated with increased risk of major cardiovascular events, cardiovascular and all-cause death in patients with stable chronic cardiovascular diesase. An analysis of ONTARGET/TRANSCEND. Circulation 2011;122(suppl.):A Cleland JG, Swedberg K, Follath F, Komajda M, Cohen-Solal A, Aguilar JC, Dietz R, Gavazzi A, Hobbs R, Korewicki J, Madeira HC, Moiseyev VS, Preda I, Van Gilst WH, Widimsky J, Freemantle N, Eastaugh J, Mason J. The EuroHeart Failure survey programme a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J 2003;24: Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Leiro MC, Drozdz J, Fruhwald F, Gullestad L, Logeart D, Metra M, Parissis J, Persson H, Ponikowski P, Rauchhaus M, Voors A, Nielsen OW, Zannad F, Tavazzi L. EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2010;12: Yancy CW, Fonarow GC, Albert NM, Curtis AB, Stough WG, Gheorghiade M, Heywood JT, McBride ML, Mehra MR, O Connor CM, Reynolds D, Walsh MN. Adherence to guideline-recommended adjunctive heart failure therapies among outpatient cardiology practices (findings from IMPROVE HF). Am J Cardiol 2010;105: