Familiar Blood Pressure Drugs Find an Array of Novel Uses
By: Mary
Duenwald
NY Times, June 25, 2002
Dr.
Marc A. Pfeffer found added benefits for a hypertension drug.
For 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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