|Year : 2018 | Volume
| Issue : 3 | Page : 88-98
Ranolazine: Multifaceted role beyond coronary artery disease, a recent perspective
Gopal Chandra Ghosh1, Raktim Kumar Ghosh2, Dhrubajyoti Bandyopadhyay3, Krishnarpan Chatterjee4, Ashish Aneja2
1 Department of Cardiology, Christian Medical College, Vellore, Tamil Nadu, India
2 MetroHealth Medical Center, Case Western Reserve University, Heart and Vascular Institute, Cleveland, OH, USA
3 Department of Internal Medicine, Mount Sinai St. Luke's, New York, USA
4 Department of Cardiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Web Publication||18-Mar-2019|
Dr. Gopal Chandra Ghosh
Christian Medical College and Hospital, Room No. 310, Hospital Annexe, Hospital Campus, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Ranolazine is a piperazine derivative approved as an antianginal. Primarily used as a second-line antianginal in stable coronary artery disease. Ranolazine blocks the late Na + current and prevents the rise of cytosolic calcium. It decreases myocardial wall tension and improves coronary blood flow. Ranolazine is effective in atrial fibrillation (AF) as an adjunct to electrical or pharmacological cardioversion. It can be used in combination with amiodarone or dronedarone. It has also been used in AF arising after coronary artery bypass grafting surgery. Role of ranolazine is also being evaluated in pulmonary arterial hypertension, diastolic dysfunction, and chemotherapy-induced cardiotoxicity. Ranolazine has some anti-glycemic effect and has shown a reduction of hemoglobin A1c in multiple trials. The antianginal effect of ranolazine has also been seen to be more in patients with diabetes compared to those without diabetes. Ranolazine is being evaluated in patients with the peripheral arterial disease with intermittent claudication and hypertrophic cardiomyopathy. Pilot studies have shown that ranolazine may be beneficial in neurological conditions with myotonia. The evidence-base on the use of ranolazine in various conditions is rapidly increasing with results of further trials eagerly awaited. Accumulating evidence may see ranolazine in routine clinical use for many conditions beyond its traditional role as an antianginal.
Keywords: Angina pectoris, Combination Assessment of Ranolazine in Stable Angina, Efficacy of Ranolazine in Chronic Angina, Monotherapy Assessment of Ranolazine in Stable Angina, ranolazine hydrochloride, sodium channel blockers
|How to cite this article:|
Ghosh GC, Ghosh RK, Bandyopadhyay D, Chatterjee K, Aneja A. Ranolazine: Multifaceted role beyond coronary artery disease, a recent perspective. Heart Views 2018;19:88-98
|How to cite this URL:|
Ghosh GC, Ghosh RK, Bandyopadhyay D, Chatterjee K, Aneja A. Ranolazine: Multifaceted role beyond coronary artery disease, a recent perspective. Heart Views [serial online] 2018 [cited 2020 Sep 23];19:88-98. Available from: http://www.heartviews.org/text.asp?2018/19/3/88/254347
| Introduction|| |
Ranolazine hydrochloride is an anti-ischemic agent. It was approved in January 2006 by the U.S. Food and Drug Administration (FDA) for the treatment of chronic stable angina. Based on current evidence, ranolazine has been included as a second-line antianginal in North-American and European guidelines for the management of chronic stable angina., Since its approval, the drug has shown benefits beyond angina relief. Extended benefits have been observed in the management of arrhythmias, especially atrial fibrillation (AF), and in diastolic dysfunction, pulmonary hypertension (PH), and chemotherapy-related cardiotoxicity. Ranolazine has also shown promise in the management of diabetes mellitus.
In this article, we present a comprehensive review of ranolazine's pharmacology, mechanism of action, and recent preclinical and clinical evidence.
| Pharmacology and Mechanism of Action|| |
Ranolazine is a piperazine derivative available as extended-release tablets of 500 or 1000 mg. Typical doses are 500–1000 mg twice daily. Plasma concentration peaks 2–5 h after oral administration with an elimination half-life of 2 h. The drug is metabolized principally in the liver and excreted principally through the kidneys [Table 1].,
Ranolazine acts by blocking late sodium channels (INa). It thus prevents downstream rise in cytosolic Ca+2 concentrations, which translates into mechanical effects including a decrease in left ventricular wall tension and increase in coronary blood flow, leading to angina relief. INa blocking also leads to stabilization of the myocardial cell membrane, likely responsible for its anti-arrhythmic effect. The late rectifier K + current inhibition contributes to its anti-arrhythmic effect. With regard to its beneficial effect in diabetes, it has been postulated that ranolazine blocks Na + channels in the pancreatic islet alpha-cells to inhibit glucagon release. Studies have also revealed its role in pancreatic beta-cell preservation, [Figure 1].
| Role as an Antianginal|| |
Ranolazine is a piperazine derivative approved by the FDA in 2006 for treatment of chronic stable angina. The Monotherapy Assessment of Ranolazine in Stable Angina trial showed that ranolazine monotherapy improved exercise duration in angina. The Combination Assessment of Ranolazine in Stable Angina (CARISA) trial demonstrated improved exercise duration with ranolazineas a component of combination therapy. In the Efficacy of Ranolazine in Chronic Angina trial, treatment with ranolazine improved self-reported angina. These data have helped establish the role of ranolazine in refractory stable angina [Table 2].
| Role Beyond Angina|| |
Ranolazine in arrhythmias
Ranolazine has a multi-channel effect on cardiomyocytes. It inhibits late INa, IKr, ICa, and INa-Ca current. There is no effect on Ito, IK1, and IKs. It reduces Na+ and Ca++ overload in cardiac myocytes which leads to its antiarrhythmic effect. Ranolazine also decreases early and delayed afterdepolarizations. Ranolazine displays selective action on atrial cardiomyocytes. A possible mechanism for this selectivity has been borne out in a study in rabbit hearts. Atrial cells showed more INa conductance, more negative activation and inactivation potentials of INa and more trapping of ranolazine in the inactivated Na channel.
There is also a possible role of ranolazine in molecular signaling pathways that prevent AF. In a rat model of Ach-CaCl2 induced AF, ranolazine improved mitochondrial function reduced oxidative stress and decreased atrial myoyte apoptosis. It also increased protective signaling via the Akt/mTOR pathway.
In chronic kidney disease patients, there is an increased incidence of AF, potentially mediated by FGF-23 on late Na and calcium channels. This increases arrhythmogenesis in pulmonary vein cardiomyocytes. By inhibiting the late Na current and preventing Ca overload, ranolazine may have a role in preventing AF in this patient subset.
A preclinical trial compared the effect of dofetilide and ranolazine on acutely induced AF in 8 horses. Ranolazine in combination with dofetilide was found to convert AF to sinus rhythm, and decrease AF vulnerability and duration compared with either drug alone. Neither drug had any effect on the atrial effective refractory period. In another preclinical study ranolazine was compared with vernakalant for cardioversion of acutely induced AF in 15 rabbit hearts. AF was induced with atrial burst pacing and acetylcholine/isoproterenol. Ranolazine and vernakalant had similar efficacy in preventing AF.
As opposed to vernakalant, ranolazine significantly increased the atrial effective refractory period. Ranolazine has been tested in combination with ivabradine in AF in pigs. A combination of the two drugs decreased ventricular rate by reducing conduction at the AV node (increased A-H interval) and decreasing the dominant AF frequency. This was achieved at clinically safe levels without decreasing cardiac contractility or prolongation of the QT interval. AF is common in heart failure and many anti-arrhythmic agents are contraindicated.
Ranolazine was studied in a canine-model right atrial and left ventricular preparation with tachycardia-induced heart failure. It suppressed induction of AF by increasing the atrial effective refractory period and atrial conduction time. No proarrhythmic effect on the ventricle was noted. In a porcine model of catecholaminergic polymorphic ventricular tachycardia (VT), ranolazine reduced VT and T wave alternans incidence. Ranolazine has also been shown noninferior to lidocaine and sotalol in preventing ischemia-reperfusion induced VT in a rat model. Two preclinical trials of ranolazine in a rat model of long QT syndrome have shown promising results. Ranolazine reduced prolongation of the QT interval, suppressed early after depolarizations and the frequency of torsades de pointes.,
Metabolic efficiency with ranolazine for less ischemia in nonST-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) was a large randomized controlled trial involving 6560 patients to evaluate the efficacy and safety of ranolazine in the nonST-elevation myocardial infarction setting. It showed that treatment with ranolazine resulted in a significantly lower incidence of VT, supraventricular tachycardia, and ventricular pauses compared to placebo. However, its addition to standard treatment for acute coronary syndromes was not effective in reducing major cardiovascular events.,
Ranolazine was evaluated in patients with coronary artery disease and paroxysmal AF who had a dual chamber pacemaker capable of detecting AF. Ranolazine 375 mg twice daily compared to placebo reduced the total time in AF and mean AF duration. There was no significant difference in QTc. In the RAFAELLO trial, 241 patients with AF who underwent electrical cardioversion were randomized 2 h after the procedure to receive either Ranolazine 375 mg twice daily, 500 mg twice daily, 750 mg twice daily or placebo. Ranolazine was safe and well tolerated. It did not prolong time to AF recurrence. The 500 mg and 750 mg arms combined showed a reduction in AF recurrence with borderline statistical significance.
Koskinas et al. showed that ranolazine has an additive effect with amiodarone in conversion of AF to sinus rhythm. Tsanaxidis et al. showed a single 1000 mg oral dose of ranolazine added to amiodarone leads to quicker return to sinus rhythm and a higher conversion rate to sinus than amiodarone alone. The addition of ranolazine had no adverse impact on left ventricular function.
Two meta-analyses have confirmed the additive benefit of ranolazine to amiodarone in AF. The addition of ranolazine quickens the time to cardioversion of AF. It also helps prevent new-onset AF in people with sinus rhythm., The HARMONY trial revealed that a combination of ranolazine and dronedarone was effective in significantly reducing AF burden compared to placebo. To evaluate the possible mechanism for this synergistic effect, patch clamp experiments from atrial myocytes of patients in sinus rhythm were conducted. They revealed increased action potential duration, decreased sarcoplasmic reticulum calcium leak and membrane hyperpolarization when ranolazine and dronedarone were used alone or in combination. These inhibitory effects may partly explain the results of HARMONY trial. Several small studies have shown that ranolazine in moderate doses significantly shortens the mean time of conversion from AF to sinus rhythm and also reduces the occurrence of AF in coronary artery bypass grafting (CABG).,,,,
Another trial evaluated the role of ranolazine in postoperative AF (POAF). Patients undergoing CABG, valve surgery, or a combination were included. The addition of ranolazine to standard therapy significantly decreased POAF frequency. There was no effect on Insensitive Care Unit stay or cardiovascular mortality, but the 30 days cardiovascular readmission rate was reduced. The Ranolazine Implantable Cardioverter-Defibrillator trial was conducted to compare the efficacy of ranolazine with placebo in preventing VT in patients with ICDs. The endpoint measured was ventricular arrhythmia requiring ICD intervention. This study has been completed, and results are awaited. Intravenous ranolazine has also been found to decrease QT prolongation in 5 patients of LQT3 in a concentration-dependent manner.
Existing evidence suggests that ranolazine is effective in the management of AF, especially in postcardioversion and post-CABG situations, and potentially additive with amiodarone and dronedarone in pharmacological cardioversion. However, these small studies are not sufficiently powered to provide conclusive evidence.
Ranolazine in ischemic reperfusion injury
Ischemia-reperfusion is associated with diastolic calcium overload and reduction in the amplitude of intracellular calcium transients. Application of ranolazine during ischemia-reperfusion significantly improved intracellular calcium handling. Ranolazine increases calcium concentrations in sarcoplasmic reticulum, thus preventing intracellular calcium overload in diastole, which in turn preserves intracellular calcium transients.
In animal studies, ranolazine shown several benefits. It reduces myocardial infarct size and improves left ventricular function. Animals in the ranolazine-treated arm were found to have a decrease in ischemia/reperfusion-induced arrhythmias and improved outcomes in heart failure.
Ranolazine for Incomplete Vessel Revascularization Post-Percutaneous Coronary Intervention (RIVER-PCI) was a large, randomized, multi-center, double-blind, phase three trial, designed to investigate the effect of ranolazine in reducing ischemia-driven revascularization and hospitalization in patients who had incomplete revascularization after PCI. This trial analyzed 2604 patients from 245 centers from 4 countries and followed them for a median of 643 days. Patients received either ranolazine 1000 mg twice daily or placebo. The primary endpoint was time to first ischemia related event, either hospitalization or revascularization, which occurred in 26% in the ranolazine and 28% in the placebo group, which was not a statistically significant difference.
Secondary analysis of the RIVER-PCI study showed the ranolazine arm had improved quality of life at 6- and 12 months postrevascularization. Improvement in angina was noted in the ranolazine arm at 6 months postrevascularization, but this benefit did not persist beyond a year. Improvements in angina was especially pronounced in diabetic patients and those with severe baseline symptoms.
Considering the outcomes from RIVER PCI trial, ranolazine may have a role in the treatment of angina after incomplete revascularization, especially in diabetic patients, but dedicated prospective studies are needed to confirm this hypothesis.
Ranolazine in pulmonary hypertension
Studies have suggested that ranolazine may have anti-arrhythmic and anti-inflammatory effects on the left heart. Although the left and right ventricle have physiological differences, pathological processes such as ischemia, diastolic calcium overload, oxidative stress, and fibrosis are equally prevalent in both left and right heart chambers. This has prompted research to assess the potential role of ranolazine in PH.
Lee et al. revealed that treatment with ranolazine reduced right ventricular (RV) hypertrophy and fibrosis in monocrotaline-induced PH in rats. They also revealed reduced levels of the B-type natriuretic peptide (BNP) in ranolazine treated rats. Rocchetti et al. showed that treatment with ranolazine prevents constitutive enhancement of the late sodium current, thus blunting myocardial remodeling in a rat model.
Evidence to define the role of ranolazine in PH patients remains preliminary. A phase I study showed that ranolazine is safe in patients with pulmonary arterial hypertension (PAH) without any acute hemodynamic changes. However, PAH patients treated with ranolazine receiving background pulmonary vasodilator therapies inconsistently reached therapeutic ranolazine levels. In another pilot study by Khan et al., ranolazine treatment was found to be safe and well tolerated in PAH patients. After 3 months of treatment with ranolazine, patients showed improvements in functional class, decrease in RV size, improvements in RV function measured by strain echocardiography, and improvement in exercise time. Despite these beneficial actions, ranolazine failed to show improvements in hemodynamic parameters.
Further studies are warranted to study the role of ranolazine in the management of PH.
Ranolazine in heart failure
Hypertensive rats with altered diastolic function treated with ranolazine showed improvements in diastolic parameters. Treatment with ranolazine improved the rate of LV pressure change (dp/dt), decreased LV end diastolic pressure (LVEDP), and improved the end-diastolic pressure-volume relationship. In addition, ranolazine treatment decreased LV hypertrophy.
The effects of ranolazine on diastolic function parameters were heterogeneous. Pilot studies demonstrated that treatment with ranolazine improved echocardiographic diastolic parameters., RALI-DHF was a small, single center, prospective, randomized, double-blind, placebo-controlled trial designed to evaluate the role of ranolazine on diastolic parameters. Patients with LV ejection fraction >45% with altered diastolic function parameters and elevated NT-Pro BNP (>220 pg/ml) were included. Ranolazine was given as continuous intravenous infusion for 24 h followed by oral therapy for next 13 days. Ranolazine infusion improved LVEDP and pulmonary capillary wedge pressure. Mean pulmonary artery pressure showed a trend toward improvement, but NT-proBNP levels did not change., Murray and Colombo showed that ranolazine added to guideline-directed pharmacotherapy for congestive heart failure, preserved and even improved left ventricular ejection fraction and autonomic measures when treatment was continued for 24 months. Venkataraman et al. showed in a small study that treatment with ranolazine improved systolic and diastolic LV dyssynchrony.
Ranolazine is also a partial fatty acid beta-oxidation inhibitor at higher serum concentration compared to the concentration required for inhibition of late sodium current. Ranolazine at higher doses may have cardioprotective actions in patients with heart failure. These experimental studies will likely help pave the way for larger clinical studies to further assess the role of ranolazine in heart failure.
Ranolazine in the prevention of chemotherapy-induced cardiotoxicity
Anthracyclines probably cause hyperactivation of late inward sodium current which ultimately leads to cytosolic calcium overload. Simultaneously, anthracyclines also induce reactive oxygen species production. Both these mechanisms are responsible for sustained oxidative and energetic stresses, and lead to cardiomyocyte and cardiac stem cell death.
In a mouse model, treatment with ranolazine prevents doxorubicin induced left ventricular dilatation and dysfunction. Treatment with ranolazine also prevents increment in atrial natriuretic peptide, BNP, connective tissue growth factor, and matrix metalloproteinase 2 mRNA elevations seen with doxorubicin treatment.
This suggests that ranolazine may be effective in preventing direct cardiomyocyte injury and may decrease cardiomyocyte wall tension exerted by chemotherapeutic agents. There is paucity of data in this area but results of the INTERACT study are awaited. INTERACT is an open label, multi-center, phase IIB study designed to assess the potentially beneficial effects of ranolzine on post-chemotherapy diastolic dysfunction.
Role in diabetes mellitus
An animal study showed that ranolazine increases pancreatic beta cell survival and improves glucose homeostasis in streptozotocin-induced diabetes in mice. A recent study by Dhalla et al. revealed that the anti-hyperglyemic effect of ranolazine in humans results predominantly from a unique blockade of Pancreatic α-cell voltage-gated Na(+) channels (NaChs), which leads to decreases in basal and postprandial glucagon secretion.
The CARISA trial revealed that ranolazine treatment was associated with a reduction in hemoglobin A1c (HBA1c) levels in patients with stable angina. In this trial, HbA1c was not a prespecified outcome and further stratification of results based on insulin or oral anti-hyperglycemic usage was not possible. A post hoc analysis of the MERLIN-TIMI 36 trial demonstrated a reduction in HbA1c of 0.64% in diabetic patients randomized to the ranolazine arm. Fasting plasma glucose was also significantly reduced by a mean of 25.7 mg/dl. The MERLIN-TIMI trial was not designed to study glycemic outcomes, which remains a limitation of this trial.,
Trials evaluating the anti-hyperglycemic effect of ranolazine monotherapy in diabetic patients have revealed that treatment with ranolazine can reduce HBA1c level by 0.51%–0.56% compared to placebo, allowing a greater number of patients to achieve their glycemic goal., This may be related to some extent to a decrease in insulin resistance. The magnitude of reduction of angina and reduction in rescue nitrate usage were greater in diabetic patients in the TERISA trial. Recently, a secondary analysis of the RIVER-PCI trial evaluated 961 diabetic patients with angina and incomplete revascularization after PCI. It showed a further reduction in angina frequency in patients with HbA1c ≥7.5% compared to those with a HbA1c <7.5%. Considering the data available on the anti-hyperglycemic effect of ranolazine, it may have a place in the management of stable ischemic heart disease with diabetes.
Ranolazine in peripheral arterial disease
Ranolazine reduces cardiac ischemia by selective deactivation of the late sodium current. Skeletal muscles also contain sodium channels which have both rapid and slow phases. Ischemia induced changes in the sodium channels of skeletal muscles may respond to ranolazine in manner similar as does ischemic myocardium. Ranolazine also improves endothelial function. In a pig model, intra-femoral injection of ranolazine causes persistent dilatation of the arterial bed compared to nitroglycerin. This may be secondary to an α1-adrenergic receptor blocking effect without altering the heart rate or systemic blood pressure. In a pilot study involving 45 patients with intermittent claudication, ranolazine 1000 mg BID showed an increase in peak walking time in comparison to placebo. Although ranolazine did not improve the ankle brachial index at rest, patients with severe intermittent claudication had an approximately 40% increase in walking time than placebo, comparable to cilostazol. Although the sample size was small, it has led to further research. The Supervised Treadmill Exercise and Ranolazine for Intermittent Claudication of Lower Extremities, a randomized trial, is being conducted to compare the efficacy of ranolazine with supervised treadmill exercise versus placebo and supervised treadmill exercise. The results are not yet published.
Ranolazine in myotonia-congenita
Myotonia Congenita (MC) is a chloride channel mutation disorder characterized by muscle hyperexcitability. It adversely impacts quality of life by excessive muscle stiffness. Muscle stiffness improves with exercise, which is also called warm-up. A slow inactivation of sodium channel is responsible for the warm-up phenomenon. Ranolazine promotes slow inactivation of sodium channel, which may offer therapeutic potential to these patients. In a mouse model, ranolazine improved muscle functioning compared to mexiletine without major side effects.
In a recent pilot study involving 13 MC patients, ranolazine showed improvement in terms of clinical and electromyography (EMG) assessment of MC. Mexiletine may not be suitable for some patients because of gastrointestinal side effects. In this population, ranolazine may serve as an alternative. Recently, a phase 2 trial is ongoing to evaluate the effect of ranolazine in MC, Paramyotonia Congenita, and Myotonic Dystrophy Type 1. Patients with the above mentioned conditions will be randomized to receive either ranolazine 500 mg twice daily for 2 weeks followed by 1000 mg twice daily for another 2 weeks versus placebo. Primary outcomes are quality of life measurements for health and neuromuscular disease, and EMG to assess for changes in muscle potentials and performance. It is a phase 2 trial to mainly assess the safety profile of the drug in these neuromuscular conditions.
Ranolazine in hypertrophic cardiomyopathy
Ranolazine was studied in transgenic mice carrying troponin T mutations responsible for hypertrophic cardiomyopathy (HCM). At therapeutic plasma concentrations, ranolazine prevented the development of HCM phenotype in these genotype positive mice. It reduced interventricular septum thickness, left ventricular fibrosis, left atrial enlargement, diastolic dysfunction, left ventricular hypercontractility, and improved left ventricular volume. An electromechanical study of human cardiomyocytes harvested from septal myectomy specimens in HCM showed electrophysiological remodelling with enhanced Ca-calmodulin kinase II dependent signaling and phosphorylation leading to abnormal calcium handling. This causes calcium overload, arrhythmogenesis, and diastolic dysfunction, which can be reversed in vitro by ranolazine. The negative inotropic action of ranolazine may decrease dynamic LV outflow tract obstruction in HCM. Ranolazine has also been shown to decrease refractory angina in HCM.
| Conclusion and Future Directions|| |
By preventing calcium overloading and reducing diastolic tension in cardiomyocytes, ranolazine is an important adjunct in the management of stable angina pectoris. Ranolazine may be particularly attractive in diabetic patients with angina since it leads to a reduction in glucose levels. Experimental studies showed promising role in the treatment of postcardioversion and post-CABG AF, heart failure, PH, peripheral arterial disease, MC, HCM, and in prevention of chemotherapy-induced cardiotoxicity.
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[Table 1], [Table 2]