Ranolazine and Ivabradine: two different modalities to act against ischemic heart disease

Abstract

Among the innovative drugs recently introduced for the management of chronic stable angina, Ranolazine and ivabradine represent two most true innovations. In fact, even if both drugs act by reducing myocardial work and thus oxygen consumption, this happens by a peculiar mechanism unlike that of conventional antischemic drugs. Ranolazine mediates its antianginal effects by the inhibition of cardiac late sodium current. This improves myocardial relaxation favoring myocardial perfusion. Ivabradine is a selective I_f channel blocker and acts by reducing firing rate of pacemaker cells in the sinoatrial node, without affecting the duration of action potential. The reduction of heart rate causes a reduction of left ventricular end diastolic pressure and increases the time useful to coronary flow by a prolongation of the diastole. A body of evidence found that two drugs are useful in ischemic patients whether at rest or during exercise. In addition, they can be used in monotherapy or in association with other conventional anti-ischemic drugs. The two medications could be used with advantage also in microvascular angina when standard therapy is ineffective. Thus, the two drugs represent an adjunctive and powerful therapeutic modality for the treatment of chronic stable angina, especially when conventional antianginal drugs were insufficient or inadequate.

Introduction

Apart from new oral anticoagulants (NOA), ranolazine [Belardinelli et al. 2006a] and ivabradine [Lopez-Boscos et al. 2004] are the most relevant pharmacologic innovations introduced in past years in cardiovascular therapy. In contrast to ivabradine, which can be used in both chronic heart failure (CHF) and coronary artery disease (CAD), ranolazine can be employed only in chronic stable angina. CAD is a debilitating illness affecting millions of patients throughout developed countries. Its incidence increases with advancing age and is about 4–5% in aged individuals, representing one of the most common cause of death together with CHF [Pagitipati and Gaziano, 2013]. Conventional antianginal drugs such as nitrates, β-blockers and calcium channel blockers reduce myocardial ischemia by significantly decreasing the main determinants of myocardial oxygen demand such as heart rate, blood pressure or myocardial contractility both at rest and during exercise [Abrams, 2005]. Ivabradine also acts by reducing heart rate and therefore, of myocardial work, consequently reducing oxygen consumption. In contrast, ranolazine acts by a novel mechanism.

Ranolazine

Ranolazine is a first-in-class antianginal drug having cardioprotective properties [Pepine and Wolff, 1999]. Ranolazine acts by the preservation of myocardial blood flow during ischemia through its effects on inhibition of late inward sodium current. This is due to blockade of the cardiac isoform of the sodium channel. This maintains sodium and calcium homeostasis, preventing myocardial cellular sodium overload. Consequently, the drug improves myocardial relaxation and reduces left ventricular diastolic myocardial stiffness [Belardinelli et al. 2006b; Hayashida et al. 1994]. This effect, in turn, improves myocardial perfusion. The anti-ischemic properties of ranolazine have been shown to be exerted without significant modifications in heart rate, blood pressure and inotropic state [European Medicine Agency 2008]. The molecule has been shown to be safe and effective in treating chronic angina both in monotherapy, as evidenced in the MARISA (Monotherapy Assessment of Ranolazine in Stable Angina) trial [Chaitman et al. 2004b], and in combination with commonly anti-ischemic cardiovascular drugs, as reported in the CARISA (Combination Assessment of Ranolazine in Stable Angina) study [Chaitman et al. 2004a].

In patients with continuing angina attacks (more than three per week), the clinical, randomized trial ERICA (Evaluation of Ranolazine in Chronic Angina) was performed. Patients enrolled were already being treated with amlodipine (10 mg daily), with or without long-acting nitrates. The results obtained showed a significant reduction in the number and severity of anginal attacks, with excellent tolerability [Stone et al. 2006]. Nevertheless together with the positive effects, the negative results on chronic angina recently reported in the RIVER-PCI trial should also be discussed. The study involved more than 2000 patients with post percutaneous coronary intervention (PCI) incomplete revascularization and a history of chronic angina. After a median follow up of 643 days, no difference between patients receiving ranolazine or placebo for the primary endpoint of ischemia-driven revascularization or hospitalization was found [Weisz et al. 2016]. The probable cause of the negative results is that the study included a mixed group patients with residual disease. In fact, almost half of patients had three-vessel disease and one-third had an untreated chronic total occlusion.

The efficacy of ranolazine as an anti-arrhythmic drug was evaluated in the MERLIN-TIMI 36 (Metabolic Efficiency with Ranolazine for Less Ischemia in No-ST Elevation Acute Coronary Syndromes) trial. The study suggested that ranolazine significantly decreases the incidence of ventricular tachycardia, supraventricular tachycardia and ventricular pauses, and contemporarily evidenced its antianginal efficacy [Morrow et al. 2009]. However, the drug may be associated with an increased incidence of torsade de pointes and so could favor ventricular arrhythmias by a slight prolongation of QT interval [Song et al. 2004]. In addition, ranolazine treatment showed a significant improvement of glycometabolic parameters as shown by the reductions in glycosylated hemoglobin [Belardinelli et al. 2006a; Chaitman et al. 2004b; Stone et al. 2006; Timmis et al. 2006]. It must also added that, in experimental studies, ranolazine was found to lower fasting and nonfasting glucose levels and to preserve pancreatic β-cells in streptozotocin-treated mice [Ning et al. 2011; Dhalla et al. 2014]. Concerning these favorable metabolic effects, Eckel and colleagues recently demonstrated that ranolazine, given in ischemic patients with type 2 diabetes and inadequate glycemic control, significantly reduced HbA_1c and other measures of glycemic homeostasis. The positive effect on the main parameter of glycemic levels is of interest since, even if CAD and diabetes are two distinct diseases, they are mechanistically linked because CAD is often favored by glycemic dysfunction [Eckel et al. 2015]. It must also be added that age alone had no relevant effects on the pharmacokinetic parameters of ranolazine. Indeed, data from several trials indicate that the efficacy of ranolazine is similar in older and younger patients, even though the adverse effects are more common in the elderly [Rich et al. 2007].

Ivabradine

Ivabradine is a compound with a chemical structure similar to that of verapamil. Ivabradine also reduces heart rate and thus oxygen consumption with a mechanism quite unlike conventional antianginal drugs [Di Francesc and Camm, 2002; Borer et al. 2003]. It is known that acute ischemic episodes can be enhanced by an increased heart rate. This induces an imbalance between myocardial oxygen supply and consumption. In contrast, a low heart rate reduces both extravascular compression and the length of time in which the heart stays in systole (consequently increasing the diastolic time, i.e. the time useful to coronary flow), thus reducing the frequency and duration of anginal episodes. Epidemiological and clinical data also suggest that an elevated heart rate is a powerful risk factor for ischemic cardiovascular events [Dyer et al. 1980]. Thus, the reduction of heart rate is greatly to be hoped in ischemic patients.

Ivabradine is a specific heart rate decreasing agent which acts on the sinoatrial node by selectively inhibiting the pacemaker I_f current in a dose-dependent manner and reducing heart rate at rest as well as during exercise, with minimal effect on myocardial contractility, blood pressure and intracardiac conduction [Riccioni, 2010; Simon et al. 1995]. Ivabradine acts on the I_f channel at concentrations that have no effect on other ionic currents, and without affecting the duration of the action potential [Thollon et al. 1997].

Several trials have demonstrated the efficacy of ivabradine in the treatment of chronic stable angina pectoris and myocardial ischemia, with or without left ventricular dysfunction [Riccioni et al. 2009; Riccioni, 2012, 2013]. The molecule is able to improve the symptoms of angina and the exercise capacity, like β-blockers [Fang et al. 2012]. Concerning this issue, the INITIATIVE trial demonstrated that ivabradine is noninferior to atenolol when used for reducing coronary ischemic symptoms [Tardif et al. 2005, 2013]. The ASSOCIATE study evaluated the effects on exercise duration of the addition of ivabradine (5 mg twice daily) to ischemic patients already receiving atenolol (50 mg/day). The results demonstrated that total exercise duration significantly increased [Tardif et al. 2013]. Ivabradine was also combined with low dose of bisoprolol in stable angina patients, confirming the amelioration of the symptom and ischemic benefits [Amonova et al. 2011]. Kachler and colleagues evaluated the efficacy and safety of ivabradine in patients suffering from symptomatic coronary disease. During every day routine use, the drug reduced heart rate and the frequency and duration of ischemic attacks [Kachler et al. 2009]. In the BEATIFUL study, the effects of ivabradine on patients with coronary disease and left ventricular dysfunction were tested. Although this trial failed to demonstrate that ivabradine was able to improve contractility, the employment of this drug was useful in decreasing admission to hospital secondary to fatal or nonfatal myocardial infarction by 36% and coronary revascularization by 30% [Fox et al. 2008]. Finally, a study compared ivabradine and the calcium channel antagonist, amlodipine. The results demonstrated that ivabradine improved exercise tolerance as well as amlodipine, but was shown to be superior with regard to the reduction of rate pressure product [Ruzyllo et al. 2007].

These and other studies have clearly demonstrated that the employment of ivabradine in ischemic patients with epicardial coronary stenoses is as effective in reducing angina and ischemic symptoms as β-blockers and calcium channel antagonists, while it did not show the adverse reactions induced by β-blockers and other antianginal drugs [Marquis-Gravel and Tardif, 2008]. Nevertheless, the SIGNIFY study performed recently to assess the morbidity–mortality benefits of the I_f inhibitor ivabradine in patients with CAD without clinical heart failure showed negative results. The trial evidenced in fact that, among patients who had stable CAD without CHF, the addition of ivabradine to standard background therapy to reduce heart rate did not improve outcomes [Fox et al. 2014]. The difference in the results between ischemics and CHF patients evaluated in the SHIFT study [Swedberg et al. 2010] is probably due to the neurohormonal activation of the SHIFT patients unlike those of the SIGNIFY study. In addition, heart rate is perhaps only a marker but not a direct risk factor in patients with stable CAD, as affirmed by Fox and colleagues [Fox et al. 2014].

Microvascular angina

A seldom encountered condition (especially in women) is microvascular angina (MVA). This is defined as typical precordial anginal pain evident during effort, with evidence of myocardial signs of ischemia at noninvasive tests and absence of coronary epicardial stenoses [Lanza and Crea, 2010]. Conventional antischemic medications remain the treatment of choice. But sometimes the symptoms remain in spite of these treatments, with significant impairment of quality of life. In this case, ivabradine or ranolazine can be used favorably with their peculiar mechanisms of action as previously described. In a recent study, Villano and colleagues showed that these two drugs significantly improved symptoms of MVA, although the magnitude of the effect was mild to moderate [Villano et al. 2013]. Of the two medications, ranolazine seemed to achieve better results; this is because it exerts its antischemic effects through mechanisms different from those of other anti-ischemic drugs, whereas ivabradine mainly potentiates a mechanism already exerted by β-blockers.

Comparison between ivabradine and ranolazine

Data comparing both drugs to each other are lacking. Chaturvedi and colleagues demonstrated only that, at two months of treatment, there was no statistically significant difference in the decrease in the frequency of anginal attacks between these two drugs. Likewise, there were no significant differences in laboratory investigations performed at baseline and after 8 weeks of intervention. However, ranolazine seems to be better tolerated than ivabradine and is superior in its adverse reactions. The most negative effect reported in patients treated with ranolazine was mainly nausea, whereas dizziness, headache, arthralgias, backache and muscle cramps were the most frequent adverse effects referred for ivabradine [Chaturvedi et al. 2013].

Final remarks

These new antianginal drugs have considerable potential as adjunctive therapy for angina, particularly in patients refractory to standard therapies and represent two powerful weapons to be added to conventional antianginal drugs to combat chronic stable angina. Because of their different and synergistic action–mechanisms in reducing anginal symptoms, these two drugs should be used together – even there is still a lack of clear experience in their use.