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http://www.nytimes.com/2002/06/25/health/25ACE.html?tntemail0

Familiar Blood Pressure Drugs Find an Array of Novel Uses

By MARY DUENWALD

or 20 years, doctors have used ACE inhibitors to control blood pressure in heart patients. But now it is becoming increasingly clear that these drugs — with names like ramipril and capoten — can do much more than merely relax the arteries, allowing blood to flow more freely.

Results of the newest studies of ACE (angiotensin converting enzyme) inhibitors, and of newer drugs known as A.R.B.'s (angiotensin receptor blockers), which work in a similar way — have shown that they can prevent heart attack, stroke and even new cases of diabetes in a variety of patients. ACE inhibitors appear also to be able to slow muscle decline in the elderly. The drugs' ability to provide all these benefits, doctors say, extends beyond their effect on blood pressure.

It is a story reminiscent of the history of aspirin, a drug that began life as a mere pain reliever and turned out to be able to help prevent heart attacks and strokes, said Dr. Salim Yusuf, director of cardiology at McMaster University in Hamilton, Ontario.

"We're at the same place with ACE inhibitors that we were with aspirin 10 to 15 years ago," he said. "We're finding that blood pressure lowering is only part of the story. We're finding that they have many mechanisms of action that are protective against cardiovascular disease."

This new understanding means, first of all, that the drugs will be coming into wider use. The American Heart Association has recently urged physicians to consider using ACE inhibitors to treat a wider population of heart attack survivors, diabetics and patients with other cardiovascular risk factors.

But the discovery that these drugs have such diverse benefits is also enhancing understanding of heart disease and diabetes. Scientists are beginning to see how one of the body's own proteins, angiotensin, the hormone that both ACE inhibitors and A.R.B.'s interfere with, can play a significant role in promoting chronic diseases. It is a story in which a substance apparently designed by natural selection to help people survive in the short term turns out to do damage over the course of many years to the arteries, the heart and other organs.

Angiotensin is a part of a cascade of proteins that the body produces when it senses that blood pressure is too low — as it would in the case of a severely bleeding injury or extreme diarrhea. It constricts the blood vessels, preventing the loss of too much blood and fluid. It is an important mechanism, but one that is possible to live without in modern times, when people no longer stand a high risk of such injury.

"When people were running from saber-toothed tigers and had no ability to stitch up a cut, angiotensin was very important," said Dr. Richard B. Devereux, professor of medicine at Weill Medical College of Cornell University. "If you're safe from such things, then it seems like you can pretty well do away with angiotensin, in adults, and not do any harm."

Doctors are finding that the damage angiotensin itself can do over the long term is considerable. In addition to raising blood pressure, it promotes the buildup of plaques in the arteries, helps instigate the rupture of those plaques, encourages blood clotting and increases the degree to which the heart muscle enlarges after a heart attack. The mechanisms of its action are unclear and are the focus of studies in laboratory animals. But some scientists suspect that angiotensin may work some of its damage by causing inflammation.

"There is good evidence that angiotensin not only causes inflammation, but it also increases the expression of other agents, such as interleukin-6, that cause inflammation," said Dr. Peter Libby, chief of cardiovascular medicine at Brigham and Women's Hospital in Boston.

ACE inhibitors block the enzyme that creates angiotensin II, the most active form of the substance. And A.R.B.'s — drugs like losartan and valsartan — prevent angiotensin from attaching to receptors on cell surfaces. The receptor blockers are newer, having come on the market in 1995. They are preferable, doctors say, for the 15 to 30 percent of patients who develop side effects from ACE inhibitors, mainly a persistent and sometimes intolerable cough. But ACE inhibitors, because they are older, are more familiar and can be less expensive.

Almost from the earliest use of ACE inhibitors, certain scientists suspected they could do more than relax the blood vessels. Studies in laboratory rats and humans, in the 1970's and 1980's, showed that the drugs could also reduce the heart muscle enlargement that typically happens after a heart attack. ACE inhibitors, these studies showed, reduced the degree of heart remodeling, and this decreased the risk of heart failure and prolonged survival time.

"Fewer people died," Dr. Marc A. Pfeffer, co-chief of medicine at the Veterans Administration Boston Health Care System, said about a trial of ACE inhibitors in heart attack survivors, which he directed a decade ago. "But also, fewer had second heart attacks. That was surprising and very exciting."

Dr. Yusuf and colleagues began the Heart Outcomes Prevention Evaluation, or HOPE, trial in the mid-1990's to look closer at ACE inhibitors' ability to prevent heart attacks. They gave the ACE inhibitor ramipril (brand name Altace) to more than 4,600 people, 55 years or older, who were found to be at risk of heart disease and stroke. The ramipril treatment significantly lowered the rates of heart attack, and it also reduced the risk of stroke. And surprisingly, the ramipril-treated patients developed significantly fewer new cases of diabetes.

Because most of the patients did not have high blood pressure to begin with, and because in the five-year course of the study their readings were reduced only a little, it appeared that the benefits could not be explained by ramipril's effect on blood pressure.

Some doctors remained skeptical about this assertion, however, because blood pressure was not a focus of the HOPE trial.

But then came the results of another trial, called LIFE, reported in The Lancet in March. In this study, all 9,200 subjects began with high blood pressure. Doctors tried to normalize their pressure readings with the A.R.B. losartan (brand name Cozaar) or with standard diuretics. After four and a half years, the losartan-treated patients had a 13 percent lower risk of death from all causes. Their risk of stroke dropped by 25 percent. When the researchers looked more specifically at the subjects who were found to have diabetes, the reduction in mortality risk was even greater, nearly 40 percent.

Dr. Devereux, one of the researchers in the LIFE trial, said: "It's the first time it's been shown that a drug can do even better in preventing cardiovascular disease than you would expect from getting blood pressure under control."

Some researchers remain skeptical of the drugs' ability to act beyond their effect on blood pressure. Dr. Michael O'Rourke, a cardiologist at St. Vincent's Hospital in Sydney, Australia, said that in the studies so far, researchers have used standard blood pressure cuffs, which measure blood pressure only in the arm. Dr. O'Rourke has developed a newer method of determining blood pressure in the heart, and he has found that ACE inhibitors and A.R.B.'s cause a more drastic effect in the heart — an effect great enough, he said, to explain all the drugs' cardiovascular benefits.

"People don't die because blood pressure is high in their arm," Dr. O'Rourke said. "They die because of high pressure in the carotid arteries, coronary arteries and left ventricle. The researchers were not measuring blood pressure in the right place. We believe that what happens with ACE inhibitors and A.R.B.'s is largely if not entirely a blood pressure lowering effect."

The HOPE and the LIFE trials showed a benefit in blocking angiotensin in diabetics. Diabetes and heart disease are closely related. People who have high blood pressure have a risk of developing adult-onset diabetes two to three times as great as average, said Dr. James R. Sowers of the State University of New York Health Science Center in Brooklyn. People with diabetes stand a risk two to four times as great as average of developing cardiovascular disease. Four of five diabetics die of cardiovascular disease.

Angiotensin now looks to be an important part of the connection between the two conditions. Diabetics have high levels of angiotensin, which sets them up for cardiovascular and metabolic problems, Dr. Sowers said. "One of the things angiotensin does is interfere with insulin's normal metabolic signaling, and that may contribute to increased insulin resistance," he said.

Evidence that angiotensin also plays a role in muscle decline in older people is just beginning to come in. In a recent study conducted at Wake Forest University Baptist Medical Center, 641 women age 65 and older with high blood pressure were put on an exercise program for one year. Those who were taking ACE inhibitors regularly were able to walk farther and lift more weight than those who were not.

Skeletal muscle cells, said Dr. Marco Pahor, chief of geriatric medicine at Wake Forest, have receptors for angiotensin. It appears, he added, that angiotensin somehow reduces muscle efficiency, perhaps by causing inflammation.

Already, many cardiologists are expanding their use of ACE inhibitors and A.R.B.'s, but Dr. Sidney C. Smith, a professor of medicine at the University of North Carolina and the chief science officer of the American Heart Association, said not everyone had gotten the message.

"I think the HOPE trial has had a major impact on physicians' decisions to use ACE inhibitors," he said. "Yet still more than a third of patients who might be candidates for ACE inhibitor therapy after a heart attack do not receive the medications at the time of discharge from the hospital."

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