Theroleofheartratemaydifferaccording to pathophysiological setting: from SHIFT to SIGNIFY

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1 European Heart Journal (2015) 36, doi: /eurheartj/ehv150 CURRENT OPINION Theroleofheartratemaydifferaccording to pathophysiological setting: from SHIFT to SIGNIFY Roberto Ferrari 1 * and Kim M. Fox 2 1 Department of Cardiology and LTTA Centre, University Hospital of Ferrara and Maria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, Italy; and 2 NHLI Imperial College, ICMS Royal Brompton Hospital, London, UK Received 31 August 2014; revised 4 December 2014; accepted 20 March 2015; online publish-ahead-of-print 28 April 2015 Introduction The results of the SIGNIFY (study assessing the morbidity mortality benefits of the I f inhibitor ivabradine in patients with coronary artery disease) trial, which were recently published in the New England Journal of Medicine, 1 raise an important pathophysiological question regarding the relationship between elevated heart rate and outcomes in cardiovascular disease. Why did heart rate reduction with ivabradine improve prognosis in patients with chronic heart failure and left ventricular (LV) systolic dysfunction in the SHIFT (systolic heart failure treatment with the I f inhibitor ivabradine trial) study, 2 but not in patients with stable coronary artery disease (CAD) without heart failure and LV systolic dysfunction in SIGNIFY? Trial results for ivabradine in patients with cardiovascular disease The patients recruited in SIGNIFY presented with stable CAD plus additional cardiovascular risk factors and resting heart rate 70 bpm. 1 The SIGNIFY investigators deliberately recruited patients with no symptoms of heart failure or LV systolic dysfunction: the population had a mean left ventricular ejection fraction (LVEF) at baseline of %. 3 All were receiving guideline-based background therapy for their condition. In this stable CAD population, ivabradine had no effect on the primary endpoint, a composite of cardiovascular death or non-fatal myocardial infarction (MI), with annual event rates of 3.0% with ivabradine and 2.8% with (hazard ratio [HR] 1.08, 95% confidence interval [CI], , P ¼ 0.20). 1 There were no significant differences between the groups in terms of any of the secondary endpoints including cardiovascular death (HR 1.10, P ¼ 0.25), non-fatal MI (HR 1.04, P ¼ 0.60), or all-cause death (HR 1.06, P ¼ 0.35). Treatment with ivabradine was associated with an increase in primary composite endpoint in a subgroup of patients with angina Canadian Cardiovascular Society (CCS) 2 and higher (63% of the whole population) vs. those on (HR 1.18, P ¼ 0.018, in patient with CCS class 2 angina or higher; P ¼ 0.02 for interaction). There was no significant effect of ivabradine on the components of the primary endpoint or the main secondary endpoints in this angina population. There was no interaction between the use of ivabradine and outcomes in seven other pre-specified sub-groups, which were defined according to age, b-blocker use at baseline, sex, heart rate at baseline, history of diabetes, previous MI, or previous coronary revascularization. The SIGNIFY results are in sharp contrast with those of SHIFT, which included a completely different population with symptomatic heart failure of ischaemic and non-ischaemic origin. SHIFT included 6558 patients with chronic heart failure, resting heart rate 70 bpm, and a baseline LVEF of %, who were also receiving guideline-based background therapy. 2 Treatment with ivabradine was associated with a highly significant effect on the primary composite outcome of cardiovascular death and hospitalization for heart failure (annual event rates 14 and 18%; HR 0.82, 95% CI, , P, ). The effect was found to be driven mainly by heart failure hospitalization, the risk of which was reduced by 26% (P, ). There was no difference in the effect of ivabradine between ischaemic and non-ischaemic heart failure, with a similar magnitude of risk reduction whatever the origin of heart failure (nonischaemic heart failure, HR 0.72, 95% CI ; ischaemic heart failure, HR 0.87, 95% CI ; P ¼ for interaction). There were a number of differences between the two studies (Table 1). 1 6 Notably, SIGNIFY used a regimen involving higher initiation and uptitration doses (7.5 and 10 mg bid, respectively) than in SHIFT. Therefore, SIGNIFY reported a lower heart rate achieved (63% of SIGNIFY patients had heart rate,55 bpm at least one visit vs. 48% of SHIFT patients) and a higher incidence of bradycardia (18% vs. 10% in SHIFT). The SIGNIFY population was also at much The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. * Corresponding author. fri@unife.it Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 The role of heart rate from SHIFT to SIGNIFY 2043 Table 1 Main features of the populations of SIGNIFY, BEAUTIFUL with heart rate 70 bpm, and SHIFT 1 6 SIGNIFY (n ) BEAUTIFUL with heart rate SHIFT (n ) 70 bpm (n )... Main inclusion criteria Age (years) Primary diagnosis CAD CAD Symptomatic HF Heart rate (bpm) LV dysfunction No (LVEF. 40%) Yes (LVEF, 40%) Yes (LVEF 35%) Characteristics at randomization a Age (years) 65.0 (7.2) 64.6 (8.6) 60.4 (11.4) Heart rate (bpm) 77.2 (7.0) 79.2 (8.6) 79.9 (9.6) LVEF (%) 56.5 (8.6) 32.0 (5.6) 29.0 (5.1) History of CAD (100%) 5392 (100%) 4732 (73%) NYHA class Class I Not assessed 762 (14%) 0 Class II Not assessed 3190 (59%) 3169 (49%) Class III Not assessed 1440 (27%) 3223 (50%) Class IV Not assessed (2%) Angina status No angina, 4812 (25%) CCS Class I, 2239 (12%) CCS Classes II to IV, (63%) Dosage of study treatment Main outcomes Primary endpoint Secondary outcomes Starting dose of 7.5 mg bid titrated to maximum of 10 mg bid or matching 5 mg bid Composite of CV mortalityand non-fatal MI endpoint, all-cause mortality lower cardiovascular risk (annual incidence for CV mortality 1.4% vs. 8.5% in SHIFT). Another major difference between the two studies is that there was heart failure in SHIFT, but not in SIGNIFY, i.e. the patients had LV dysfunction in SHIFT, but normal LV function in SIGNIFY. Heart rate reduction was associated with an improvement in prognosis in patients with low LVEF in SHIFT, but had no impact on risk in patients with normal LVEF in SIGNIFY. As ivabradine has no haemodynamic effects other than heart rate reduction through inhibition of the I f channel, this implies that effects of elevated heart rate differ according to LV function (Figure 1). The results of the BEAUTIFUL (morbidity mortality evaluation of the I f inhibitor ivabradine in patients with coronary disease and leftventricular dysfunction) trial 4 can be regarded as being intermediate No angina, 4680 (87%) Limiting angina, 712 (13%) Starting dose of 5 mg bid titrated to maximum of 7.5 mg bid or matching 2.5 mg bid Composite of CV mortality, hospital admission for HF, or hospital admission for MI endpoint, all-cause mortality Not assessed Starting dose of 5 mg bid titrated to maximum of 7.5 mg bid or matching 2.5 mg bid Composite of CV mortality or hospital admission for HF endpoint; all-cause mortality; HF mortality; composite of CV mortality, hospital admission for HF, or hospital admission for non-fatal MI Recruitment Recruitment period October 2009 to April 2012 January 2005 to December 2006 October 2006 to June 2009 Median duration of follow-up 27.8 months (IQR 21 35) 19 months (IQR 15 24) 23 months (IQR 18 28) 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). to those of SHIFT and SIGNIFY (Table 1, Figure 1), since the patients in that trial have stable CAD with LV systolic dysfunction (LVEF ¼ 32% and New York Heart Association heart failure classes I to III). As there was no inclusion criterion regarding heart rate in BEAUTIFUL (beyond a heart rate 60 bpm), for proper comparison, Table 1 includes the pre-specified sub-group of BEAUTIFUL patients with elevated heart rate ( 70 bpm). In these patients, ivabradine did not affect the primary composite endpoint of cardiovascular death, hospitalization for acute MI, and hospitalization for heart failure (event rates 17.2 and 18.5%; HR 0.91, 95% CI , P ¼ 0.17). An echocardiographic sub-study of BEAUTIFUL also reported evidence that ivabradine could reverse cardiac remodelling in patients with LV dysfunction. 7

3 2044 R. Ferrari and K.M. Fox Figure 1 Comparison of left ventricular function at baseline in SIGNIFY, BEAUTIFUL, and SHIFT, expressed as ejection fraction (top panel) and the effect of heart rate reduction with ivabradine on prognosis in SHIFT, BEAUTIFUL (patients with heart rate 70 bpm), and SIGNIFY, expressed as absolute risk reduction in primary composite outcomes (bottom panel). CAD, coronary artery disease; CV, cardiovascular; HF, heart failure; LVSD, left ventricular systolic dysfunction; MI, myocardial infarction. The role of heart rate in left ventricular systolic dysfunction The role and significance of an increase in heart rate in heart failure is complex. In heart failure, heart rate reflects the degree of neuroendocrine stimulation, i.e. sympathetic activation, which is known to be beneficial in the short term, but detrimental in the long term. 8 The elevation of heart rate is closely associated with stroke volume, and so its early increase could be considered as a compensatory mechanism. However, this is only true in the initial stages; prolonged neuroendocrine activation has deleterious effects on the myocytes resulting in ventricular changes for the worse and remodelling of the ventricle, another complex phenomenon whereby the ventricles progressively enlarge and ejection fraction reduces. It follows that, in these later stages, an increased heart rate is identified as a marker of the progression of disease and adverse prognosis. This has been clearly demonstrated by the results of the SHIFT study, showing that the higher baseline heart rate, the worse the outcome and, conversely, that the more heart rate could be reduced by ivabradine (which lacks any other effects), the greater the reduction in risk. 9 This is because elevation of heart rate itself has pathological effects, including generation of a further deterioration of LV systolic function, which in turn increases heart rate as the ventricle enters a vicious circle of decline. This so-called tachycardia-mediated cardiomyopathy has been reported in a number of animal models and clinical studies Exploration of the effect of different pacing rates in heart failure patients with implanted pacemakers has demonstrated that heart rate per se impacts LV dysfunction, with increases in volumes and reduction in ejection fraction at higher rates of pacing. 14,15 As heart failure progresses, the force-frequency relationship by which the normal heart regulates cardiac function becomes negative and the compensatory mechanism of increased heart rate is lost; myocardial contractility no longer improves with increasing heart rate. On the contrary, it further deteriorates, leading to progression of LV dysfunction. 13 The situation is further aggravated by a heart rateassociated increase in energy deprivation, inducing hypoxia, which stimulates local production of a range of cytokines, free radicals, and vasoconstrictors implicated in the development of LV remodelling. 16 Our data are supported by studies in patients with LV dysfunction. 17 Furthermore, an analysis from a registry of 3079 post-mi patients explored the interaction between the impact of heart rate on 5-year mortality and the presence or absence of LV dysfunction. Elevated heart rate at discharge had no impact on outcomes in

4 The role of heart rate from SHIFT to SIGNIFY 2045 patients with preserved LV function, but was associated with an 80% increase in patients with LV dysfunction (i.e. 18% per 10 bpm). 18 In the experimental setting, pure heart rate reduction with ivabradine improved cardiac function by significantly decreasing LV systolic diameter, increasing fractional shortening, and preservation of cardiac output. 16,19 This was associated with a positive impact on LV morphology with reduced collagen density and increased capillary density. 16 Similar cardiac benefits were also observed in experimental post-mi remodelling, 20,21 including normalization of biomarkers relevant to heart failure, such as circulating norepinephrine, brain natriuretic peptide, as well as inflammatory cytokines, with preservation of cardiac energy metabolism, which is profoundly depleted during heart failure. 19 Reversal of cardiac remodelling with ivabradine has also been confirmed in the setting of clinical LV dysfunction. In an echocardiographic sub-study of 400 participants in the SHIFT trial, 22 ivabradine was found to significantly improve LV end diastolic volume index ( with ivabradine vs ml/m 2 with, P ¼ 0.002) and LVEF ( % vs %, P, 0.001). Moreover, patients with the largest relative reduction in LV volumes on treatment had the lowest primary event rates, implying that heart rate reduction with ivabradine breaks the vicious circle, and modifies disease progression in heart failure. A similar favourable impact of ivabradine on LV remodelling has also been reported in CAD patients with LV dysfunction 7 and in post-mi patients. 23 It follows that, today, elevated heart rate is considered as an independent risk factor in heart failure with LV dysfunction. The role of heart rate in coronary artery disease In stable CAD, heart rate is a well-established determinant of ischaemia. In line with experimental data, clinical results indicate that elevations of heart rate during physical or emotional stress induce ischaemia and angina. 24 Consistent with this, heart rate reduction is a recognized strategy for the prevention of ischaemia and therefore of angina symptoms. Heart rate reduction with ivabradine has been demonstrated to improve angina symptoms, 25,26 since it reduces both resting heart rate and on exercise, which is when ischaemia is most likely to occur. In line with this, a heart rate of bpm is currently recommended for optimal anti-anginal efficacy of b-blockers and ivabradine in stable CAD. 27,28 Furthermore, experimental and clinical data suggested that heart rate may be involved in the progression of atherosclerosis and plaque rupture leading to MI. 29,30 This was the underlying rationale for the SIGNIFY study. The results confirm the symptomatic benefit of ivabradine, as shown by an improvement in angina class, but do not show a prognostic benefit (Figure 1) opening the question of whether heart rate under these conditions is a risk marker or merely an epiphenomenon of an underlying pathophysiological process. Interestingly, even the hypothetical prognostic benefits of b-blockers in stable CAD patients have been extrapolated by rather old studies on patients with MI, but never demonstrated in stable CAD, in contrast with the well-accepted prognostic impact on heart failure. In line with the SIGNIFY results, registry data suggest that there is no prognostic benefit of b-blockers in the stable coronary population. 31 The SIGNIFY results show that elevated resting heart rate is just a risk marker in stable CAD, and not a risk factor. Indeed, the increased heart rate in the SIGNIFY population cannot have been generated by an impairment of LV function, as described for heart failure. While it is unclear as to why these patients have elevated resting heart rate ( 70 bpm), it may well be that this is what the body requires for proper coronary function and its further reduction is irrelevant for prognosis but relevant for symptom improvement. Elevated heart rate certainly has a number of other pathophysiological effects, notably in the vascular system, 32 and correlates with other cardiovascular risk factors such as atherogenic blood lipid profile, blood glucose, insulin levels, and obesity. 29,33,34 These associations probably contribute to its role as a marker of CAD. Conclusion The results of the SIGNIFY trial have added to our knowledge of the role of heart rate in cardiovascular disease. Elevated heart rate is an important risk factor for ventricular remodelling in heart failure, and therefore for a poor prognosis in that setting. On the other hand, in cardiovascular disease without LV dysfunction or overt heart failure, increased heart rate is determinant of symptoms, and appears to be a marker of other processes that influence the development of MI (e.g. diabetes and smoking). This merits further exploration by meta-analysis in the ivabradine trials. The SIGNIFY and SHIFT results are set to lead to a better understanding of the interaction between elevated heart rate and LV function. Funding K.F. is an NIHR senior investigator supported by the NIHR Biomedical Research Unit at the Royal Brompton Hospital. Conflict of interest: none declared. References 1. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014;371: 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 -controlled trial. 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