Ischemic heart disease is a heterogeneous condition with multiple etiologies that may contribute to an imbalance in myocardial oxygen supply and demand, resulting in depletion of myocardial cellular energy stores. Management of this disease state is aimed primarily at improving myocardial oxygen supply through revascularization of underlying obstructive atherosclerosis, in conjunction with interventions to reduce myocardial oxygen demand. Chronic treatment is directed at reducing recurrent ischemic symptoms. Despite advances in anti-thrombotic therapy, coronary revascularization, and other preventive therapies, the risk of recurrent events in this population remains substantial, in particular among those patients with indicators of higher risk (e.g. ST-segment depression, or arrhythmias).
Ranolazine is a piperazine derivative that exerts anti-ischemic actions without a clinically significant effect on heart rate or blood pressure. At clinically relevant concentrations, ranolazine is an inhibitor of the slowly inactivating component of the cardiac sodium current (late INa), which may reduce the deleterious effects associated with the intracellular sodium and calcium overload that accompany and may promote myocardial ischemia. Ranolazine is available as an anti-anginal agent for patients with chronic angina. The Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial demonstrated the safety of ranolazine in patients after ACS and also showed it's anti-arrhythmic properties. In addition to the safety properties of ranolazine, the study showed that ranolazine had a significant anti-ischemic effect and patient's on therapeutic dosing.
In an analysis of the 6560 patients in MERLIN-TIMI 36, using a digital continuous electrocardiographic Holter monitor for ischemia (Lifecard CF, Delmar Reynolds was applied to patients at the time of randomization and remained in place for 7 days, including after hospital discharge). Findings showed that patients treated with ranolazine had significantly lower incidences of arrhythmias. Specifically, fewer patients had an episode of ventricular tachycardia lasting ≥8 beats, supraventricular tachycardia or new-onset atrial fibrillation. In addition, pauses ≥3 seconds were less frequent with ranolazine. Based on this report, further studies of the antiarrhythmic effects of ranolazine were warranted.
Premature ventricular complexes (PVCs) are a frequent occurrence in the presence of ischemic heart disease. A very high PVC burden can be symptomatic or occasionally result in a cardiomyopathy. The mechanism by which PVCs cause cardiomyopathies or symptoms is not well understood, but may be related to an increase in myocardial strain or demand. Reduction in PVC burden has been associated with both improvement in ejection fraction and symptoms. Ranolazine has also been shown to reduce PVC burden in patients already on optimal medical therapy. The estimate of the minimal number of PVCs required to be associated with a cardiomyopathy is around 10%. In fact, subjects that had evidence for PVCs on baseline 12 lead electrocardiogram were found to have a significantly higher risk of cardiovascular events.
Current strategies for managing complex cardiomyopathies driven by arrhythmias have been complicated by intolerance to medical therapy as well as the requirement for frequent titration and the development of tolerance. Patients with ischemic heart disease have limited options for antiarrhythmic medical therapy. Prior trials of flecainide and eicainide in patients with ischemic heart disease for control of ventricular arrhythmias resulted in a significant and deleterious proarrhythmic effect current options for management line on amiodarone which has significant liver, thyroid, and lung toxicities or sotalol which can have significant bronchospastic effects as well as QT prolongation or tedious and which has to be carefully dose in the setting of renal insufficiency to avoid significant QT prolongation and the risk for proarrhythmia.
While ICD therapy has been appropriate for patients with reduced ejection fraction and evidence for unstable ventricular arrhythmias/sudden cardiac death, frequent or low level ventricular arrhythmias such as nonsustained VT or frequent PVCs would not be treated by ICD therapy. Escalation of traditional nodal therapies such as beta blockers or calcium channel blockers is his often limited by marginal systolic blood pressures and/or symptoms.
With the increasing prevalence of ischemic heart disease, it is critically important to identify therapies that have a neutral response to heart rate and blood pressure, good safety profile, and can reduce ischemia and the burden ventricular arrhythmias. Ultimately, the hope is that they will reduce strain induced ischemic heart changes. To that end, investigation of the effects of ranolazine in patients with ischemic heart disease and an elevated burden of PVCs is of great interest.
