Effect of Ranolazine, an Antianginal Agent With Novel Electrophysiological Properties, on the Incidence of Arrhythmias in Patients With Non–ST-Segment–Elevation Acute Coronary Syndrome
Results From the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) Randomized Controlled Trial
Background— Ranolazine, a piperazine derivative, reduces ischemia via inhibition of the late phase of the inward sodium current (late INa) during cardiac repolarization, with a consequent reduction in intracellular sodium and calcium overload. Increased intracellular calcium leads to both mechanical dysfunction and electric instability. Ranolazine reduces proarrhythmic substrate and triggers such as early afterdepolarization in experimental models. However, the potential antiarrhythmic actions of ranolazine have yet to be demonstrated in humans.
Methods and Results— The Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis in Myocardial Infarction (TIMI) 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non–ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG (Holter) recording was performed for the first 7 days after randomization. A prespecified set of arrhythmias were evaluated by a core laboratory blinded to treatment and outcomes. Of the 6560 patients in MERLIN-TIMI 36, 6351 (97%) had continuous ECG recordings that could be evaluated for arrhythmia analysis. Treatment with ranolazine resulted in significantly lower incidences of arrhythmias. Specifically, fewer patients had an episode of ventricular tachycardia lasting ≥8 beats (166 [5.3%] versus 265 [8.3%]; P<0.001), supraventricular tachycardia (1413 [44.7%] versus 1752 [55.0%]; P<0.001), or new-onset atrial fibrillation (55 [1.7%] versus 75 [2.4%]; P=0.08). In addition, pauses ≥3 seconds were less frequent with ranolazine (97 [3.1%] versus 136 [4.3%]; P=0.01).
Conclusions— Ranolazine, an inhibitor of late INa, appears to have antiarrhythmic effects as assessed by continuous ECG monitoring of patients in the first week after admission for acute coronary syndrome. Studies specifically designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.
Received June 29, 2007; accepted August 7, 2007.
Ranolazine, a piperazine derivative, is a novel antianginal agent that reduces anginal frequency and improves exercise performance in patients with chronic stable angina.1–3 Ranolazine appears to reduce myocardial ischemia via inhibition of the late phase of the inward sodium current (late INa) during cardiac repolarization.4–6 In several disease states, including ischemia and heart failure, late INa in ventricular myocytes is augmented, which increases sodium entry and raises the intracellular concentration of sodium. Intracellular sodium accumulation leads to an increase in reverse-mode sodium-calcium exchange and thus to an increase in the cytosolic calcium concentration.6,7 Increased intracellular calcium in ventricular myocytes can impair mechanical relaxation and promote electric instability by prolonging the cardiac action potential and/or provoking spontaneous calcium release from the sarcoplasmic reticulum. These events provide both the substrate (dispersion of transmyocardial repolarization) and the triggers (early and late afterdepolarization) to potentially precipitate ventricular arrhythmias.5
Clinical Perspective p 1652
By preferentially inhibiting late INa, ranolazine has been shown in single cells, isolated hearts, and animal models to reduce intracellular sodium and calcium overload caused by induced ischemia, heart failure, or reactive oxygen species that prolong INa.4,8,9 Moreover, in contrast to a drug like sotalol, the addition of ranolazine in these experimental models suppresses early afterdepolarization and other proarrhythmic electrophysiological phenomena.8 The potential antiarrhythmic actions of ranolazine, however, have yet to be evaluated in humans. We therefore investigated the incidence of arrhythmias, as detected by continuous ECG (cECG) monitoring, as part of a randomized, double-blind, placebo-controlled trial.10,11
In the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis in Myocardial Infarction (TIMI) 36 trial, 6560 patients hospitalized with a non–ST-elevation acute coronary syndrome (ACS) were randomized to ranolazine or placebo in addition to standard medical therapy. In brief, patients with moderate to high-risk clinical features were enrolled within 48 hours of their last ischemic symptoms and treated in a blinded manner with intravenous followed by oral ranolazine or matching placebo. Full inclusion and exclusion criteria, as well as study procedures, have previously been published.10,11 Patients received standard medical and interventional therapy according to local practice guidelines. The primary objective of the MERLIN-TIMI 36 trial was to assess the effect of ranolazine on the composite of cardiovascular death and recurrent ischemic events compared with placebo.11 A cECG, or Holter, recording (Lifecard CF, DelMar Reynolds/Spacelabs, Issaqua, Wash) was to be performed for the first 7 days after randomization in all patients to assess for ischemia as part of an efficacy analysis and for arrhythmias as part of a safety analysis.10,11 Analysts and cardiologists blinded to treatment assignment and clinical outcomes performed arrhythmia analyses of all cECG recordings in the TIMI ECG core laboratory.
The primary outcome of the cECG assessment was the incidence of clinically significant arrhythmias as detected by cECG monitoring that were prespecified as an episode of ventricular tachycardia at least 3 beats in length, any supraventricular tachycardia >120 bpm and lasting at least 4 beats, new-onset atrial fibrillation, an episode of bradycardia of <45 bpm lasting at least 4 beats, complete heart block, or a ventricular pause ≥2.5 seconds. Ventricular tachycardias were subsequently categorized according to current guidelines12 by length (at least 4 beats, at least 8 beats, and sustained [>30 seconds]), as well as by morphology for episodes lasting ≥8 beats (monomorphic versus polymorphic). Ventricular pauses were subsequently categorized by length (lasting ≥3 seconds) and by the principal mechanism of action (sinus node dysfunction, atrioventricular node dysfunction, or other mechanism).
The mean clinical follow-up was ≥12 months. A blinded clinical events committee adjudicated sudden cardiac death, which was defined as a sudden, unexpected death that was either (1) witnessed and occurring within 60 minutes from the onset of new symptoms and in the absence of a clear cause other than cardiovascular or (2) unwitnessed and occurring within 24 hours of being observed alive in the absence of preexisting progressive circulatory failure or other noncardiovascular causes of death.
All arrhythmia analyses were based on patients with evaluable cECG data. Continuous data were compared with a t test for normally distributed data and a Wilcoxon rank-sum test for nonnormally distributed data. Dichotomous variables were compared with a χ2 test. All analyses comparing treatment strategy and the incidence of arrhythmias were performed with a Cochran-Mantel-Haenszel test stratifying by the intention to use an early invasive strategy before randomization.10 Hazard ratios and 95% confidence intervals (CIs) were estimated by use of a Cox proportional-hazards regression model. Mortality rates are presented as Kaplan-Meier failure rates at 12 months.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Of the 6560 patients in MERLIN-TIMI 36, 6351 (97%) had cECG recordings that were interpretable for analysis. cECG monitoring was not performed in 105 patients (1.6%), and technical failure prevented analysis of 104 recordings (1.6%). Baseline characteristics of the 6351 patients with valid cECG recordings are presented in Table 1 and were similar to those of the entire patient population.11 The median duration of cECG recording was 6.8 days.
Treatment with ranolazine resulted in a significantly lower incidence of tachyarrhythmias compared with placebo (Table 2). Specifically, fewer patients assigned to ranolazine had an episode of ventricular tachycardia lasting ≥4 or ≥8 beats compared with placebo (the Figure). Few patients in MERLIN-TIMI 36 had either sustained ventricular tachycardia lasting ≥30 seconds or polymorphic ventricular tachycardia lasting ≥8 beats during cECG monitoring, and no difference existed between patients treated with ranolazine or placebo (Table 2). Sustained polymorphic ventricular tachycardia was detected on cECG in 10 patients (0.32%) assigned to ranolazine and 7 patients (0.22%) assigned to placebo (P=0.46). Two of these cases were reported clinically as torsade de pointes, 1 in each treatment group. Of the 17 patients with sustained polymorphic tachycardia, 15 cases occurred in the setting of ST depression or elevation. Three cases occurred with a preceding QT interval >600 milliseconds, 2 of which had concurrent ischemia. One of these 3 patients was assigned to placebo; 2 were assigned to ranolazine.
The incidence of ventricular tachycardia lasting ≥8 beats was similar in patients with or without ischemia detected on cECG monitoring (≥1-mm ST depression or elevation lasting ≥1 minute) (107 of 1351 [7.3%] versus 324 of 4569 [6.2%]; P=0.37) with a consistent reduction in the rate of ventricular tachycardia ≥8 beats with ranolazine among patients with ischemia (6.3% versus 8.3%; relative risk [RR], 0.76; 95% CI, 0.52 to 1.10; P=0.12) or no ischemia (5.0% versus 8.3%; RR, 0.60; 95% CI, 0.48 to 0.74; P<0.001) (P for interaction=0.29). No significant difference existed between treatment groups in the number of patients with sudden cardiac death (56 [1.7%] in the ranolazine group versus 65 [1.8%] in the placebo group).
Among several high-risk subgroups, including patients with prior heart failure, reduced left ventricular function, prolonged QTc interval at baseline, and high TIMI Risk Score (5–7), a consistent reduction was present in the incidence of ventricular tachycardias lasting ≥8 beats in patients treated with ranolazine with no difference in sudden cardiac death (Table 3).
In addition, patients treated with ranolazine were less likely to have an episode of supraventricular tachycardia lasting ≥4 beats at a rate of >120 bpm, new-onset atrial fibrillation, ventricular pauses ≥2.5 seconds or ≥3 seconds, and a bradycardic episode of <45 bpm lasting ≥4 beats (Tables 2 and 4⇓).
Among patients with established coronary artery disease at moderate to high risk for death or recurrent ischemic events in the MERLIN-TIMI 36 trial, ranolazine, an inhibitor of late INa, appears to have antiarrhythmic effects as assessed by cECG monitoring of patients in the first week after admission. In particular, patients treated with ranolazine had fewer episodes of ventricular tachycardia lasting at least 8 beats, supraventricular tachycardia, and ventricular pauses lasting at least 3 seconds.
This is the first clinical report of the effect of ranolazine on the incidence of cardiac arrhythmias, and it supports the experimental data that have identified several potential antiarrhythmic properties of ranolazine.4,8,13 The electrophysiological basis for drug-related suppression or induction of arrhythmias is complex. Contributory factors include conditions (congenital, acquired, and drug induced) that alter ion channel function, dispersion of repolarization, and pathological structural changes in the myocardium that alter electric impulse conduction. The 2 ion channel currents that are inhibited by ranolazine at clinically therapeutic concentrations (2 to 6 μmol/L) are late INa (ranolazine IC50=6 μmol/L) and the delayed rectifier potassium current (IKr) (IC50=12 μmol/L).8 Inhibition of IKr prolongs ventricular action potential duration, whereas inhibition of late INa has the opposite effect and shortens the action potential duration. The net effect of ranolazine on action potential duration depends on the relative magnitude of reductions in inward (INa) and outward (IKr) currents during repolarization.6 In normal ventricular epicardial and endocardial myocardium, the reduction in IKr predominates; thus, the net effect is that ranolazine lengthens the action potential duration in epicardium and endocardium. In contrast, in midmyocardium (M cells) and Purkinje fibers, the reduction in INa predominates, and ranolazine actually reduces action potential duration in these tissues. In addition to its direct effects to inhibit late INa and IKr, ranolazine has been shown in preclinical studies to reduce calcium overload induced by ischemia and reperfusion and thereby to attenuate electric dysfunction that is secondary to elevation of the intracellular calcium concentration.9,13
The net effect of ranolazine on the surface ECG is the known small prolongation of QTc by 2 to 6 ms.6 However, prolongation of QTc in the absence of other changes may not reflect the underlying electric susceptibility of the myocardium to arrhythmias, and in particular ventricular tachycardia and torsade de pointes. In the report by Antzelevitch et al,5 sotalol, an inhibitor of IKr, both prolonged action potential duration and increased the risk of early afterdepolarization, which can precipitate torsade de pointes. In that experimental study, ranolazine suppressed sotalol-induced prolongation of the action potential and early afterdepolarization. In canine ventricular wedge preparations, ranolazine, in contrast to sotalol,14 reduced another proarrhythmic substrate, transmural dispersion of repolarization.8 In this experimental model, treatment with ranolazine did not induce torsade de pointes and prevented ventricular tachycardia induced by programmed electric stimulation. Thus, despite the observation that ranolazine lengthens the QTc interval, preclinical evidence suggests that the overall electrophysiological action of the drug is not to increase but to suppress arrhythmic activity. The potential clinical relevance of these experimental findings is supported by the present results of the MERLIN-TIMI 36 trial, which demonstrate that ranolazine use was associated with a decrease rather than an increase in the incidence of arrhythmic activity in cECG recordings.
The use of most antiarrhythmic agents is limited by the risk of life-threatening arrhythmias or toxicity with prolonged exposure. Class Ia, Ic, and III antiarrhythmic agents suppress ventricular ectopy or reduce atrial fibrillation, but several, particularly class Ia and Ic agents such as flecainide and encainide and class III agents such as sotalol, may increase susceptibility to life-threatening arrhythmia14 or actually increase the risk of death after MI.15–17 In the patients in MERLIN-TIMI 36 with cECG recordings, ranolazine reduced nonsustained ventricular arrhythmias. Sustained polymorphic tachycardia occurred infrequently during the high-risk period of the first 7 days in MERLIN-TIMI 36 and in almost all cases was in the presence of ongoing ischemia detected on cECG. Although this analysis does not exclude the potential for drug-induced arrhythmia, we find no evidence for a significant excess risk of polymorphic ventricular tachycardia with ranolazine during the time of cECG monitoring in these high-risk patients. Moreover, the numerically, but not statistically, lower incidence of sudden cardiac death in patients treated with ranolazine over the entire study period provides important data supporting the apparent safety of longer-term treatment with ranolazine in high-risk patients with established coronary artery disease.11
The primary objective of the MERLIN-TIMI 36 trial was to assess the effects of ranolazine on cardiovascular death and recurrent ischemic events. Although the effects on arrhythmias are intriguing, they are exploratory and warrant trials specifically designed to assess the potential effect of ranolazine as an antiarrhythmic agent. It is possible that the anti-ischemic effect of ranolazine contributed to the observed reduction in arrhythmia, but the similar reduction in the incidence of ventricular tachycardia with ranolazine in patients with and without ischemia as detected on cECG suggests that ranolazine has direct antiarrhythmic properties.
The effects of ranolazine to inhibit late INa (and calcium overload) and IKr are plausible mechanisms by which the drug may reduce the risk of both supraventricular and ventricular tachycardias.8 The mechanism to explain the reduction of bradyarrhythmias, however, remains to be determined. Agents such as β-blockers, calcium channel blockers, amiodarone, and lidocaine suppress tachycardias but typically, and in contrast to ranolazine, decrease heart rate and actually increase bradyarrhythmias. We found no imbalance among antianginal agents with negative chronotropic properties to potentially explain this finding. Further research examining the effects of ranolazine on pacemaker activity and atrioventricular nodal conduction is needed to understand better the observed reduction in bradyarrhythmias by ranolazine.
In more than 6300 patients admitted with non–ST-elevation ACS, treatment with ranolazine resulted in significantly lower incidence of ventricular tachycardia, supraventricular tachycardia, and significant ventricular pauses. Studies specifically designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.
Source of Funding
MERLIN-TIMI 36 was supported by CV Therapeutics.
The TIMI Study Group reports receiving significant research grant support from Accumetrics, Amgen, AstraZeneca, Bayer Healthcare, Beckman Coulter, Biosite, Bristol-Myers Squibb, CV Therapeutics, Eli Lilly, GlaxoSmithKline, Inotek Pharmaceuticals, Integrated Therapeutics, Merck & Co, Merck-Schering Plough Joint Venture, Millennium Pharmaceuticals, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi-Aventis, Sanofi-Synthelabo, and Schering-Plough. Dr Scirica reports receiving honoraria for educational presentations from CV Therapeutics. Dr Morrow reports receiving honoraria for educational presentations from CV Therapeutics and Sanofi-Aventis, serving as a consultant for GlaxoSmithKline and Sanofi-Aventis, and being on an advisory board for Genentech. Dr Belardinelli is an employee of and owns stock in CV Therapeutics. Drs Hod, Molhoek, Hedgepeth, and Verheugt report receiving research support from CV Therapeutics. Dr Gersh reports being on an advisory board of and owns stock in CV Therapeutics. Dr Braunwald reports receiving honoraria from and serving as a consultant to AstraZeneca, Bayer AG, Daichii Sankyo, Merck, Pfizer, and Schering-Plough. The other authors report no conflicts.
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Ranolazine is an antianginal agent that inhibits the late phase of the inward sodium current (late INa) during cardiac repolarization. In experimental models, ranolazine reduces proarrhythmic substrates and triggers such as early afterdepolarization, but the potential antiarrhythmic actions of ranolazine have yet to be demonstrated in humans. In the Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Elevation Acute Coronary Syndrome (MERLIN)–Thrombolysis in Myocardial Infarction (TIMI) 36 trial, 6560 patients hospitalized with a non–ST-elevation acute coronary syndrome were randomized to ranolazine or placebo. Continuous ECG (Holter) recording was performed in 97% of patients for the first 7 days after randomization. Treatment with ranolazine resulted in significantly lower incidences of arrhythmias; specifically, fewer patients had an episode of ventricular tachycardia lasting ≥8 beats, supraventricular tachycardia, or significant bradycardic episode. A similar reduction in ventricular tachycardia with ranolazine was seen in several high-risk populations, including patients with a low ejection fraction and patients with a history of heart failure. There was no difference in the rate of sudden cardiac death between treatment groups during the average clinical follow-up of 12 months. Although these findings offer the first clinical support to the hypothesis that ranolazine is an antiarrhythmic agent, studies specifically designed to evaluate the potential role of ranolazine as an antiarrhythmic agent are warranted.
Guest Editor for this article was Harvey D. White, Dsc.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788.