The Healthy Heart: Preventing, detecting, and treating coronary artery disease

(This article was first printed in the Special Health Report from Harvard Medical School "The Healthy Heart: Preventing and Treating Coronary Artery Disease." For more information or to order, please go to www.health.harvard.edu/HH.)

Medications for heart disease

Although lifestyle changes are an essential first step in treating coronary artery disease, you may need to take medications to reach your cholesterol and blood pressure goals and otherwise reduce your risk. In fact, most people with heart disease need to take more than one medication. The specific combination of drugs will depend on your particular symptoms and risk factors. Some of the most commonly prescribed medications are described below. For more information on these and other drugs, see Tables 10, 11, and 12.

Blood pressure medications

For many years, doctors used diuretics — sometimes known as water pills — to treat high blood pressure. Although diuretics remain a mainstay of blood pressure treatment because they are cheap and effective, a flood of other drugs have become available since the 1980s. In addition, a large meta-analysis comparing the various options concluded that the five categories of drugs currently available are equally effective for most people. Work with your doctor to determine the best type of medication for you.

It is important to keep in mind, though, that most people with hypertension do not get their blood pressure under control with the starting dose of the first drug chosen. At that point, two philosophies exist about what to try next. Some doctors increase the dosage of the first drug to see if it will bring blood pressure down to target levels. The advantage of this approach is simplicity, as the person being treated takes one pill per day. A second approach is to use low doses of two or more blood pressure drugs that work in different ways. This approach minimizes the likelihood of side effects, but may be harder to follow, as it requires taking two or more pills per day. It may also be more expensive for the person being treated, as he or she may face additional copayments or out-of-pocket expenses for the drugs. A compromise approach is to use combination medicines that include, for example, both an ACE inhibitor and a low-dose diuretic (see "Combination medications"). This is convenient, but many combinations are available only in brand-name forms and are thus more expensive.

Diuretics

Thiazide diuretics work by reducing the amount of water in the body and increasing the flow of urine. These medications also reduce high blood pressure so effectively that they are recommended as initial treatment for most people with hypertension, either alone or in combination with another blood pressure medication. Many are now available in generic form, which means they are inexpensive. Commonly used thiazide diuretics include chlorthalidone (Hygroton, Thalitone) and hydrochlorothiazide (Microzide, HydroDIURIL), although there are many others.

Study after study has shown that diuretics are effective. Indeed, a 2002 report from ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) in the Journal of the American Medical Association showed that diuretics were just as effective as two newer medications: the calcium-channel blocker amlodipine (Norvasc) and the ACE inhibitor lisinopril (Prinivil, Zestril). What's more, diuretics boost the effectiveness of other antihypertensive medications, so you benefit more from multidrug therapies. But diuretics do have some drawbacks. If you have trouble with urination, diuretics may aggravate the situation. These drugs can also lower potassium levels (possibly causing leg cramps), although potassium-sparing diuretics are available. Finally, diuretics can cause fatigue and may raise blood sugar, increasing the risk for diabetes. Even with all the caveats, however, diuretics provide the foundation of treatment for high blood pressure.

Angiotensin-converting–enzyme (ACE) inhibitors

These blood pressure drugs dilate blood vessels. They work by blocking production of angiotensin, a blood vessel–constricting protein. In addition to controlling high blood pressure, ACE inhibitors have long been prescribed for people with heart failure. Studies have shown that these drugs also help in other situations. They help to preserve heart function after heart attacks, protect the kidneys in people with diabetes, and slow the progression of atherosclerosis. The most common problem is a persistent cough, which prompts 1 in 10 people to stop taking ACE inhibitors.

Angiotensin-receptor blockers (ARBs)

Angiotensin-receptor blockers (ARBs) provide an alternative to ACE inhibitors. ARBs work in a slightly different way from ACE inhibitors to restore normal blood flow: Instead of blocking production of angiotensin, ARBs prevent this protein from exerting its blood vessel–constricting effects in the body. When ARBs were first introduced, it was not clear whether they worked as well as ACE inhibitors. Two major clinical trials reported in 2003 that they do — at least for some people.

The CHARM study (short for Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) compared the ARB candesartan (Atacand) with a placebo in more than 7,600 people with long-term heart failure. In the candesartan group, 23% died during the three-year study, compared with 25% in the placebo group. That survival advantage may not sound like much, but apply it to five million Americans with heart failure and it translates into longer lives for thousands. The VALIANT study (short for Valsartan in Acute Myocardial Infarction Trial) involved more than 15,000 heart attack survivors with heart failure or damaged left ventricles (compromising the heart's ability to pump blood). The researchers found that people taking the ARB valsartan (Diovan) fared just as well in terms of health outcomes (such as prevention of another heart attack) as those taking the ACE inhibitor captopril (Capoten).

ACE inhibitors remain the recommended first-line therapy for most people because they are much less expensive and have a longer track record than ARBs. But the CHARM and VALIANT studies showed that ARBs provide good alternatives if you can't take an ACE inhibitor. ARBs include candesartan, valsartan, irbesartan (Avapro), and losartan (Cozaar).

Avoiding common pitfalls

One of the great medical success stories of our time is the ability to diagnose and treat heart disease and to gauge a person's risk of developing it in the future. But preventive measures and therapies can only be successful if people use them. A continuing medical challenge is helping people avoid a variety of common pitfalls: ignoring key symptoms, deferring recommended tests, or neglecting to take medications as prescribed. Any or all of these things can keep you from reaping the full benefit of decades of medical research and practice.

"The drugs worked. Can I stop now?"

If you've reached your target blood pressure or cholesterol level, it's tempting to stop taking your medicine. But doing so can cause your blood pressure or cholesterol to rise again — along with your risk for heart disease. Check with your doctor before deciding to cut back or eliminate any medication.

"I'm having side effects."

Tell your doctor about side effects that you find bothersome. Chances are, you can use a different medication that's more bearable. One of the best ways to minimize unpleasant side effects from heart medications is to avoid taking other drugs that interact adversely with them. Many drugs commonly prescribed for the prevention or treatment of heart disease should not be taken with other medications.

"It must be heartburn."

Ignoring chest pain is another common pitfall. Most people know that it might be a sign of angina or heart attack — or of nothing more than indigestion. But anyone having chest pain should err on the side of caution by calling the doctor and having an evaluation for heart disease. If you disregard chest pain or pretend it's not that big a deal, you could be denying yourself the chance for early — and potentially lifesaving — treatment.

Beta blockers

Beta blockers are among the most commonly used drugs for controlling cardiac ischemia and hypertension. There are many types of beta blockers on the market, but all act by interfering with epinephrine (adrenaline), a hormone that normally stimulates the heart to beat faster and stronger. Beta blockers slow the heart rate and decrease cardiac output, lowering blood pressure and decreasing the amount of work the heart must do. By lowering the oxygen needs of the heart, beta blockers help prevent or relieve ischemia.

In some people, however, beta blockers also have side effects, such as erectile dysfunction and fatigue. In particular, people with asthma, heart failure, or diabetes should be cautious about taking this class of medications because of the possibility that such drugs could worsen these conditions.

However, some of the newer beta blockers are less likely to cause side effects because they act more selectively on the heart than on other parts of the body. These "partially selective" beta blockers include metoprolol (Lopressor, Toprol XL) and atenolol (Tenormin). In any case, these drugs are so effective in treating coronary artery disease that — despite their potential side effects — they are often tried in people with problems such as heart failure or diabetes because their benefits outweigh the risks.

Calcium-channel blockers

Calcium-channel blockers are vasodilators: By dilating the coronary arteries, they increase blood flow to the heart and cut its workload by reducing blood pressure and the force of the heart's contractions. The first generation of calcium-channel blockers were short-acting; some studies suggested they might be hazardous in certain people with heart disease. But the newer, long-acting calcium-channel blockers appear safe and effective in controlling high blood pressure. As a result, they have been endorsed as a first-line treatment for blood pressure.

In contrast to beta blockers, there is thus far no evidence that calcium-channel blockers improve survival after a heart attack in people with coronary artery disease. But they are useful for people who don't get adequate relief from beta blockers or nitrates. And calcium-channel blockers are more effective than beta blockers for preventing angina due to coronary spasm.

They also help people with high blood pressure who can't tolerate the side effects of relatively high doses of beta blockers or nitrates. Calcium-channel blockers are less likely to cause depression and fatigue than beta blockers are, and they have fewer side effects than nitrates do. They're also more convenient than nitrates, in most cases needing to be taken only once a day.

Cholesterol medications

Since statins were first introduced in the late 1980s, they have become the treatment of choice for lowering cholesterol, simply because they are so effective. Even so, they don't work for everyone; other medications are available to lower cholesterol and may be more beneficial for you, depending on your circumstances. If you have high triglycerides in addition to high LDL, for instance, the class of drugs known as fibric acid derivatives may help (see "Fibric acid derivatives"). If you have low HDL cholesterol, niacin is an option. Other medications such as colesevelam (WelChol) and ezetimibe (Zetia) lower LDL substantially and can be combined with statins to lower these levels even further (see "A cholesterol-lowering combination").

Statins

Statins, known medically as HMG-CoA reductase inhibitors, work by preventing the liver from making cholesterol (see Figure 8) and by forcing the liver to draw LDL cholesterol from the blood. These medications not only significantly lower LDL levels but also improve your overall cholesterol profile by lowering total cholesterol, slightly boosting HDL, and slightly lowering triglycerides — although by differing amounts. Since they were introduced in 1987, the statins have proved to be better at reducing cholesterol than other medications. What's more, studies have revealed that these medications have other benefits: They stabilize cholesterol-filled plaque in artery walls, promote the growth of new blood vessels, and calm inflammation. All of these actions help to reduce the risk for coronary artery disease and heart attack or stroke. Small wonder that statins are considered one of the most important advances in drug therapy since the 1970s.

Figure 8: How statins work

Most of the cholesterol circulating in your blood has been made by your liver, not digested from the food you eat. An enzyme called HMG-CoA reductase plays a key role in deciding how much cholesterol the liver makes.

But statins are not miracle pills, and they're not for everyone. They don't always lower cholesterol enough, and they cause troubling side effects in some people. It's also important to remember that eating healthy foods, exercising regularly, and losing weight if necessary are the best — and should be the first — approaches to treating high cholesterol and reducing the risk for heart attack or stroke. Consider the options carefully and talk with your doctor about whether to take a statin and, if so, which one to take.

Should you take a statin? It depends on a number of factors. In general, the higher your LDL cholesterol, and the greater your chances of having a heart attack or stroke, the more you'd benefit from taking a statin. Talk with your doctor about these drugs if you

  • have had a heart attack or get chest pain
  • have had coronary artery bypass surgery or artery-opening angioplasty
  • have heart disease, diabetes, chronic kidney disease, or vascular disease and your LDL is above 100 mg/dL
  • have high LDL (above 160 mg/dL) despite lifestyle changes
  • are at high risk of developing heart disease (even though your cholesterol is in the normal range) because of smoking, high blood pressure, a family history of early heart disease, or other factors.

Six statins are now available in the United States: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). Another medication, Vytorin, combines ezetimibe and simvastatin in a single pill (see "A cholesterol-lowering combination"). All six statins have similar effects on cholesterol and similar side effects. For most people, which statin you take isn't nearly as important as whether you take it every day, how you take it (see "Getting the most from your statin," below), and how well you help it along with diet and exercise (see "Lifestyle changes to protect yourself"). And it's important to remember that although the PROVE IT study (see "The lower the cholesterol, the better") is sometimes depicted as the "clash of the statins," the real message for people at risk for heart disease was to drive LDL levels as low as possible. With all that in mind, here's a quick guide for differentiating among the statins.

Potency. Some statins are more potent than others, in that the same dose of a medication lowers cholesterol by different amounts. A 20-mg tablet of Pravachol, for example, lowers LDL by 24% on average, while a 20-mg tablet of Lipitor lowers it by 46%. But potency isn't nearly as important as efficacy — the maximum amount a statin can lower LDL at its highest FDA-approved dose. Lipitor and Crestor rank highest in this regard. But here's the rub: You don't necessarily need to pick the strongest statin. A "weaker" one may be less expensive and more than enough to get you to your target.

Cost. Statin tablets can cost anywhere between $500 and $1,500 per year. How much you actually pay can depend on the deals your health insurer has made.

Side effects. This issue can be a deciding factor for some people trying to choose among the statins. All six statins can increase levels of liver proteins — a change that affects 2 out of 100 people — although it is not clear if this represents a real problem. Liver failure, a serious problem, is extremely rare in people using statins.

Muscle pain is more problematic. About 5 of every 100 people who take a statin report having muscle pain, but it is not clear whether this is caused by statin use. In large clinical trials, muscle pain was reported by as many people taking a placebo as it was by those taking a statin. (The aches and pains of growing older may be to blame.) Still, some people have muscle aches right after starting a statin that disappear when they stop taking the medication. Severe muscle damage — a condition known as rhabdomyolysis, which can be deadly unless treated — affects about 8 of every 10,000 people taking a statin. One popular statin, cerivastatin (Baycol), was voluntarily removed from the market in 2001 because it was associated with rhabdomyolysis. Crestor came under fire in 2004 when critics charged that it was more likely than other statins to cause rhabdomyolysis and kidney failure. After reviewing the data, however, the FDA issued a public advisory concluding that Crestor was as safe as the other statins in most cases, but warning that to reduce risk, the lowest doses should be prescribed in people older than 65, those who have hypothyroidism or kidney disease, and Asian Americans.

If you take a statin in combination with a fibrate drug such as gemfibrozil (Lopid) or fenofibrate (TriCor), you and your doctor should be especially alert to symptoms of persistent muscle aches and pains, which could indicate rhabdomyolysis. A blood test for creatine kinase, a protein released by injured muscle, can reveal whether damage has occurred.

Because various statins are broken down in the liver in different ways, some statins are more likely to be affected by other drugs or foods. Grapefruit juice, for example, increases blood levels of Mevacor, Zocor, and Lipitor, but doesn't usually affect the other statins. Your doctor may suggest a particular statin based on other medications you are taking.

Finally, all medications affect different people in different ways. Some people taking statins have experienced constipation, upset stomach, dizziness, insomnia, rashes, and even hair loss. Because these could be reactions to either the active agent or the inactive ingredients, changing to a different statin may help. If not, try another cholesterol-lowering drug.

Getting the most from your statin

You can do several things to make sure your particular statin is working the best it can.

  • Take Mevacor with food. This almost doubles the amount of medication that gets into your bloodstream.
  • Take some statins at night. It's best to take Mevacor, Pravachol, Zocor, and Lescol with your evening meal. That's because these statins block a key cholesterol-making enzyme in the liver that is most active at night. Lipitor and Crestor last long enough in the body that it doesn't matter when you take them.
  • Beware of drug interactions. Mention all other medications you are taking when talking with your doctor about a statin, to avoid potentially harmful interactions. If you are on other medications, you may want to try Pravachol, which is less likely than the other statins to interact with other medications.

Fibric acid derivatives

This family of drugs blocks the production and activity of proteins that transport cholesterol. The two most commonly prescribed fibric acid derivatives are gemfibrozil (Lopid) and fenofibrate (TriCor). Others are under investigation. Fibric acid derivatives are mainly prescribed for people with high triglyceride levels. They reduce triglycerides by 20%–50% and raise HDL levels by 10%–15%, but have only a modest effect on LDL.

Gemfibrozil and fenofibrate, which come in pill form, are generally taken once or twice a day with meals. Most people don't experience side effects, although a few develop dyspepsia (feelings of fullness, bloating, or heartburn after eating), dizziness, or changes in sensations such as touch and taste. These drugs can also increase the risk for gallbladder disease and, when used with a statin, can cause rare cases of the muscle-wasting disease rhabdomyolysis. They can also augment the effects of blood-thinning drugs such as warfarin.

Although these side effects are uncommon, everyone taking a fibric acid derivative should have checks of liver function and blood counts before and during therapy. And people on blood-thinning medications should have their prothrombin time (a measure of clotting ability) monitored closely.

Niacin

The B vitamin niacin, also called nicotinic acid, is an essential part of a healthy diet. At daily doses of 1,500–4,500 mg — well above the Recommended Dietary Allowance (14 mg for women and 16 mg for men) — crystalline nicotinic acid acts as a drug instead of a vitamin. Niacin alone can reduce LDL levels by 15% or so, lower triglycerides even more, and boost HDL by as much as 20%. Taken in addition to a statin, niacin lowers LDL another 10%. It works by cutting the liver's production of VLDL, which is ordinarily converted into LDL.

Although you can buy niacin in any grocery or health store, to obtain the necessary dose, it's best to go with a preparation approved by the FDA (see Table 11). Niacin is safe, except for people with chronic liver disease or certain other conditions, including diabetes and peptic ulcer. It's also inexpensive. However, it has numerous side effects. It can cause rashes and may aggravate gout, diabetes, or peptic ulcers. A sustained-release preparation (Niaspan) may have fewer side effects, but it can cause liver damage, especially when combined with a statin.

What's the evidence?

Hormone replacement therapy

Experts once thought that hormone replacement therapy (HRT) helped to prevent heart disease in menopausal women. But several large trials reported in the late 1990s concluded that HRT doesn't help prevent heart problems, and it may even cause them — sparking a great deal of confusion and controversy. Then, after two landmark studies conducted as part of the national Women's Health Initiative also concluded that HRT may be harmful, doctors stopped recommending hormone therapy except for the short-term treatment of menopausal symptoms. Here's a brief look at these two studies.

Journal of the American Medical Association, July 17, 2002

Scope: The estrogen-plus-progestin study involved 16,608 healthy menopausal women.

Findings: Halted early in July 2002. Researchers reported an increased heart risk for women taking combined hormones: 7 additional heart attacks for every 10,000 women, 8 more strokes, and 18 more blood clots in the lungs or legs. (The study also found a small increase in breast cancer for the same group of women, although the risks for hip fracture and colorectal cancer decreased.)

Journal of the American Medical Association, April 14, 2004

Scope: The estrogen-only study involved 10,739 women who had undergone hysterectomy but were otherwise healthy.

Findings: Halted early in February 2004. Researchers concluded the hormone provided no protection against heart disease and increased the risk for stroke. For every 10,000 women, taking estrogen resulted in 12 more strokes, 6 more blood clots in the legs, and — for the first two years — slightly increased the risk for heart disease. This initial cardiac risk subsided with time, and by the end of the study, researchers found that estrogen neither protected against nor raised a woman's chances of developing heart disease. (The study also found that estrogen alone had no impact on colorectal cancer and an uncertain impact on breast cancer risk, but that it did reduce the risk for hip fracture.)

The bottom line

Given the evidence, the FDA, the American Heart Association, and the American College of Cardiology — among other professional organizations — now advise physicians not to prescribe hormone replacement therapy solely to prevent heart attacks and coronary artery disease. If you need HRT to alleviate symptoms of menopause such as hot flashes, the FDA recommends that it be used for the shortest time possible and at the lowest effective dose.

Bile acid binders

Bile acid binders are synthetic resins that bind chemically with cholesterol-rich bile acids in the intestine, preventing their reabsorption. To replace the bile acids lost in this way, the body draws upon its store of cholesterol, thus lowering cholesterol levels in the blood. Medications in this class include cholestyramine (Questran), colesevelam (WelChol), and colestipol (Colestid). Typically, they lower LDL cholesterol by 15%–30%, depending on the daily dose and whether they are combined with a statin.

But bile acid binders are rarely used, because of their many side effects. These include constipation, heartburn, and a bloated feeling. The soluble fiber psyllium, found in laxatives such as Metamucil, Perdiem, and others, can lessen these side effects. However, bile acid binders can also interfere with the action of many drugs, especially digitalis, beta blockers, warfarin, thiazide diuretics, anticonvulsants, and thyroid hormone supplements. And people with high triglyceride levels should not take this type of medication because it tends to elevate triglycerides.

Ezetimibe (Zetia)

If you are one of the people who has not been helped at all by statins, it may be because your genes and biology make you resistant to the drugs' effects. In 2002 the FDA approved a medication that has proved to be the most helpful in people who least benefited from statin treatment.

Zetia works by blocking the cholesterol in food from crossing the intestinal wall and getting into the bloodstream. Using a mathematical model, researchers at the Florida Lipid Institute showed that people whose LDL budged little with a statin had higher than expected drops in LDL after adding Zetia. This seesaw connection between the statins and Zetia makes some sense, because people for whom statins don't work well are great at absorbing cholesterol from the intestines into the bloodstream. Zetia blocks this process.

Information on the side effects of Zetia is limited. Although it seems safe so far, clinical studies have been small and mostly short-term. Compared with people taking a placebo, those taking Zetia reported slightly more fatigue, gastrointestinal problems, infections such as sinusitis, and muscle and back pain. Although the low rate of side effects is reassuring, the true side effect profile won't be known until hundreds of thousands of people take the drug for several years.

Zetia reduces LDL levels about 20% alone; studies show that when combined with a statin, it lowers LDL another 15%–23%. Talk with your doctor about whether a combination strategy might be helpful for you, particularly if you have not responded dramatically to a statin alone. One combination medication is currently available that combines ezetimibe with a statin in a single pill (see below).

A cholesterol-lowering combination

Most available combination drugs for heart health treat high blood pressure (see "Combination medications"). In 2004, the FDA approved Vytorin, the first combination drug to control cholesterol. The drug was designed to offer a one-two punch: It combines simvastatin, which blocks production of cholesterol in the liver, and ezetimibe, which blocks absorption of cholesterol in the intestines. Although some studies have reported that Vytorin lowers cholesterol more than a statin alone, it remains unclear whether this medication, or even the combination strategy, will prevent more heart attacks and deaths than other treatment approaches.

Selective estrogen receptor modulators (SERMs)

Sometimes called "designer estrogens," selective estrogen receptor modulators (SERMs) block the effects of estrogen in some parts of the body, such as the breasts, but not in others (which is why they are called selective). One of these drugs, raloxifene (Evista), decreases levels of both total and LDL cholesterol, but does not increase HDL. However, the net effect on overall heart disease risk is unknown at this point.

Other cardiovascular medications

Some cardiovascular medications function as antiplatelet drugs, which prevent tiny blood cells known as platelets from clumping together — the first step in the formation of a blood clot. Others dilate blood vessels or provide two medicines in one pill.

Aspirin

Aspirin is an old standby, yet it continues to surprise. This common, inexpensive drug helps protect survivors of heart attack and stroke from subsequent heart attacks and death, and even helps reduce the number of deaths that occur within the first hours following a heart attack. Although aspirin is best known as an antiplatelet drug, it may also subdue the inflammation that is central to coronary artery disease.

Randomized trials have provided clear evidence of aspirin's value in both preventing heart attacks in men and treating coronary artery disease in both sexes. Over all, dozens of studies, involving tens of thousands of people, have shown that low-dose aspirin reduces the risk for heart disease and stroke by about 25%. A standard dose of aspirin to prevent heart attack is 81 mg per day, about what you'd find in a baby aspirin.

Although aspirin is best known as an antiplatelet drug, it may also subdue inflammation.

Guidelines from nearly every major medical group urge people with heart disease or at high risk for it to take aspirin. Although a major study reported in 2005 concluded that the advice is not as clear-cut for how to prevent first heart attacks in women (see "Advice for women," below), the prevailing consensus remains that in general, unless you are allergic to aspirin or it causes you problems, you should take it if you

  • have had a heart attack
  • have had an ischemic (clot-caused) stroke or a mini-stroke (transient ischemic attack)
  • have angina (chest pain)
  • have had a coronary artery bypass or angioplasty
  • have diabetes
  • are at high risk for heart disease (see Table 6 or 7).

Despite aspirin's benefits, it also has some drawbacks. The evidence that its benefits exceed its risks is much stronger in men than in women, at least in terms of primary prevention (avoiding a first cardiovascular event). It can increase the risk for stroke and significant gastrointestinal bleeding. Even people who take aspirin occasionally with no problems could experience bleeding complications with regular use over prolonged periods. In particular, it may not be a good choice for people with uncontrolled hypertension (a major cause of hemorrhage into the brain). In such people, aspirin could more likely cause dangerous bleeding than prevent a heart attack. In addition, aspirin occasionally irritates the stomach lining without causing bleeding. However, these side effects can be reduced with the use of coated aspirin, which minimizes stomach irritation.

Advice for women. The first large-scale randomized study to specifically examine aspirin's effectiveness in preventing first heart attacks in healthy women, reported in the New England Journal of Medicine in 2005, showed that the risk/benefit analysis for aspirin is not as straightforward in women as it is in men. The study involved almost 40,000 healthy women ages 45 and older, who took 100 mg of aspirin or a placebo every other day. To their surprise, the researchers found that aspirin did not affect the risk for a first heart attack one way or the other in the group as a whole, although it did reduce the risk for stroke by 17%. Yet when the researchers did subgroup analyses, they discovered that aspirin significantly reduced the risk for first heart attack, stroke, and other cardiovascular events in women who were 65 and older. This benefit has to be weighed, however, against an increased risk for gastrointestinal bleeding.

So what do you do? If you're a woman who has already had a heart attack, stroke, or some other cardiovascular event, the advice remains the same: Take aspirin to reduce the risk for a second event. (A large study that looked at such secondary prevention concluded that aspirin benefits both men and women.) But if you're considering taking aspirin to prevent a first event, the advice is less clear-cut. Talk with your physician to determine whether — in your case — the benefits outweigh the risks.

Aspirin resistance. Some people are resistant to aspirin's anticlotting effects. So far the research indicates that aspirin fails to affect platelets' tendency to clump, or does so only partially, in 5%–40% of people who take it. These people therefore don't have the same reduction in heart attack and stroke risk that other people gain from aspirin use.

There are probably several reasons why aspirin resistance occurs. The body's response to aspirin may change over time. Some people have trouble absorbing aspirin from the digestive tract. Smoking blunts the effect of aspirin on platelets, as do being overweight and having high cholesterol or high blood pressure. A variety of genes influence how the body responds to aspirin. Finally, a few studies have indicated that a common nonsteroidal anti-inflammatory drug (NSAID), ibuprofen, may block aspirin's protective effects. The occasional dose of ibuprofen isn't likely to do this, but daily use could.

Although two laboratory tests are available to measure how well aspirin may be working for you, the idea of aspirin resistance is so new that many doctors either aren't aware of it or are waiting for more evidence that it's real before ordering these tests. So what do you do in the meantime? First, talk with your doctor about being tested for aspirin responsiveness. Second, if you need to take an NSAID for arthritis or some other condition, pick one that doesn't interfere with aspirin, such as naproxen (Aleve, Naprosyn) or diclofenac (Cataflam, Voltaren). Third, don't stop taking aspirin — regardless of whether you can get tested or what the results are. Aspirin probably works in several ways to prevent heart attacks. If do you find you are aspirin resistant, talk with your doctor about other antiplatelet medications.

Other antiplatelet medications

Several other options are available to inhibit platelets, but these tend to be more expensive than aspirin and are not as well studied. These include dipyridamole (Persantine, or Aggrenox when combined with aspirin) and clopidogrel (Plavix). One thing to keep in mind, however, is that all the possible side effects of these newer medications are not yet well known. A 2005 study in the New England Journal of Medicine, for instance, reported that people taking Plavix developed 12 times as many ulcers as people who took aspirin and a heartburn pill. Although the study was small, it does make sense to be cautious whenever any new medication hits the market. Certainly this point is underscored by what happened with COX-2 inhibitors (see "Cautions about COX-2 inhibitors," below).

Cautions about COX-2 inhibitors

Many people take medications for both heart disease and arthritis. Typically, nonsteroidal anti-inflammatory drugs (NSAIDs) are used to relieve the pain and inflammation of arthritis. This class of medications includes old standbys such as aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve, Naprosyn), as well as the newer COX-2 inhibitors rofecoxib (Vioxx), celecoxib (Celebrex), and valdecoxib (Bextra).

Currently the only COX-2 inhibitor available in the United States is Celebrex. Vioxx and Bextra are no longer available, and Celebrex carries a warning because, unfortunately, there is a risk to inhibiting only the COX-2 enzyme: This increases the risk for heart attacks and strokes.

It is still possible to treat your arthritis pain even if you have heart disease. But a few common-sense precautions — and perspective — may help.

First, remember that most NSAIDs, not just the COX-2s, may have some risk for the cardiovascular system — the one exception being low-dose aspirin, which helps prevent blood clots (see "Aspirin"). NSAIDs may cause the kidneys to retain water and thereby increase blood pressure. In fact, when the FDA issued a health advisory about the COX-2s in December 2004, it also warned that preliminary results from a long-term study of naproxen indicated this medication might promote cardiovascular disease. (The matter was still under investigation as this report went to press, but despite the FDA's warning, most evidence suggests naproxen is actually protective against heart attacks.) So if you take an NSAID, try to do so at the lowest dose possible and only as needed. Second, many people turned to the COX-2s because these drugs were marketed as providing better pain and inflammation relief than other NSAIDs. In fact, the older NSAIDs are just as effective in many cases; the main advantage of COX-2s is that they aren't as likely to cause bleeding ulcers.

So what are your pain relief options? The following strategy should help most people:

  • Start with acetaminophen (Tylenol), which is not an NSAID but relieves pain effectively.
  • If acetaminophen doesn't provide sufficient relief, try ibuprofen or another NSAID. Just remember to mention this to your doctor, so your blood pressure can be monitored.
  • If taking these drugs in the past caused gastrointestinal bleeding or gave you an ulcer, ask your doctor for advice. Sometimes taking an NSAID with a meal, or taking another medication to protect your stomach, can quell gastric distress.

Nitroglycerin

In recent decades, many new heart drugs have been introduced, but they haven't undercut the importance of nitroglycerin and other nitrate compounds. For more than a century, these drugs have been the most important medications for treating coronary artery disease. Nitroglycerin is best known as the little white pills that people carry with them and slip under the tongue when they have bouts of chest pain.

Nitrates help prevent or stop ischemia in several ways. They relax the muscles in the walls of the blood vessels, causing arteries and veins to dilate. When the coronary arteries dilate in response to nitroglycerin, the heart's blood supply increases. Nitrates also reduce the heart's work by lowering the body's blood pressure and the pressure within the heart's chambers. As a result, the heart requires less oxygen and places fewer demands on the coronary arteries.

Because nitrates dilate blood vessels throughout the body, they can cause a wide range of side effects, such as headache, dizziness, and even fainting spells. When people first start taking nitroglycerin, they are usually advised to sit down to avoid falling. Sitting is better than lying down because raising the legs to the level of the heart causes more blood to flow to the heart, increasing its workload.

The problem of tolerance. The effects of regular nitroglycerin tablets come and go quickly, but other forms of nitroglycerin, such as patches and timed-release pills, have longer-lasting effects. Unfortunately, research has shown that around-the-clock exposure to nitrates (as is provided by the patch) produces tolerance, or resistance to their effects. Nitrate tolerance can be minimized if you take nitroglycerin during the day but stop taking it at night, for instance, by removing the patch. These "nitrate holidays" help the body recover its ability to respond to the medication.

Newer nitrate delivery systems, including long-acting isosorbide mononitrates (Ismo, Imdur) accomplish the same thing with a single dose each day. One risk with this approach is that you might be left unprotected during the first hour or so after awakening — a high-risk time for heart attacks. This problem is often addressed by using other long-acting anti-anginal medications in conjunction with the nitrates.

Nitrates and erectile dysfunction medications. If you are taking a nitrate on a regular basis, it is important that you do not use some of the top-selling medications available to treat erectile dysfunction: tadalafil (Cialis), vardenafil (Levitra), or sildenafil (Viagra). These medications can cause a life-threatening drop in blood pressure when used in addition to a nitrate (see "What about sex?"). If you are taking nitroglycerin and are having problems with erectile dysfunction, talk with your doctor about alternatives.

Combination medications

A number of combination medications are available to treat coronary artery disease. Most aim to control high blood pressure by combining a diuretic with a beta blocker, a calcium-channel blocker, ACE inhibitor, ARB, or a different type of diuretic. One combination drug aims to lower unhealthy LDL cholesterol while boosting healthy HDL levels. The combination drug Caduet is intended to lower blood pressure and cholesterol at the same time. Others are in the development pipeline.

Is a combination drug right for you? It depends on your situation. Many people take more than one drug to control blood pressure or cholesterol, for instance. If you find you routinely miss doses or get confused about which medications you have taken, it may make sense to take a combination pill.

Cost is another consideration, especially if you have to make a copayment each time you purchase a medication. Using a combination drug means you would make one copayment instead of two. But if you pay for your medication yourself, or if your health plan charges a higher copayment for brand-name drugs than for generics (as is often the case), a combination could prove more expensive. And keep in mind that some combination drugs include one or more brand-name drugs for which less expensive generic versions are available. Indeed, combination drugs represent a growth industry for drug makers: They can help a company extend high-profit sales of a drug whose patent is about to expire.

Another drawback to combination medications is that it is hard to tinker with the dose, and changing dosage is a fact of life for people using cardiovascular drugs. People often start with low doses of particular medications and then increase them as needed to control one or more factors such as blood pressure, cholesterol, or blood sugar. But in a combination drug, the doses are paired: You can't increase one medication without increasing the other.

So what do you do? Combination drugs probably aren't a good idea if you are just starting drug therapy for a condition, or if your doctor needs to change the dose often. On the other hand, if you have been taking two well-established medications at stable doses for some time, a combination that delivers both of them at the right doses is worth looking into, especially if it contains generic versions of the drugs.

(This article was first printed in the Special Health Report from Harvard Medical School "The Healthy Heart: Preventing and Treating Coronary Artery Disease." For more information or to order, please go to www.health.harvard.edu/HH.)

Heart Disease: A guide to preventing and treating coronary artery disease

Heart Disease: A guide to preventing and treating coronary artery disease

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