The Management of Angina Pectoris

US Pharm. 2010;35(10):78-87.

Angina pectoris refers to a group of symptoms that present when the heart muscle does not get enough oxygen. The clinical manifestation is chest discomfort caused by transient myocardial ischemia.¹ Angina is not a disease, but rather a syndrome marking an underlying condition, such as coronary artery disease (CAD), in which there is an imbalance between the supply and demand of oxygen.²

According to the American Heart Association (AHA), more than 6 million people in the United States experience angina, with more women than men affected. Each year, CAD causes approximately 600,000 deaths in the U.S., and the annual cost of the disease exceeds $100 billion.³

Symptoms of angina include chest discomfort, aching, pressure/squeezing, bandlike sensation, tightness, constriction, or fullness; sensation of heavy weight on chest; strangling sensation; burning in chest or elsewhere; knot in center of chest; lump in throat; and toothache.¹ Ischemia occurs when blood flow is reduced or cannot be increased. Angina is usually induced by an increase in myocardial oxygen requirements.⁴ There are a number of reasons for this increase, including fixed obstruction in the coronary arteries, vasoconstriction, thrombus formation, and platelet aggregation. Prolonged ischemia may result in myocardial infarction (MI). Angina may be precipitated or worsened by coexisting conditions such as poorly controlled hypertension (HTN), anemia, or thyrotoxicosis.⁴

Angina may be classified into three major types: stable, or effort, angina; unstable angina; and Prinzmetal’s, or variant, angina.³ Pharmacologic therapy varies by type.

Some patients have more than one type of angina. Patients with “mixed” angina have a well-established upper limit of exercise beyond which they experience angina; however, they suffer from a variable proportion of unpredictable anginal attacks that occur spontaneously or at levels of activity that are well tolerated.⁵ Over time, one type of angina may develop into another. This article will discuss characteristics of and treatment options for the three types of angina.

Types of Angina

Stable: One key feature of chronic stable angina is total symptom reversibility; another feature is repetition of the attacks over time (usually months to years).⁴ The pain is intense but not sharp, often described as pressure or a heavy weight on the chest that is accompanied by burning and tightness. This type of attack, which lasts 0.5 to 3 minutes, usually is precipitated by exertion and relieved by rest or sublingual (SL) nitroglycerin.

Stable angina characteristically is caused by a fixed obstruction in one or more coronary arteries. While the restricted blood flow is adequate for oxygenation of the unstressed heart, it is insufficient for the increased demand posed by such events as exercise, emotional stress, exposure to cold, and consumption of a heavy meal. Risk factors include HTN, elevated serum cholesterol, smoking, physical inactivity, and overweight.⁶

Unstable: Angina is considered unstable if any of the following occur: new-onset angina that presents as severe and frequent attacks; pattern changes, with an increase in the frequency, intensity, and/or duration of previously stable angina; or recurring or prolonged angina at rest.⁷

Unstable angina is one component of a group of clinical symptoms known as acute coronary syndrome (ACS). ACS also involves ST-segment elevation MI (STEMI) and non-STEMI.⁷ In most patients, ACS results from disruption of an atherosclerotic plaque, which leads to platelet adhesion and aggregation, thrombus formation, and vasoconstriction. This disruption causes partial occlusion of one or more coronary arteries, restricting blood flow to the extent that it fails to meet the oxygenation demands of even the unstressed heart. While the ischemia is insufficient to cause myocardial damage, the patient is at increased risk (10%-20%) for MI or sudden death. Appropriate therapy can reduce this risk to 5% to 7%.

Prinzmetal’s: This rare form of angina is caused by a coronary vasospasm that reduces the coronary artery blood flow. The spasm may be superimposed on a coronary artery that already has a fixed obstruction caused by thrombi or plaque formation. The patient may complain of pain while at rest or performing daily activities, as well as with exertion.⁸ The pain and discomfort are severe and may not be relieved by medication. Typically, an ECG will show transient ST-segment elevation, and there is a risk of progression to MI. Prolonged vasospasm may lead to ventricular arrhythmias, heart block, or death.⁸

Other: In addition to the forms of angina described above, patients may experience angina decubitus, also called nocturnal angina. This occurs in the recumbent position and is not related to rest or exertion. Heightened ventricular volume increases oxygen requirements and produces angina, possibly indicating cardiac decompensation. Elevating the head of the bed may be useful for patients who have predominately nocturnal attacks.⁹ Some periods of myocardial ischemia may be asymptomatic, a condition known as silent myocardial ischemia.

Treatment

The successful management of angina depends largely on correct identification of the type of angina the patient has. Treatment options include lifestyle modification, pharmacologic agents, cardiac procedures, and cardiac rehabilitation. The primary goal of treatment is “to return patients to their usual activities with minimal angina, chest pain, or discomfort,” according to the AHA.¹⁰ Specific goals include reducing the risk of sudden death, preventing MI, and lessening symptom frequency and severity.

Therapeutic agents may be divided into antianginal drugs and vasoprotective drugs. While antianginals are widely used to manage both stable and unstable angina, vasoprotective agents are underprescribed.⁴ Pharmacists can appropriately advise prescribers in this regard.

In the U.S., three classes of antianginal drugs—organic nitrates, beta-blockers (BBs), and calcium channel blockers (CCBs)—as well as the newest antianginal, ranolazine, are approved for the treatment of stable angina.² These agents reduce heart rate (HR), blood pressure (BP), and coronary vascular resistance and redistribute coronary blood flow from subepicardial to subendocardial regions.¹¹ While these medications have not been shown to reduce cardiac mortality, their administration does improve treadmill performance. Cardioprotective agents used in the management of angina include aspirin, heparin, and anticholesterol drugs.

Managing Stable Angina: Current recommendations for the management of stable angina advise “medical treatment with antianginal drugs and strategies to reduce adverse clinical outcomes including smoking cessation, daily aspirin, treatment of dyslipidemias and hypertension.”² Since all three classes of antianginals seem to be equally effective, the presence of comorbid conditions dictates the choice of drug for optimal therapy.² However, the American College of Cardiology/AHA (2002) and the European Society of Cardiology (2006) recommend that BBs be used as first-line therapy.¹² If this regimen is insufficient or contraindicated, a dihydropyridine CCB followed by a long-acting nitrate may be added. Combination therapy should be suggested for patients who are poorly managed.⁴ Percutaneous revascularization procedures with or without stent placement or coronary artery bypass (CAB) surgery should be offered to patients who cannot take antianginals.²

Aspirin, a relatively inexpensive form of vasculoprotective therapy, has been shown to reduce adverse clinical outcomes in patients with stable angina.² A daily dose of 81 mg to 321 mg is recommended for patients without specific contraindications to aspirin therapy. Alternatively, clopidogrel 75 mg once daily may be used in patients unable to take aspirin. The combination of aspirin and clopidogrel has not been shown to have a benefit over aspirin alone.¹³

One lifestyle modification is to engage in regular exercise, beginning at 20 to 30 minutes and increasing gradually. Patients should be advised regarding dietary modifications and smoking cessation.⁴ In patients with high LDL levels, statins are recommended to reduce the incidence of adverse coronary events.⁴ ACE inhibitors are useful for patients with chronic stable angina and a history of MI, HTN, left ventricular systolic dysfunction, or diabetes, as well as for patients with impaired renal function in whom the use of these agents is not contraindicated.⁴

Managing Unstable Angina: An attack of unstable angina is a medical emergency; because it can quickly lead to MI, the patient should be admitted to the hospital immediately. Initial therapy should focus on preventing MI or death. Antiplatelet drugs and analgesics are essential for relieving ischemia and preventing the recurrence of adverse ischemic events.¹⁴ Patients should be given 300 mg of chewable or soluble aspirin as soon as possible, followed by heparin, dalteparin or enoxaparin, SL nitroglycerin, and a BB, unless otherwise contraindicated.¹⁵ Clopidogrel may be used in patients unable to tolerate aspirin. Patients treated with heparin have a decreased risk of MI and a higher incidence of minor bleeding.¹⁶

Following discharge, patients may require anticoagulant warfarin therapy to maintain an international normalized ratio of 2.0 to 3.0.¹⁵ If nitroglycerin does not effectively relieve pain, morphine may be used, provided that the underlying cause of ischemia is treated also.¹⁵ Nondihydropyridine CCBs (diltiazem, verapamil) should be used in patients with continuing or frequently recurring ischemia or in those in whom BBs are contraindicated.¹⁵ In the presence of pulmonary congestion, an ACE inhibitor (or an angiotensin receptor blocker, in patients intolerant to ACE inhibitors) should be administered within the first 24 hours.¹⁵ Lipid-lowering therapy, such as a statin, may be required in patients with an LDL greater than 100 mg/dL. Cardiac procedures should be performed in high-risk patients at an early stage.

Managing Prinzmetal’s Angina: CCBs have long been preferred for treating Prinzmetal’s angina.¹⁷ SL nitroglycerin or IV nitrates may be used for initial relief of an acute attack.¹⁸ Similar to unstable angina, Prinzmetal’s angina may respond to long-acting nitrates, but response to BBs varies. Because magnesium deficiency may be involved in variant angina, supplementation is recommended. If the angina does not respond to drug therapy, surgical intervention may be required. In Prinzmetal’s angina, anticoagulants are valuable for preventing subsequent infarction. While nitroglycerin may be life-saving, long-acting nitrates have a role in prophylaxis. Antiarrhythmic drugs are indicated for patients who develop arrhythmias during an attack. Lifestyle modifications such as weight reduction; a low-fat, low-cholesterol, low-calorie diet; carefully monitored exercise; and smoking cessation should be considered.⁸

BBs: These agents reduce oxygen demand during both exercise and rest by blocking beta-1 receptors. This results in a lowering of HR, reduction of myocardial contractility, and attenuation of rise in systolic BP during exercise.⁴ BBs are useful for reducing the frequency and severity of exertional angina that is not controlled by nitrates. BBs are either lipophilic or hydrophilic, and some BBs have intrinsic sympathomimetic activity. Irrespective of these differences, all drugs in this class seem to be equally effective for managing angina.¹⁹ Cardioselective agents, including atenolol and metoprolol, are preferred in patients with stable angina who also have reactive or obstructive airway disease, diabetes mellitus, or peripheral arterial disease.² The dose should be gradually increased until anginal episodes have been reduced or until unacceptable side effects occur; effectiveness should be measured using exercising HR, not resting HR.²⁰ Importantly, sudden withdrawal of BB therapy may precipitate an angina attack; therefore, the dose should be decreased gradually. Patients taking BBs may complain of fatigue, erectile dysfunction, sleep disturbances, and vivid dreams. Since BBs may increase coronary resistance, they should be avoided in Prinzmetal’s angina.²¹

Nitrates: Nitroglycerin and other organic nitrates exert their effects primarily through venous dilation that reduces left ventricular volume (preload) as well as myocardial-wall tension, reducing oxygen requirements (demand). A smaller dilation of arterioles reduces both peripheral vascular resistance and left ventricular pressure at systole (afterload). Nitrates also facilitate collateral circulation, improving regional coronary blood flow to ischemic areas and alleviating spasm.^2,4,21

SL, transmucosal, and IV nitrates are used to manage acute angina attacks.⁴ They are useful for treating stable angina, but may be less effective for Prinzmetal’s angina. IV nitroglycerin is indicated for the immediate treatment of unstable angina, as well as for long-term therapeutic relief. Oral or buccal tablets, topical ointment, or transdermal patches may be used to prevent anticipated attacks. Long-acting nitrates should be added to a BB or CCB in patients with inadequate symptomatic control.²¹

Severe, sudden headaches are a common side effect of nitrate therapy; often dose-related, they have been reported in up to 82% of patients in placebo-controlled trials. Nearly 10% of patients are unable to tolerate nitrates because of disabling headaches or dizziness. In other patients, headaches are mild-to-moderate in severity and either resolve or diminish in intensity with continued nitrate therapy.²² Tolerance to nitrates may be avoided by incorporating nitrate-free intervals of 10 to 14 hours.²¹

CCBs: This class has two primary actions that are important in the management of angina: (1) CCBs prevent coronary spasm by blocking the influx of calcium, and (2) they dilate peripheral arterioles, thereby reducing oxygen demand.⁴ Further, the nondihydropyridine agents verapamil and diltiazem reduce HR and rate-pressure product during exercise, resulting in a reduced myocardial oxygen demand. CCBs, therefore, are particularly useful for Prinzmetal’s and unstable angina. Additionally, they may be as effective as nitrates and BBs in stable angina.² There are three types of CCBs: dihydropyridines (e.g., nifedipine, amlodipine, felodipine, isradipine); benzothiazepines (e.g., diltiazem); and phenylalkylamines (e.g., verapamil).²³ In contrast to BBs, the effects of each of these classes of CCB vary greatly.

Nifedipine has a lesser effect on the myocardium and works primarily on the blood vessels.² Unlike verapamil and diltiazem, it may be safely combined with BBs and other negatively inotropic drugs since it does not lower HR.² In fact, nifedipine may increase HR in some patients, producing tachycardia, a side effect that can be offset by the use of a BB.^2,7

Verapamil is a negatively inotropic CCB that reduces cardiac output, slows HR, and impairs atrioventricular conduction.² Patients taking verapamil for angina must be closely monitored for signs of developing cardiac decompensation, such as fatigue, lethargy, shortness of breath, and edema.¹ Coadministration of other negatively inotropic drugs such as BBs worsens these symptoms.² Additionally, verapamil may cause constipation, and patients may experience increased oxygen demand while straining.⁴

Diltiazem has a lower negative inotropic effect than verapamil, and it rarely causes myocardial depression.² However, since it increases the risk of bradycardia, diltiazem should not be combined with BBs.^2,7

The use of verapamil and diltiazem generally is not recommended in patients with left ventricular systolic dysfunction, as these drugs worsen heart failure and increase mortality. If the patient has a high degree of AV block, these agents may induce complete AV block.²

CCBs should be withdrawn carefully, since sudden withdrawal has been shown to exacerbate angina.²³

Ranolazine: This is the latest antianginal drug approved by the FDA. While its exact mechanism of action is unknown, ranolazine is thought to decrease cardiac demand by acting on cellular metabolism. Unlike CCBs, nitrates, and BBs, ranolazine’s effect is not due to a reduction in HR or BP or to vasodilation.²⁴ It may reduce the excess late sodium influx, thereby decreasing calcium overload and increasing left ventricular wall tension. This leads to decreased myocardial oxygen requirements in marginally ischemic myocytes, which can potentially reduce vascular compression, allowing more coronary blood flow to the affected area. The usual dose is 500 mg to 1,000 mg twice daily. Patients may experience dizziness, headaches, constipation, and nausea.¹² Ranolazine has the potential to prolong the QT interval; therefore, it should be used only in patients unresponsive to other antianginals. Ranolazine is contraindicated in patients with preexisting QT prolongation or hepatic impairment, and it should not be used with other drugs that prolong the QT interval or with CYP3A inhibitors such as diltiazem. In patients with diabetes, ranolazine has the additional benefit of lowering glycosylated hemoglobin.¹²

Other Agents: Nicorandil is a potassium channel opener with a nitrate component. It has both arterial and venous vasodilating effects and is as effective as other antianginal drugs in controlling angina symptoms. While nicorandil has not been approved for use in the U.S., it is widely used in Europe and Asia.²

A number of new drugs are under investigation for the management of angina. They include trimetazidine, ivabradine, fasudil, and molsidomine.^1,12

Surgical Procedures: Measures that restore conductive blood flow are recommended only if drug therapy fails. These procedures include percutaneous transluminal coronary angioplasty (PTCA; also known as stent placement) and CAB. In PTCA, a catheter with a balloon is passed down the blocked artery. Once the balloon reaches the blockage, it is inflated to compress the surrounding fatty tissue. This creates a bulge in the artery and increases blood flow. Since coronary spasm may occur during the procedure, nitrates and CCBs are commonly administered beforehand. Patients undergoing this procedure are at higher risk for thrombotic complications.²⁵ Antithrombotics, such as a combination of aspirin and clopidogrel, may be administered to reduce cardiovascular events. Ticlopidine, which is associated with more gastrointestinal side effects, is reserved for patients who are allergic to clopidogrel.¹⁶ Recently, the FDA approved the thienopyridine prasugrel for such patients. The advantage of prasugrel over clopidogrel is that it prevents nonfatal MIs, but prasugrel has a much higher risk of bleeding.²⁶ Angioplasty is usually recommended in patients with single-vessel disease.

In CAB, the blood flow is rerouted around the occlusion. If the underlying cause of the blockage is not appropriately managed, there is a high possibility of restenosis. CAB is the preferred procedure for patients with multiple blockages.^12,21

Such techniques as enhanced external counterpulsation, spinal cord stimulation, and transmyocardial laser revascularization have been used in the management of angina.^1,12

Conclusion

It is important for the pharmacist to recognize and understand which type of angina the patient is suffering from. This enables the pharmacist to correctly dispense and review the medications. The pharmacist carries out an important function by ensuring that the drugs prescribed do not interact adversely. Additionally, the pharmacist is in an ideal position to counsel patients on the correct administration of their medications.

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