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
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.