Truffa et al The treatment of chronic stable angina aims to increase myocardial oxygen supply by vasodilation (eg, nitrates, calcium channel blockers), to reduce coronary artery obstruc- tion (eg, percutaneous coronary intervention or coronary artery bypass grafting), and to decrease myocardial oxygen demand (eg, beta-adrenergic receptor blockers, calcium chan- nel blockers).7–9 The goals of such treatment are to improve quality of life by reducing the severity and/or frequency of symptoms, to increase functional capacity, and to improve the prognosis of the patient, by preventing myocardial infarc- tion and death. Medical management, aimed at preventing future clinical events, is pivotal in all patients with coronary artery disease and includes antiplatelet agents (aspirin and clopidogrel), beta-adrenergic receptor blockers, angiotensin-converting enzyme inhibitors and/or renin-angiotensin-aldosterone system blockers, nitrates, calcium channel antagonists, and lipid-lowering agents.6,10 In addition, specific treatment may be needed to control angina symptoms. Antianginal drug treatment should be tailored to the needs of each patient and should be monitored individually. Short-acting nitrate therapy should be prescribed for all patients for immediate relief of acute symptoms as tolerated. Although different drugs have been shown to have additive antianginal effects in clinical tri- als, this may not necessarily be so in an individual patient. Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) is also an option for the relief of angina when medical therapy fails,11 but as demonstrated in the COURAGE trial, when used on the background of optimal medical therapy, does not reduce death or myocardial infarction compared with optimal medical therapy alone.6,10,12 Still, despite management with existing medical and revascularization options, millions of patients experience acute and chronic anginal symptoms. It is known, for example, that more than 25% of patients after revascularization, even if on optimal medical therapy, can develop a new ischemic symptom in five years.7,13 This observation underpins the ongoing need to develop new anti- anginal drugs. Most recently, ranolazine has been developed as one such option. Ranolazine Pharmacology and antianginal effects Ranolazine is a novel antianginal agent, with a different mechanism of action from the common agents, that reduces ischemia in patients with chronic angina.14,15 Although it has weak alpha-adrenergic and beta-adrenergic antagonist properties, under normal physiological conditions, these 536 submit your manuscript | www.dovepress.com Dovepress Dovepress properties are dominated by its effects on the autonomic nervous system.16–18 Therefore, it is not classified as a beta- adrenergic receptor blocker, calcium channel antagonist, or a vasodilator.19 Ranolazine preferentially blocks the cardiac late sodium current at concentrations that do not inhibit the peak transient current.20 This novel mechanism of action is postulated to reduce angina symptoms by avoiding ischemia- induced sodium and overload in cardiac myocytes during ischemia.7,15,21 Ranolazine is also believed to inhibit par- tially fatty acid oxidation,22 resulting in a shift in substrate metabolism towards glucose during ischemia that may also contribute to reduction in angina symptoms. Regardless of the postulated mechanism, based on its abil- ity to improve exercise performance, increase the time until angina recurs, and reduce angina frequency (alone and on top of other standard antianginal agents),9,19,22 ranolazine was approved by the US Food and Drug Administration in 200623 for use in patients with chronic stable angina. Importantly, in the trials that led to its approval, ranolazine did not appear to affect heart rate or blood pressure, and was generally well tolerated. The primary safety concern was prolongation of the rate-corrected QT interval (QTc) with ranolazine treat- ment, without clinical cases of torsades de pointes. This safety signal was later addressed in the MERLIN-TIMI (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) 36 trial discussed later.8 Metabolism Several routes for elimination of ranolazine have been identified. It is metabolized both in the liver through the cyto- chrome P450 3A enzyme pathway and in the intestine,21,24,25 and more than 70% of the drug is excreted as metabolites in the urine.21 Clearance of ranolazine is reduced by renal insuf- ficiency and moderate hepatic impairment; therefore, careful dose adjustment is required in patients with mild to moder- ate renal insufficiency or hepatic impairment. Ranolazine is contraindicated in patients with severe renal insufficiency or moderate to severe hepatic impairment.15,26 Many drugs are also known to interact with its metabo- lism and affect its clearance, increasing ranolazine plasma concentrations, including ketoconazole, diltiazem, and verapamil. Concomitant use of ranolazine can increase the plasma concentration of simvastatin and digoxin.15,21 Randomized clinical trials In the last decade, several randomized clinical trials have been conducted in patients with chronic stable angina Vascular Health and Risk Management 2011:7