BIRMINGHAM, U.K. -- One-time use of a drug that stops clots from forming
has significantly reduced life-threatening complications from angioplasty
both immediately and up to three years after treatment, researchers from
The Cleveland Clinic Foundation and Duke University Medical Center reported
Monday.
New data from two clinical trials that tested the value of a monoclonal
antibody called ReoPro were prepared for presentation at scientific sessions
this week at the annual European Society of Cardiology meeting in Birmingham,
United Kingdom.
The findings in the trial called EPILOG (Evaluation in PTCA to Improve Long-term
Outcome with ReoPro GP IIb/IIIa blockage) show that one-month after treatment,
overall death, recurrent heart attacks and urgent repeat angioplasty or
by-pass surgery were reduced by up to 59 percent in all patients who were
treated with an injection and 12 hours of infusion of ReoPro, compared to
patients who didn't receive the drug.
The 30-day data also demonstrated that for every 1,000 patients who received
ReoPro at the time of their angioplasty, 50 fewer patients suffered heart
attacks, 36 fewer needed follow-up, emergency angioplasties or by-pass surgery,
and five more people were alive compared to 1,000 patients who did not receive
ReoPro.
Data from the trial called EPIC (Evaluation of c7E3 for Prevention of Ischemic
Complications), which followed high-risk patients for years after angioplasty,
found that after three years, there were 100 fewer cases of repeat procedures
(angioplasty or by-pass surgery) among those who received ReoPro. Furthermore,
there was a 60 percent reduction in mortality in EPIC patients who had suffered
from acute heart attacks or unstable angina at the time of their angioplasty.
"These findings are highly promising; a new way to make angioplasty
a safer and more lasting treatment for heart disease," said Dr. Eric
J. Topol, chairman of the department of cardiology at The Cleveland Clinic
Foundation. Topol and Dr. Robert Califf, director of the Duke Clinical Research
Institute, were co-leaders for the studies.
Both trials were double-blinded, placebo-controlled and randomized. EPIC
enrolled 2,099 high-risk patients at 56 hospitals in the United States.
In EPILOG, 2,792 patients at varied risks were studied at 69 hospitals in
the United States and Canada.
Angioplasty is an increasingly popular technique to relieve the plaque blockages
that clog arteries around the heart. More than 800,000 patients worldwide
are annually treated with the procedure, which uses a small balloon to open
blocked vessels. However, new blockages in the form of blood clots quickly
occur in up to 10 percent of patients, resulting in an increased risk of
death from a heart attack. Such blockages often require an emergency heart
bypass operation or another angioplasty procedure.
Because substantial numbers of patients treated with ReoPro will not have
to return to the hospital for such complications, the researchers said they
believe that the price of the drug-- more than $1,000 per treatment in the
United States -- will provide an ultimate savings to society in the cost
of treating heart disease.
Califf called the study a "milestone in heart research." After
the first study, EPIC, found that the combination of ReoPro and high-doses
of the blood thinner heparin was significantly beneficial in preventing
new clots but caused excess bleeding in some high-risk patients, scientists
went back to the drawing board, and designed EPILOG as a follow-up study.
EPILOG showed that the same use of ReoPro, but combined with lower doses
of heparin, was much more effective in protecting patients from both recurrent
clots and bleeding. The beneficial effect was so substantial that an independent
committee of experts monitoring the study stopped the trial early.
"We were able to take an experimental drug that appeared very promising
but had drawbacks in its first trial because of bleeding, and tailor the
treatment and study it again," Califf said. "The result is that
we now have a proven therapy that I think should be routinely used with
most angioplasty procedures.
"This is a wonderfully protective drug that heralds a new era for angioplasty
in which better devices, such as stents, and drugs are used in combination."
Califf said. "Amazingly, the benefit of its use just gets stronger
as time passes. It seems not only to stop the initial formation of clots,
but also prevents the recurrence of blockage in the vessel months or years
later."
The EPIC study was funded by Centocor Inc., of Malvern, Pa., which manufactures
ReoPro. EPILOG was funded by both Centocor and Eli Lilly and Co., of Indianapolis,
Ind., which markets the drug.
The presentation in Europe was the first presentation of complete data on
both studies. Initial and six-month results on the 2,099 EPIC patients were
published in the April 7, 1994, issue of the New England Journal of Medicine
and on April 9, 1994, in The Lancet. A report in the August 15, 1996, issue
of Circulation, using the six-month data from EPIC, found that while the
drug reduces short and long-term complications, it cost the health care
system no more than standard treatment.
The new EPIC data showed that the number of complications -- heart attacks,
repeat angioplasty and death -- that were prevented by using ReoPro remains
significantly high through the three years these high-risk patients have
been followed, researchers said. At 6 months, 23 percent of complications
were prevented, compared to 20 percent after one year, 14 percent after
two years, and 13 percent after three years.
Initial results of EPILOG, presented in March at the annual meeting of the
American College of Cardiology, showed that in 1,500 patients studied, there
was a relative decrease of 68 percent in death and heart attack among patients
who were treated with ReoPro. That is almost twice the benefit shown in
the EPIC study, which included only high-risk patients. Importantly, the
risk of bleeding was significantly reduced in these patients, according
to Topol.
Complete results from all 2,792 patients now show that there was a 70 percent
reduction in complications for patients who used low doses of heparin, and
a 50 percent reduction in those who were treated with higher doses of heparin.
This proves that ReoPro works best when combined with lower doses of heparin,
Califf said.
ReoPro is the first monoclonal antibody approved by the U.S. Food and Drug
Administration that can be used as an active disease treatment therapy,
Califf said. Also known in its experimental form as c7E3 Fab, it is derived
from mouse and human immune cells.
ReoPro works by sticking to a receptor on platelets like a key fits into
a lock. This receptor, called the glycoprotein IIb/IIIa receptor, normally
binds to "adhesion molecules" such as fibrinogen, which forms
bridges with other platelet cells, producing a clot. ReoPro is an antibody
molecule that plugs itself into the receptor, taking the place of the adhesion
molecule.