Plasma Omega-3 Fatty Acids and the Risk of Cardiovascular Events in Patients After an Acute Coronary Syndrome in MERLIN-TIMI 36.

Background Plasma omega-3 polyunsaturated fatty acids (ω3-PUFAs) have been shown to be inversely correlated with the risk of cardiovascular death in primary prevention. The risk relationship in the setting of an acute coronary syndrome is less well established. Methods and Results Baseline plasma ω3-PUFA composition (α-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) was assessed through gas chromatography with flame ionization detection in a case-cohort study involving 203 patients with cardiovascular death, 325 with myocardial infarction, 271 with ventricular tachycardia, and 161 with atrial fibrillation, and a random sample of 1612 event-free subjects as controls from MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation-Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36), a trial of patients hospitalized with non-ST-segment-elevation -acute coronary syndrome. After inverse-probability-weighted multivariable adjustment including all traditional risk factors, a higher relative proportion of long-chain ω3-PUFAs (eicosapentaenoic acid, docosapentaenoic acid, docosahexaenoic acid) were associated with 18% lower odds of cardiovascular death (adjusted [adj] odds ratio [OR] per 1 SD, 0.82; 95% CI, 0.68-0.98) that was primarily driven by 27% lower odds of sudden cardiac death (adj OR per 1 SD, 0.73; 95% CI, 0.55-0.97). Long-chain ω3-PUFA levels in the top quartile were associated with 51% lower odds of cardiovascular death (adj OR 0.49; 95% CI, 0.27-0.86) and 63% lower odds of sudden cardiac death (adj OR, 0.37; 95% CI, 0.16-0.56). An attenuated relationship was seen for α-linolenic acid and subsequent odds of cardiovascular (adj OR, 0.92; 95% CI, 0.74-1.14) and sudden cardiac death (adj OR, 0.91; 95% CI, 0.67-1.25). No significant relationship was observed between any ω3-PUFAs and the odds of cardiovascular death unrelated to sudden cardiac death, myocardial infarction, atrial fibrillation, or early post-acute coronary syndrome ventricular tachycardia. Conclusions In patients after non-ST-segment-elevation-acute coronary syndrome, plasma long-chain ω3-PUFAs are inversely associated with lower odds of sudden cardiac death, independent of traditional risk factors and lipids. Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00099788.

Ranolazine in the prevention and treatment of atrial fibrillation: A protocol for meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia and a major cause of morbidity and mortality in clinical practice. This study aims to determine the ranolazine for prevention and treatment of atrial fibrillation. METHOD: This study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-analysis for Protocols. Chinese electronic Database (CBM, Wanfang, and CNKI) and international electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) will be searched for all relevant published articles. We will apply no language or the year of publication restrictions. Study selection, data collection, and assessment of study bias will be conducted independently by a pair of independent reviewers. The Cochrane risk of bias (ROB) tool will be used for the risk of bias assessment. The quality of evidence will be evaluated by Grading of Recommendations Assessment Development and Evaluation (GRADE) system. The statistical analysis of this meta-analysis will be calculated by Review manager version 5.3. RESULTS: The results of this study will be published in a peer-reviewed journal. CONCLUSION: This review will evaluate the value of ranolazine interventions for patients with AF, and provide meaningful conclusions or high-level evidence for clinical practice and further research. TRIAL REGISTRATION: This study protocol was registered in open Science framework (OSF), (Registration DOI: 10.17605/OSF.IO/T6W9Q).

In vivo characterization of anti-atrial fibrillatory potential and pharmacological safety profile of INa,L plus IKr inhibitor ranolazine using the halothane-anesthetized dogs.

To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having INa,L plus IKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that INa,L suppression may attenuate IKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action.

Achieving Optimal Medical Therapy: Insights From the ORBITA Trial.

Background In stable coronary artery disease, medications are used for 2 purposes: cardiovascular risk reduction and symptom improvement. In clinical trials and clinical practice, medication use is often not optimal. The ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) trial was the first placebo-controlled trial of percutaneous coronary intervention. A key component of the ORBITA trial design was the inclusion of a medical optimization phase, aimed at ensuring that all patients were treated with guideline-directed truly optimal medical therapy. In this study, we report the medical therapy that was achieved. Methods and Results After enrollment into the ORBITA trial, all 200 patients entered a 6-week period of intensive medical therapy optimization, with initiation and uptitration of risk reduction and antianginal therapy. At the prerandomization stage, the median number of antianginals established was 3 (interquartile range, 2-4). A total of 195 patients (97.5%) reached the prespecified target of ≥2 antianginals; 136 (68.0%) did not stop any antianginals because of adverse effects, and the median number of antianginals stopped for adverse effects per patient was 0 (interquartile range, 0-1). Amlodipine and bisoprolol were well tolerated (stopped for adverse effects in 4/175 [2.3%] and 9/167 [5.4%], respectively). Ranolazine and ivabradine were also well tolerated (stopped for adverse effects in 1/20 [5.0%] and 1/18 [5.6%], respectively). Isosorbide mononitrate and nicorandil were stopped for adverse effects in 36 of 172 (20.9%) and 32 of 141 (22.7%) of patients, respectively. Statins were well tolerated and taken by 191 of 200 (95.5%) patients. Conclusions In the 12-week ORBITA trial period, medical therapy was successfully optimized and well tolerated, with few drug adverse effects leading to therapy cessation. Truly optimal medical therapy can be achieved in clinical trials, and translating this into longer-term clinical practice should be a focus of future study. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02062593.

Confounders and Pharmacological Characterization When Using the QT, JTp, and Tpe Intervals in Beagle Dogs.

INTRODUCTION: Corrected QT (QTc) interval is an essential proarrhythmic risk biomarker, but recent data have identified limitations to its use. The J to T-peak (JTp) interval is an alternative biomarker for evaluating drug-induced proarrhythmic risk. The aim of this study was to evaluate pharmacological effects using spatial magnitude leads and DII electrocardiogram (ECG) leads and common ECG confounders (ie, stress and body temperature changes) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals. METHODS: Beagle dogs were exposed to body hyper- (42 °C) or hypothermic (33 °C) conditions or were administered epinephrine to assess confounding effects on heart rate corrected QTca, JTpca, and Tpeca intervals. Dofetilide (0.1, 0.3, 1.0 mg/kg), ranolazine (100, 140, 200 mg/kg), and verapamil (7, 15, 30, 43, 62.5 mg/kg) were administered to evaluate pharmacological effects. RESULTS: Covariate adjusted QT (slope -12.57 ms/°C) and JTpca (-14.79 ms/°C) were negatively correlated with body temperature but Tpeca was minimally affected. Epinephrine was associated with QTca and JTpca shortening, which could be related to undercorrection in the presence of tachycardia, while minimal effects were observed for Tpeca. There were no significant ECG change following ranolazine administration. Verapamil decreased QTca and JTpca intervals and increased Tpeca, whereas dofetilide increased QTca and JTpca intervals but had inconsistent effects on Tpeca. CONCLUSION: Results highlight potential confounders on QTc interval, but also on JTpca and Tpeca intervals in nonclinical studies. These potential confounding effects may be relevant to the interpretation of ECG data obtained from nonclinical drug safety studies with Beagle dogs.

A case of vasospastic angina. Vasospasm physiopathology: a new therapeutic role for ranolazine?

We report the case of a 40-year-old man, transferred from another hospital to our ICU because of acute coronary syndrome. Coronarography did not show coronary stenosis. Twenty-four hours monitoring EKG allowed diagnosis of Prinzmetal angina and appropriate therapy was administered. Six months after discharge due recurrence of symptoms, ranolazine was added to therapy. After one year the patient is symptoms free.

Ranolazine protects against diabetic cardiomyopathy by activating the NOTCH1/NRG1 pathway.

AIMS: Diabetic cardiomyopathy (DCM) is a common diabetes complication that can cause arrhythmia, heart failure, and even sudden death. Ranolazine is an antianginal agent used to treat chronic stable angina and has been demonstrated as an effective treatment for many cardiovascular diseases. However, the mechanism by which ranolazine alleviates DCM is unclear, motivating this study investigating the effects of ranolazine in DCM. MATERIALS AND METHODS: DCM rats were treated with one of three doses of ranolazine (10, 30, and 90 mg/kg/day) for 12 weeks. B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), cysteinyl aspartate specific proteinase-3 (Caspase-3), Notch homolog 1 (NOTCH1), and Neuregulin 1 (NRG1) expression was assayed using western blot and qRT-PCR. Cardiac changes were assayed using echocardiography, CT, HE staining, and Masson's trichrome staining. TUNEL staining and flow cytometry were used to detect cell apoptosis. NOTCH1 inhibitor (DAPT) was used to explore the mechanism of ranolazine. KEY FINDINGS: Compared with the DCM group, the ranolazine groups had no obvious weight loss and significantly decreased blood glucose levels. Ranolazine prevented diabetes-caused cardiac injury. Ranolazine also decreased the number of apoptotic cells and altered the expression of apoptosis-related mRNAs and proteins. Ranolazine-induced NOTCH1 activated NRG1 and inhibited the downstream apoptosis-related pathway, while DAPT partially inhibited ranolazine-induced NOTCH1 and NRG1 expression. SIGNIFICANCE: To our knowledge, this study is the first to demonstrate that ranolazine protects against DCM-induced apoptosis by activating the NOTCH1/NRG1 signaling pathway. Moreover, our study identified new mechanisms involved in DCM.

18ß-Glycyrrhetinic Acid Improves Cardiac Diastolic Function by Attenuating Intracellular Calcium Overload.

Ranolazine, a late sodium current inhibitor, has been demonstrated to be effective on heart failure. 18ß-glycyrrhetinic acid (18ß-GA) has the similar inhibitory effect on late sodium currents. However, its effect on diastolic function is still unknown. This study aimed to determine whether 18ß-GA can improve the diastolic function and to explore the underlying mechanisms. Eighty male Sprague Dawley (SD) rats of Langendorff model were randomly divided into the following groups: group A, normal cardiac perfusion group; group B, ischemia-reperfusion group; group C, ischemia-reperfusion with anemoniasulcata toxin II (ATX-II); group D, ranolazine group; and group E, 18ß-GA group with four different concentrations. Furthermore, a pressure-overloaded rat model induced by trans-aortic constriction (TAC) was established. Echocardiography and hemodynamics were used to evaluate diastolic function at 14th day after TAC. Changes of free intracellular calcium (Ca2+) concentration was indirectly detected by laser scanning confocal microscope to confirm the inhibition of late sodium currents. With the intervention of ATX-II on ischemia reperfusion injury group, 5 µmol/L ranolazine, and 5, 10, 20, 40 µmol/L 18ß-GA could improve ATX-II-induced cardiac diastolic dysfunction. 630 mg/kg glycyrrhizin tablets could improve cardiac diastolic function in the pressure-overloaded rats. 18ß-GA and ranolazine had similar effects on reducing the free calcium in cardiomyocytes. The study demonstrates that 18ß-GA and glycyrrhizin could improve diastolic dysfunction induced by ischemia-reperfusion injury in Langendorff-perfused rat hearts and pressure-overloaded rats. The mechanism may be attributed to the inhibition of enhanced late sodium currents.

Dose-Dependent Effects of Ranolazine on Reentrant Ventricular Arrhythmias Induced After Subacute Myocardial Infarction in Rabbits.

Ranolazine has been found to prevent ventricular arrhythmias (VAs) during acute myocardial infarction (AMI). This study aimed to investigate its efficacy on VAs induced several days post-MI. For this purpose, 13 anesthetized rabbits underwent coronary artery ligation. Ten of these animals that survived AMI were reanesthetized 3 to 7 days later for electrophysiologic testing. An endocardial monophasic action potential combination catheter was placed in the right ventricle for simultaneous pacing and recording. Monophasic action potential duration, ventricular effective refractory period (VERP), and VAs induced by programmed stimulation were assessed. Measurements were performed during control pacing, and following an intravenous infusion of either a low-dose ranolazine (2.4 mg/kg, R1) or a higher dose ranolazine (4.8 mg/kg cumulative dose, R2). During control stimulation, 2 animals developed primary ventricular fibrillation (VF), 6 sustained ventricular tachycardia (sVT), and 2 nonsustained VT (nsVT). R1 did not prevent the appearance of VAs in any of the experiments; in contrast, it aggravated nsVT into sVT and complicated sVT termination in 2 of 6 animals. Sustained ventricular tachycardia cycle length and VERP were only slightly decreased after R1 (112 ± 5 vs 110 ± 6 ms and 101 ± 11 vs 98 ± 10 ms, respectively). R2 suppressed inducibility of control nsVT, VF, and sVT in 2 animals. In 4 animals with still inducible sVT, R2 significantly prolonged VT cycle length by 150 ± 23 ms (P < .01), and VERP by 120 ± 7 ms (P < .001) versus control. In conclusion, R2 exerted antiarrhythmic efficacy against subacute-MI VAs, whereas R1 rather aggravated than prevented these arrhythmias. Ventricular effective refractory period prolongation could partially explain the antiarrhythmic action of R2 in this rabbit model.

Effects of ranolazine on cardiac function in rats with heart failure.

OBJECTIVE: To investigate the effects of ranolazine on the cardiac function and myocardial apoptosis in rats with heart failure and its possible mechanisms. MATERIALS AND METHODS: Thirty Wistar rats were randomly divided into sham operation (negative control; NC), chronic heart failure (CHF), and ranolazine groups. Suprarenal abdominal aortic coarctation was used to induce CHF in rats. Five weeks later, rats in the ranolazine group received ranolazine (50 mg/kg) daily, whereas those in the CHF group received normal saline. After 4 weeks, changes in hemodynamic parameters, cardiac structure and pathology, myocardial apoptosis, and protein expression were assessed. RESULTS: The left ventricular end-diastolic pressure (LVEDP) significantly increased in the CHF group; whereas the maximal rate of left ventricular pressure rise and fall (±dp/dtmax) decreased, compared to those in the NC group. Ranolazine significantly reduced LVEDP and increased ±dp/dtmax (p<0.01), compared to those in the CHF group. Severe impairment of cardiomyocytes was observed in the CHF group with evident inflammation; however, ranolazine reversed these deficits. Rats in the CHF group exhibited an increase in TUNEL-positive cells, which was inhibited by ranolazine, where the apoptotic index significantly decreased in ranolazine-treated rats (p<0.01). Also, ranolazine downregulated caspase-9 expression and upregulated pAKT and Bcl-2 expression in rat cardiomyocytes. Moreover, ranolazine significantly inhibited myocardial apoptosis and caspase-9 expression, promoted AKT phosphorylation, and upregulated pAKT and Bcl-2 expression in vitro, compared to those in the control group (p<0.001). LY294002 inhibited ranolazine-induced suppression of myocardial apoptosis (p<0.001). CONCLUSIONS: Ranolazine improved cardiac function and inhibited myocardial apoptosis in rats with CHF, which could be attributed to the regulation of AKT phosphorylation.

De-escalation of antianginal medications after successful chronic total occlusion percutaneous coronary intervention: Frequency and relationship with health status.

BACKGROUND: Successful chronic total occlusion (CTO) percutaneous coronary intervention (PCI) can markedly reduce angina symptom burden, but many patients often remain on multiple antianginal medications (AAMs) after the procedure. It is unclear when, or if, AAMs can be de-escalated to prevent adverse effects or limit polypharmacy. We examined the association of de-escalation of AAMs after CTO PCI with long-term health status. METHODS: In a 12-center registry of consecutive CTO PCI patients, health status was assessed at 6 months after successful CTO PCI with the Seattle Angina Questionnaire and the Rose Dyspnea Scale. Among patients with technical CTO PCI success, we examined the association of AAM de-escalation with 6-month health status using multivariable models adjusting for revascularization completeness and predicted risk of post-PCI angina (using a validated risk model). We also examined predictors and variability of AAMs de-escalation. RESULTS: Of 669 patients with technical success of CTO PCI, AAMs were de-escalated in 276 (35.9%) patients at 1 month. Patients with AAM de-escalation reported similar angina and dyspnea rates at 6 months compared with those whose AAMs were reduced (any angina: 22.5% vs 20%, P = .43; any dyspnea: 51.8% vs 50.1%, P = .40). In a multivariable model adjusting for complete revascularization and predicted risk of post-PCI angina, de-escalation of AAMs at 1 month was not associated with an increased risk of angina, dyspnea, or worse health status at 6 months. CONCLUSIONS: Among patients with successful CTO PCI, de-escalation of AAMs occurred in about one-third of patients at 1 month and was not associated with worse long-term health status.

Anti-metastatic effect of ranolazine in an in vivo rat model of prostate cancer, and expression of voltage-gated sodium channel protein in human prostate.

BACKGROUND: Voltage-gated Na+ channels (VGSCs) are functionally upregulated in rat and human prostate cancer (PCa) where channel activity promotes cellular invasiveness in vitro and metastasis in vivo. Ranolazine is a clinically used VGSC inhibitor/anti-anginal drug, which has been shown previously to inhibit breast cancer metastasis in vivo. METHODS: Using the Dunning model of rat PCa, the effect of ranolazine applied systemically (by gavage) was tested on the development of primary tumours and metastases following subcutaneous inoculation of Mat-LyLu cells into Copenhagen rats. In addition, human prostate tissue microarrays were used to determine VGSC protein expression in cancerous versus non-cancerous tissue. Several public databases were searched to compare Nav1.7/ SCN9A expression levels in 'normal' vs. PCa tissues. RESULTS: Ranolazine (2.5 and 5 µM) decreased the number of lung metastases by up to 63%. In contrast, primary tumourigenesis was not affected. Ranolazine also reduced the percentage of cells in the metastases expressing Nav1.7, the main VGSC subtype expressed in PCa, but the expression level was higher. In prostate tissue microarrays, VGSC protein expression was significantly higher in cancerous versus non-cancerous tissue. There was no correlation between the VGSC expression and either prostate-specific antigen or Gleason score. In public databases, little information could be found on Nav1.7 protein expression in PCa. In addition, the database information on Nav1.7 mRNA (SCN9A) expression levels did not correlate with previously reported upregulation in PCa cells and tissues. CONCLUSIONS: The main conclusions were (i) ranolazine inhibited metastasis and (ii) it was a subpopulation of cells with particularly high levels of Nav1.7 protein that reached the metastatic sites. These data extend earlier studies and suggest that Nav1.7 expression could serve as a functional biomarker of metastatic PCa and that VGSC blockers may be useful as anti-metastatic agents.

Single dose oral ranolazine pharmacokinetics in patients receiving maintenance hemodialysis.

PURPOSE: Ranolazine is a novel anti-angina treatment approved in the United States for chronic stable angina. Ranolazine pharmacokinetics have not been studied previously in patients who receive maintenance hemodialysis. This study describes the pharmacokinetics of ranolazine and three major metabolites (CVT-2738, CVT-2512, CVT-2514) in patients receiving thrice weekly hemodialysis. METHODS: Eight participants receiving maintenance hemodialysis completed this prospective, open-label study (study identifier NCT01435174 at Clinicaltrials.gov). Three participants received a single tablet of ranolazine 500 mg (followed by an interim analysis), and five received 2 tablets of ranolazine 500 mg. Blood samples were collected over 65 h to determine the pharmacokinetic characteristics during and between hemodialysis sessions. Non-compartmental analysis was used to determine the individual pharmacokinetic parameters. RESULTS: Ranolazine off-hemodialysis elimination phase half-lives were 3.6 and 3.9 h for 500 mg and 1000 mg doses, respectively. The time to maximum concentration ranged from 2 to 18 hours and the average maximum concentration was 0.65 ± 0.27 mcg/mL and 1.18 ± 0.48 mcg/mL for ranolazine 500 mg and 1000 mg dose, respectively. The mean hemodialysis percent reduction ratio for the ranolazine 500 mg dose was 52.3 ± 8.1% and for the ranolazine 1000 mg dose was 69.2 ± 37.6%. CONCLUSIONS: Data on ranolazine dosing in patients receiving maintenance hemodialysis is almost non-existent. Given the extent of pharmacokinetic variability observed with the 500 mg and 1000 mg oral doses of ranolazine, neither can be recommended as a starting dose in patients receiving maintenance hemodialysis. Guided by the information gained form this study about the extent of hemodialytic drug clearance, further multi-dose clinical trials of ranolazine are needed to optimize therapeutic outcomes in this patient population.

Late sodium channel blockade improves angina and myocardial perfusion in patients with severe coronary microvascular dysfunction: Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction ancillary study.

BACKGROUND: In a prior trial of late sodium channel inhibition (ranolazine) among symptomatic subjects without obstructive coronary artery disease (CAD) and limited myocardial perfusion reserve index (MPRI), we observed no improvement in angina or MPRI, overall. Here we describe the clinical characteristics and myocardial perfusion responses of a pre-defined subgroup who had coronary flow reserve (CFR) assessed invasively. METHODS: Symptomatic patients without obstructive CAD and limited MPRI in a randomized, double-blind, crossover trial of ranolazine vs. placebo were subjects of this prespecified substudy. Because we had previously observed that adverse outcomes and beneficial treatment responses occurred in those with lower CFR, patients were subgrouped by CFR <2.5 vs ≥2.5. Symptoms were assessed using the Seattle Angina Questionnaire and the SAQ-7, and left-ventricular volume and MPRI were assessed by magnetic resonance imaging (MRI). Coronary angiograms, CFR, and MRI data were analyzed by core labs masked to treatment and patient characteristics. RESULTS: During qualifying coronary angiography, 81 patients (mean age 55 years, 98% women) had invasively determined CFR 2.69 ±â€¯0.65 (mean ±â€¯SD; range 1.4-5.5); 43% (n = 35) had CFR <2.5. Demographic and symptomatic findings did not differ comparing CFR subgroups. Those with low CFR had improved angina (p = 0.04) and midventricular MPRI (p = 0.03) with ranolazine vs placebo. Among patients with low CFR, reduced left-ventricular end-diastolic volume predicted a beneficial angina response. CONCLUSIONS: Symptomatic patients with CFR <2.5 and no obstructive CAD had improved angina and myocardial perfusion with ranolazine, supporting the hypothesis that the late sodium channel is important in management of coronary microvascular dysfunction. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01342029.

Persistence of a Posaconazole-Mediated Drug-Drug Interaction With Ranolazine After Cessation of Posaconazole Administration: Impact of Obesity and Implications for Patient Safety.

The antianginal agent ranolazine (Ranexa®) is metabolized primarily by cytochrome P450-3A (CYP3A) enzymes. Coadministration with strong CYP3A inhibitors, such as ketoconazole and posaconazole, is contraindicated due to risk of QT prolongation from high levels of ranolazine. This study evaluated the time course of recovery from the posaconazole drug interaction in normal-weight and otherwise healthy obese subjects. Subjects received single doses of ranolazine in the baseline control condition, again during coadministration of posaconazole, and at 4 additional time points during the 2 weeks after posaconazole discontinuation. With posaconazole coadministration, the geometric mean ratio of ranolazine area under the concentration curve (AUC) increased by a factor of 3.9 in normals and by 2.8 in obese subjects. Posttreatment washout of posaconazole was slow in normals (mean half-life 36 hours) and further prolonged in obese subjects (64 hours). Recovery of ranolazine AUC toward baseline was delayed. AUC remained significantly elevated above baseline in normal-weight and obese subjects for 7-14 days after stopping posaconazole. Current product labeling does not address the need for delay or a reduced dose of ranolazine after discontinuation of a strong CYP3A inhibitor before ranolazine can be safely administered. We recommend that administration of ranolazine should be limited to 500 mg twice daily for 7 days after posaconazole discontinuation in patients with body mass index 18.5-24.9 kg/m2 and for 12 days in patients with body mass index ≥35 kg/m2 after ranolazine is resumed.

Ranolazine: A true pluripotent cardiovascular drug or jack of all trades, master of none?

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide. Although the majority of patients with CVD are treated with interventional procedures, a substantial number require medical therapy in terms of both prognosis and symptomatic relief. However, commonly used agents such as ß-blockers and calcium channel blockers reduce blood pressure in patients whose resting pressures are often already low. Ranolazine is a promising agent that does not have significant effects on blood pressure or heart rate. Use of this drug has been documented in various cardiovascular conditions, including ischaemic heart disease, heart failure and arrhythmias. This review article aimed to examine current evidence on the use of ranolazine in various cardiovascular conditions in order to determine whether it is a true pluripotent cardiovascular agent or, on the other hand, a "jack of all trades, master of none."

Antiarrhythmic Effects of Combining Dofetilide and Ranolazine in a Model of Acutely Induced Atrial Fibrillation in Horses.

BACKGROUND: Antiarrhythmic compounds against atrial fibrillation (AF) often have reduced efficacy and may display cardiac and/or noncardiac toxicity. Efficacy can be improved by combining 2 compounds with distinct mechanisms, and it may be possible to use lower doses of each compound, thereby reducing the likelihood of adverse side effects. The purpose of this study was to investigate whether the effective doses of dofetilide and ranolazine can be reduced if the drugs are combined. METHODS: Dofetilide, ranolazine, and a combination of these were administered in 4 incremental dosing regimens to horses with acutely pacing-induced AF. Time to cardioversion, atrial effective refractory period, and AF vulnerability and duration were assessed. RESULTS: Of 8 horses, 6 cardioverted to sinus rhythm after infusion with a combination of 0.889 µg/kg dofetilide and 0.104 mg/kg ranolazine. Two horses cardioverted with 0.104 mg/kg ranolazine alone, and 3 cardioverted with 0.889 µg/kg dofetilide alone. The combination therapy decreased AF vulnerability (P < 0.05) and AF duration (P < 0.05). No change in atrial effective refractory period was detected with any of the drugs. CONCLUSIONS: The combination of dofetilide and ranolazine showed increased antiarrhythmic effects on acutely induced AF in horses, affecting time to cardioversion, AF vulnerability, and AF duration.