Ivabradine in chronic stable angina: Effects by and ...

International Journal of Cardiology 215 (2016) 1–6

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Review

Ivabradine in chronic stable angina: Effects by and beyond heart rate reduction Paolo G. Camici a,⁎,1, Steffen Gloekler b, Bernard I. Levy c, Emmanouil Skalidis d, Ercole Tagliamonte e, Panos Vardas f, Gerd Heusch g,1 a

Vita Salute University, San Raffaele Hospital, Milan, Italy Cardiology, Cardiovascular Department, University Hospital Bern, Bern, Switzerland PARCC, INSERM U970, Vessels and Blood Institute, Hôpital Lariboisière, Paris, France d Cardiology Department, University Hospital of Heraklion, Crete, Greece e Cardiology Division, “Umberto I” Hospital, Nocera Inferiore, SA, Italy f Cardiology Department, University Hospital of Heraklion, Greece g Institute for Pathophysiology, West German Heart and Vascular Centre Essen, University of Essen Medical School, Essen, Germany b c

a r t i c l e

i n f o

Article history: Received 8 February 2016 Accepted 2 April 2016 Available online 11 April 2016 Keywords: Angina pectoris Anti-anginal drug Beta-blocker Coronary artery disease Coronary blood flow Coronary collateral circulation

a b s t r a c t Heart rate plays a major role in myocardial ischemia. A high heart rate increases myocardial performance and oxygen demand and reduces diastolic time. Ivabradine reduces heart rate by inhibiting the If current of sinoatrialnode cells. In contrast to beta-blockers, ivabradine has no negative inotropic and lusitropic effect for a comparable heart rate reduction. Consequently, diastolic duration is increased with ivabradine compared to beta-blockers. This has potential consequences on coronary blood flow since compression of the vasculature by the surrounding myocardium during systole impedes flow and coronary blood flow is mainly diastolic. Moreover, ivabradine does not unmask alpha-adrenergic vasoconstriction and, unlike beta-blockers, maintains coronary dilation during exercise. In comparison with beta-blockers, ivabradine increases coronary flow reserve and collateral perfusion promoting the development of coronary collaterals. Ivabradine attenuates myocardial ischemia and its consequences even in the absence of heart rate reduction, possibly through reduced formation of reactive oxygen species. In conclusion, ivabradine differs from other anti-anginal agents by improving coronary blood flow and by additional pleiotropic effects. These properties make ivabradine an effective anti-anginal and anti-ischemic agent for the treatment of patients with coronary artery disease. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Stable angina pectoris is the most common manifestation of ischemic heart disease. Although the annual mortality rate is relatively low, with an annual incidence of non-fatal myocardial infarction between 0.5 [1] and 2.6% [2], anginal symptoms are often disabling. Obstructive atherosclerotic disease of the epicardial coronary arteries and dysfunction of the coronary microcirculation are the main pathogenetic mechanisms responsible for the reduction of coronary flow reserve (CFR) [3] and the initiation of myocardial ischemia under stress or exercise (Fig. 1). Typically, ischemia and angina develop during conditions of increased cardiac workload due to the mismatch between oxygen demand and supply imposed by the limited CFR (Fig. 2). ⁎ Corresponding author at: Università Vita Salute San Raffaele, Via Olgettina 58, 20132 Milano, Italy. E-mail address: [email protected] (P.G. Camici). 1 These two authors have contributed equally to the manuscript.

http://dx.doi.org/10.1016/j.ijcard.2016.04.001 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.

The aims of treatment, which includes lifestyle changes, drugs and coronary revascularization by either percutaneous or surgical techniques, are to relieve anginal symptoms and improve quality of life. Drugs that attenuate anginal symptoms act mainly by improving the mismatch between oxygen demand and supply and include nitrates, beta-adrenoceptor and calcium channel blockers and potassium channel openers [4]. On a background of optimal medical therapy, revascularization by percutaneous coronary interventions (PCI) improves anginal symptoms [4]. However, in a substantial proportion of patients, the prevalence of angina at follow-up remains high despite successful revascularization. In the COURAGE trial more than 25% of patients were still experiencing angina 1 year after PCI, and at 5-year follow-up the incidence of angina was not significantly different from that in patients who did not undergo a revascularization procedure [5]. These findings suggest that, although revascularization is effective in removing coronary stenosis and its hemodynamic consequences, other mechanisms, including coronary microvascular dysfunction, contribute to the pathogenesis of ischemia and angina in these patients.

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P.G. Camici et al. / International Journal of Cardiology 215 (2016) 1–6

Fig. 1. Mechanisms of myocardial ischemia. In addition to the “classic mechanisms” of myocardial ischemia involving the epicardial arteries (i.e. atherosclerotic disease and vasospastic disease), coronary microvascular dysfunction (CMD) has recently emerged as an additional mechanism of myocardial ischemia. As in the case of the other two mechanisms, CMD (alone or in combination with the other two) can lead to transient myocardial ischemia as in patients with CAD or cardiomyopathy or to severe acute ischemia as observed in Takotsubo syndrome [3].

More recently, the sinus node inhibitor ivabradine, which reduces heart rate (HR) both at rest and during exercise, has been proven to have anti-anginal efficacy [6,7] and may be used in combination with beta blockers or as an alternative in patients who do not tolerate beta blockade [4]. Although the main anti-anginal mechanisms of ivabradine are reduction of myocardial oxygen consumption and improvement of coronary blood flow, more recent experimental and clinical investigations have demonstrated that ivabradine may reduce myocardial ischemia and its consequences not only through HR reduction, but also through additional pleiotropic mechanisms that contribute to improve coronary vascular and myocardial structure and function [8,9]. The aim of the present paper is to review the effects of ivabradine on coronary blood flow and ventricular function in patients with chronic ischemic heart disease. 2. Prolongation of diastolic duration and improvement of coronary blood flow at rest The intramural coronary microvasculature is compressed by the contracting myocardium throughout systole such that almost no coronary blood flow occurs during systole. Thus coronary blood flow occurs mostly during diastole and, therefore, diastolic time is of major

importance for a correct coronary physiology [10]. Beta-blockers and some calcium antagonists reduce HR decreasing myocardial oxygen demand while increasing diastolic time. The subendocardial left ventricular myocardium is particularly vulnerable to ischemia; an increase in diastolic duration and then in coronary blood flow is especially beneficial for subendocardial layers. In a normal heart, it has been estimated that a 1% increase of the diastolic time fraction increases the subendocardial flow by 2.6 to 6% [11]. Both the driving pressure gradient and the duration of diastole are integrated into the diastolic pressure–time integral, which is the essential mechanical determinant of coronary blood flow [12–14]. The effects of ivabradine and the beta-blocker atenolol on diastolic duration have been compared in dogs [15]. Ivabradine increased diastolic duration at rest and during exercise to a greater extent than atenolol, with similar HR reduction for both drugs [15]. As a result of the increased diastolic duration, ivabradine caused a greater increase in coronary blood flow for the same reduction in HR compared with atenolol. A recently published randomized, double-blind, crossover study by Dillinger et al. [16] demonstrated an increase in diastolic duration with ivabradine in patients with coronary artery disease (CAD) receiving beta-blockers. Treatment with ivabradine over 3 weeks resulted in a 41% increase in diastolic duration and a 39% increase in the index of

Fig. 2. The ischemic cascade. Temporal sequence of pathophysiological events initiated by an oxygen supply/demand imbalance.


myocardial viability (Buckberg's index) (Fig. 3). The increase in the Buckberg's index with ivabradine, which reflects an improved myocardial supply/demand ratio, is also in line with better perfusion and a positive impact on myocardial ischemia with ivabradine [8]. These results are of major importance when the oxygen supply to myocardium reaches the ischemic threshold in patients with angina pectoris. 3. Attenuation of endothelial dysfunction Ivabradine may prevent deterioration of endothelial function. In dyslipidemic mice expressing human apoprotein B-100 (inducing oxidative stress and endothelial dysfunction), three months treatment with ivabradine completely prevented the deterioration of endothelium-dependent vasodilation in renal and cerebral arteries [17]. The protective effect of ivabradine was not fully reproduced by metoprolol, despite similar HR reduction, possibly due to inhibition of betaadrenoceptor-mediated activation of endothelial NO synthase. In another model, untreated apolipoprotein E-deficient mice fed a ‘western-type’ high-fat diet exhibited severe hypercholesterolemia and atherosclerotic plaques; ivabradine treatment reduced the formation of reactive oxygen species in aortic tissue compared with vehicle-treated animals, improved endothelial function, and reduced atherosclerotic plaque area in the aortic root and ascending aorta [18]. Data from recently published open studies in patients suggest a positive effect of ivabradine on endothelial function also in patients with stable CAD [19,20]. 4. Improvement of coronary blood flow during exercise and coronary flow reserve Beta blockers do not reduce catecholamine concentrations, but antagonize their actions at beta-adrenergic receptors while leaving their actions at alpha-adrenergic receptors unopposed. Therefore, the balance of beta-adrenergic vasodilation and alpha-adrenergic vasoconstriction is shifted towards vasoconstriction after beta blockade, as known to every practicing physician from patients complaining about Raynaud's syndrome or cold finger tips after beta blockade. Beta blockade also unmasks alpha-adrenergic vasoconstriction in epicardial coronary arteries and the coronary microcirculation as demonstrated in experimental dog models [21,22] and in humans [23]. In contrast, ivabradine does not unmask alpha-adrenergic vasoconstriction [24]. In conscious chronically instrumented dogs, beta blockade resulted in constriction of large and small coronary arteries during exercise, while ivabradine still permitted coronary vasodilation during exercise despite similar HR reduction [24]. Importantly, the alpha-adrenergic vasoconstriction is enhanced in the presence of endothelial dysfunction, a hallmark of cardiovascular risk factors [25]. Therefore this effect of

Fig. 3. Prolongation of diastolic perfusion time with ivabradine in patients with stable CAD during a single heart beat at rest [16]. LVET indicates left ventricular ejection time.

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ivabradine is especially important in human atherosclerotic coronary vessels [23]. Consequently, the ability of ivabradine to preserve coronary dilation during exercise is of major therapeutic importance in patients with CAD. CFR is the ratio of coronary blood flow during (near) maximal vasodilatation (generally achieved by administration of adenosine or dipyridamole) to baseline flow and is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation [26,27]. An abnormal CFR can be due to narrowing of the epicardial coronary arteries or, in the absence of angiographically demonstrable obstructive CAD, may reflect dysfunction of the coronary microcirculation. The latter can be caused by structural (e.g. vascular remodeling with reduced lumen to wall ratio) or functional (e.g. vasoconstriction or reduced vasodilation) changes, which may involve neurohumoral factors and/or endothelial dysfunction [28]. Skalidis et al. [29] studied the effect of treatment with ivabradine on CFR in the “non-culprit vessel” in 21 patients with stable CAD. Treatment increased hyperemic coronary flow velocity in response to intracoronary adenosine and CFR (3.51 ± 0.81 versus 2.78 ± 0.61 at baseline, p b 0.001) (Fig. 4). The measurement of CFR was repeated at a pacing HR similar to baseline, accomplished by pacing the right atrial appendage via a temporary pacing lead. CFR during atrial pacing was still significantly improved compared to baseline. The above results were confirmed by Tagliamonte et al. [30] in a more recent randomized, controlled study in 59 patients with stable CAD where the effects of bisoprolol and ivabradine on CFR were compared. After one month of treatment, CFR was increased in both groups, but significantly more in the ivabradine group than the bisoprolol group (3.52 ± 0.64 versus 3.35 ± 0.70, respectively; p b 0.01), despite a similar reduction of HR. 5. Improvement of the coronary collateral function Coronary collaterals are anastomotic connections between portions of the same coronary artery or between different coronary arteries. The development of a coronary collateral circulation is a natural mechanism that compensates, more or less completely, the limitation of coronary flow when coronary stenosis progresses [31]. There is a relationship between the development of collaterals and outcome and long-term survival in patients with stable CAD [32]. HR reduction improves collateral perfusion at a given collateral status and increases collateral development over time. With a given collateral circulation, HR reduction increases collateral perfusion by increasing the driving

Fig. 4. Ivabradine improves CFR in patients with stable CAD [29]. Box-plots of coronary flow velocity reserve (CFR) at baseline (Baseline) and after one week of treatment with ivabradine, both at the intrinsic heart rate (Ivabradine) and at a paced rate identical to that at baseline (Ivabr-pace).

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pressure gradient for collateral perfusion, both by attenuating metabolic vasodilation and increasing perfusion pressure at the origin of collaterals at the donor side and by attenuating extravascular compression and decreasing pressure at the orifice of collaterals at the recipient side [33,34] (Fig. 5). The relationship between bradycardia and the development of a coronary collateral circulation has been demonstrated both in animal models and in patients with CAD. Lamping et al. [35], in an experimental dog model, showed that bradycardia accelerates the development of the coronary collateral circulation during a gradual coronary occlusion by upregulating growth factors (especially the vascular endothelial growth factor; VEGF) and their receptors. In a retrospective study, that included CAD patients with HR either ≤ 50 beats/ min or ≥60 beats/min, the collateral circulation developed more in patients with lower HR (97% for patients with HR ≤50 beats/min versus 55% for those with HR ≥60 beats/min; p b 0.005) [36]. These results suggest that there is an association between low HR and growth of collateral vessels in patients with CAD. There is, however, a large variability among patients, and many patients with CAD develop an insufficient coronary collateral circulation. Therefore, the improvement of coronary collateral circulation with a pharmacological therapy would be useful in the treatment of CAD. Lowering HR increases diastolic coronary flow velocity and may possibly also increase coronary endothelial shear stress. Shear stress activates endothelial cells that, in turn, produce nitric oxide and VEGF, induce macrophage accumulation and remodeling of vessels, thus leading to arteriogenesis. In this context, a heart rate-reducing drug without coronary vasoconstriction could, theoretically, have a positive effect on collateral function [36,37]. Ivabradine has been shown to promote the development of coronary collaterals both in experimental models and in clinical trials. In an apolipoprotein E-deficient mouse model with hind limb ligation, Schirmer et al. [38] reported that ivabradine-induced HR reduction stimulated collateral artery growth, whereas metoprolol failed to improve endothelial function and perfusion. In a study in post-infarct remodeled

hearts, the impact of HR reduction by ivabradine on left ventricular function, angiogenesis and coronary resistances was studied. Reduction of HR with ivabradine promoted growth of coronary vessels in the surviving portion of the left ventricular myocardium [39]. These experimental data are in line with clinical findings. In a recent proof-of-concept study, Gloekler et al. [40] examined the effect of HR reduction by ivabradine on coronary collateral function. In this randomized placebo-control study in 46 patients with stable CAD, the mean HR change, after a 6-month follow-up, was +0.2 beats/min in the placebo group and −8.1 beats/min in the ivabradine group. Coronary collateral function was assessed by invasive measurement of a collateral flow index (CFI) during balloon occlusion by means of a pressure guide wire distal to the balloon-occluded artery. The CFI showed no difference in the placebo group (0.140 ± 0.097 at baseline to 0.109 ± 0.067, p = 0.12). In contrast, CFI increased from 0.107 ± 0.077 at baseline to 0.152 ± 0.090 in the ivabradine group (p = 0.0461). The difference in CFI between the 6-months follow-up and baseline was − 0.031 ± 0.090 in the placebo group and + 0.040 ± 0.094 in the ivabradine group (p = 0.0113). There was an inverse relationship between the change in HR at 6-months follow-up and the change in CFI. Therefore, HR reduction by ivabradine had a positive effect on coronary collateral function in patients with chronic stable CAD. Consistently, this improvement of CFI was accompanied by diminished ECG signs of ischemia. In a study which assessed 365 coronary arteries of 285 patients and evaluated the collateral function by CFI, Gloekler et al. [41] demonstrated an inverse correlation between resting HR and CFI in patients that were not treated with beta blockers. This relationship was abolished by beta blockers, most probably due to their vasoconstrictor effect. 6. Attenuation of systolic dysfunction and stunning Randomized trials have shown the beneficial effects of HR reduction with ivabradine in stable CAD with left ventricular dysfunction [42] and

Fig. 5. Heart rate and coronary collateral flow. Schematic representation of changes in the driving pressure gradient for collateral blood flow and of microvascular resistance in normal myocardium (left) and in post-stenotic myocardium (right). There is an autoregulatory decrease in microvascular resistance of the post-stenotic myocardium. With increasing heart rate, metabolic vasodilation and a decrease of microvascular resistance occur in healthy myocardium, resulting in decreased pressure at the origin of collaterals. In contrast, in poststenotic myocardium, no further dilation is possible, and the reduction in diastolic duration prevails; subsequently, microvascular resistance and the pressure at the orifice of collaterals into the post-stenotic coronary vasculature are increased [34].


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Fig. 6. Longitudinal segmental strain in remote and ischemic segments. Panel a: values of longitudinal segmental strain in remote segments [46]. Panel b: values of longitudinal segmental strain in ischemic segments (all data are means ± SD).

heart failure [43]. Treatment with ivabradine in the SHIFT trial achieved an 18% decrease in the primary endpoint of cardiovascular death and heart failure hospitalization in patients with systolic heart failure and HR N 70 bpm. Studies in dogs treated with ivabradine have demonstrated a reduction of left ventricular dyskinesia and duration of postischemic myocardial stunning following treadmill exercise [44]. Therefore, ivabradine may limit the progression to left ventricular dysfunction in patients with CAD through effective reduction of repetitive ischemia and post-ischemic stunning [45]. In a recent study in patients with exercise-inducible ischemia, ejection fraction N 40% and HR N70 bpm, Maranta et al. [46] tested the effect of ivabradine on exercise-induced left ventricular dysfunction and on post-ischemic stunning. After pharmacologic washout, echocardiography was performed at rest, at peak treadmill exercise and during recovery until return to baseline. After 2 weeks of ivabradine (7.5 mg bid) stress echocardiography was repeated at the same workload achieved during washout. Peak global and segmental (ischemic versus remote normal segments) left ventricular longitudinal strain (LS) was assessed by 2D speckle tracking analysis. At washout, LS was significantly impaired in ischemic compared to remote segments at peak stress and for several minutes during recovery. After ivabradine a smaller, albeit still significant, impairment of LS in ischemic segments was observed at peak while no difference with remote segments was present during recovery (Fig. 6). In summary, the results of this study provide evidence that ivabradine reduces both acute left ventricular dysfunction and postischemic stunning in patients with CAD and exercise-inducible ischemia. It can be hypothesized that this mechanism might contribute to reduce chronic left ventricular dysfunction in patients with CAD. In this setting the drug might limit the development of hibernating myocardium which is believed to result from repeated episodes of ischemia and stunning [45,47]. Reduced formation of reactive oxygen species which are pathogenetic for stunning may contribute to the beneficial effect of ivabradine [9].

7. Conclusion Ivabradine is an anti-anginal agent with an original pharmacodynamic profile since it decreases HR without a negative inotropic effect and without a coronary vasoconstrictor effect. Ivabradine increases diastolic duration and coronary blood flow and preserves coronary dilation during exercise. In addition, ivabradine increases coronary flow reserve and improves collateral perfusion. Ivabradine differs from other antianginal agents by improving coronary blood flow and by additional pleiotropic effects. These properties make ivabradine an effective antianginal and anti-ischemic treatment in patients with CAD.

Conflict of interest statement PGC, SG and GH have served as consultants and on the speakers' board for Servier. BL, ES and PV have served as consultants for Servier.

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