Centocor ReoPro plus low-dose heparin reduces angioplasty complications 70% -- EPILOG final data.

CENTOCOR REOPRO PLUS LOW-DOSE HEPARIN REDUCES ANGIOPLASTY COMPLICATIONS by 70%, investigators reported at the annual European Society of Cardiology meeting in Birmingham, England the week of Aug. 23. The Evaluation in PTCA to Improve Long-term Outcome with ReoPro GP IIb/IIIa blockage, or EPILOG, study randomized ReoPro patients to low-dose or high-dose heparin.

"There was a 70% reduction in complications for patients who used low doses of heparin, and a 50% reduction in those who were treated with higher doses of heparin," investigators Eric Topol, MD, Cleveland Clinic Foundation, and Robert Califf, MD, Duke University Clinical Research Institute, concluded.

EPILOG patients were randomized to three arms: placebo plus standard (high-dose) heparin, ReoPro plus high-dose heparin, and ReoPro plus low-dose heparin. Low-dose heparin patients received a 70 units/kg bolus; high-dose patients received a bolus of 100 units/kg. Low-dose patients were titrated to a lower ACT target as well. An average low dose of heparin would include about 5,000 units, compared to an average of around 10,000 units at high-dose levels.

The researchers presented final results of EPILOG and the Evaluation of c7E3 for Prevention of Ischemic Complication, or EPIC, study. EPILOG was halted in December 1995 due to efficacy after review of initial results from 1,500 patients ("The Pink Sheet" Dec. 18, 1995, In Brief). EPILOG was to have enrolled 4,800 patients; by the time the trial was halted, 2,792 patients had been treated at 69 U.S. and Canadian hospitals.

EPILOG was a follow-up study to EPIC to determine if lower doses of heparin could prevent the excess bleeding seen in some high-risk patients in EPIC. EPILOG also enrolled a broader range of patients: while EPIC focused on high-risk patients, EPILOG enrolled patients regardless of risk factors. Based on EPIC, ReoPro was approved Dec. 22, 1994 for reduction of acute cardiac ischemic complications in patients undergoing angioplasty at high-risk for abrupt artery closure. Lilly markets the drug.

EPILOG tracked two bleeding endpoints: any major bleed and non-CABG major bleed. In the final analysis of EPILOG data, patients on placebo plus high-dose heparin had a 3.1% rate of any major bleed and a 1.1% rate of non-CABG major bleed. ReoPro plus high-dose heparin had a 3.5% rate of any bleeding and a 1.9% rate of non-CABG bleeding. ReoPro plus low-dose heparin had a 2% rate of major bleeds and 1.1% rate of non-CABG bleeds, Centocor said.

"Bleeding events, the primary side effect from the EPIC trial, may be reduced by early sheath removal and early discontinuation of heparin, weight-adjusted heparin dosing, weight-adjusted ReoPro infusions for patients less than 80 kg and improved patient access site management," Centocor said, summarizing the recommendations made in a February "Dear Doctor" letter discussing the safety results from the recently-discontinued study.

Long-term follow up of the 2,099 high-risk EPIC patients "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" of follow-up, the researchers reported. "At six months, 23% of complications were prevented, compared to 20% after one year, 14% after two years and 13% after three years."

At 30 days, ReoPro patients in the EPILOG study had a 59% reduction in "overall death, recurrent heart attacks and urgent repeat angioplasty or bypass surgery," the investigators told ESC. "The 30-day data also demonstrated that for every 1,000 patients who received ReoPro at the time of their angioplasty, 50 fewer patients needed follow-up, emergency angioplasties or bypass surgery, and five more people were alive compared to 1,000 patients who did not receive ReoPro."

EPIC and EPILOG used a ReoPro dosing regimen of an I.V. bolus "administered 10-60 minutes before the start of a high-risk PTCA procedure, followed by a continuous intravenous infusion for 12 hours," Centocor said. The Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment (CAPTURE) trial used a different regimen: ReoPro infusion "approximately 24 hours prior to PTCA until one hour following the procedure," the company added. Maarten Simoons, MD, Erasmus University, Rotterdam, presented final results of CAPTURE at the ESC meeting.

Centocor plans to submit EPILOG and CAPTURE data to FDA by year-end in an application for expanded labeling for ReoPro. EPILOG six-month data will be presented at the American Heart Association meeting in November in New Orleans. The announcement of the preliminary data already has positively affected ReoPro sales, which Centocor estimated would be $40 mil. in the second quarter ("The Pink Sheet" June 17, T&G-9).

CAPTURE also was halted in December due to efficacy in the first 1,050 patients ("The Pink Sheet" April 8, T&G-10). The trial had enrolled 1,266 of a planned 1,400 patients who were undergoing PTCA due to unstable angina. In addition to measuring reduction in complications, "CAPTURE was designed to determine ReoPro's ability to stabilize refractory unstable angina patients prior to the procedure," Centocor said. "CAPTURE results at six months show a 30% decreased incidence of myocardial infarction and no change in death or the need for subsequent angioplasty," Simoons reported at ESC.

While the six-month CAPTURE data (a secondary endpoint) do not reflect the long-term results seen in EPIC, the effect of the CAPTURE regimen was expected to be found at the time of PTCA, Centocor maintained. According to the Dutch researcher, "75% of the ischemic events that did occur following the administration of ReoPro took place during the PTCA rather than after the procedure."

Final data for the primary 30-day endpoint "are consistent with results seen at the interim analysis of the trial," according to Simoons' presentation. CAPTURE patients on ReoPro "experienced a 29% reduction in ischemic complications, compared to patients who received placebo." Death and MI decreased 50% in the ReoPro arm; the need for urgent intervention was reduced by 26%.