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Angina Pectoris: A Review of Current and Emerging Therapies
John O. Parker, MD
Cost of Illness of Chronic Angina
Harold S. Javitz, PhD; Marcia M. Ward, PhD; Jennifer B. Watson, PhD; and Mirou Jaana, PhD
Review of Recent US Cost Estimates of Revascularization
Paul C. Nagle, BSBA; and Abigail W. Smith, BA
A Systematic Review of the Economic Burden of Chronic Angina
Matthew W. Reynolds, PhD; Diana Frame, MEM; Rachel Scheye, BA; M. Evelyn Rose, PharmD; Samuel George, MD; Jennifer B. Watson, PhD; and Mark A. Hlatky, MD

Angina Pectoris: A Review of Current and Emerging Therapies

John O. Parker, MD

Angina pectoris is a debilitating indication of the presence of ischemic heart disease that affects millions of Americans. Although a number of pharmacologic treatments are available, the annual number of revascularization surgeries continues to rise in the United States. Other management strategies, such as spinal cord stimulation, enhanced external counterpulsation, metabolic modulators, and gene therapy, are being explored.

(Am J Manag Care. 2004;10:S332-S338)

Ischemic heart disease is the leading cause of death in the United States1 and angina pectoris is a common symptom of this disease.2,3 "Angina" is used to describe clinical symptoms such as discomfort in the chest, jaw, shoulder, back, or arms that are induced by physical exertion or emotional stress and subside with rest or treatment with nitroglycerin.4 Some patients do not experience discomfort but complain of breathlessness or tire with activity. These symptoms are the result of underlying myocardial ischemia and are sometimes called anginal equivalents.

The American Heart Association (AHA) estimates that 6.8 million Americans suffer from angina and that 400 000 new patients present with stable angina each year.1 Significantly more women have the condition than men, both in total numbers and as an age-adjusted percentage.1 Angina limits normal daily activities; thus, it has a negative impact on quality of life (QOL). It has been shown that 1 year after coronary revascularization, roughly one third of patients with angina are not able to return to work.5 Not surprisingly, the societal impact and economic costs of angina are staggering. In the American College of Cardiology (ACC)/AHA 2002 Guideline Update for the Management of Patients with Chronic Stable Angina, Gibbons and colleagues state, "angina affects many millions of Americans with associated annual costs that are measured in tens of billions of dollars."4

Angina treatment involves a number of strategies.4 In general, the first step in angina management includes assessing patient risk factors, such as smoking, hypertension, dyslipidemia, diabetes mellitus, obesity, and physical inactivity. While alterations in these risk factors may improve symptoms and reduce cardiac events, the majority of patients with chronic stable angina require specific antianginal medications. It is recommended that beta-adrenergic blocking drugs be used as first-line therapy for patients with angina because these agents have been shown to have cardioprotective effects.4 Other standard therapies for chronic angina include calcium channel blocking agents and organic nitrates,4 but such medical therapy often does not provide adequate symptomatic relief. A number of novel therapies are directed at angina treatment, including new pharmacologic agents, gene therapy, enhanced external counterpulsation (EECP), spinal cord stimulation, and innovations in revascularization therapy. This article reviews the classification of angina pectoris and briefly describes standard and novel treatment strategies for this debilitating health problem.

Understanding Angina. Whereas there has been considerable research regarding angina, the exact mechanism of pain perception in patients with myocardial ischemia is still poorly understood. However, cardiac ischemic discomfort may be perceived in the heart, chest wall, arms, and back because of the close proximity of the spinal nerve receptors to these areas.6 Chest pain caused by myocardial ischemia is classified as stable or unstable angina.4 Patients with unstable angina have a much higher risk of acute cardiac events than patients with stable angina pectoris. Such risk can be further stratified as low, moderate, or high, depending on the frequency and severity of pain and on the presence of certain electrocardiographic abnormalities. Unstable angina is commonly described based on the way it presents. This includes new onset angina or angina that has increased in frequency and severity despite medical therapy, or angina that occurs at rest (Table 1). Angina is frequently defined using Canadian Cardiovascular Society (CCS) functional class (Table 2),7 a system that has been used for more than 3 decades. In 2002, a new CCS definition for grade IV angina was suggested that includes a set of detailed activities, "angina occurs while walking less than 1 block…or while walking in the house, or doing light chores or personal care" rather than the previous description: "Inability to carry on any physical activity without discomfort— anginal symptoms may be present at rest."8 While other grading systems have been defined, the CCS functional classification has been the most widely used by clinicians and investigators.

Figure

Figure

Treatment of Angina Pectoris. Decreasing the frequency and severity of angina improves QOL for patients with angina. Although smoking cessation, weight control, stress management, moderate exercise, and appropriate management of hypertension, dyslipidemia, and diabetes mellitus may reduce symptoms and ischemic events, pharmacotherapy with antianginal agents is usually required. Beta-adrenergic blocking agents, calcium channel blocking agents, and short- and long-acting nitrates are the foundation of medical therapy for patients with chronic angina.4 Although each has a different mechanism of action, these agents have multiple effects that tend to decrease cardiac workload and, therefore, lower myocardial energy requirements and/or increase coronary blood flow or improve its distribution. These effects help lessen the mismatch between myocardial oxygen requirements and oxygen supply. Unfortunately, many patients require more than 1 drug to control symptoms,9 and patients with comorbid conditions often require a host of other medications as well. Indeed, a variety of agents, including antiplatelet/antithrombotic agents, angiotensin-converting enzyme inhibitors, and lipid-lowering drugs, are important therapeutic adjuncts in the treatment of patients with chronic angina.4 Ultimately, the potential for adverse drug interactions and side effects associated with polypharmacy may limit the ability of a patient with chronic angina to tolerate appropriate medical therapy.

Beta-adrenergic blocking agents are recommended as first-line therapy in the ACC/AHA guidelines.4 These drugs, however, have absolute or relative contraindications in patients with asthma, chronic obstructive pulmonary disease, severe peripheral vascular disease, and in some patients with diabetes mellitus. In such cases, calcium channel blocking agents are often prescribed and certain calcium channel blockers, such as the dihydropyridines, may be associated with flushing and peripheral edema.4 Diltiazem has been associated with heart failure in patients with abnormal left ventricular systolic function.10 Sublingual nitroglycerin, either as a tablet or spray, is effective in the treatment of acute episodes of angina and is also beneficial for short-term prophylaxis. However, the oral and transdermal organic nitrate preparations, although effective, are associated with the development of tolerance when prescribed in a fashion designed to provide therapeutic effects for 24 hours each day.11 A more detailed review of the efficacy of drug therapy for management of chronic angina is available in the ACC/AHA guidelines.4 Overall, using traditional therapies to manage pain in patients with chronic angina is commonly associated with inadequate symptom control, poor tolerance, and limited compliance. The treatment shortcomings for patients who suffer from chronic angina have resulted in the development of innovative therapies that are now being studied.

New Pharmacologic Agents. Metabolic modulators represent a potential new class of drugs with a novel approach to the treatment of angina symptoms in the United States.12,13 In the presence of myocardial ischemia, glucose oxidation is a more efficient way of generating energy units adenosine triphosphate than free fatty acid oxidation.14 Unlike most current classes of angina therapy, metabolic modulators may be effective without depending on reductions in heart rate or blood pressure.13,15

Trimetazidine, a metabolic modulator available outside of the United States, has demonstrated anti-ischemic effects in a number of studies of patients with angina. The drug has been shown to increase effort tolerance and to delay the appearance of ischemic symptoms and electrocardiographic (ECG) changes.12,14,16,17 In addition, patient safety and tolerance with trimetazidine has been good.18,19 The efficacy of trimetazidine has also been demonstrated in patients with diabetes, who showed improved exercise capacity and duration after 4 weeks of treatment.20 Left ventricular dysfunction has improved during therapy with trimetazidine.21,22

Gene Therapy. Therapeutic angiogenesis regimens have focused mainly on the administration of a single growth factor with select isoforms of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). At present, VEGF and FGF have been the most extensively studied angiogenic agents.23 Growth factor proteins may be given directly or through gene-based approaches using naked plasmid deoxyribonucleic acid or a viral vector that encodes the gene so that it can be taken up by the recipient endothelial cells. These endothelial cells offer the potential for persistent expression of the angiogenic gene.23,24 These agents may be administered directly to the myocardium by epicardial, endocardial, or intracoronary injection. Some trials have shown beneficial effects in patients with angina,24 but adequately powered, randomized, placebo-controlled clinical studies must be completed to clarify the effectiveness of such therapy.

Enhanced External Counterpulsation. EECP is another novel treatment for patients with ischemic heart disease who have chronic angina and are unresponsive to other therapies. EECP is carried out by encircling the legs with compression devices, inflating them during diastole to 300 mm Hg, and deflating them during systole.25 This unloads the left ventricle during ventricular systole, and this augmentation of pressure is thought to improve coronary blood flow during diastole. In the only published randomized clinical trial of EECP,25 which involved 139 patients with class II to III angina, the control group was treated by compressing the lower extremities at 75 mm Hg, and the experimental group was treated by compressing the lower extremities at 300 mm Hg. While clinical symptoms and treadmill exercise times improved and a variable effect on myocardial perfusion imaging studies was reported, the absence of proper blinding during this study makes the results uncertain. The mechanisms thought to be responsible for the improvement of symptoms include enhancement of endothelial function, promotion of collateral flow, improvement in ventricular function, and peripheral effects similar to those seen with physical exercise.26 For EECP to be effective, patients require daily in-clinic treatments over several weeks, which is a schedule that might be difficult for many patients to maintain.

 
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