The Pursuit of Optimum Outcomes in Stable Angina

The coronary arteries of patients with stable angina pectoris contain one or more severe obstructive atherosclerotic lesions, which limit the increase in blood flow required during periods of increased demand such as exercise or emotional stress. The resulting imbalance between myocardial oxygen supply and demand produces myocardial ischemia and its consequences, such as anginal pain and/or shortness of breath. In addition, the coronary arteries of these patients contain numerous non-obstructive atheromas, which grow at different rates. Rapid growth or disruption of these non-obstructive intraluminal atheromas leads to fissuring of the endothelial surface and exposes the intraluminal thrombogenic plaque material to the circulating blood. Subsequent platelet deposition, and occasionally superadded thrombosis may lead to partial or complete coronary occlusion, and this clinically manifests as acute coronary syndrome (ACS) or sudden death. Optimum treatment must, therefore, target not only the relief of symptoms by anti-ischemic mechanisms but also prevention or reduction of the incidence of serious adverse outcomes such as death and ACS. Smoking cessation, daily use of aspirin and lipid-lowering therapy, especially with statins, reduce mortality and the incidence of ACS in patients with stable angina, but usually have no effect on symptoms. In contrast, anti-anginal drugs, (β-blockers, long-acting nitrates and calcium channel blockers) reduce exercise-induced ischemia and angina frequency during daily life, and increase angina-free exercise time; however, it is unknown whether these drugs have any influence on mortality or the incidence of myocardial infarction in patients with stable angina. Coronary bypass surgery and percutaneous coronary interventions produce symptomatic improvement but do not reduce mortality or the incidence of myocardial infarction compared with medical treatment. These procedures are associated with an increase in immediate mortality and morbidity. Anti-anginal drugs can cause adverse effects and they are contraindicated when certain comorbid conditions exist with stable angina. Metabolic modulators, especially 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitors, and partial fatty acid oxidation (pFOX) inhibitors do not alter hemodynamics and can be administered to patients with reversible airway disease, reduced left ventricular function and other disease states. Published studies reported that the 3-KAT inhibitor trimetazidine and the pFOX inhibitor ranolazine had a wide margin of safety, and reduced exercise-induced ischemia, prolonged angina-free walking time and reduced angina frequency during daily activities. These drugs are available for clinical use in several countries excluding the USA, and have been utilized as monotherapy and in combination with other anti-anginal drugs. It is, however, unknown whether they influence mortality or morbidity in patients with stable angina. Also, it remains unknown whether these agents exert anti-anginal effects in patients who are not candidates for a revascularization procedure. If proven effective in well conducted trials, this class of drugs will be a useful addition to currently available strategies for treating patients with stable angina.