Ranolazine Therapy Research Articles

Ranolazine therapy is associated with a reduced new diagnosis of diabetes mellitus in chronic coronary syndrome patients: the results of a real-world analysis of an Italian population

Abstract Background Ranolazine (Ran) is an anti-anginal drug acting as a late sodium current inhibitor at a cell membrane level. Some experimental and clinical studies showed an antihyperglycemic effect of the drug, possibly mediated by the increase of insulin secretion, the inhibition of glucagon release, and the protective action on beta-cell function. These effects, additive to the anti-anginal properties of Ran in patients with chronic coronary syndrome (CCS), could modulate and improve glucose metabolic balance. Indeed, data exploring at a population level the association of the drug with diabetes mellitus (DM) incidence are effectively lacking. Aims Aim of this study was to evaluate in CCS patients if the use of Ran, compared with other treatments (No-Ran), was associated with a lower incidence of DM in an Italian real-world clinical setting. Methods Patients included in the database of the National Health System were evaluated (N=6.1 million; about 10% of the Italian population); the recorded information concerned hospitalizations with the related diseases, clinical events, outpatient visits and drug therapy. Patients hospitalized for any cause and discharged with a diagnosis of angina between 2011 and 2020 (ICD-9-CM codes: 413-414) were included in the study after having proved the absence of DM in their medical history. Study population was divided into the Ran (at least one drug prescription) and in the No-Ran cohorts. The mean follow up was 4.3 years for the Ran and 5.0 years for the No-Ran cohorts, respectively. Results The study population included N=171,015 patients (mean age: 72 years, men: 66%). Among them, N=148,808 (No-Ran cohort) were treated with other therapies while N=22,207 (Ran cohort) received Ran. After propensity score matching, Ran (N=6,384) and No-Ran (N=25,536) cohorts did not differ for age, Charlson comorbidity index, use of aspirin and other antithrombotic agents, statins, beta-blockers, Ca-antagonists and nitrates. The incidence of a new diagnosis of DM during the follow-up period was 10.5 and 15.8% in the Ran and in the No-Ran cohorts, respectively (p<0.001). The Cox-regression analysis showed that Ran therapy was associated with a 30% risk reduction to present a new diagnosis of DM (HR=0.70, 95%CI: 0.64-0.76, p<0.001), independently of age, Charlson comorbidity index, heart failure, previous stroke, use of ivabradine, Ca-antagonists and nitrates. Conclusions This real-world study, performed in a whole subset of the Italian population, showed that, in the long-term, the incidence of a new DM diagnosis was lower in Ran users. This association could contribute to explain the benefits of the drug in patients with CCS.

Ranolazine effects on exercise tolerance and angina frequency in Taiwanese stable angina: A bridging study of the CARISA randomized trial

BackgroundThe effectiveness of Ranolazine on chronic angina had been proved and launched in the United States. This study aimed to determine whether add-on Ranolazine could also be effective in Taiwanese population with persisting angina symptoms despite taking conventional antianginal agents. MethodsThis is a multi-center, randomized, parallel, double-blind comparative study. The endpoint is to compare the change from the baseline of the exercise treadmill test (ETT) performing duration between add-on ranolazine and placebo at week 12. Results46 patients were evaluable for the efficacy and safety endpoints. The mean change from baseline in ETT duration at week 12 was increased in the treatment and control group, and their mean difference was 20.8 s. All data in the Taiwanese population was like those in the CARISA study (24.0 s). The safety evaluation revealed that patients were tolerable to the add-on ranolazine therapy. The AE incidence for both ranolazine and placebo was 34.8%. The data were comparable to the past studies despite the limited statistical power. ConclusionThe add-on ranolazine therapy shows the potential to raise the exercise performance and tolerance of patients with chronic angina.

239 VASOSPASTIC ANGINA: A CASE OF COMPLETE FUNCTIONAL ASSESSMENT

Abstract Introduction Vasospastic angina is defined as a focal or diffuse spasm of the arterial wall of an epicardial coronary artery due to muscle cells hyperreactivity caused by an increased calcium sensitivity. Clinical presentation typically consists in chronic story of rest and/or effort typical chest pain, episodes of ST elevated or not ST elevated myocardial infarction, arrhythmias or cardiac arrest; an increased vagal tone, drugs, allergic reactions or the exposure to extreme cold also can trigger vasospasm. Clinical case 73 years old dyslipidemic woman; in past medical history thyroidectomy and radiotherapy for carcinoma and right quadrantectomy with radiotherapy and hormonal therapy for breast cancer. In 2017 admission to cath-lab for non-ST elevation myocardial infarction (NSTEMI) with the evidence of mild left coronary artery disease without critical obstructive stenosis (MINOCA). For the persisting of effort angina and dyspnea (NYHA and CCS II-III), started Diltiazem therapy (60 mg x3) with clinical benefit. In 2020, due to the onset of new episodes of angina, started Ranolazine therapy. In June 2022, for the worsening of clinical symptoms, was evaluated with a Coronary CT, that showed a 65% stenosis at right coronary-acute marginal bifurcation and mild disease on left coronary artery, and then was admitted for an elective coronary angiography, with no evidence of epicardial artery critical stenosis. At the functional evaluation FFR, CFR and IMR (>0.80, 2.5 and 18) demonstrated normal coronary flow reserve and good microcirculation function. For the suspicion of vasospastic angina, acetylcholine test was performed with the evidence of mid-distal left anterior descending artery total occlusion, angina onset and ECG changes, promptly regressed with nitrates administration (Figure 1). Patient was discharged with the optimization of medical therapy with Diltiazem 120 mg x3, with clinical benefit. Conclusions To date vasospastic angina remains underdiagnosed. Functional evaluation of coronary arteries plays a fundamental role in the diagnostic algorithm of the disease and should always be investigated in case of patients with typical symptoms and the absence of critical epicardial stenosis. Further investigations are required to better explain pathogenesis and to identify affected patients in shorter times to ensure early optimized medical therapy.

Effect of ranolazine on Tp-e interval, Tp-e/QTc, and P-wave dispersion in patients with stable coronary artery disease.

IntroductionRanolazine is an antianginal drug and also exhibits antiarrhythmic effect by affecting action potential time, refractory period, and repolarization reserve. We evaluated the effect of ranolazine therapy on myocardial repolarization parameters (Tp‐e, QT, QTc intervals, Tp‐e/QT, and Tp‐e/QTc ratios), index of cardiac electrophysiological balance (iCEB) (QT/QRS, QTc/QRS) and P‐wave dispersion (PWD) in patients with stable coronary artery disease (CAD).MethodsThis study included 175 patients, aged between 35 and 90 years who were followed with stable CAD for at least 3 months. Ninety patients had been receiving ranolazine for at least 1 month, and 85 patients had never received ranolazine. All patients' basic demographic data, risk factors, medications, and echocardiographic parameters recorded. Myocardial repolarization parameters, P‐wave times, and PWD were analyzed from 12 lead electrodes.ResultsThere was no variation between the groups in terms of basic demographic parameters and CAD risk factors. Tp‐e interval (87.3 ± 14.4 vs. 90.8 ± 12.4 msn, P < .001), Tp‐e/QT (0.22 ± 0.04 vs. 0.23 ± 0.03; P = .03), Tp‐e/QTc (0.21 ± 0.04 vs. 0.22 ± 0.04 P = .001), and PWD (39.2 ± 13.7 vs. 43.5 ± 12.9 P = .028) were significantly lower in the ranolazine group. But iCEB was similar in both groups. In multivariate analysis after adjusted confounding factors such as age and BMI, Tp‐e/QTc ratio, QTc, Pmax, and PWD were found significantly in ranolazine group again.ConclusionTp‐e/QTc ratio, QTc, Pmax, and PWD were significantly lower in stable CAD patients under ranolazine therapy. In stable CAD patients, the prognostic significance of ranolazine for arrhythmic events requires further evaluation of these parameters through long‐term follow‐up and large‐scale prospective studies.

Long-Term (3 Years) Outcomes of Ranolazine Therapy for Refractory Angina Pectoris (from the Ranolazine Refractory Registry)

Ranolazine is approved for patients with chronic stable angina but has not been formally studied in patients with refractory angina pectoris (RAP). Patients with RAP have limited therapeutic options and significant limitations in their quality of life. The Ranolazine Refractory Angina Registry was designed to evaluate the safety, tolerability, and effectiveness of ranolazine in RAP patients in order to expand treatment options for this challenging patient population. Using an extensive prospective database, we enrolled 158 consecutive patients evaluated in a dedicated RAP clinic. Angina class, medications, major adverse cardiac events including death, myocardial infarction, and revascularization were obtained at 12, 24, and 36 months. At 3 years, 95 (60%) patients remained on ranolazine. A ≥2 class improvement in angina was seen in 48% (38 of 80 patients with known Canadian Cardiovascular Society class) of those who remained on ranolazine. Discontinuation due to side effects, ineffectiveness, cost, and progression of disease were the principle reasons for discontinuation, but primarily occurred within the first year. In conclusion, ranolazine is an effective antianginal therapy at 3-year follow-up in patients with RAP and may reduce cardiac readmission.

The therapeutic efficnecy of ranolazine in comparison with conventional therapy in diabetic individuals with ischemic heart disease; a randomized clinical trial

Introduction: Patients with diabetes mellitus (DM) have higher risk of coronary artery disease (CAD) and angina than the general population. Objectives: We sought to assess the impact of ranolazine as an antianginal agent to diminish hemoglobin A1c (Hb A1c) level in diabetic individuals under treatment with metformin and gliclazide. Patients and Methods: This study was a randomized parallel-group clinical trial to compare the therapeutic effects of ranolazine versus conventional treatment in patients with concomitant T2DM and stable angina. TERISA (type 2 diabetes mellitus evaluation of ranolazine in subjects with chronic stable angina) was employed to assess the efficiency of ranolazine in lowering the frequency of angina attacks. The study was performed on diabetic patients with symptomatic angina under treatment with either sublingual nitroglycerin or up to two types of antianginal agents. The patients in the intervention group received 1000 mg ranolazine twice a day while patients in the control group were administrated with conventional treatment. Reduction in baseline Hb A1c level was determined at 4 and 8 weeks after the interventions. Results: Ranolazine therapy resulted in up to 15% absolute reduction in Hb A1c level in diabetic patients who had baseline HbA1c level &gt;7%. Ranolazine was more efficient in reducing Hb A1c in patients with poorly controlled disease (i.e. HbA1c&gt;8%, P=0.017). Ranolazine did not affect the glycemic status of patients concomitantly treated with antidiabetic therapy (P=0.560). Conclusion: Concurrent administration of ranolazine along with anti-diabetic treatments (i.e. metformin and gliclazide) was safe to reduce the level of HbA1c in patients with poorly controlled diabetes and stable angina.

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

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. 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. 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.

Ranolazine Therapy Reduces Non-ST-Segment-Elevation Myocardial Infarction and Unstable Angina in Coronary Disease Patients with Angina.

High sympathetic tone and cardiac autonomic neuropathy (CAN) are associated with major adverse cardiac events (MACE). We have shown ranolazine (RAN) improves autonomic function. RAN was introduced to 51 successive anginal CD patients (RANCD). A control group of 54 successive nonanginal CD patients (NORANCD) continued baseline therapy. Mean study duration was 6.1 years, which included semi-annual autonomic function measures (ANX 3.0, ANSAR Medical Technologies, Inc., Philadelphia, PA) and yearly myocardial perfusion SPECT studies (MPI). MACE were experienced by 29% RANCD patients versus 46% NORANCD patients (p = 0.0105). The patients from both groups with abnormal parasympathetic and sympathetic (P&S) measures and MACE totaled 52 of those patients with MACE versus 17% of those patients without MACE (p = 0.0274). Abnormal MPI was demonstrated in 35% of those with abnormal (P&S) measures and MACE versus 12% without MACE. Sympathovagal balance (SB) was lower, indicating higher, relative parasympathetic tone (known to be cardioprotective) in the RANCD group. Acute coronary syndromes occurred 4.5 times as often in NORANCD patients. High SB occur more frequently than abnormal MPI in CD patients experiencing MACE. In addition to increased myocardial blood flow as its proposed mechanism of angina relief, RAN improves P&S measures, a potentially new mechanism whereby RAN improves outcomes.

Is the Pleotropic Effect of Ranolazine is Due to its Antioxidant Action

AbstractBACKGROUND: Ranolazine is indicated as antianginal drug. We observed that it has other pleotropic effects also. So, we want to study the effect of Ranolazine in improvement of left ventricular (LV) function in obstructive coronary artery (CAD) diseased patients along with ACC/AHA guidelines of treatment. And to see the mode of improvement in LV function is due to its antioxidant effect.MATERIALS AND METHODS: We recruited CAD patient between the age group 18-80 yrs with LV dysfunction in whom ischemic component was treated. Cases received ranolazine 500 mg two times a day and controls without the drug. Both groups received standard drug therapy according to ACC/AHA guidelines of treatment CAD. For all these patients at basal and at 6 months of follow up, all baseline and demographic parameters, clinical features and symptomatology with blood chemistry parameters were collected. In addition Two Dimensional echocardiography (EF, MAV), Treadmill test (METs) and plasma oxidative stress levels (MDA) will be performed at 0 day (day of recruitment) and at 6 months. MDA concentration was tested by using the method described by Draper and Hadley based on TBA reactivity. Normal Range of MDA is 3.60 ± 0.90 Nano mole/ml.RESULTS: 100 cases and 40 controls were recruited for this study. Male: Female ratio was 3.4:1 in cases and in controls. The mean age of cases was 56.8 ± 9.6 yrs in cases and 55.1 ± 12 yrs in controls. There was no difference in demographic features and risk factor profile in between the cases and controls expect smoking ( high in cases). Even in echo EF was comparable but MAV is more in cases than controls (9.5 ±2.1 vs 8.8±1.8) which are also not statistically significant.There is statistically significant improvement of EF either by dimension (48.3 ± 9.6 vs 43.8±8.4 %, p= 0.008) or volume (p=0.018) method of estimation and peak mitral annular velocity in cases (9.8±1,8 vs 8.7± 1.8 cm/sec, p= 0.001) who received additional ranolazine therapy than controls.MDA at 6 months in cases was decreases to 3.4±0.8 nano mole/dl where as in controls increased to 3.9±0.7 nano mole/dl. Out of 100 cases we could able to get Treadmill test done only for 89 patients with modified Bruce protocol and there was a statistically significant improvement in the number of metabolic equivalents at 6 months in cases comparison to basal exercise capacity (6.8± 2.4 vs 8.2 ± 8.1 METS, p= 0.05).ConclusionsRanolazine can act as not only an anti anginal drug but also it was shown to have positive effects on improving LV function (improvement in EF and mitral annular velocities) and improving the exercise capacity (increased METs by TMT). These effects may be due to reduction in the oxidative stress (decreased MDA levels).

Ranolazine and Its Effects on Hemoglobin A1C.

To review the antihyperglycemic effect of ranolazine in type 2 diabetes mellitus (T2DM). An EMBASE search was conducted between January 1966 through December 2015 using the search termsranolazine, diabetes, andhemoglobin A1C(A1C). Additional references were identified from a review of literature citations. A search of clinicaltrials.gov was conducted to identify unpublished studies assessing ranolazine in diabetes. All English-language observational and randomized controlled trials assessing the effects of ranolazine on A1C were evaluated. Four published and 3 unpublished trials were identified. In all except 1 study, ranolazine 750 to 1000 mg twice daily was associated with a statistically significant decrease in A1C compared with placebo (placebo-corrected change in A1C: -0.28 to -0.7). In the trial in which a significant difference was not observed, patients assigned to ranolazine received a lower maintenance metformin dose compared with patients not assigned to ranolazine. A greater percentage of patients randomized to ranolazine achieved an A1C<7% compared with the placebo group (41.2%-59% vs 25.7%-49%). Ranolazine was not associated with an increase in the incidence of hypoglycemia and was well tolerated overall. The mechanism for lowering of A1C has not been determined. Ranolazine therapy may decrease A1C among patients with T2DM without an increase in hypoglycemia. For patients with T2DM and chronic stable angina, ranolazine may be of use given its utility in cardiovascular disease and benefit in A1C lowering.

Abstract 17401: Ranolazine: A Novel Anti-ischemic Drug in Preventing Post-operative Af in Patients Undergoing Coronary Artery Bypasses Grafting: Meta-analysis

Introduction: Atrial fibrillation (AF) is common after coronary artery bypass grafting (CABG). Ranolazine is a novel drug used in the treatment of angina, which also has antiarrhythmic properties. Recent studies demonstrated the benefit of ranolazine in preventing post-operative AF (POAF) in patients undergoing CABG. Hypothesis: To assess the role of ranolazine in preventing POAF in patients undergoing CABG surgery. Methods: We performed comprehensive search of PubMed, MEDLINE, and Cochrane library database on the study assessing the effectiveness of ranolazine in preventing POAF by comparing it with standard therapy. Meta-analysis was performed by fixed effect model by entering POAF events and the total population from each study. Data are expressed as Odds ratio (OR) with 95% confidence interval (CI). Results: A total of three studies with 628 patients (259 pts in ranolazine group, 369 pts in standard therapy group) were included in the meta-analysis. In pooled analysis, ranolazine was associated with 54% reduction in post-operative AF events compared to standard therapy [odds ratio = 0.46 (0.31, 0.70), P&lt;0.001]. The number needed to be treated was 7.14. In one of the study, more patients in ranolazine group (52.2%) had symptomatic hypotension three days after the surgery. Conclusions: Ranolazine may prove beneficial in the prevention of POAF following CABG. However, because of small number of studies further research with large randomized clinical trial is warranted to determine specific dose and duration of ranolazine therapy.

Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study.

Ranolazine, a late inward sodium current and fatty acid oxidation inhibitor, may improve right ventricular (RV) function in pulmonary arterial hypertension (PAH); however, the safety and efficacy of ranolazine in humans with PAH is unknown. Therefore, we sought to (1) determine whether ranolazine is safe and well tolerated in PAH and (2) explore ranolazine's effect on symptoms, exercise capacity, RV structure and function, and hemodynamic characteristics. We therefore conducted a 3-month, prospective, open-label pilot study involving patients with symptomatic PAH (n = 11) and echocardiographic evidence of RV dysfunction. We evaluated the safety and tolerability of ranolazine and compared symptoms, exercise capacity, exercise bicycle echocardiographic parameters, and invasive hemodynamic parameters between baseline and 3 months of ranolazine therapy using paired t tests. Of the 11 patients enrolled, one discontinued ranolazine therapy due to a drug-drug interaction after 3 days of therapy. All 10 of the remaining patients continued therapy for 3 months, and 8 (80%) of 10 completed all study tests. After 3 months, ranolazine administration was safe and associated with improvement in functional class (P = 0.0013), reduction in RV size (P = 0.015), improved RV function (improvement in RV strain during exercise at 3 months; P = 0.037), and a trend toward improved exercise time and exercise watts on bicycle echocardiography (P = 0.06 and 0.01, respectively). Ranolazine was not associated with improvement in invasive hemodynamic parameters. In conclusion, in a pilot study involving PAH, ranolazine therapy was safe and well tolerated, and it resulted in improvement in symptoms and echocardiographic parameters of RV structure and function but did not alter invasive hemodynamic parameters. ClinicalTrials.gov Identifier: NCT01174173.

PP.21.28

Objective: In cases of hypertrophic non obstructive cardiomyopathia a diastolic relaxation disorder as a sign of left ventricular dysfunction is well known. The analysis of the diastolic relaxation disorder is possible by using doppler ultrasonography without interference of the patient, who can report subjectively about dyspnoea and angina pectoris equivalent. An influence on the diastolic relaxation disorder may be induced by the drug ranolazine. Ranolazine inhibits the ischemic generated late sodium influx (I Na late) and reduces consequently the ischemic induced intracellular sodium and calcium overload. On this mechanism the calcium effected diastolic left ventricular wallaclampsia will be decreased. The agency of ranolazine is similar to the calcium antagonists, however without influencing blood pressure and heart rate. Design and method: In this context we report a 56-year-old hypertensive patient with increasing dyspnoea under exercise, weakness and angina counterparts. A hypertrophic non obstructive cardiomyopatia (type I according to Maron) with pronounced diastolic dysfunction could be secured within the framework of the complete diagnosis. After enlightenment we administered ranolazine (Ranexa 375 mg, twice a day). A tissue doppler echocardiography measurement was performed before and under the additional ranolazine therapy. Results: Ijn the entire observation period, the cardiovascular parameters were stable, normotonic, and normofrequent. The patient reported an increased quality of life. After 7 days an improvement of the E‘A‘index (as a dimensional criterion for the relaxation) was found in the tissue doppler echocardiographic follow-up. The normalization of the È‘A‘index (initial 0.3975 +/- 0.1106 to 0.705 +/- 0.06 under therapy) was documented significantly (p < 0.05). Conclusions: The addition of ranolazine showed a subjective benefit concerning the reported dyspnoea and angina equivalents in line with the diastolic relaxation disorder. Objectively a relevant amelioration of the tissue doppler ultrasonic parameters was observed. This observation may be important concerning the therapy of hypertensie induced heart failure with diastolic relaxation disorder. Ranolazine inhibits the pathophysiologically increased intracellular sodium influx in late (I Na late) and reduces in this way the calcium overload of the hypertensive cell. Due to this mechanism the calcium effected diastolic left ventricular wallaclampsia will be decreased.

Pharmacology of Combined Amiodarone Hydrochloride and Ranolazine Therapy in Atrial Fibrillation

This review article presents the pharmacology of combined Amiodarone Hydrochloride and Ranolazine therapy specialy in Atrial Fibrillation. Amiodarone Hydrochloride is Anti Arrhythmic agent. Ranolazine is a Anti Anginal agent. The Antianginal agent was used in Ischaemia. Amiodarone Hydrochloride is Antiarrhythmic agent and use in Arrhythmia and Atrial fibrillation. If Amiodarone Hydrochloride is administered in large quantities, the condition of patient become worse by occurrence of adverse effect of Thyroid toxicity due to presence of Iodine moiety in Amiodarone. The use of Ranolazine in combination with Amiodarone Hydrochloride has been proved to provide beneficial effect in Atrial Fibrillation. The combination therapy has fewer adverse effect. The mechanism of Amiodarone Hydrochloride and Ranolazine is quite different. Amiodarone Hydrochloride inhibit potassium channel and inactivated-state blocker of cardiac sodium channel while Ranolazine inhibit late inward sodium current(INa) in cardiac cell and activated-state blocker of cardiac sodium channel. The combination of both have decrease dose dependent side effect of Amiodarone Hydrochloride. Both the drugs were approved by US government and has been used in Atrial Fibrillation in US. The main objective of this review article is to provide pharmacological information of combined therapy of Amiodarone Hydrochloride and Ranolazine to researcher in development of combined dosage form of this.

CrossTalk opposing view: The late sodium current is not an important player in the development of diastolic heart failure (heart failure with a preserved ejection fraction)

CrossTalk opposing view: The late sodium current is not an important player in the development of diastolic heart failure (heart failure with a preserved ejection fraction)

Efficacy and Safety of Ranolazine in Patients With Chronic Stable Angina

Chronic stable angina (CSA) impairs patient quality of life, is associated with increased patient mortality, and is a prominent symptom of coronary artery disease (CAD), the latter being prevalent worldwide in patients. Currently, therapeutic options for patients with CSA include β-blockers, calcium channel blockers, nitrates, and ranolazine. Ranolazine is a first-in-class piperazine derivative that inhibits the late inward sodium current in cardiac cells and is considered an effective and safe option for treating patients with CSA. As with any first-in-class agent, it is important for the practitioner to be familiar with the safety profile of the drug. Therefore, the objective of our article is to review safety data on the use of ranolazine in patients with CSA. Clinical data show that ranolazine is well tolerated: major treatment-associated adverse events include dizziness, nausea, headache, and constipation. Ranolazine treatment is also associated with QTc-interval prolongation; however, QTc-interval prolongation with ranolazine does not appear to have clinical consequences–in fact, several studies suggest that ranolazine therapy may have an antiarrhythmic effect in patients. Notably, ranolazine is hemodynamically neutral in that it exerts its antianginal effect without significantly impacting patient heart rate or blood pressure. In addition, small decreases in glycosylated hemoglobin levels have been seen in patients with type 2 diabetes mellitus. Overall, ranolazine (in doses of 500 mg and 1000 mg, twice daily) is a safe and effective option for monotherapy or add-on therapy to reduce anginal symptoms in patients with CSA.

Impact of Ranolazine on Clinical Outcomes and Healthcare Resource Utilization in Patients with Refractory Angina Pectoris

Ranolazine is a novel antianginal medication approved for the treatment of chronic angina. There are only limited data concerning the efficacy of ranolazine in reducing healthcare resource utilization in patients with refractory angina pectoris. The primary objective of this analysis was to evaluate the efficacy and safety of ranolazine in refractory angina pectoris. In addition, the impact of ranolazine on healthcare resource utilization was assessed. Consecutive patients with refractory angina pectoris treated with ranolazine at two cardiology practices in the state of Nebraska were included in this analysis. The Canadian Cardiovascular Society (CCS) angina class and frequency and type of healthcare resource consumption were determined during the 12 months prior to and the 12 months after initiation of ranolazine. A total of 150 pts (64% men) with a mean age of 66±12 years were included in this analysis. All patients had previously undergone coronary revascularization. Nitrates, β-adrenoceptor antagonists (β-blockers), and calcium antagonists (calcium channel blockers) were being used in 83, 97, and 75% of patients, respectively. During ranolazine treatment, a significant improvement in CCS angina class was observed, with 23 patients improving by one class and no patient experiencing a deterioration in functional class (p=0.025). A total of 53 side effects occurred in 28 (19%) patients receiving ranolazine. Of those patients with side effects, four required dose reduction and seven required drug discontinuation. The frequency of clinic visits and emergency room visits was lower during ranolazine treatment, but the differences in frequency were not significant. The number of patients hospitalized and the number of hospitalizations were significantly lower during ranolazine therapy than in the pre-ranolazine study period (p=0.002). Ranolazine improved the CCS angina class and reduced hospitalizations over a 12-month follow-up period in a group of patients with difficult-to-treat refractory angina pectoris.

A Rare Neurological Complication of Ranolazine

Myoclonus is not a known side effect of ranolazine. We report a case of myoclonus in a 72-year-old female who underwent cardiac catheterization for angina and was started on ranolazine after the procedure. Two days after ranolazine therapy on 1000 mg per day in divided doses, myoclonus developed, which severely impaired her normal activity. Her symptoms resolved 2 days after discontinuation of ranolazine. Ranolazine was resumed after discharge from hospital with recurrent myoclonus after two days of therapy. The causal relationship between ranolazine and myoclonus was suggested by cessation of myoclonus after ranolazine was discontinued.

Neurologic Adverse Effects of Ranolazine in an Elderly Patient with Renal Impairment

Ranolazine, an antianginal agent, has activity at muscle and neuronal sodium channels. Congenital genetic mutations to sodium channels in humans and supratherapeutic ranolazine concentrations in animal models have produced similar neurologic adverse reactions. We describe a case of neurologic adverse effects in an 81-year-old woman with coronary artery disease, renal impairment, and mild neurologic disease who received ranolazine for symptomatic control of a non-ST-segment elevation myocardial infarction. Just over 48 hours after a dose increase, she experienced new-onset dysarthia, dysmetria, hallucinations, worse tremors, and difficulty with word finding. Her workup for acute stroke and infectious causes was negative. Her symptoms abated 2days after ranolazine was discontinued. The patient was at risk for ranolazine adverse effects due to the high dose administered and her advanced age, renal impairment, and baseline mild neurologic disease. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient's neurologic adverse events and the ranolazine therapy. To our knowledge, this is the first case report illustrating rare but debilitating neurologic adverse effects of ranolazine. Health care practitioners should be aware of the adverse effects of ranolazine and avoid doses greater than500mg twice/day in patients older than80years or those with a creatinine clearanceof less than 30ml/minute.

Abstract 18974: A Pilot Study of the Effects of Ranolazine on Right Ventricular Structure and Function, Exercise Capacity, and Symptoms in Pulmonary Arterial Hypertension

Introduction: Right ventricular (RV) failure is a major cause of death in pulmonary arterial hypertension (PAH). RV ischemia, which is common in PAH, plays a major role in the development of RV failure. We hypothesized that ranolazine, a late Na+ current inhibitor, would be beneficial in patients with PAH by increasing RV perfusion. Methods: We prospectively enrolled 10 patients with World Health Organization (WHO) Group I PAH and symptoms of angina (or anginal equivalent) in an observational, 3-month study of the effects of ranolazine (1000 mg PO BID) in PAH. All patients were on chronic pulmonary vasodilator therapy. At baseline and 3 months, patients underwent functional class assessment, 6-minute walk test, bicycle echocardiography with speckle-tracking for assessment of RV mechanics, right heart catheterization, and adenosine perfusion cardiac MRI. Data was compared at baseline vs. 3-months using paired t-tests. Results: The mean age was 47±13 y, and 80% were female. At baseline, patients had moderate or greater PAH (Table 1) with evidence of RV dysfunction (7/10 patients had reduced RV fractional area change [&lt;0.35], and all patients had septal flattening indicative of RV overload). Ranolazine was well tolerated in 90% of patients (7 patients tolerated the full dose and 2 patients required a dose reduction due to side effects, after which the drug was well tolerated). Ranolazine was discontinued in 1 patient due to a medication interaction. After 3 mo. of ranolazine therapy, symptoms improved, exercise capacity increased, RV size decreased, and tricuspid annular plane systolic excursion (TAPSE) increased (Table 1). There were no changes in invasive hemodynamics, and no major adverse events. Conclusions: Ranolazine is well tolerated and safe in patients with WHO Group I PAH. After 3 mo. of therapy, ranolazine improved RV size and function and resulted in symptomatic improvement. These findings support the development of clinical trials for ranolazine in PAH.