ANGINA TREATMENT OVERVIEW

Chest pain that originates from the heart muscle is called angina pectoris. Angina is a signal that the heart muscle is not getting sufficient blood flow, specifically sufficient oxygen. Lack of oxygen is termed ischemia. Blood flow is most often reduced by coronary artery disease (CAD), which causes a narrowing of the arteries that carry blood to the heart muscle (figure 1). Narrowing in the coronary arteries occurs as a result of calcium and fatty deposits, called plaques. In more severe cases, heart attack (myocardial infarction), heart failure, or rhythm abnormalities can cause sudden cardiac death.

Angina may be provoked by an activity or exercise or any other physical or mental stress, which increases the heart's demand for blood. Angina can be "stable" or "unstable". Angina is unstable when there is a change in the usual pattern, such as a change in frequency, occurrence with less exertion, or occurrence at rest. Unstable angina, which may or may not be associated with damage to the heart muscle (or heart attack), is called acute coronary syndrome and requires immediate evaluation in a hospital. (See "Patient information: Chest pain (Beyond the Basics)".)

A number of articles about coronary artery disease are available separately. (See "Patient information: Chest pain (Beyond the Basics)" and "Patient information: Angina treatment — medical versus interventional therapy (Beyond the Basics)" and "Patient information: Aspirin and cardiovascular disease (Beyond the Basics)" and "Patient information: Coronary artery bypass graft surgery (Beyond the Basics)" and "Patient information: Heart stents and angioplasty (Beyond the Basics)".)

WHICH TREATMENT IS RIGHT FOR ME?

All treatments for coronary heart disease have the same goals: to improve quality of life and relieve symptoms, particularly angina. The medicines used to treat coronary heart disease and angina reduce the risk of dying for many people with these conditions.

The choice between taking a medicine and having a surgery to open narrowed or blocked blood vessels depends upon a number of individual factors. These are discussed in detail separately. (See "Patient information: Angina treatment — medical versus interventional therapy (Beyond the Basics)" and "Patient information: Heart stents and angioplasty (Beyond the Basics)".)

MEDICINES FOR STABLE ANGINA

There are currently four types of medicines used to treat stable angina:

• Nitrates
• Beta blockers
• Calcium channel blockers
• Ranolazine

Nitrates or beta blockers are usually preferred for initial treatment of angina, and calcium channel blockers may be added if needed. The number and type of medicines used are often tailored to how frequently angina occurs in an average week.

• One or fewer — People who have one or fewer angina episodes per week are usually advised to take sublingual (under the tongue) nitroglycerin when an episode of angina occurs and immediately before activities that could cause angina. (See 'Nitrates' below.)
• Two or more — People who have two or more angina episodes per week are usually advised to take longer-acting antianginal medicines. This may include a long-acting nitrate or a beta blocker.
• Treatment with added medicines — If angina persists while taking one medicine, a second medicine may be added. Combined treatment may relieve angina more effectively than a single medicine.

If angina persists on two medicines, a third medicine or coronary angiography may be recommended. Angiography can help determine how severe coronary artery disease is and if a stent or bypass surgery is needed.

NITRATES

Nitrates improve blood flow by relaxing and dilating (expanding) veins and arteries, including the coronary arteries. They reduce the amount of blood returning to the heart. Several different nitrate preparations are available.

Sublingual nitroglycerin — Sublingual (under the tongue) nitroglycerin (NTG) is usually recommended to treat sudden attacks of angina and to prevent angina while engaging in activities that typically trigger angina, such as mowing the lawn, playing sports, or walking up a hill (especially in the cold).

Sublingual NTG is a small pill that is placed under the tongue where it rapidly dissolves and is absorbed. The membranes underneath the tongue must be moist to facilitate this process, so a drink of water is recommended to moisten a dry mouth. Sublingual NTG becomes effective within two to five minutes and its effects last 15 to 30 minutes. There is no risk of explosion with NTG pills.

For people with frequent angina, a physician may recommend repeating the dose of NTG for a total of two or three doses every five minutes before calling 911. If chest pain lasts more than five minutes after taking up to three NTG pills, call 911 immediately, unless a different plan has been discussed with a physician. The emergency medical services (EMS) personnel in your community will respond as rapidly as possible, and will take you to the nearest hospital.

It is very important to store NTG pills properly since they are sensitive to light, moisture, and heat. Most pills should be stored in a dark, tightly capped bottle in the refrigerator; you should carry a small number with you at all times. You should renew your sublingual NTG prescriptions every three to six months and discard any tablets that crumble easily. NTG pills that are still effective cause a mild tingling sensation when placed under the tongue.

Sublingual NTG is also available in a spray form. This spray is less popular than the pill form, although it is equally effective; it has a shelf life of two to three years and does not require refrigeration.

Oral nitrates — Oral nitrates have a longer-lasting effect than sublingual NTG, and are equally effective in controlling angina on a chronic basis. Oral nitrates are available in two forms: isosorbide dinitrate (ISDN) and isosorbide-5-mononitrate (ISMN).

Isosorbide dinitrate — ISDN, often taken two or three times per day, begins acting within 15 to 30 minutes and lasts for three to six hours. ISDN allows you to exercise for up to eight hours. The body tends to develop a tolerance (decreased sensitivity) to ISDN when it is used continuously over 24 hours, but a carefully planned dose schedule may prevent this problem. (See 'Nitrates and tolerance' below.)

Isosorbide-5-mononitrate — ISMN usually begins acting within 30 minutes and its effects last six to eight hours. The body tends to develop a tolerance (decreased sensitivity) to ISMN when it is used continuously over 24 hours. A carefully planned dose schedule and use of extended release forms of ISMN may prevent this problem. The extended release form of ISMN is taken only once per day.

Transdermal nitroglycerin — Transdermal NTG (NTG patch) is a convenient type of long-lasting nitrate treatment. These patches deliver a constant dose of NTG.

Transdermal NTG begins acting within 30 minutes and its effects last for 8 to 14 hours. Wearing a patch continuously leads to tolerance, so patches must be removed each day to allow for a "nitrate-free" interval. Since most people experience angina with activity, the patch is usually applied in the morning and removed in the evening. In contrast, people who have nocturnal (nighttime) angina should apply the patches at night and remove them in the morning.

Nitrates and tolerance — Continuous nitrate treatment leads to tolerance of the drug within 24 to 48 hours; at this time, normal doses of nitrates are no longer effective. Tolerance is a problem with long-acting nitrates (oral and transdermal nitrates), which is why a nitrate-free interval is necessary. Nitrate tolerance does not usually develop with sublingual NTG.

The best way to avoid tolerance is to use long-acting nitrates intermittently, by scheduling 8-hour to 12-hour nitrate-free breaks, frequently done during periods of sleep. Some people notice that angina worsens during this nitrate-free period, which is a phenomenon called rebound angina. This can be treated by increasing the dose of other drugs. Several medications and antioxidant vitamins are being evaluated for their ability to prevent nitrate tolerance; however, they are still investigational and they are not yet widely available.

Timing of nitrates — People who have stress or exertional angina (angina during activity or exercise) are usually advised to take nitrates during the day, whereas people with nighttime angina or heart failure are usually advised to take nitrates in the evening. Nitrates may alleviate certain nighttime symptoms of heart failure, such as shortness of breath when lying down or waking up breathless in the middle of the night.

Side effects — The most common side effects of nitrates are headache, lightheadedness, flushing, and an increase in heart rate. Elderly people are often susceptible to lightheadedness and should be especially careful in hot weather. Alcohol may also worsen dizziness and lightheadedness.

Nitrates can also cause a decrease in blood pressure and may cause some people to faint (especially when other medications that lower blood pressure are being used or the patient is dehydrated). Paradoxically, nitrates can worsen angina in some people. These side effects tend to improve over time, but it is still important to discuss any side effects you are having with your healthcare provider.

The combination of nitrates and medications for erectile dysfunction (eg, Viagra®, Cialis®, Levitra®) is particularly hazardous. Erectile dysfunction medications must be avoided while taking a nitrate medication (short or long-acting). If you take nitrates and are considering treatment for erectile dysfunction, speak with your healthcare provider. (See "Patient information: Sexual problems in men (Beyond the Basics)".)

BETA BLOCKERS

Beta blockers reduce the heart rate, blood pressure, and the force of the heart's contractions, thereby decreasing the amount of oxygen the heart requires to pump blood. Along with nitrates, beta blockers are usually the first choice for the treatment of stable angina, and are particularly beneficial in people who have angina during exercise or activity.

Another important benefit of beta blockers is that they improve survival and prevent another heart attack in people who have suffered a recent heart attack.

Most beta blockers are available as long-acting preparation that is taken once per day.

Classes — There are different types of beta blockers and, although all are equally effective in the treatment of angina, there are settings in which one type is more or less desirable.

• Nonselective beta blockers (such as propranolol) block all types of beta receptors throughout the body and are therefore more likely to cause side effects. As a general rule, these drugs should not be used in patients who have asthma since they may block the effect of adrenaline in the lungs, possibly causing an asthma attack.
• At low doses, cardioselective beta blockers (such as atenolol and metoprolol) selectively block the beta receptors found in the heart and are less likely to cause side effects. These medications may be better than nonselective beta blockers for people with obstructive lung disease, asthma, poor circulation, diabetes, and depression. However, at the high doses often needed to control angina, these medications lose their selectivity and may also block other types of beta receptors throughout the body, producing more side effects.
• Some beta blockers (such as acebutolol and pindolol) are less likely to depress cardiac function or cause a slow resting heart rate and may be a better choice for people who have specific cardiac conditions or are more sensitive to the effects of beta blockers.
• Some beta blockers (such as labetalol or carvedilol) also block alpha receptors, which are another type of receptor found in the blood vessels. These medications have the added benefit of dilating blood vessels.

Side effects — Most people notice only mild side effects when taking beta blockers. However, all classes of beta blockers can cause side effects. Most of the side effects are directly related to their beta blocking action; these side effects may be cardiac (those that affect the heart) and/or noncardiac (those that affect other systems). Other side effects are unrelated to the beta blocking action.

Cardiac effects — The cardiac benefits of beta blockers in angina limit their use in people with certain heart conditions.

• Heart failure — Beta blockers can worsen heart failure in a small percentage of people with preexisting damage of the heart muscle (decompensated heart failure). However, careful therapy with beta blockers is still recommended due to the benefit of improved survival.
• Slowing of the heart rate — Beta blockers slow the resting heart rate and are therefore must be used cautiously or avoided in people who have a slow baseline heart rate and those who take other medications that slow the heart rate.
• Beta blocker withdrawal — People who abruptly stop taking beta blockers may experience a dangerous withdrawal syndrome that can lead to worsening of angina, heart attack, and death. Side effects after abrupt withdrawal are most likely to occur in people who take short-acting beta blockers at a high dose and are less likely to occur in people who take long-acting beta blockers at a low dose. It is very important to talk to a healthcare provider before stopping a beta blocker.

Noncardiac effects — Most of the more common side effects of beta blockers occur when these medications block beta receptors throughout the body.

• Constriction of airways — Beta blockers can block receptors in the lung, preventing the airways from relaxing and making it difficult to breathe. Therefore, many beta blockers are not recommended for people with lung disease.
• Circulatory problems — Beta blockers may worsen symptoms in people who have poor circulation in their extremities or pain in their legs with walking. Beta blockers with stimulatory effects and cardioselective beta blockers used at low doses are less likely to have this effect. People who have vascular spasm (Raynaud phenomenon) may find their problem while using a beta blocker. (See "Patient information: Raynaud phenomenon (Beyond the Basics)".)
• Impotence — Beta blockers can cause impotence in men. This side effect occurs in more than 10 percent of men, although the frequency varies with the beta blocker used. However, it is safe to take beta blockers in combination with medications for erectile dysfunction (eg, Viagra®, Cialis®, Levitra®) as long as the person does not also take a nitrate.
• Central nervous system effects — Beta blockers can cause dreams, hallucinations, insomnia, and fatigue. These side effects may be more common in older people.
• Worsening of angina — Beta blockers can promote arterial spasm and may actually worsen angina in people with variant angina (angina caused by spasm). This is an uncommon problem.
• Drug interactions — Beta blockers can interact with certain other cardiac drugs, including calcium channel blockers and some drugs used to treat arrhythmias (irregular heart beat).

CALCIUM CHANNEL BLOCKERS

Calcium channel blockers dilate arteries and lower blood pressure, which decreases the force of the heart's contractions. They also dilate veins, reducing the amount of blood returning to the heart, which reduces the workload of the heart. Some calcium channel blockers slow the heart rate, which also reduces the work of the heart.

Nitrates or beta blockers are usually recommended first for people with stable angina. Calcium channel blockers are an alternative if there are side effects or other conditions that limit the use of beta blockers and nitrates. Calcium channel blockers may also be used if nitrates and beta blockers do not control angina when used in combination.

Dihydropyridines — The dihydropyridine calcium channel blockers include amlodipine, felodipine, nifedipine, nicardipine, and nitrendipine. These work to dilate blood vessels; this effect is greater for dihydropyridines than for other classes of calcium channel blockers. They also slightly decrease the strength of the heart's contractions. Dihydropyridines have little effect on the conduction of electrical impulses in the heart.

Although dihydropyridines are effective for the treatment of angina, some may not be as effective as beta blockers.

• Side effects — The side effects of the dihydropyridines are related to their powerful dilation of blood vessels. These effects occur in up to 20 percent of people and include flushing, dizziness and lightheadedness, headache, and peripheral edema (swelling of the feet and ankles). This type of edema cannot be relieved with diuretics. (See "Patient information: Edema (swelling) (Beyond the Basics)".)

Verapamil — Verapamil slows the heart's conduction of electrical impulses, decreases the force of the heart's contractions, and dilates blood vessels. Although it is less effective than beta blockers for slowing the heart rate, it is a safe and effective alternative; the choice between beta blockers and calcium channel blockers depends upon individual factors. Verapamil is effective for variant (vasospastic) angina. Verapamil is available in sustained release form, which is taken once per day.

• Side effects — Constipation is the major side effect of verapamil, occurring in over 25 percent of people taking the medication. Other side effects are similar to those occurring with the dihydropyridines, although peripheral edema (swelling of the extremities) is uncommon.

Depression of cardiac function is a concern with verapamil. Verapamil decreases the force of the heart's contractions and slows its conduction of electrical impulses. These effects can produce a pronounced slowing of heart rate, heart block (impaired electrical conduction in the heart), and worsening of heart failure. Verapamil must be used cautiously or avoided in people with cardiac conditions such as sick sinus syndrome and atrioventricular block. It is generally not used in combination with beta blockers.

Diltiazem — The effects of diltiazem lie between those of the dihydropyridines and those of verapamil, neither markedly dilating blood vessels nor markedly depressing cardiac function. Diltiazem dilates blood vessels (especially coronary arteries), decreases the heart's force of contraction, and slows the heart's conduction of electrical impulses.

Diltiazem is not as effective as beta blockers in the treatment of stable angina, but may be preferable because it causes fewer side effects. Diltiazem is available in sustained release form that is taken once per day.

• Side effects — When compared to dihydropyridines and verapamil, diltiazem has a lower frequency of side effects and has a more balanced effect, neither markedly dilating blood vessels nor markedly depressing cardiac function.

Combined treatment with beta blockers — The dihydropyridines and, in some cases, diltiazem can be used in combination with beta blockers for better control of angina. Verapamil, however, is usually not combined with beta blockers because combining the two drugs can markedly slow the heart rate. The selection of a specific combination of medications depends upon individual factors.

Beta blockers versus calcium channel blockers — Beta blockers are more effective than calcium channel blockers for reducing the frequency of angina, but similar in terms of improving exercise tolerance and decreasing the need for NTG. However, people taking calcium channel blockers, especially nifedipine, are much more likely to stop taking the medication because of side effects.

RANOLZAINE

Ranolazine is the most recent addition to the medical treatment of angina. It has a complicated mechanism of action. Patients on a combination of beta blockers, calcium channel blockers, or nitrates who continue with angina, may benefit from the addition of ranolazine. (See "New therapies for angina pectoris", section on 'Ranolazine'.)

ASPIRIN

Narrowed coronary arteries often develop a blood clot before a heart attack. Aspirin helps to prevent blood clotting, keeping these narrowed arteries open and lowering the risk of a heart attack. Healthcare providers often recommend daily aspirin for people with stable angina. (See "Patient information: Aspirin and cardiovascular disease (Beyond the Basics)".)

OTHER MEASURES TO SLOW OR REVERSE CAD

Regardless of whether medical or interventional therapy is chosen, it is very important that people with coronary artery disease follow guidelines to reduce the risk that their heart disease will worsen. These guidelines, which should be discussed with a healthcare provider, include the following:

• Treat high blood pressure (see "Patient information: High blood pressure treatment in adults (Beyond the Basics)")
• Treat high cholesterol (see "Patient information: High cholesterol and lipids (hyperlipidemia) (Beyond the Basics)")
• Quit smoking (see "Patient information: Quitting smoking (Beyond the Basics)")
• Lose excess weight (see "Patient information: Weight loss treatments (Beyond the Basics)")
• Reduce stress
• Exercise regularly (see "Patient information: Exercise (Beyond the Basics)")
• Avoid or minimize activities that provoke angina, such as exercising during cold weather or exercising vigorously, particularly after a meal
• Learn to use nitroglycerin preventively

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Chest pain (The Basics)
Patient information: Coronary heart disease (The Basics)
Patient information: Medicines after a heart attack (The Basics)
Patient information: Medicines for angina (chest pain) (The Basics)
Patient information: Angioplasty and stenting for the heart (The Basics)
Patient information: Treatment choices for angina (chest pain) (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient information: Chest pain (Beyond the Basics)
Patient information: Angina treatment — medical versus interventional therapy (Beyond the Basics)
Patient information: Aspirin and cardiovascular disease (Beyond the Basics)
Patient information: Coronary artery bypass graft surgery (Beyond the Basics)
Patient information: Heart stents and angioplasty (Beyond the Basics)
Patient information: Sexual problems in men (Beyond the Basics)
Patient information: Raynaud phenomenon (Beyond the Basics)
Patient information: Edema (swelling) (Beyond the Basics)
Patient information: High blood pressure treatment in adults (Beyond the Basics)
Patient information: High cholesterol and lipids (hyperlipidemia) (Beyond the Basics)
Patient information: Quitting smoking (Beyond the Basics)
Patient information: Weight loss treatments (Beyond the Basics)
Patient information: Exercise (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Beta blockers in the management of stable angina pectoris
Bypass surgery versus percutaneous intervention in the management of stable angina pectoris: Clinical studies
Bypass surgery versus percutaneous intervention in the management of stable angina pectoris: Recommendations
Calcium channel blockers in the management of stable angina pectoris
Cardiac syndrome X: Angina pectoris with normal coronary arteries
Cardiac syndrome X: Angina pectoris with normal coronary arteries: Pathogenesis
Coronary heart disease and myocardial infarction in young men and women
Diagnostic approach to chest pain in adults
Differential diagnosis of chest pain in adults
Electrocardiogram in the diagnosis of myocardial ischemia and infarction
Epidemiology of coronary heart disease
Initial evaluation and management of suspected acute coronary syndrome in the emergency department
Medical therapy versus revascularization in the management of stable angina pectoris
Nitrates in the management of stable angina pectoris
Overview of the care of patients with stable ischemic heart disease
Pathophysiology and clinical presentation of ischemic chest pain
Prognosis after myocardial infarction
Stress testing for the diagnosis of coronary heart disease
Stress testing to determine prognosis and management of patients with known or suspected coronary heart disease

The following organizations also provide reliable health information.

• National Library of Medicine

     (www.nlm.nih.gov/medlineplus/healthtopics.html)

• National Heart, Lung, and Blood Institute

     (www.nhlbi.nih.gov)

• American Heart Association

     (www.americanheart.org)

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