Coronary Artery Disease and Angina

Description

Alternative Names

Other Medications

Nitrates have been used in the treatment of angina for over a hundred years. These drugs release nitric oxide, thereby relaxing the smooth muscles in blood vessels.

Many nitrate preparations are available; the most commonly used are nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate. Nitrates can be absorbed from the gastrointestinal tract (oral tablet), skin (ointment or patch), and from under the tongue (sublingual tablet or spray).

Rapid Acting Nitrates. Rapid-acting nitrates are used to treat acute attacks. Nitroglycerin is the most widely used agent for this purpose. It can be administered under the tongue (sublingually or as a spray) or pocketed between the upper lip and gum (buccally) and can relieve angina within minutes. The procedure for taking nitroglycerin during an attack is as follows:

• At the onset of an angina attack, the patient administers one sublingual or buccal tablet or one metered dose of the spray.
• If the pain is not relieved within five minutes the patient takes a second dose; a third can be taken after another five minutes if symptoms persist.
• If pain continues after a total of three doses in 15 minutes, the patient should go to the nearest emergency room at once.

Nitroglycerin is very volatile so its potency can be easily lost. A patient should take the follow precautions:

• Keep no more than 100 tablets on hand stored in their original container.
• When first opened, the cotton filler should be discarded, and the cap screwed on tightly immediately after each use.
• A supply should always be kept close at hand in case of an attack, with the rest kept in a cool dry place.

Intermediate to Long-Term Nitrates. Sublingual tablets of isosorbide dinitrate have a somewhat slower onset of action than nitroglycerin and are useful for preventing exercise angina. Ointments, patches, and oral tablets are used for longer-term prevention of angina attacks:

• Transdermal patches are applied in the morning to any hair- or injury-free area on the chest, back, stomach, thigh, or upper arm. Hands should be washed after each patch or ointment application and sites of application should be rotated to avoid skin irritation.
• Nitroglycerin ointment is applied by measuring out an even amount on an applicator paper and then placing, not rubbing or massaging, it on the chest, stomach, or thigh. Any ointment that remains from the previous application should be removed.

Long-acting forms may lose their effectiveness over time, so physicians generally schedule nitrate-free breaks to prevent tolerance. Some concern exists that nitrate-free periods might increase the risk for angina and adverse heart events. One large study, however, found no increased danger when patients used a nitroglycerine patch with scheduled breaks. The use of drugs known as ACE inhibitors, normally used for high blood pressure, may help prevent tolerance to nitrates. (Some studies suggest that vitamin C or E might also help.)

Side Effects. Nitrates have many side effects, some of which can be serious.

Common side effects of nitrates include headaches, dizziness, nausea and vomiting, blurred vision, fast heartbeat, sweating, and flushing on the face and neck. Low blood pressure and dizziness can be relieved by lying down with the legs elevated. Note: These effects can be significantly worsened by alcohol, beta-blockers, calcium channel blockers, sildenafil (Viagra), and certain antidepressants. Your doctor may prescribe medicines to lessen these side effects. Contact your doctor if these side effects are persistent or severe.

Serious side effects requiring immediate medical help include fever, joint or chest pain, sore throat, skin rash (especially on the face), unusual bleeding or bruising, weight gain, and swelling of the ankles.

Withdrawal. Withdrawal from nitrates should be gradual. Abrupt termination may cause angina attacks.

Beta-Blockers

Beta-blockers are useful for preventing angina attacks and reducing high blood pressure. They reduce the oxygen demand of the heart by slowing the heart rate and lowering blood pressure. They are now well known for reducing deaths from heart disease and from heart surgeries, including angiography and coronary bypass. Beta-blockers are the drugs of choice for older patients with stable angina and may also be beneficial for people with silent ischemia. They can be used effectively in combination with nitrates or calcium channel blockers. Of great concern is a 2003 study reporting their underuse in women, including those at very high risk for heart attack.

Of note: Beta-blockers are less useful for the treatment of Prinzmetal's angina. Also, in patients with high blood pressure, other drugs, notably diuretics, are associated with higher survival rates.

Specific Beta-blockers. Beta-blockers include propranolol (Inderal), labetalol (Normodyne, Trandate), acebutolol (Sectral), atenolol (Tenormin), metoprolol (Toprol-XL, Lopressor), and bisoprolol (Zebeta). Carvedilol (Coreg), a newer agent known as a nonselective beta-blocker, appears to be as safe as the older beta-blockers and may prove to have additional advantages. A nasal spray form of propranolol appears to be very beneficial in helping to reduce exercise-induced angina attacks.

Side Effects. In spite of the significant benefits of these agent, they are greatly underused, possibly because of reports of distressing side effects that include the following:

• Some beta-blockers lower HDL cholesterol (the beneficial cholesterol) by about 10%. The effect is most marked in smokers.
• Fatigue and lethargy are the most common neurologic side effects. Some people experience vivid dreams and nightmares, depression, and memory loss.
• Dizziness and lightheadedness, especially when getting up from a lying down position.
• Exercise capacity may be reduced.
• Sexual dysfunction has been reported but actual studies report only a slight increased risk.
• Other side effects may include cold extremities, asthma, decreased heart function, and gastrointestinal problems (e.g., heartburn, gas, diarrhea, or constipation). Although depression has been reported, it does not appear to occur at any higher rates than in the general population.

If side effects occur, the patient should call a physician, but it is extremely important not to stop the drug abruptly. Angina, heart attack, and even sudden death have occurred in patients who discontinued treatment without gradual withdrawal.

Calcium Channel Blockers (CCBs)

Calcium channel blockers reduce heart rate and slightly dilate the blood vessels of the heart, thereby decreasing oxygen demand and increasing oxygen supply. They also reduce blood pressure. CCBs vary chemically, however, and although some are helpful, others may even be dangerous for certain patients with angina.

Click the icon to see an image of the anterior heart arteries.

• Long-acting nifedipine (Adalat, Procardia) and nisoldipine (Sular) and newer CCBs, such as amlodipine (Norvasc) and nicardipine (Cardene), may be beneficial for some patients with angina. They can be considered alone for patients who cannot tolerate beta-blockers, but may provide the best results when used in combination with a beta-blocker. Studies suggest that they reduce the need for repeat angioplasties. There effects on other outcomes, including mortality rates and heart attack, are less clear.
• Short-acting CCBs, including short-acting forms of verapamil, diltiazem, nifedipine, and nicardipine are helpful for many patients with Prinzmetal's angina. It should noted, however, that short-acting forms of certain CCBs, such as nifedipine and nisoldipine, have been associated with severe and even dangerous side effects, including an increase in heart attacks and sudden death in some patients with unstable angina. They also increase the risk for adverse effects in patients with stable angina. Short-acting CCBs are, therefore, not used for stable or unstable angina.

There is no strong evidence that any calcium channel blockers improve survival rates. Overdose can cause dangerously low blood pressure and slow heart beats. Patients with heart failure have a higher risk for death with these agents and should not take them. No one taking any calcium channel blocker should withdraw abruptly because such action could dangerously increase the risk of high blood pressure. Note: Grapefruit and Seville, or sour, oranges (often used in marmalade), boosts the effects of CCBs, sometimes to toxic levels. (Regular oranges do not appear to pose any hazard.)

Angiotensin Converting Enzyme (ACE) Inhibitors

Angiotensin converting enzyme (ACE) inhibitors are important heart protective drugs, particularly for people with diabetes. They reduce the production of angiotensin, a chemical that causes arteries to constrict, and so are commonly used to lower blood pressure. Evidence now further suggests that they have additional protective effects, however, and that they reduce risk for heart attack, stroke, complications of diabetes, and death in patients at high risk for heart disease. (Unlike beta-blockers and nitrates, however, calcium channel blockers have no specific effects on angina.)

ACE inhibitors include captopril (Capoten), ramipril (Altace), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), perindopril (Aceon), and lisinopril (Prinivil, Zestril).Most studies have been conducted using ramipril, but other agents are also promising.

Some research has also suggested that ACE inhibitors improved heart and lung muscle function, which should be very helpful for patients with existing heart failure. (A 2002 study also indicated that these agents may help preserve general muscle strength in older individuals.)

Side Effects. Side effects of ACE inhibitors are uncommon but may include an irritating cough, excessive drops in blood pressure, and allergic reactions. Of great concern is research suggesting that aspirin interfere with ACE inhibitors (and other so-called NSAIDs) increases the risk for heart failure in patients taking ACE inhibitors. An encouraging 2003 analysis, however, reported that ACE inhibitors still significantly reduced risks for adverse heart events, including hospitalizations for heart failure, regardless of whether the patients also took aspirin or not.

Statins and Other Cholesterol and Lipid-Lowering Agents

In 2002, The National Cholesterol Education Program's Adult Treatment Panel issued its latest recommendations. The results of these guidelines would increase the number of Americans taking LDL-lowering agents from 15 million to 36 million, with significant increases occurring in people under 45 and over 65 years old and among men in all age groups. A number of agents are available for lowering cholesterol and other dangerous fat molecules (lipids).

Click the icon to see an image of cholesterol.

They include the following:

• Statins are now the standard agents for most people who require LDL-lowering therapy. Bile-acid binding resins or niacin may be considered. (Another LDL-lowering agent, probucol, is usually limited to people with genetic disorders that cause severely high cholesterol levels.) If LDL-goals are not achieved, combinations of a statin with a bile-acid resin such ezetimibe (Zetia) or niacin should be considered.
• Fibrates or niacin are beneficial for people who need to lower triglycerides and increase HDL.

[For more detailed information on other cholesterol-lowering agents and cholesterol in general see the Well-Connected Report, Cholesterol, Other Lipids, and Lipoproteins.]

Statins. Statins inhibit the liver enzyme HMG-CoA reductase, which is used in the manufacturing of cholesterol. They are the most effective drugs for the treatment of high cholesterol, and, according to a 2003 major analysis over 200 studies, they reduce risk for heart events by 60% and stroke by 17%.

Two studies in 2002 and 2003, however, muddied these positive findings. In one, lowering moderately-high LDL cholesterol levels with a statin did not improve survival rates among high-risk patients. Some experts believe that statin treatment was not aggressive enough in this study. In the other 2003 study, however, cholesterol levels--whether high or low--had no effect on mortality rates among heart attack survivors over 65. More research is needed on these findings.

Still, most experts estimate a 25% or more reduction in mortality rates when patients take statins after a heart attack. They may even become important agents for many people at risk for heart disease who have normal cholesterol levels or below. In fact, the benefits of statins may go beyond simply improving cholesterol levels.

Statins include lovastatin (Mevacor), simvastatin (Zocor), and pravastatin (Pravachol). These are the most studied statins and have proven effectiveness and good safety record. Newer synthetic statins including fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor) are proving to be very beneficial.

In many studies, the side effects reported by statin users were nearly the same as those taking placebo (inactive agents). Those reported include gastrointestinal discomfort, headaches, skin rashes, muscle aches, sexual dysfunction, drowsiness, dizziness, nausea, constipation, and peripheral neuropathy (numbness or tingling in the hands and feet).

The primary safety concern with statins has involved an uncommon condition called myopathy, which can cause muscle damage and in some cases, muscle and joint pain. Severe cases of myopathy warrant discontinuation. Patients should tell their physicians about any unusual muscle discomfort or weakness and if their urine becomes brown-colored.

Statins also can effect the liver, particularly at higher doses, so periodic liver function tests should be administered.

Infection-Fighting Agents

Influenza Vaccinations (Flu Shots). Evidence now suggests influenza vaccinations help protect against adverse heart events (including after heart surgeries), stroke, and death from all causes in the elderly. Still, studies suggest that only two thirds of this group are vaccinated, mostly because of unwarranted fears of ineffectiveness or adverse effects.

Antibiotics. The antibiotics prescribed for Chlamydia pneumoniae are being investigated for prevention of heart attacks in patients with heart disease and evidence of infection. Studies in 2001 and 2002 are suggesting they may have effects on blood vessels that may benefit people with coronary heart disease and evidence of infection.

Experimental Agents

Gene Therapy and Angiogenesis.Proteins known as growth factors are being investigated for their ability to grow new blood vessels for supplying oxygen to the heart. After promising small trials, two large studies of genetically engineered forms of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF [GenerX]) failed to detect any benefits. Studies on therapies that actually genetically encode these proteins are underway.

Testosterone Supplements. Some trials using testosterone supplements or patches have reported improved exercise-induced blood flow in the coronary arteries and improvement in angina in some cases. Supplements of this male hormone, however, may increase the risk for prostate cancer. Experts suggest that testosterone be used only in older men with significant deficiencies in testosterone.

Selective Estrogen-Receptor Modulators (SERMs). Selective estrogen-receptor modulators (SERMs), including raloxifene (Evista), have been designed to produce the benefits of estrogen without its risks. They are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. Raloxifene may have some heart benefits, although it poses a risk for deep vein blood clots, which may have long-term implications on heart problems. A major study is underway to determine its effects on the heart.