Myocardial energy balance and metabolism as causes of myocardial ischemia.

The current approach to myocardial ischemia has been influenced by the misconception of a close link between ischemia and coronary atherosclerotic obstructions. Recent guidelines have, however, acknowledged the multifactorial nature of this condition, with an identifiable cause present in less than half of angina patients, and a large fraction with angina of unknown origin. Because of this background, focusing on cardiac energy metabolim offers new opportunities to manage myocardial ischemia even when its cause is unknown.

The antianginal ranolazine fails to improve glycaemia in obese liver-specific pyruvate dehydrogenase deficient male mice.

AIMS: Recent studies have demonstrated that stimulating pyruvate dehydrogenase (PDH, gene Pdha1), the rate-limiting enzyme of glucose oxidation, can reverse obesity-induced non-alcoholic fatty liver disease (NAFLD), which can be achieved via treatment with the antianginal ranolazine. Accordingly, our aim was to determine whether ranolazine's ability to mitigate obesity-induced NAFLD and hyperglycaemia requires increases in hepatic PDH activity. METHODS: We generated liver-specific PDH-deficient (Pdha1Liver-/- ) mice, which were provided a high-fat diet for 12 weeks to induce obesity. Pdha1Liver-/- mice and their albumin-Cre (AlbCre ) littermates were randomized to treatment with either vehicle control or ranolazine (50 mg/kg) once daily via oral gavage during the final 5 weeks, following which we assessed glucose and pyruvate tolerance. RESULTS: Pdha1Liver-/- mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) when compared to their AlbCre littermates. Of interest, ranolazine treatment improved glucose tolerance and mildly reduced hepatic triacylglycerol content in obese AlbCre mice but not in obese Pdha1Liver-/- mice. The latter was independent of changes in hepatic mRNA expression of genes involved in regulating lipogenesis. CONCLUSIONS: Liver-specific PDH deficiency is insufficient to promote an NAFLD phenotype. Nonetheless, hepatic PDH activity partially contributes to how the antianginal ranolazine improves glucose tolerance and alleviates hepatic steatosis in obesity.

Ranolazine exerts atrial antiarrhythmic effects in a rat model of monocrotaline-induced pulmonary hypertension.

Atrial arrhythmias are a hallmark of heart diseases. The antiarrhythmic drug ranolazine with multichannel blocker properties is a promising agent to treat atrial arrhythmias. We therefore used the rat model of monocrotaline-induced pulmonary-hypertension to assess whether ranolazine can reduce the incidence of ex vivo atrial arrhythmias in isolated right atrium. Four-week-old Wistar rats were injected with 50 mg/kg of monocrotaline, and isolated right atrium function was studied 14 days later. The heart developed right atrium and right ventricular hypertrophy, and the ECG showed an increased P wave duration and QT interval, which are markers of the disease. Moreover, monocrotaline injection caused enhanced chronotropism and faster kinetics of contraction and relaxation in isolated right atrium. Additionally, in a concentration-dependent manner, ranolazine showed chronotropic and ionotropic effects upon isolated right atrium, with higher potency in the control when compared with experimental model. Using a burst pacing protocol, the isolated right atrium from the monocrotaline-treated animals was more susceptible to develop arrhythmias, and ranolazine was able to attenuate the phenotype. Thus, we concluded that the rat model of monocrotaline-induced pulmonary-hypertension develops right atrium remodelling, which increased the susceptibility to present ex vivo atrial arrhythmias, and the antiarrhythmic drug ranolazine ameliorated the phenotype.

Diabetes mellitus aggravates ranolazine-induced ECG changes in rats.

PURPOSE: Diabetes mellitus (DM) is known to affect the pharmacokinetics of drugs. In this study, we evaluated the effect of DM on the liver content of CYP 3A2 enzyme. We also explored the ECG changes after administration of ranolazine in non-DM and DM rats. METHODS: First phase: 24 male Wistar rats were separated into 4 groups. The control group (n = 6) received normal saline and the DM groups (n = 18) were treated with a single dose (55 mg/kg) of streptozocin (STZ; i.p. injection), then were held for 10, 20, and 30 days, respectively. After study duration for each group, the liver CYP 3A2 protein content was determined using western blotting. Second phase: 48 male Wistar rats were classified into two groups of non-DM and DM; and each group was divided into 4 subgroups (n: 6). Experimental groups received oral doses of 20, 40, and 80 mg/kg ranolazine. DM and non-DM control groups received normal saline. Treatment lasted for 28 days, and then the ECG was recorded. RESULTS: Experimental DM induced by STZ caused a significant decrement in liver CYP3A2 protein content of rats on days 10 and 20 (P < 0.01), and 30 (P < 0.05) compared to the control animals. Significant increases in QT and corrected QT (QTc) intervals (P < 0.01), and bradycardia (P < 0.01) without any significant effect on PR and QRS intervals were observed in DM in comparison with non-DM groups after ranolazine treatment. CONCLUSIONS: In summary, DM induction in animals resulted in CYP 3A2 inhibition and the prolongation of QT and QTc interval as well as bradycardia after ranolazine treatment.

Ranolazine-induced lipid storage myopathy presenting with respiratory failure and head drop.

Ranolazine is an anti-ischemic drug often used along with statins in patients with ischemic heart disease. Ranolazine-induced proximal myopathy or rhabdomyolysis have been rarely reported, but toxic effects of statins could not be completely ruled out in those cases. We report a 68-year-old man with ranolazine-induced myopathy who presented with respiratory insufficiency and head drop. Creatine kinase level was normal. The Patient continued to worsen despite statin cessation but markedly improved after stopping ranolazine. Muscle biopsy showed excessive lipid accumulation predominantly in type 1 myofibers. The precise mechanism of toxicity is not clear. Treating physicians should be aware of this rare but potentially debilitating adverse effect of ranolazine. Prognosis is good upon discontinuation of the offending drug.

Pharmacokinetics and Safety of Extended-release Ranolazine in Korean and White Healthy Subjects.

PURPOSE: Ranolazine, an inhibitor of late inward sodium current, is an antianginal agent. In this study, the pharmacokinetic (PK) properties and tolerability of single- and multiple-dose ranolazine were compared between healthy Korean and white subjects. METHODS: An open-label, ascending single- and multiple-dose study was conducted with healthy male Korean and white subjects. Subjects were administered 375-750 mg of ranolazine once in a single-dose and twice daily in multiple-dose based on their dose groups. Blood samples for the PK assessment were collected up to 48 h after dosing. The geometric mean ratio and its 90% confidence interval in Korean to white subjects for Cmax, Cmax,ss, AUClast, and AUC0-12h,ss of ranolazine were calculated. A population PK analysis was also performed. Safety profiles were assessed throughout the study. FINDINGS: A total of 70 Korean and 48 white subjects completed the study. Ranolazine exposure was similar between Korean and white subjects in all dose groups; however, ranolazine exposure at 750 mg was observed to increase by up to 29% in Korean subjects compared with that in white subjects. On the basis of previous studies, these differences in ranolazine exposure between the 2 ethnic groups may not result in any clinically significant difference. Furthermore, ethnicity was not significantly correlated with the PK properties of ranolazine in the ranolazine PK model. In addition, no significant difference was found in the safety profile of ranolazine between the 2 ethnic groups. IMPLICATIONS: The PK properties of ranolazine had no clinically significant difference, and no difference was found in the safety profiles of ranolazine between Korean and white subjects. It is anticipated that ranolazine can be administered in Korean subjects without dose adjustment. ClinicalTrials.gov identifier: NCT02817932.

The Effect of Ranolazine on Glycemic Control: a Narrative Review to Define the Target Population.

Ranolazine is an anti-anginal medication that reduces the sodium-dependent calcium overload via the inhibition of the late sodium current. After its approval for the treatment of chronic angina in 2006 in the USA, ranolazine has been reported to have several pleiotropic effects on various cardiac conditions, such as atrial fibrillation, ventricular arrhythmias, diastolic and microvascular dysfunction, and pulmonary arterial hypertension. Recently, several studies reported some promising results on the potential benefits of ranolazine on glycemic control. Though the mechanism of the antihyperglycemic effect is still unknown, ranolazine may exert the effect through ß cell preservation, inhibition of glucose secretion, and enhancement of insulin secretion in a glucose-dependent manner. Given the increased risk of cardiovascular disease in patients with diabetes, it will be useful if one medication can simultaneously improve chronic angina and diabetes. Therefore, ranolazine could be a favored choice among other anti-anginal agents for patients with comorbidity of chronic angina and diabetes mellitus. In this review, we summarize the available data from clinical studies and provide valuable insight into defining the target population for the antihyperglycemic effect of ranolazine.

Ranolazine, ACE Inhibitors, and Angiotensin Receptor Blockers.

BACKGROUND: Ranolazine is an anti-angina agent with many metabolites creating the potential for off-target effects. The U.S. Food and Drug Administration (FDA) reviews sometimes contain clinically relevant data not found in other sources. METHODS: We reanalyzed data in an FDA review of the placebo-controlled MERLIN trial of ranolazine to display differences in adverse event rates graphically. RESULTS: Rates of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)-related adverse events (eg, angioedema, dry cough, renal impairment, hypotension, anemia, and serum potassium > 5.5 mmol/L) were higher in patients receiving ranolazine and an ACEI or ARB. Rates of adverse events that should be decreased by ACEI/ARBs (eg, hypokalemia, hypertension, and serum potassium < 3.5 mmol/L) were lower in patients receiving ranolazine and an ACEI or ARB compared to rates in patients receiving placebo and an ACEI or ARB. CONCLUSIONS: Ranolazine potentiates the effects of ACEIs and ARBs. Clinicians should monitor for this potentiation when initiating treatment with ranolazine and an ACEI or ARB.

Use of FDA's Sentinel System to Quantify Seizure Risk Immediately Following New Ranolazine Exposure.

INTRODUCTION: Neurological complications including seizures have been reported with ranolazine. We sought to quantify the risk of seizure-related hospitalizations or emergency department events following ranolazine exposure in the Sentinel System (2006-2015). STUDY DESIGN AND SETTING: Eligibility criteria were new use of ranolazine after 183 days washout period and absence of seizure diagnoses, anti-epileptic drugs, or seizure-related disorders during the baseline period. RESULTS: Among 52,155 ranolazine users, we identified 28 seizures in the 1-32 days after new ranolazine dispensing: 12 occurring in days 1-10 (high-risk window), 11 in days 11-20 (moderate-risk window) and 5 in the control window (days 21-32). Assuming an equal likelihood of seizure events across the 32-day observation window, we estimate an attributable risk of 0.9 excess cases per 10,000 exposed users. Using a self-controlled risk interval design with exact logistic regression, seizures were elevated in the high-risk window (relative risk [RR] 2.88 (95% confidence interval [CI] 1.01-8.33) compared with the control window. No significant increased risk was observed in the moderate window. Half of the seizure cases had a diagnosis of renal disease, although seizure risk was not significant (RR 3.20 [CI 0.82-14.01]). A majority of patients in both risk windows were 75 years or older. CONCLUSION: Our study suggests risk among younger ranolazine patients is rare. Given the imprecision of the risk estimates, we interpret the elevated seizure risk following ranolazine exposure with caution. Further analysis in a larger elderly population is warranted.

Effect of Ranolazine on Ischemic Myocardium IN Patients With Acute Cardiac Ischemia (RIMINI-Trial): A Randomized Controlled Pilot Trial.

BACKGROUND: Coronary artery disease is the most prevalent manifestation among cardiovascular diseases. Despite modern treatment, risk of ischemic complications in patients with acute coronary syndrome (ACS) remains important. The late Na+ current blocker ranolazine has shown to reduce the risk of recurrent ischemia and worsening of angina in patients with non-ST-segment elevation ACS by possibly improving myocardial perfusion, but up to now no trial has addressed whether this enhanced perfusion also leads to a decrease in ischemic myocardium of patients with ACS. We designed a pilot trial (Reduction of Ischemic Myocardium with Ranolazine-Treatment IN patients with acute myocardial Infarction, ClinicalTrials.gov Identifier: NCT01797484) for feasibility and proof of concept that a 6-week ranolazine add-on therapy would reduce the area of ischemic myocardium in patients with ACS. METHODS AND RESULTS: The trial was designed in a 2-armed, controlled and randomized way. Twenty participants with unstable angina, proof of acute cardiac ischemia, and myocardial dyskinesia by speckle-tracking echocardiography were included. Ten participants received the study drug ranolazine additionally to standard treatment. The control group received standard treatment without additional study medication. Speckle-tracking echocardiography was performed before coronary intervention, before the first dose of ranolazine, and after 6 weeks of ranolazine treatment. Ranolazine was administered safely during acute myocardial infarction. Speckle-tracking echocardiography proved to be suitable for evaluation of myocardial dyskinesia. Patients receiving ranolazine showed a trend to higher normal fraction of the cumulative global strain than patients in the standard treatment group (15% vs 11%). No major complications relating study medication were observed. CONCLUSION: In conclusion, in this preliminary hypothesis-driven study, 6-week ranolazine therapy was shown to decrease the area of dyskinetic myocardium in patients with ACS by trend. Global strain rate measurement using speckle-tracking echocardiography can be applied measuring those effects and is, compared to other techniques, safe and harmless. Our data provide a sound basis for a follow-up trial.

Microvascular ischemia in patients with successful percutaneous coronary intervention: effects of ranolazine and isosorbide-5-mononitrate.

OBJECTIVE: About one-third of patients undergoing percutaneous coronary interventions (PCIs) for flow-limiting coronary stenosis continue to develop signs of myocardial ischemia (MI) during exercise stress test [EST], despite successful coronary revascularization. Coronary microvascular dysfunction is a likely major cause of the persistence of EST-induced MI in these patients. PATIENTS AND METHODS: We studied 15 patients (14 men, age 67±5 years) fulfilling the following strict inclusion criteria: (1) recent PCI (<6 months), with drug-eluting stent, of coronary artery stenoses for stable angina, with evidence of full success (no residual stenosis >20% in any vessel); (2) persistence of ST-segment depression induction during EST. After a basal investigation, patients received either ranolazine (375 mg bid) or isosorbide-5-mononitrate (ISMN, 20 mg bid) for 3 weeks in a single-blind, randomized crossover study. Clinical assessment, symptom-limited EST, echocardiographic color-Doppler, with tissue-Doppler examination, and coronary microvascular dilator response to adenosine (CFR-ADO) and cold pressor test (CFR-CPT), assessed by transthoracic echo-Doppler, were obtained at baseline and the end of the 3-week therapy with each drug. RESULTS: Compared to both baseline and ISMN, ranolazine showed a longer time to 1 mm ST-segment depression (404±116 s vs. 317±98 and 322±70 s, respectively; p<0.01). No differences were observed in coronary microvascular function and diastolic left ventricular function between the 2 drugs and compared to baseline. CONCLUSIONS: Our data show that ranolazine, but not ISMN, improved time to ischemia during EST. This effect, however, was independent of any effects on coronary microvascular and diastolic function.

Amiodarone plus Ranolazine for Conversion of Post-Cardiac Surgery Atrial Fibrillation: Enhanced Effectiveness in Reduced Versus Preserved Ejection Fraction Patients.

PURPOSE: Ranolazine (RAN) added to amiodarone (AMIO) has been shown to accelerate termination of postoperative atrial fibrillation (POAF) following coronary artery bypass surgery in patients without heart failure (HF). This study aimed to investigate if treatment efficacy with AMIO or AMIO + RAN differs between patients with concomitant HF with reduced or preserved ejection fraction (HFrEF or HFpEF). METHODS: Patients with POAF and HFrEF (n = 511, 446 males; 65 ± 9 years) and with HFpEF (n = 301, 257 males; 66 ± 10 years) were enrolled. Onset of AF occurred 2.15 ± 1.0 days after cardiac surgery, and patients within each group were randomly assigned to receive either AMIO monotherapy (300 mg in 30 min + 1125 mg in 36 h iv) or AMIO+RAN combination (500 mg po + 375 mg, after 6 h and 375 mg twice daily thereafter). Primary endpoint was the time to conversion of POAF within 36 h after initiation of treatment. RESULTS: AMIO restored sinus rhythm earlier in HFrEF vs. in HFpEF patients (24.3 ± 4.6 vs. 26.8 ± 2.8 h, p < 0.0001). AMIO + RAN converted POAF faster than AMIO alone in both HFrEF and HFpEF groups, with conversion times 10.4 ± 4.5 h in HFrEF and 12.2 ± 1.1 h in HFpEF patients (p < 0.0001). Left atrial diameter was significantly greater in HFrEF vs. HFpEF patients (48.2 ± 2.6 vs. 35.2 ± 2.9 mm, p < 0.0001). No serious adverse drug effects were observed during AF or after restoration to sinus rhythm in any of the patients enrolled. CONCLUSION: AMIO alone or in combination with RAN converted POAF faster in patients with reduced EF than in those with preserved EF. Thus, AMIO + RAN seems to be a valuable alternative treatment for terminating POAF in HFrEF patients.

Antiarrhythmic effects of ranolazine used both alone for prevention of atrial fibrillation and as an add-on to intravenous amiodarone for its pharmacological cardioversion: a meta-analysis.

INTRODUCTION: Recent evidence from relatively small randomized controlled trials would seem to support a useful role of ranolazine for the prevention and treatment of atrial fibrillation (AF). The present study is aimed at providing information about the possible beneficial anti-arrhythmic properties of ranolazine. In particular, the meta-analysis carried out in this study focuses on the application of ranolazine to prophylaxis and treatment of atrial fibrillation. EVIDENCE ACQUISITION: Both methods randomized controlled trials (RCTs) and non-randomized observational studies concerning the effects of ranolazine on AF were included in the meta-analysis. In each of the considered studies, a comparison was made between a group of patients taking ranolazine and a second group treated instead with another antiarrhythmic therapy, or assigned to placebo. Efficacy outcomes were the risk of new-onset AF, the probability of conversion to sinus rhythm of patients with recent occurrence (≤48 h) of AF and the time to conversion to sinus rhythm. Safety endpoints were death, adverse events, QTc prolongation and hypotension. EVIDENCE SYNTHESIS: Ten studies (8 RCTs and 2 nonrandomized observational studies) were gathered on the whole. Ranolazine was effective in preventing the occurrence of AF when compared to controls (RR=0.60; 95% CI: 0.43-0.83; P=0.002). Subgroup analysis showed a more pronounced preventive effect of ranolazine against AF in the postoperative setting of coronary artery bypass grafting (CABG) surgery (RR=0.39; 95% CI: 0.18-0.83; P=0.02) when compared to non-postoperative AF (RR=0.76; 95% CI: 0.63-0.92; P=0.04). Ranolazine enhanced the chances of successful cardioversion when added to intravenous amiodarone compared to amiodarone alone (RR 1.18; 95% CI: 1.05-1.33; P=0.004) and significantly decreased the time to cardioversion (SMD= -10.35 h; 95% CI: -18.13 hours to -2.57 hours; P<0.001). Overall risks of death, adverse events, and QTc prolongation were shown to be similar in the comparison between patients treated with ranolazine and controls. CONCLUSIONS: Ranolazine given orally at appropriate doses showed the property to significantly quicken the conversion of AF to sinus rhythm when combined with the IV amiodarone, compared to IV amiodarone alone. Furthermore, in patients in sinus rhythm, ranolazine proved to reduce the frequency of new onset AF as well as of its recurrences, especially in patients undergone CABG surgery, known to be at high risk of developing postoperative AF. In addition, ranolazine use seems to be safe and associated with relatively few adverse events.

Ranolazine in Symptomatic Diabetic Patients Without Obstructive Coronary Artery Disease: Impact on Microvascular and Diastolic Function.

BACKGROUND: Treatments for patients with myocardial ischemia in the absence of angiographic obstructive coronary artery disease are limited. In these patients, particularly those with diabetes mellitus, diffuse coronary atherosclerosis and microvascular dysfunction is a common phenotype and may be accompanied by diastolic dysfunction. Our primary aim was to determine whether ranolazine would quantitatively improve exercise-stimulated myocardial blood flow and cardiac function in symptomatic diabetic patients without obstructive coronary artery disease. METHODS AND RESULTS: We conducted a double-blinded crossover trial with 1:1 random allocation to the order of ranolazine and placebo. At baseline and after each 4-week treatment arm, left ventricular myocardial blood flow and coronary flow reserve (CFR; primary end point) were measured at rest and after supine bicycle exercise using 13N-ammonia myocardial perfusion positron emission tomography. Resting echocardiography was also performed. Multilevel mixed-effects linear regression was used to determine treatment effects. Thirty-five patients met criteria for inclusion. Ranolazine did not significantly alter rest or postexercise left ventricular myocardial blood flow or CFR. However, patients with lower baseline CFR were more likely to experience improvement in CFR with ranolazine (r=-0.401, P=0.02) than with placebo (r=-0.188, P=0.28). In addition, ranolazine was associated with an improvement in E/septal e' (P=0.001) and E/lateral e' (P=0.01). CONCLUSIONS: In symptomatic diabetic patients without obstructive coronary artery disease, ranolazine did not change exercise-stimulated myocardial blood flow or CFR but did modestly improve diastolic function. Patients with more severe baseline impairment in CFR may derive more benefit from ranolazine. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01754259.

Ranolazine therapy in drug-refractory ventricular arrhythmias.

AIMS: Ranolazine is an antiischemic and antianginal agent, but experimental and preclinical data provided evidence of additional antiarrhythmic properties. The aim of this study was to evaluate the safety and efficacy of ranolazine in reducing episodes of ventricular arrhythmias in patients with recurrent antiarrhythmic drug-refractory ventricular arrhythmias or with chronic angina. METHODS: Seventeen implantable cardioverter defibrillator (ICD) recipients, who had experienced a worsening of their ventricular arrhythmia burden, and 12 ICD recipients with angina were enrolled. Patients were followed up for 6 months after the addition of ranolazine (postranolazine). Data were compared with before its administration (preranolazine). RESULTS: In the Arrhythmias group, a significant reduction was found in the median number of ventricular tachycardia episodes per patient (4 vs. 0, P = 0.01), and in ICD interventions in terms of both antitachycardia pacing (2 vs. 0, P = 0.04) and shock delivery (2 vs. 0, P = 0.02) after the addition of ranolazine. Moreover, fewer patients experienced episodes of nonsustained ventricular tachycardia (71 vs. 41%, P = 0.04), ventricular tachycardia (76 vs. 24%, P = 0.01), ICD antitachycardia pacing (47 vs. 18%, P = 0.02), and ICD shocks (47 vs. 6%, P = 0.03). In the Angina group, none of the patients developed major ventricular arrhythmias while on ranolazine treatment. No adverse effects were observed. CONCLUSION: In this small study, ranolazine proved to be effective, well tolerated, and safe in reducing ventricular arrhythmia episodes and ICD interventions in patients with recurrent antiarrhythmic drug-refractory events. In addition, none of the patients with chronic angina developed major ventricular arrhythmias.

Ranolazine for stable angina pectoris.

BACKGROUND: Stable angina pectoris is a chronic medical condition with significant impact on mortality and quality of life; it can be macrovascular or microvascular in origin. Ranolazine is a second-line anti-anginal drug approved for use in people with stable angina. However, the effects of ranolazine for people with angina are considered to be modest, with uncertain clinical relevance. OBJECTIVES: To assess the effects of ranolazine on cardiovascular and non-cardiovascular mortality, all-cause mortality, quality of life, acute myocardial infarction incidence, angina episodes frequency and adverse events incidence in stable angina patients, used either as monotherapy or as add-on therapy, and compared to placebo or any other anti-anginal agent. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and the Conference Proceedings Citation Index - Science in February 2016, as well as regional databases and trials registers. We also screened reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) which directly compared the effects of ranolazine versus placebo or other anti-anginals in people with stable angina pectoris were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies, extracted data and assessed risk of bias. Estimates of treatment effects were calculated using risk ratios (RR), mean differences (MD) and standardised mean differences (SMD) with 95% confidence intervals (CI) using a fixed-effect model. Where we found statistically significant heterogeneity (Chi² P < 0.10), we used a random-effects model for pooling estimates. Meta-analysis was not performed where we found considerable heterogeneity (I² ≥ 75%). We used GRADE criteria to assess evidence quality and the GRADE profiler (GRADEpro GDT) to import data from Review Manager 5.3 to create 'Summary of findings' tables. MAIN RESULTS: We included 17 RCTs (9975 participants, mean age 63.3 years). We found very limited (or no) data to inform most planned comparisons. Summary data were used to inform comparison of ranolazine versus placebo. Overall, risk of bias was assessed as unclear.For add-on ranolazine compared to placebo, no data were available to estimate cardiovascular and non-cardiovascular mortality. We found uncertainty about the effect of ranolazine on: all-cause mortality (1000 mg twice daily, RR 0.83, 95% CI 0.26 to 2.71; 3 studies, 2053 participants; low quality evidence); quality of life (any dose, SMD 0.25, 95% CI -0.01 to 0.52; 4 studies, 1563 participants; I² = 73%; moderate quality evidence); and incidence of non-fatal acute myocardial infarction (AMI) (1000mg twice daily, RR 0.40, 95% CI 0.08 to 2.07; 2 studies, 1509 participants; low quality evidence). Add-on ranolazine 1000 mg twice daily reduced the fervour of angina episodes (MD -0.66, 95% CI -0.97 to -0.35; 3 studies, 2004 participants; I² = 39%; moderate quality evidence) but increased the risk of non-serious adverse events (RR 1.22, 95% CI 1.06 to 1.40; 3 studies, 2053 participants; moderate quality evidence).For ranolazine as monotherapy compared to placebo, we found uncertain effect on cardiovascular mortality (1000 mg twice daily, RR 1.03, 95% CI 0.56 to 1.88; 1 study, 2604 participants; low quality evidence). No data were available to estimate non-cardiovascular mortality. We also found an uncertain effect on all-cause mortality for ranolazine (1000 mg twice daily, RR 1.00, 95% CI 0.81 to 1.25; 3 studies, 6249 participants; low quality evidence), quality of life (1000 mg twice daily, MD 0.28, 95% CI -1.57 to 2.13; 3 studies, 2254 participants; moderate quality evidence), non-fatal AMI incidence (any dose, RR 0.88, 95% CI 0.69 to 1.12; 3 studies, 2983 participants; I² = 50%; low quality evidence), and frequency of angina episodes (any dose, MD 0.08, 95% CI -0.85 to 1.01; 2 studies, 402 participants; low quality evidence). We found an increased risk for non-serious adverse events associated with ranolazine (any dose, RR 1.50, 95% CI 1.12 to 2.00; 3 studies, 947 participants; very low quality evidence). AUTHORS' CONCLUSIONS: We found very low quality evidence showing that people with stable angina who received ranolazine as monotherapy had increased risk of presenting non-serious adverse events compared to those given placebo. We found low quality evidence indicating that people with stable angina who received ranolazine showed uncertain effect on the risk of cardiovascular death (for ranolazine given as monotherapy), all-cause death and non-fatal AMI, and the frequency of angina episodes (for ranolazine given as monotherapy) compared to those given placebo. Moderate quality evidence indicated that people with stable angina who received ranolazine showed uncertain effect on quality of life compared with people who received placebo. Moderate quality evidence also indicated that people with stable angina who received ranolazine as add-on therapy had fewer angina episodes but increased risk of presenting non-serious adverse events compared to those given placebo.

Novel Use of Ranolazine as an Antiarrhythmic Agent in Atrial Fibrillation.

OBJECTIVE: To review the limitations of current antiarrhythmic drugs in atrial fibrillation (AF) and discuss the rationale and clinical trials supporting the use of ranolazine in AF. DATA SOURCES: MEDLINE was searched from 1980 to September 2016 using the terms ranolazine, atrial fibrillation, coronary artery bypass grafting, and valve surgery. STUDY SELECTION AND DATA EXTRACTION: English-language studies and reviews assessing antiarrhythmic drugs, including ranolazine, were incorporated. DATA SYNTHESIS: The use of ranolazine monotherapy has been evaluated in 2 clinical trials. In the RAFFAELLO trial, higher doses of ranolazine showed a trend toward lower AF recurrence versus placebo ( P = 0.053), but further evidence is needed to support its use as a sole therapeutic agent. Ranolazine has shown utility in a limited number of studies as an adjunctive agent, which is critical for those in whom standard therapy is inadequate or the adverse event profile precludes optimized standard therapy. In the HARMONY trial, ranolazine 750 mg and dronedarone 225 mg twice daily reduced the AF burden by 59.1% from baseline ( P = 0.008 vs placebo). In a trial by Koskinas and colleagues, patients receiving ranolazine 1500 mg once and intravenous amiodarone had a higher conversion rate than those receiving amiodarone alone ( P = 0.024). There are also promising studies for the prevention and treatment of post-cardiothoracic surgery AF, which require further investigation. CONCLUSIONS: Ranolazine's pharmacological properties and available evidence suggest potential for its use in AF.

Ranolazine reduces atrial fibrillatory wave frequency.

AIMS: Antiarrhythmic medications for the treatment of atrial fibrillation (AF) have limited efficacy and rare but potentially life-threatening side effects. Ranolazine is an antianginal agent that may have antiarrhythmic activity in AF. METHODS AND RESULTS: Using the Duke Enterprise Data Unified Content Explorer database, we analysed a cohort of AF patients on ranolazine. Patients served as their own historic control. Electrocardiograms (ECGs) were analysed before and after ranolazine initiation to determine the effect of ranolazine on dominant frequency (DF), f-wave amplitude, and organizational index (OI). We identified 15 patients with ECGs in AF before and after ranolazine. Ranolazine was associated with lower DF by an average of 10% (5.10 ± 0.74 vs. 5.79 ± 0.96 Hz, P = 0.04) but not with changes in OI (0.47 ± 0.11 vs. 0.50 ± 0.12, P = 0.71) or amplitude (0.47 ± 0.43 vs. 0.41 ± 0.40 mV, P = 0.82). Ranolazine was also associated with lower DF in patients (n = 10) not on concomitant antiarrhythmic therapy (5.25 ± 0.78 vs. 6.03 ± 0.79 Hz, P = 0.04). CONCLUSION: Ranolazine is associated with lower AF DF but no change in OI or fibrillatory wave amplitude. Prospective trials are needed to evaluate ranolazine's potential as a novel antiarrhythmic drug for AF.