Turning to Drugs for Heart Failure
While there have been setbacks in recent research, drugs remain the most common effective heart-failure treatment.
Reviewed By Michael Smith
Heart failure remains a serious and incurable disease, but heart-failure treatment with medications has been a tremendous success story. "I think that the drugs we've used have made an enormous impact on people with heart failure ," says Marvin A. Konstam, MD, chief of cardiology and director of cardiovascular development at Tufts-New England Medical Center. "That's something we shouldn't lose sight of."
Research into heart-failure treatment with drugs has suffered a few setbacks in recent years, as medications considered to have great potential did not prove as effective as hoped. Implantable devices like defibrillators, LVADs, and biventricular pacers are also generating a great deal of excitement as new ways to treat the condition.
But given the novelty and expense of implantable devices, it's likely that heart-failure treatment for most people will consist of drugs alone in the near future, according to Michael R. Bristow, MD, PhD, from the University of Colorado Health Sciences Center. The good news is that standard drugs for heart-failure treatment are effective and new ones are under development.
Heart-failure treatment with medication depends on a person's condition, whether you suffer from the more common systolic heart failure -- in which the heart has difficulty pumping -- or the rarer diastolic heart failure -- in which the heart is stiff and has trouble expanding to fill with blood.
Both conditions are helped by angiotensin-converting enzyme inhibitors (ACE inhibitors), which in the last decade have become the linchpin of heart-failure treatment. The success of ACE inhibitors in reducing sickness and death from heart failure demonstrated the significant role that hormones play in worsening heart failure and changed the focus of heart-failure treatment.
Some of the body's natural responses to a failing heart actually cause the condition to worsen. One is the body's release of hormones that constrict the blood vessels, making it harder for the weakened heart to pump blood. ACE inhibitors and other similar drugs block the effects of these hormones and widen the vessels, easing the heart's workload.
Beta-blockers are another prominent heart-failure treatment. In addition to lowering blood pressure and decreasing heart rate, these drugs also lessen the effects of the hormones that result from heart failure. Beta-blockers are tremendously useful drugs, resulting in almost a 50% reduction in the risk of death in people with heart failure.
Another common drug used in heart-failure treatment is diuretics, which help remove water and sodium from the blood. Still another drug, digoxin, is sometimes used to slow irregular heartbeats and increase the force of the heart's contractions. Depending on your condition, other medications may be necessary.
A possible substitute for people who cannot tolerate ACE inhibitors are angiotensin II receptor blockers (ARBs), which, like ACE inhibitors, affect the hormonal balance. Jay N. Cohn, MD, professor in the cardiovascular division at the University of Minnesota Medical School, led a major study of the ARB Diovan. He tells WebMD that he does not see ARBs as only a substitute for ACE inhibitors, but as a drug that can be used in combination with them when beta-blockers are not used. However, experts agree that ACE inhibitors, ARBs, and beta-blockers should not be taken together.
Some are less sure about the use of ARBs. "The ARBs should not, in my opinion, be routinely substituted for ACE Inhibitors," says Konstam. "Although they're linked by a common effect, they are different classes of drugs. While they look like they may be effective, for now they should be considered as second line treatment for heart failure."
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Some of the most significant breakthroughs in drugs for heart-failure treatment have come from the aldosterone blockers, such as Aldactone (spironolactone), and more recently, Inspra. Like ACE inhibitors, these drugs work by affecting the hormones in the bloodstream, in this case, aldosterone, which can cause the retention of salt and water and other ill effects.
While Aldactone can have some unpleasant side effects -- such as impotence and gynecomastia (breast swelling in men) -- Inspra does not cause them. Both drugs can cause an increase in potassium levels, so patients need to be monitored. One significant difference between the drugs is price: Aldactone, having been around for decades as a high blood-pressure drug, is significantly cheaper than Inspra, which was approved in September 2002.
Bertram Pitt, MD, who has led major studies of both of these drugs for heart-failure treatment believes Aldactone may still be the best drug for those who aren't concerned about side effects. But for some, side effects are an important issue.
While the reduction in side effects is important, the greater significance of the study, according to Pitt, is that it demonstrates the importance of blocking aldosterone. The most recent study testing Inspra is the second that shows aldosterone blockade makes a difference, Pitt tells WebMD. "There were a lot of people on the fence before, and I think this study will lead to more clinical investigation."
More study of Inspra is needed since this drug has largely been studied in people who had suffered from a recent heart attack and not heart failure. But the results are exciting for people with heart failure, according to Konstam. "In the last 10 years of drug therapy, there have been three big stories," he says. "First were the ACE Inhibitors, then the beta-blockers in the mid-90s, and now the aldosterone [blockers]."
Aggressive Heart-Failure Treatment
Experts are consistently stressing the importance of treating heart failure aggressively.
If you look at the heart-failure trials over the last 15 years, combining ACE inhibitors, and beta-blockers with devices used in heart-failure treatment, the rate of death has dropped 68%, says Bristow. "That's spectacular progress."
"But that's only progress in clinical trials," Bristow tells WebMD. "The problem is that these effective treatments are not getting out to the community. There continue to be only about 50% to 60% of patients who should be on ACE inhibitors who are actually on them, and 30% to 40% of the people who should be using beta-blockers who are actually are."
Part of the problem is that beta-blockers can cause side effects and getting the right dosage can be difficult. As a result, doctors may be reluctant to prescribe them.
"Side effects can be problematic with beta-blockers since they can actually make you feel worse," says Susan Bennett, RN, DNS, an Indiana University nursing school professor.
Still, experts generally agree that heart-failure treatment has become more aggressive in recent years as the message has gotten to physicians. "Sure, there's always room for improvement," says Konstam. "But I see positive trends in the speed with which clinicians respond to new treatment information."
The Bulging Medicine Cabinet
A potential problem with the success of drugs for heart-failure treatment is that it means the number of drugs that people are taking has increased. When new drugs are developed, they are typically not compared in head-to-head studies with old drugs. As a result, old drugs don't get replaced; instead, the new drugs are often added to existing heart-failure treatment. This can add up to a lot of pills to swallow. The greater the number of pills, of course, the harder it becomes to stick to a drug regimen.
"This can be a real problem," says Bennett. "A lot of these patients are elderly, they don't feel well, and they may not be able to see well. Following a complicated drug regimen can be hard for them."
"We're facing an era when patients are going to be taking multiple drugs and perhaps even have devices too," Cohn tells WebMD. "We're making therapy very complicated."
But while Pitt agrees that additional medicines may complicate heart-failure treatment, he feels that complexity is the cost of progress. "If I can show you that I'm adding a benefit to [death and sickness] with another drug, I'm not going to apologize for that," he says. He also observes that drug cocktails have become common in the treatment of other diseases, such as cancer.
Hitting the Wall?
Drug research has had some setbacks in recent years. "One of the things that's clearly happened in the last few years is that we hit the wall with drug therapy," says Bristow. "The last six or so trials of promising drugs have been negative."
Konstam agrees. We've had some disappointments in recent years from some drugs that held a lot of promise in heart-failure treatment, he says.
Although the synthetic hormone Natrecor -- which mimics the effects of natriuretic peptide, a hormone that dilates the blood vessels -- has received some attention, its usefulness is unclear.
"I don't think that Natrecor represents a breakthrough in management," says Cohn. "I know many physicians who don't quite see why it's any better than the traditional, less expensive drugs that we currently have that do the same thing." For now, Natrecor is only administered intravenously in the hospital.
Drugs have been so successful in heart-failure treatment that some experts worry that attempts to improve it much more will be tricky. "I think that the development of ACE inhibitors and ARBs and beta-blockers, when they're used and combined, that we've reduced the risk of death dramatically," says Cohn. "I think attempts to lower it further are going to be difficult."
The Future of Drug Treatment
But the significance of these failures is the subject of some debate among heart-failure experts.
"I think our vision is very short," says Pitt. "A lot of people ... were saying that we had exhausted the potential of neurohormonal blockade and that ACE inhibitors and beta-blockers were as good as we could get. That wasn't true."
Pitt sees potential in other drugs used to affect hormonal levels, including statins, which are used to treat high cholesterol. Some of the hormonal drugs that have had disappointing results in trials are also being studied further.
Other drug studies are focusing on the possibilities of more effectively treating diastolic dysfunction, which is often overshadowed by the more common systolic dysfunction. Researchers and doctors have only recently begun to truly understand diastolic dysfunction -- which occurs when the heart loses its ability to relax and fill with blood.
"There are a number of approaches that are in the early stages of testing and we're just going to have to wait and see," Pitt says. "But I suspect that over the next few years, we're going to find more and more effective drugs."
And despite the setbacks, there is still great reason to be optimistic about the effectiveness of drugs in heart-failure treatment.
"If you look at the big picture in the last 12 years, we've made enormous progress in treating heart failure," says Konstam. "Back then, we didn't really know if we could improve the outcome of the disease. Today, I have many patients in my practice who -- while they're not cured -- are cured from a functional perspective. We couldn't even imagine that not too many years ago."
Originally published May 2003.
Medically updated Sept. 30, 2004.
SOURCES: Susan J. Bennett, DNS, RN, Professor in the School of Nursing, Indiana University, Indianapolis; affiliated scientist, Indiana University Center for Aging Research. Michael R. Bristow, MD, PhD, University of Colorado Health Sciences Center, Denver, Colorado; co-chair of the COMPANION study. Jay N. Cohn, MD, Professor, Cardiovascular Division in the Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; past president of the Heart Failure Society of America. Marvin A. Konstam, MD, Chief of Cardiology, New England Medical Center; Director of Cardiovascular Development, Tufts-New England Medical Center; President of the Heart Failure Society of America. Bertram Pitt, MD, Professor of Internal Medicine, University of Michigan; Principal Investigator for EPHESUS and RALES trials. Eric A. Rose, MD, Chairman of the Department of Surgery, Columbia University College of Physicians and Surgeons; Surgeon-in-Chief, Columbia Presbyterian Medical Center, New York-Presbyterian Hospital; principal investigator for REMATCH trial. John Watson, MD, Director of the Clinical and Molecular Medicine Program in the National Heart, Lung and Blood Institute's Division of Heart and Vascular Diseases; project officer for the REMATCH trial.
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