Figure 7.1
Role of ivabradine in cardiovascular pathology. I f channels, in the sinoatrial node, are responsible for an inwardly direct current. The selective binding of ivabradine to I f channels, makes it a pure heart-rate–reducing agent. The heart rate reduction by ivabradine can reverse accelerated atherosclerosis and therefore a reduction of adverse cardiovascular events
By reducing heart rate, ivabradine reduces myocardial oxygen demand. It also maximizes oxygen supply and myocardial perfusion by prolonging diastolic time and by enabling coronary vasodilation during exercise [17]. In contrast, β-blockers tend to prolong systole because of their negative effect on myocardial contractility. In consequence, diastole is shorter with β-blockers than with ivabradine at rest and during exercise for a similar heart rate reduction [17].
Endothelial dysfunction has been demonstrated in CAD. In experimental studies, ivabradine has been shown to protect endothelial function. Treatment with ivabradine for 3 months prevented deterioration of endothelium-dependent vasodilation in the renal and cerebral arteries in dyslipidaemic mice [18]. Furthermore, recently has been demonstrated that oral ivabradine enhances the resolution of the marked inflammatory response associated with acute coronary syndrome [19, 20]. These data suggest that ivabradine can ameliorate the vascular component of inflammation in line with observations of previous studies in animal models [21, 22].
Pharmacokinetic Properties and Tolerability
Ivabradine exhibits linear pharmacokinetics over an oral dose range of 0.5–24 mg, with rapid absorption after administration of a single oral dose [23]. In fasting conditions, the time to peak drug concentration is approximately 1 h, with an absolute bioavailability of the filmcoated tablets of around 40 % following gastrointestinal and hepatic first-pass metabolism. In fed conditions, the time to peak plasma drug concentration is prolonged by approximately 1 h and the plasma concentration of ivabradine is increased by 20–30 % [23].
Ivabradine has a half-life of 2 h in plasma and an effective half-life of 11 h. Renal clearance of ivabradine is 70 mL/min, and the total clearance is 400 mL/min. After oral administration, approximately 4 % of the ivabradine dose is excreted unchanged in urine. Compared with younger individuals, no appreciable differences in the pharmacokinetic profile of ivabradine were observed in the elderly (aged ≥65 years) or very elderly (≥75 years) [23].
Renal impairment (creatinine clearance 15–60 mL/min) has a minimal effect on the pharmacokinetics of both ivabradine and its main metabolite, as renal clearance accounts for a small part (20 %) of the elimination of both products. As regards hepatic impairment and ivabradine, patients with mild hepatic impairment require no dose adjustment. Caution is advocated when treating patients with moderate hepatic impairment, and ivabradine is contraindicated in patients with severe hepatic insufficiency [23].
Ivabradine has a favourable tolerability profile, as observed during its clinical development [24]. It is safe and well tolerated when administered as a monotherapy [25, 26] or when administered in combination with atenolol [27], bisoprolol [28], other β-blockers [29] or other cardiovascular therapies [30]. Ivabradine is also well tolerated in patients with comorbidities including asthma and chronic obstructive pulmonary disease [31] or in patients with diabetes mellitus, without any particular safety concerns or adverse effects on glucose metabolism [32].
The two most common adverse events associated with the recommended doses of ivabradine are bradycardia and visual symptoms [24]. Bradycardia is an expected adverse event of any heart rate-reducing treatment. However, in the clinical programme of ivabradine, only 3–4 % of patients receiving therapeutic doses of ivabradine (5 or 7.5 mg twice daily) experienced symptomatic bradycardia. Furthermore, there were very low rates of discontinuation in these studies due to this adverse event [33, 34]. The visual symptoms associated with ivabradine are due to the action of ivabradine on retinal ion channels (I h current), which belong to the same family as those responsible for the I f current in the sino-atrial node. In the clinical trials of ivabradine, visual symptoms (mainly phosphenes) were reported in a small proportion of patients. These symptoms were generally mild and resolved spontaneously during or after treatment. Less than 1 % of patients receiving ivabradine in clinical trials discontinued treatment because of visual symptoms [25–30, 35].
Efficacy of Ivabradine in CAD with Monotherapy
The anti-anginal and anti-ischemic efficacy of ivabradine has been confirmed in patients with stable angina and monotherapy (Table 7.1).
Table 7.1
Summary of the main studies of ivabradine in coronary artery disease with monotherapy
Author | Study summary |
|---|---|
Borer et al., 2003 [25] | Randomised double-blind, placebo-controlled trial, 360 patients with a ≥3-month history of chronic stable angina were randomly assigned to receive ivabradine (2.5, 5, or 10 mg BID) or placebo for 2 weeks, followed by an open-label 2- or 3-month extension on ivabradine (10 mg BID) and a 1-week randomized withdrawal to ivabradine (10 mg BID) or placebo. In the per-protocol population (n = 257), time to 1-mm ST-segment depression increased in the 5 and 10 mg BID groups (P < 0.005); time to limiting angina increased in the 10 mg BID group (P < 0.05). |
Tardif et al., 2005 [26] | Randomised, double-blinded trial, 939 patients with stable angina were randomized to receive ivabradine 5 mg bid for 4 weeks and then either 7.5 or 10 mg bid for 12 weeks or atenolol 50 mg od for 4 weeks and then 100 mg od for 12 weeks. Patients underwent treadmill exercise tests at randomization (M(0)) and after 4 (M(1)) and 16 (M(4)) weeks of therapy. Increases in total exercise duration at trough at M(4) were 86.8 ± 129.0 and 91.7 ± 118.8 s with ivabradine 7.5 and 10 mg, respectively and 78.8 ± 133.4 s with atenolol 100 mg. The number of angina attacks was decreased by two-thirds with both ivabradine and atenolol. |
Ruzyllo et al., 2007 [36] | Patients with a ≥3-month history of chronic, stable effort-induced angina were randomised to receive ivabradine 7.5 mg (n = 400) or 10 mg (n = 391) twice daily or amlodipine 10 mg once daily (n = 404) for a 3-month, double-blind period. Bicycle exercise tolerance tests were performed at baseline and monthly intervals. At 3 months, total exercise duration was improved by 27.6 ± 91.7, 21.7 ± 94.5 and 31.2 ± 92.0 s with ivabradine 7.5 and 10 mg and amlodipine, respectively, both ivabradine groups were comparable to amlodipine (p-value for noninferiority <0.001). Similar results were observed for time to angina onset and time to 1 mm ST-segment depression. |
Skalidis et al., 2011 [37] | During diagnostic coronary angiography (baseline), 21 patients with stable coronary artery disease underwent coronary flow velocity measurements in a non-culprit vessel, using a Doppler guidewire, at rest (r) and after adenosine administration to achieve maximal hyperaemia (h). During programmed coronary intervention in the culprit vessel, the same measurements were repeated 1 week after treatment with ivabradine (5 mg twice daily). |
Ivabradine treatment significantly improves hyperaemic coronary flow velocity and coronary flow reserve in patients with stable coronary artery disease. These effects remain even after heart rate correction indicating improved microvascular function. |
In a placebo-controlled, randomized, dose-ranging study conducted in 360 patients with stable CAD and chronic stable angina, Borer et al. [25] showed that ivabradine produced dose-dependent improvements in exercise tolerance parameters. This reduction in angina and ischemia was associated with significant reductions in rate-pressure product at peak exercise and increases in total work performed in an exercise tolerance test among ivabradine-treated patients. Furthermore, in the open-label extension phase (2–3 months) of this study, ivabradine reduced angina attacks from 4.14 to 0.95 attacks per week and consumption of short-acting nitrates from 2.28 to 0.50 U per week [25].
Tardif et al., in a double-blind, randomised, active-controlled, parallel-group and multicentre study, demonstrated that after 16 weeks of treatment, patients receiving ivabradine 7.5 or 10 mg twice daily or atenolol 100 mg/day had similar increases in total exercise duration and the number of angina attacks per week. Even though ivabradine was noninferior, after 4 months of treatment, all exercise tolerance test parameters showed a trend toward improvement with ivabradine compared with atenolol [26].
Ruzyllo et al., in a large multicentre, international, double-blind, randomized, parallel-group trial in 1,195 patients with stable angina, studied the efficacy of ivabradine versus amlodipine. They demonstrated, that ivabradine was not inferior to amlodipine in improving exercise tolerance as well as increasing time to angina onset, time to limiting angina and time to 1-mm ST-segment depression. Furthermore, ivabradine produced a greater reduction of rate-pressure product than amlodipine [36]. Recently, Skalidis et al. [37] assessed the effect of ivabradine on coronary blood flow velocity and coronary flow reserve in patients with stable CAD. This study showed that ivabradine significantly reduced heart rate and improved hyperaemic and resting coronary flow velocity and coronary flow reserve in these patients after 1 week of treatment.
Efficacy of Ivabradine in CAD with Combination Therapy
The anti-anginal and anti-ischemic efficacy of ivabradine has been confirmed in patients with stable angina and combination therapy (Table 7.2).
Table 7.2
Summary of the main studies of ivabradine in coronary artery disease with combination therapy
Author | Study summary |
|---|---|
Lopez-Bescos et al., 2007 [30] | Randomized double-blind, parallel-group study 386 patients with chronic stable angina were randomized to either ivabradine 5 mg b.i.d. (n = 198, group 1) or ivabradine 7.5 mg b.i.d. (n = 188, group 2) for 12 months. Safety was assessed on the basis of reported adverse events at 1, 3, 6, 9 and 12 months. Ivabradine was well tolerated. Resting heart rate was reduced by 9 bpm in group 1 and 12 bpm in group 2. At month 12 relative to month 0 there was a significant reduction in the number of angina attacks per week. |
Tardif et al., 2009 [27] | Randomised double-blinded trial, 889 patients with stable angina receiving atenolol 50 mg/day were randomized to receive ivabradine 5 mg b.i.d. for 2 months, increased to 7.5 mg b.i.d. for a further 2 months, or placebo. Patients underwent treadmill exercise tests at the trough of drug activity using the standard Bruce protocol for randomization and at 2 and 4 months. Total exercise duration at 4 months increased by 24.3 ± 65.3 s in the ivabradine group, compared with 7.7 ± 63.8 s with placebo (P < 0.001). Ivabradine was superior to placebo for all exercise test criteria at 4 months (P < 0.001 for all) and 2 months (P-values between <0.001 and 0.018). Ivabradine in combination with atenolol was well tolerated. |
Amosova et al., 2011 [28] | Twenty-nine patients with stable angina and moderate left ventricular systolic dysfunction already on bisoprolol 5 mg od were randomized into 2 groups. Group 1 (n = 17) received ivabradine (5–7.5 mg bid) in addition to bisoprolol 5 mg od, while in group 2 (n = 12) bisoprolol was uptitrated first to 7.5 mg and then 10 mg od. Patients underwent a treadmill test, 6-min walking test, and echocardiography at baseline and after 2 months. Mean resting heart rate decreased in both groups, from 76.6 ± 4.6 to 59.3 ± 2.5 bpm (P < 0.001) in group 1 and from 75.9 ± 3.0 to 60.5 ± 2.3 bpm (P = 0.002) in group 2. However, more patients became asymptomatic in group 1 than in group 2. Addition of ivabradine also improved exercise capacity. Chronotropic reserve significantly improved with ivabradine, but not with bisoprolol 10 mg. |
Werdan et al., 2012 [29] | Non-interventional, multicenter, prospective study included 2,330 patients with stable angina pectoris treated with a flexible dose of ivabradine twice daily in addition to beta-blocker for 4 months. The parameters recorded included heart rate, number of angina attacks, nitrate consumption, tolerance, and quality of life. After 4 months ivabradine reduced heart rate, the number of angina attacks and nitrate consumption was reduced At baseline (i.e., on beta-blocker), half of the patients (51 %) were classified as Canadian Cardiovascular Society (CCS) grade II; 29 % were CCS grade I. After 4 months’ treatment with ivabradine, most of the patients were CCS grade I (68 %). |
Fox et al., 2014 [38] | Randomized, double-blind, placebo-controlled trial of ivabradine, added to standard background therapy, in 19,102 patients who had both stable coronary artery disease without clinical heart failure and a heart rate of 70 beats per minute or more The primary end point was a composite of death from cardiovascular causes or nonfatal myocardial infarction. After a median follow-up of 27.8 months, there was no significant difference between the ivabradine group and the placebo group in the incidence of the primary end point (6.8 % and 6.4 %, respectively; hazard ratio, 1.08; 95 % confidence interval, 0.96–1.20; P = 0.20), nor were there significant differences in the incidences of death from cardiovascular causes and nonfatal myocardial infarction. Ivabradine was associated with an increase in the incidence of the primary end point among patients with activity-limiting angina but not among those without activity-limiting angina (P = 0.02 for interaction). |
The double blind, randomized, multicentre, placebo-controlled ASSOCIATE (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a beTa-blockEr) trial was conducted in 889 patients with stable angina already receiving atenolol [27]. All included patients had a positive symptom-limited exercise test while receiving atenolol 50 mg once daily. These patients were randomized to receive either ivabradine 5 mg twice daily for 2 months, which was then increased to 7.5 mg twice daily for an additional 2 months (449 patients), or placebo (440 patients) and underwent exercise testing at the trough of drug activity at 2 and 4 months. Ivabradine significantly increased the total exercise duration as well as all other exercise test criteria such as time to limiting angina, time to angina onset and time to 1 mm ST-segment depression compared with placebo. Therefore, this study clearly demonstrated that ivabradine treatment in patients with stable angina receiving the β-blocker resulted in a significant long-term improvement in total exercise duration in standardized Bruce protocol exercise testing [27].
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