Congestive Heart Failure

Description

Alternative Names

Medications

Among the most important drug classes in the treatment of Stage B through D heart failure are angiotensin-converting enzyme (ACE) inhibitors. An analysis of the major studies suggested that ACE inhibitors may reduce the risk of death, heart attack, and hospital admissions by 28% in patients with existing congestive heart failure.

These agents block the effects of the renin-angiotensin-aldosterone system, which is thought to play a powerful role in the development of heart failure. By preventing the formation of an artery-constricting substance called angiotensin II, blood vessels widen and blood pressure drops, decreasing the workload of the heart. ACE inhibitors also improve heart and lung muscle function, which should be very helpful for patients with existing heart failure.

For most people with existing high blood pressure and no evidence for heart failure (Stage A), diuretics would be a better option. In an important 2003 study, diuretics achieved a lower risk for heart failure--and also stroke and angina--than an ACE inhibitor. However, another 2003 comparison study reported fewer heart attacks and lower risk for death with ACE inhibitors than with diuretics, particularly in elderly Caucasian men. More research is needed to confirm the specific benefits of each agent.

In any case, ACE inhibitors are particularly important for patients with diabetes. A large study, for example, reported that diabetic patients who took these drugs had fewer heart attacks and lower all-cause mortality rates compared to those who took other anti-hypertensive agents. ACE inhibitors also may help slow progression of kidney disease, independently of their effect on blood pressure. (Some experts believe, in fact, that angiotensin may be the common factor linking diabetes and high blood pressure. This natural chemical not only influences all aspects of blood pressure control but it also interferes with insulin's normal metabolic signaling.)

Brands. ACE inhibitors include captopril (Capoten), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), ramipril (Altace), perindopril (Aceon), and lisinopril (Prinivil, Zestril).

Candidates. Experts believe that at least 50% to 75% of patients with congestive heart failure should be treated with ACE inhibitors.

• Studies have reported benefits in a wide range of heart failure patients, including those with less severe symptoms, patients with diabetes, the elderly, women, and individuals with or without coronary artery disease. (They may not be African Americans, however.)
• The drugs may improve outcomes in patients with risk factors for or evidence of impending heart failure but who have not yet developed symptoms.

Studies have indicated, however, that physicians (especially those who are not cardiologists) actually prescribe them for far fewer patients than is recommended. Women, for example, are less likely to get ACE inhibitors than Caucasian males. And when they are being prescribed, some studies indicate they are not prescribed in high enough doses to be most effective. Even worse, about 15% of patients were being prescribed expensive calcium-channel blockers, which may even be harmful for some patients with heart failure.

Side Effects of ACE Inhibitors. The primary adverse effect of ACE inhibitors is low blood pressure, which can be severe in some patients, particularly when therapy is first initiated.

The most distressing side effect is an irritating cough, which some people find intolerable. Interestingly, although all ACE inhibitors may have this side effect, sometimes switching to another brand will reduce this symptom. Iron supplements or the drug picotamide may prove to help reduce the frequency of coughs.

Severe side effects are rare and include the following:

• Although ACE inhibitors can protect against kidney disease, they also increase potassium retention in the kidneys. This increases the risk for cardiac arrest if potassium levels become too high. Because of this action, they are not generally given with potassium-sparing diuretics or potassium supplements.
• A rare but severe side effect that has been observed is called granulocytopenia, which is an extreme reduction in infection-fighting white blood cells.
• In rare cases (0.3%), patients suffer a sudden and severe allergic reaction called angioedema that causes swelling in the eyes and mouth and may close off the throat.

Note: Of great concern is research suggesting that aspirin (and other so-called NSAIDs) increases the risk for heart failure in patients taking ACE inhibitors. NSAIDs are commonly used by patients with heart disease to prevent heart attacks.

Beta Blockers

At one time, beta blockers were not used for most people with heart failure because these drugs reduce the pumping action of the heart in the short run. However, studies are now finding certain beta blockers may have significant benefits for heart failure patients, and in fact may be responsible for a dramatic drop in mortality rates in patients with severe heart failure. Specific beneficial actions for heart failure patients include the following:

• They have a proven track record for treating high blood pressure, angina, arrhythmias, and for prevention of heart attack in high-risk patients.
• Early use of beta blockers may even help prevent left ventricular remodeling, one of the damaging processes that leads to heart failure, in patients with idiopathic dilated cardiomyopathy and in those who suffered a first heart attack.
• These agents may also block important inflammatory immune factors called cytokines, including the one called tumor necrosis factor (TNF). TNF has been heavily implicated in the damage done during the process leading to heart failure.
• Beta blockers may prevent norepinephrine (adrenaline) from binding to heart cells. Elevated levels of norepinephrine, a stress hormone, can overstimulate the failing heart and are associated with severe heart failure.

It should be noted that for any significant benefits, beta blockers need to be used in combination with other agents, such as ACE inhibitors, diuretics, or both. The effects of beta blockers on certain populations, such as the elderly or African Americans, requires further study.

Beta Blocker Brands. Beta blockers are categorized as nonselective and selective (which are older agents).

• Carvedilol and Other Nonselective Beta Blockers. Carvedilol (Coreg) is known as a nonselective beta blocker and was the first approved beta blocker for heart failure patients.
• Long-acting Metoprolol and Selective Beta Blockers. Studies are finding that some older and less expensive beta blockers called selective beta blockers may also reduce mortality rates. Long-acting metoprolol (Lopressor) has not been specifically approved for patients with heart failure. Bisoprolol (Zebeta) is another selective beta blocker that might be beneficial in these patients. Atenolol (Tenormin) is the most commonly prescribed beta blocker in general, but its effect on heart failure is unknown.

Small studies comparing metoprolol with carvedilol report significant and similar improvement in both groups with lower survival rates from both drugs. Both drugs increase the distance that patients can walk to the same degree, although over time, heart efficiency may be greater in patients who take carvedilol. A major comparison study is underway.

Candidates. Experts now recommend beta blockers for all patients with stable heart failure and who do not have substantial fluid retention or recent worsening of heart failure that have required digoxin or digitalis.

Problems with Beta-Blockers and Patients who Should Avoid Beta Blockers. Because they can narrow bronchial airways and constrict blood vessels, patients with asthma, emphysema, and chronic bronchitis should use them with care and should use a selective drug. Other patients who may not be good candidates include people with brady-arrhythmias (very slow heart rate) or heart block who are not on a pacemaker and patients with diabetes who have frequent episodes of hypoglycemia.

Some beta-blockers tend to lower HDL cholesterol (the beneficial cholesterol) by about 10%; the effect is most marked in smokers.

Beta blockers must be carefully monitored and the dosages regulated very carefully, because heart failure may actually worsen in the early stages of treatment. Angina, heart attack, and even sudden death have occurred in patients who discontinued treatment without gradual withdrawal.

Common Side Effects. Fatigue and lethargy are the most common psychologic side effects. Some people experience vivid dreams and nightmares, depression, and memory loss. Dizziness and lightheadedness may occur upon standing. Exercise capacity may be reduced. Other side effects may include coldness in the extremities (legs and toes; arms and hands), asthma, decreased heart function, and gastrointestinal problems. Sexual dysfunction was a problem with older beta-blockers, but does not appear to be significant with newer agents.

If side effects become very distressing, the patient should call a physician, but it is extremely important not to stop the drug abruptly.

Diuretics

Diuretics act on the kidneys to rid the body of excess salt and water. These agents have been the mainstays of high blood pressure treatment. A landmark 2002 study reported that patients who take them have a lower incidence of heart failure, heart disease, and stroke after five to six years compared to those who took a calcium-channel blocker or an ACE inhibitor.

They have also long been used to relieve fluid retention, a hallmark of congestive heart failure, and aggressive use of diuretics, even in people taking ACE inhibitors, can reduce hospitalizations and improve exercise capacity. In addition, certain diuretics, notably spironolactone (Aldactone) block aldosterone, a hormone involved in the remodeling process of the heart, a primary mechanism in heart failure. This agent is proving to be beneficial for patients in late stages of heart failure.

Diuretic Types. Diuretics come in many brands and are generally inexpensive. Some need to be taken once a day, some twice a day. Diuretics are virtually always used in combination with other drugs. Three primary types of diuretics exist:

• Potassium-sparing agents. Potassium-sparing diuretics, especially spironolactone (Aldactone), are proving to be important for Stage C and D congestive heart failure. Spironolactone has shown dramatically lower mortality rates from heart events, particularly in combination with an ACE inhibitor. Its benefits for patients with heart failure derive from its ability to block aldosterone, a hormone involved with salt retention and heart muscle growth. Spironolactone has shown evidence of reducing production of collagen--a protein that in excess can cause organ scarring. Other potassium-sparing agents include amiloride (Midamor), and triamterene (Dyrenium).
• Thiazides. Thiazides often serve as the basis for high blood pressure treatment, either taken alone for mild to moderate hypertension or used in combination with other types of drugs. There are many thiazides and thiazide-related drugs. There are many thiazides and thiazide-related drugs; some common ones are chlorothiazide (Diuril), chlorthalidone (Hygroton), indapamide (Lozol), and hydrochlorothiazide (Esidrix, HydroDiuril). These agents are usually prescribed for patients with mild heart failure and good kidney functioning.
• Loop diuretics. Loop diuretics block sodium transport in parts of the kidney; they act faster than thiazides and have a great diuretic effect. It is important therefore to control the medication and avoid dehydration and potassium loss. Loop diuretics include bumetanide (Bumex), furosemide (Lasix), and ethacrynic acid (Edecrin). They are generally used for severe heart failure, especially when kidney function is impaired. One 2000 study reported that twice-daily infusions of furosemide over six to 12 days improved symptoms in patients with severe heart failure who had not responded to other treatments. One-year survival rates after the treatment were 80%.

Administration. Treatment is usually started at a low dose and increased until urine output rises and the patient loses weight because of fluid loss. If the patient does not respond quickly enough, more than one diuretic may be required, or it may need to be given intravenously. Diuretics are usually taken long term, with the patient monitored periodically for fluid retention.

Problems with Diuretics. The loop and thiazide diuretics deplete the body's supply of potassium, which, if left untreated, increases the risk for arrhythmias. Arrhythmias are heart rhythm disturbances that can, in rare instances, lead to cardiac arrest. In such cases, physicians will either prescribe lower doses of the current diuretic, recommend potassium supplements, or use potassium-sparing diuretics either alone or in combination with a thiazide. Potassium-sparing drugs have their own risks, which include dangerously high levels of potassium in people with existing elevated levels of potassium or in those with damaged kidneys. It should be noted, however, that, in general, all diuretics are more beneficial than harmful.

Common Side Effects. Common side effects of diuretics are fatigue, depression, irritability, urinary incontinence, loss of sexual drive, breast swelling in men, and allergic reactions. Diuretics can trigger attacks of gout. They may also increase the risk of gastrointestinal (GI) bleeding. Diuretics may raise cholesterol level and, used alone, they have no effect on enlarged heart size (hypertrophy). Arrhythmias can also occur as an interaction between diuretics and certain drugs, including some antidepressants, anti-arrhythmic drugs themselves, and digitalis.

Digitalis

Digitalis is derived from the foxglove plant. It has been used to treat heart disease since the 1700s. Digoxin (Lanoxin) is the most commonly prescribed digitalis preparation. It is referred to as an inotropic drug and has the following benefits:

• It increases the strength of the hearts contraction.
• It decreases heart size.
• It reduces certain heart rhythm disturbances (arrhythmias).
• It allays symptoms and reduces the need for hospitalizations slightly.

Unfortunately, digitalis does not reduce mortality rates, although it does reduce hospitalizations and worsening of heart failure. Controversy has been ongoing for more than 100 years over whether the benefits of digitalis outweigh its risks and adverse effects.

Candidates. Digitalis may be useful for the following patients:

• Patients with left-side (systolic) dysfunction who do not respond to other agents (diuretics, ACE inhibitors).
• Heart failure patients with atrial fibrillation.

Digitalis may be harmful in the following patients:

• Patients with right-side heart failure.
• Patients who stop taking digoxin after using it in combination with ACE inhibitors are at risk for worsening heart failure.

Side Effects and Problems. While digitalis is generally a safe drug, it can have toxic side effects caused by overdose or other accompanying conditions. The most serious side effects are arrhythmias (abnormal heart rhythms that can be life-threatening). Early signs of toxicity may be irregular heartbeat, nausea and vomiting, stomach pain, fatigue, visual disturbances (e.g., yellow vision, seeing halos around lights, flickering or flashing of lights), and emotional and mental disturbances.

Factors that increase the risk of toxicity include the following:

• Advanced age.
• Low blood potassium levels (which can be caused by diuretics).
• Hypothyroidism.
• Anemia.
• Valvular heart disease.
• Impaired kidney function.
• Digitalis interacts with many other drugs, including quinidine, amiodarone, verapamil, flecainide, amiloride, and propafenone.

Using a blood test to monitor drug levels limits toxicity to about 2% of patients taking the drug. For most patients with mild to moderate heart failure, low-dose digoxin may be as effective as higher doses. If side effects are mild, patients should still consider continuing with digitalis if they experience other benefits.

Vasodilators: Hydralazine and Nitrates

Vasodilators improve both the quality and duration of life for heart failure patients. They open the arteries and veins, thereby reducing the hearts workload and allowing more blood to reach the tissues. A combination of two vasodilators, hydralazine (e.g., Apresoline, Alazine) and isosorbide dinitrate (e.g., Iso-Bid, Isorbid, Dilatrate), improves symptoms and may prolong life. Combinations are more effective than either drug used alone and are recommended when patients cannot tolerate ACE inhibitors. They may have particular benefits for African-American patients.

Intravenous nitroglycerin (Nitro-Bid Iv, Nitrostat IV, Tridil) and intravenous nitroprusside (Nitropress) are useful in short-term therapy of acute heart failure and acute pulmonary edema. Intravenous nitroglycerin tends to lose effectiveness quickly, but one study showed that patients who were also given oral hydralazine continued to tolerate this drug.

Other Agents Sometimes Used

Angiotensin-Receptor Blockers. Drugs known as angiotensin-receptor blockers (ARBs), also known as angiotensin II receptor antagonists, are similar to ACE inhibitors in their ability to lower blood pressure. They may have fewer or less-severe side effects than ACE inhibitors, especially coughing. The ARBs include valsartan (Diovan), losartan (Cozaar), candesartan (Atacand), telmisartan (Micardis), and irbesartan (Audpro). Studies are reporting benefits, including improvements in both symptoms and survival. Although it is not clear whether they are any better than the less expensive ACE inhibitors, evidence is accumulating to indicate that they may reasonable alternatives to ACE inhibitors. At this time, valsartan is the only ARB approved as an alternative to ACE inhibitors for heart failure patients.

Calcium-Channel Blockers. Calcium works on heart muscle and on blood vessels to affect blood pressure and the heart muscles ability to contract. Calcium-channel blockers are commonly used to control high blood pressure and angina. Unfortunately, they are currently over-prescribed for patients with heart failure. A major study reported that they were not as effective as a diuretic in preventing heart failure. Certain calcium-channel blockers may in fact, worsen heart failure; these include nifedipine, diltiazem, and verapamil. Newer generation calcium-channel blockers may have some benefits. Lercanidipine, for example, is a unique CCP that may be effective and safe for a wider range of patients than with other CCBs and may have properties that protect against heart failure.

Drugs Used to Treat Arial Fibrillation. Drugs used to treat irregular heart beats (arrhythmias), which are a particular danger for congestive heart patients, have not been very successful in prolonging survival when used as part of the treatment regimen for congestive heart failure. Exceptions are two drugs, amiodarone (Cordarone) and dofetilide (Tikosyn) used for atrial fibrillation, an important cause of arrhythmias in heart failure patients. Studies on amiodarone have reported improved mortality rates in patients with severe heart failure and atrial fibrillation. A combination of amiodarone with a pacemaker-type device (called cardioversion) may even restore normal heartbeats in such patients, even in heart failure patients with atrial fibrillation who are in poor health.

Drugs Used to Improve Lung Function

Ipratropium. Ipratropium (Atrovent), a drug normally used by asthma patients, was tested in a small study of smokers and nonsmokers with congestive heart failure for improving lung function. Breathing improved in all patients who were administered four puffs of the drug using an inhaler. The drug has no known adverse effects on the heart, and there were no other side effects in this group. More studies are needed.

Theophylline. Theophylline, also an asthma drug, was found to improve oxygen levels and lung function in heart failure patients who also experienced central sleep apnea, the disordered breathing syndrome associated with left-side heart failure.

Drugs Used for Decompensated Heart Failure and Pulmonary Edema

Treating Decompensated Heart Failure. Decompensated heart failure is a life-threatening condition in which the heart fails over the course of minutes or a few days, often as the result of a heart attack or sudden and severe heart valve problems. Agents used for this emergency situation include intravenous diuretics, dobutamine, milrinone, nitroglycerin, and sodium nitroprusside. A genetically engineered natriuretic peptide called nesiritide (Natrecor) is proving to be particularly effective. Agents under investigation, such as levosimendan, a unique drug called a calcium sensitizer, may prove to be beneficial additions.

Treating Pulmonary Edema. Treatment of pulmonary edema (fluid in the lungs), another life-threatening emergency, sometimes requires intravenous injections of vessel-widening nitrates (nitroglycerin and nitroprusside). Newer classes of drugs currently being investigated for decompensated heart failure, such as natriuretic peptides and calcium sensitizers, are also under study for pulmonary edema.

Experimental Agents

A number of new agents are being tested for heart failure patients. A 2001 study suggested that 70% of patients who participate in such trials may feel better, whether or not their drug is objectively effective. To date, studies have been modest or disappointing on certain agents that appear to have specific actions that block the disease process leading to heart disease. They include omapatrilat, etanercept (a cytokine blocker), endothelin receptor blockers, and arginine-vasopressin antagonists.

Aldosterone Blockers. Aldosterone is a hormone that is critical in regulating the body's balance of salt and water. Excessive levels may play important roles in hypertension and heart failure. Additional agents that block this hormone are being developed. Eplerenone (Inspra) is the first to be approved. Its actions are similar to potassium-sparing diuretics, and like these agents, it poses some risk for high potassium levels, which in some cases can be dangerous.

Neutral Endopeptidase Inhibitors (NEPs). Neutral endopeptidase inhibitors (NEPs) combine the activity of ACE inhibitors with actions that produce higher levels of an enzyme called atrial natriuretic peptide. The effects of atrial natriuretic peptide are the following:

• It opens blood vessels.
• Induces fluid elimination.
• Opposes the actions of the compensating systems responsible for ongoing damage of the failing heart.

NEPs under investigation include omapatrilat (Vanlev), candoxatril, and ecadotril. Preliminary studies of omapatrilat, however, are reporting little advantages compared to ACE inhibitors in patients with heart failure. Side effects are very similar to those of ACE inhibitors, including coughing.

Statins. Statins are important drugs used to lower cholesterol and to prevent heart disease leading to heart failure, even in people with normal cholesterol levels. Specific statins include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), luvastatin (Lescol)and atorvastatin (Lipitor). They are proving to have many other health benefits as well. Some evidence suggests the have properties that may benefit patients with congestive heart failure.

Testosterone Injections. Small studies suggest that testosterone injections (anabolic therapy) in elderly men with existing heart failure may be helpful in increasing heart output and relieving depression.

Allopurinal. Allopurinal, a standard agent for gout, may prove to have properties that help patients with congestive heart failure. The drug blocks the xanthine oxidase (XO), which may improve blood flow and heart muscle efficiency in patients with hyperuricemia (high blood levels of uric acid). Hyperuricemia is common in heart failure.