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Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes - The MERLIN-TIMI 36 randomized trial

Harvard University, Cambridge, Massachusetts, United States
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 05/2007; 297(16):1775-83. DOI: 10.1001/jama.297.16.1775
Source: PubMed

ABSTRACT Ranolazine is a novel antianginal agent that reduces ischemia in patients with chronic angina but has not been studied in patients with acute coronary syndromes (ACS).
To determine the efficacy and safety of ranolazine during long-term treatment of patients with non-ST-elevation ACS.
A randomized, double-blind, placebo-controlled, multinational clinical trial of 6560 patients within 48 hours of ischemic symptoms who were treated with ranolazine (initiated intravenously and followed by oral ranolazine extended-release 1000 mg twice daily, n = 3279) or matching placebo (n = 3281), and followed up for a median of 348 days in the Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial between October 8, 2004, and February 14, 2007.
The primary efficacy end point was a composite of cardiovascular death, myocardial infarction (MI), or recurrent ischemia through the end of study. The major safety end points were death from any cause and symptomatic documented arrhythmia.
The primary end point occurred in 696 patients (21.8%) in the ranolazine group and 753 patients (23.5%) in the placebo group (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.83-1.02; P = .11). The major secondary end point (cardiovascular death, MI, or severe recurrent ischemia) occurred in 602 patients (18.7%) in the ranolazine group and 625 (19.2%) in the placebo group (HR, 0.96; 95% CI, 0.86-1.08; P = .50). Cardiovascular death or MI occurred in 338 patients (10.4%) allocated to ranolazine and 343 patients (10.5%) allocated to placebo (HR, 0.99; 95% CI, 0.85-1.15; P = .87). Recurrent ischemia was reduced in the ranolazine group (430 [13.9%]) compared with the placebo group (494 [16.1%]; HR, 0.87; 95% CI, 0.76-0.99; P = .03). QTc prolongation requiring a reduction in the dose of intravenous drug occurred in 31 patients (0.9%) receiving ranolazine compared with 10 patients (0.3%) receiving placebo. Symptomatic documented arrhythmias did not differ between the ranolazine (99 [3.0%]) and placebo (102 [3.1%]) groups (P = .84). No difference in total mortality was observed with ranolazine compared with placebo (172 vs 175; HR, 0.99; 95% CI, 0.80-1.22; P = .91).
The addition of ranolazine to standard treatment for ACS was not effective in reducing major cardiovascular events. Ranolazine did not adversely affect the risk of all-cause death or symptomatic documented arrhythmia. Our findings provide support for the safety and efficacy of ranolazine as antianginal therapy.
clinicaltrials.gov Identifier: NCT00099788.

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    • "However, in the present study, syncope was not reported in the ranolazine group. This could be attributed to the dose of 500 mg BD used in our study compared to 500 / 750 / 1000 mg BD used in the MERLIN–TIMI 36 trial [30]. Syncope and postural hypotension have been found to occur with ranolazine probably due to it's α blockade action at a higher dose of 2000 mg [9]. "
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    ABSTRACT: Cardiovascular diseases have become the leading cause of death around the globe and diabetes mellitus (DM) is considered to be a coronary artery disease (CAD) risk equivalent. Ranolazine, an anti anginal drug has been found to reduce Glycated haemoglobin (HbA1c) in diabetes patients with chronic angina. However the effect of another antianginal drug trimetazidine, on glycemic status is not clear. To compare the effect of ranolazine and trimetazidine on glycemic status in diabetic patients with CAD. Patients diagnosed with CAD and diabetes mellitus attending Cardiology Out Patient Department (OPD), Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Puducherry, India were recruited for this randomized open label parallel arm trial. The study conducted from January-2012 to April-2013 had 47 eligible patients diagnosed with CAD and diabetes mellitus. They were randomized to receive either ranolazine 500 mg BD or trimetazidine 35 mg BD for 12 weeks. HbA1c levels, fasting blood glucose (FBG), lipid profile, QT and QTc intervals were measured at baseline and after 12 weeks. Unpaired t-test was used to compare the baseline characteristics of between the groups while comparison within the groups were done using Paired t-test. Wilcoxon and Mann Whitney U-tests were used for non parametric data. Graph pad instat version-3 was used for statistical analysis. Values were expressed as mean ± SD. A p < 0.05 was considered statistically significant. The study could not find any change in HbA1c levels in both ranolazine and trimetazidine groups. The adverse effects reported from patients on ranolazine include angina, constipation, postural hypotension, headache, dizziness, nausea and weakness while patients on trimetazidine complained of constipation, weakness, palpitations, angina, dizziness, nausea, dyspepsia, headache, gastric discomfort, joint pain, etc. In patients with chronic angina and diabetes mellitus Ranolazine 500mg BD and Trimetazidine 35mg BD did not show any effect on HbA1c and fasting blood glucose lebel.
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    • "Recently, several experimental studies have revealed a potent antiarrhythmic action of ranolazine [5] [7]. The first clinical evidence of ranolazine's antiarrhythmic efficacy has been highlighted in the MERLIN-TIMI 36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST- Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36) trial, which revealed that ranolazine may suppress both supraventricular and ventricular arrhythmias in patients with non-ST-segment elevation acute coronary syndrome [8] [9] [10] [11]. *Address correspondence to this author at Cardiology Department, Ippokrateio Hospital, Vas. "
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    ABSTRACT: Ranolazine, a newly introduced, FDA-approved antianginal agent, has more recently been shown to have additional beneficial antiarrhythmic actions attributed to its inhibitory effect on both peak and late sodium current. The first clinical evidence of ranolazine's antiarrhythmic efficacy has been provided by the MERLIN-TIMI 36 trial, which showed that ranolazine may suppress both supraventricular and ventricular arrhythmias in patients with non-ST-segment elevation acute coronary syndrome. An interesting observation of available studies is that ranolazine seems to be more effective in pathological conditions, such as heart failure, ischemia, tachyarrhythmias or long QT3 syndrome, and has little effect on normal myocytes. Importantly, the drug may have an antiarrhythmic effect without causing proarrhythmia. The mechanisms involved in the antiarrhythmic action of ranolazine, experimental and clinical data for its antiarrhythmic efficacy in suppressing atrial fibrillation and ventricular tachyarrhythmias, are herein reviewed. Current data from small randomized trials indicate that further larger randomized controlled trials are needed that will examine the antiarrhythmic effects of ranolazine and its potential use in patients with arrhythmias.
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    • "The 'thorough QT study' in healthy volunteers is now rapidly evolving as the discriminatory tool to differentiate 'safe' from 'unsafe' drugs, despite well known and described limitations with this biomarker; vardenafil, as one example, causes a mild QT prolongation in this study, despite the absence of any nonclinical 'signals' and has been extensively used during several years without any clear association with proarrhythmias. There are also other examples of drugs that mildly prolong the QT interval, but for which either extensive experience from clinical practice (for example, moxifloxacin, sodium pentobarbital and ebastine) (Paakkari, 2002; FDA, 2003) or clinical studies in high risk groups (for example, ranolazine (Morrow et al., 2007)) support the lack of proarrhythmic liability. In the case of ranolazine, the lack of proarrhythmia is probably based on other mitigating properties of the drug (Antzelevitch et al., 2004); however, the evidence to support this claim will require extensive clinical experience and may always be clouded by the issue of the existent background incidence of TdP in the general patient population. "
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    ABSTRACT: Drug-induced torsades de pointes (TdP) remains a significant public health concern that has challenged scientists who have the responsibility of advancing new medicines through development to the patient, while assuring public safety. As a result, from the point of discovering a new molecule to the time of its registration, significant efforts are made to recognize potential liabilities, including the potential for TdP. With this background, the ILSI (HESI) Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. A workshop was therefore convened at which four topics were considered including: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia and Key Considerations for Demonstrating Utility of Pre-Clinical Models. The series of publications in this special edition has established the background, areas of debate and those that deserve scientific pursuit. This is intented to encourage the research community to contribute to these important areas of investigation in advancing the science and our understanding of drug-induced proarrhythmia.
    British Journal of Pharmacology 07/2008; 154(7):1550-3. DOI:10.1038/bjp.2008.215 · 4.99 Impact Factor
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