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This article will not include a discussion of the clinical evaluation of a patient with stable angina, of lifestyle interventions, of antiplatelet, anticoagulant, and lipid-lowering drugs, and of revascularization strategies, all of which are dealt with in other chapters. Instead, we will focus on the narrower challenge of reducing the symptom of angina using pharmacologic agents, both traditional and novel. Nitrates are vasodilators, thus they increase coronary perfusion and blunt any rise in left 20 ventricular preload and end-diastolic pressure caused by the negative inotropic action of the -blockers. The Medical Treatment of Stable Angina Novel Anti-Ischemic Therapy Decreasing Myocardial Oxygen Demand and Increasing Oxygen Supply Pharmacologic prevention of symptoms of angina during periods of exertion has classically involved the use of agents that reduce myocardial oxygen demand and/or increase myocardial oxygen supply in response to exercise. Importantly, all available classes of traditional antianginal agents have similar effects on exercise duration. Thus, there is no clear indication that one drug is superior to the others based on this outcome. These objectives are modulated by two different mechanisms: symptoms of ischemia are due to an insufficient oxygen supply/demand ratio, whereas acute coronary syndromes are due to vulnerable plaque erosion and rupture, resulting in thrombotic coronary occlusion. Major determinants of myocardial oxygen demand are heart rate, contractility, and wall tension; minor determinants are basal metabolism and activation energy. Oxygen supply may be increased by coronary vasodilatation or by increasing the duration of myocardial perfusion during diastole by slowing the heart rate. Antianginal agents either reduce myocardial oxygen demand or increase myocardial oxygen supply to reduce symptoms of angina pectoris and signs of ischemia. Frequently, a combination of these drugs is necessary for symptom control, but hard data on the use of all three classes together are lacking. Although efficacious, traditional anti-ischemic agents do not produce relief in all patients, and individual variation in responsiveness is well known. The combination of -blockers with nitrates is favored because both agents lower myocardial oxygen demand and increase subendocardial blood flow through different mechanisms. The -blockers prevent potential reflex tachycardia from nitrate-induced hypotension. In addition, persistent angina occurs in approximately 10% to 25% of patients subjected to coronary bypass surgery and/or percutaneous interventions, and 60% to 80% require antianginal therapy 1 year after the procedure. These drugs have considerable potential as adjunctive therapy for angina, particularly in patients who are refractory to standard therapies, and they may be a primary therapeutic option in certain circumstances because they generally do not adversely affect blood pressure, pulse rate, or left ventricular systolic function. Investigational Anti-Ischemic Therapy Because of the inability of current antianginal drugs to optimally control chronic angina in all cases, such as in patients with severe coronary artery disease not amenable to revascularization, or with high risk of death and repeated hospital admissions, there is an unmet need for new drugs with different, but complementary, mechanisms of action devoid of the limitations of current treatments (with no or minimal hemodynamic effects) and that can be safely added to current therapy. In this chapter, in addition to addressing some of the newest prescribable antianginal drugs,we will briefly review drugs currently under development for the treatment of chronic angina. The choice of disease-modifying treatments that influence prognosis raises a few problems. Different mechanisms of action for the anti-ischemic drugs allow treatment to be targeted to the individual patient, dependent on comorbidities and cardiac function. A combination of anti-ischemic drugs might improve the benefit of treatment with an additive or even synergistic effect.
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In the absence of increases in intracellular calcium, Rho (a member of the Ras superfamily of small G proteins) activates Rho kinase, which in turn deactivates myosin phosphatase. In response to ischemia, bone marrow derived endothelial progenitor cells migrate and proliferate to form endothelial cells, resulting in neo-revascularization. These include angiogenic growth factors, gene therapies, and cell-based therapies. This section reports the results of clinical trials comparing one agent with another and comparing combination therapy with monotherapy. None of the trials has been conclusive, though intracoronary administration of growth factors has been deemed safe. However, nifedipine was associated with a greater incidence of acute myocardial ischemia. Treadmill exercise testing and the number of anginal attacks 20 were improved to a similar extent by the two drugs. Fewer ischemic episodes, as measured by Holter monitoring, were observed in 46% of patients in the propranolol group. This has been recognized by most of the recent guidelines for the medical management of stable angina, discussed hereafter. Ranolazine One hundred fifty-eight patients with symptom-limited exercise on -blocker therapy were randomized into a double-blind, three-period, crossover study of 400 mg of immediate-release ranolazine three times daily, 100 mg daily of atenolol, or placebo, each administered for 1 week. Patients achieved significantly longer total exercise duration during ranolazine therapy and longer total exercise duration than during atenolol therapy (mean difference 21. Treatment that minimizes symptoms, improves quality of life, and decreases long-term morbidity and mortality is desirable. Lifestyle changes and critical interventions, such as percutaneous revascularization and surgical techniques, are also part of optimal management of patients with chronic ischemic heart disease. Prescribe sublingual nitroglycerin or nitroglycerin spray for immediate relief of angina in patients with stable ischemic heart disease. Yet short-term improvement in exercise tolerance is an observed benefit of the combination. For patients in whom two antianginal drugs fail to control symptoms and who are either awaiting or contraindicated for revascularization, a therapeutic trial of a third antianginal medication may be considered. The clinician should take into account contraindications to these novel agents, patient preferences, and drug costs. ManageMent European Guidelines the European medical community has a larger armamentarium of antianginal therapies. Ranolazine may hold promise for reduction in angina symptoms, particularly for those patients who cannot tolerate upward titration of conventional antianginal agents due to depressive effects on heart rate and blood pressure (Weak Recommendation, Moderate-Quality Evidence).
