PREVENT II Trial
The PRoject of Ex-vivo Vein graft ENgineering via Transfection (PREVENT) II trial found that a double-stranded piece of DNA called the E2F duplex decoy significantly reduced failure of vein grafts after coronary artery bypass surgery (CABG), according to Eberhard Grube, MD, of the Heart Center in Sieburg, Germany, during the American Heart Association’s 2001 Scientific Sessions in Anaheim, Calif. During the Late-Breaking Clinical Trials Plenary Session on November 12, 2001, Dr Grube said that his decoy blocks vascular smooth muscle proliferation, which is the core problem in vein graft failure.
The graft is treated during CABG after the vein has been removed from the leg. A solution containing the E2F decoy is placed in a tube with a stopcock on one side and a syringe at the other, which is used to apply pressure. The vein is placed in the tube and pressure is applied via the syringe to ≈6 lbs/in2 for 10 minutes, Dr Grube said. That is enough to insure that 80% of the cells in the graft will take up the decoy. The transfected graft then is used to bypass blocked coronary arteries.
In the study, 101 patients who had undergone CABG were randomly assigned to the treatment group, and 99 were assigned to placebo. In angiographic studies performed on 61 placebo patients and 75 treated patients who received a total of 309 grafts, the E2F decoy was associated with a 30% relative reduction in a composite index of vein graft failure and death, said Dr Grube. In addition, there was a 30% reduction in the size of vessel wall volume.
According to Dr Grube, the results are similar to those in the PREVENT I trial, which used E2F to treat bypass veins in peripheral artery disease. He said the trial suggests that E2F may reduce long-term morbidity and mortality associated with high rates of human coronary artery vein graft failure.
Elizabeth Nabel, MD, of the National Heart, Lung and Blood Institute, said that this phase II study suggests a marked clinical efficacy of the E2F decoy in these bypass grafts. “It confirms the safety and minimal toxicity observed in previous studies,” she said, as designated discussant of the trial. “Clearly, the results of this study warrant an additional phase III study. It is an outstanding example of translational medicine from the discovery of the gene at the bench and its application to design of a molecular treatment that can be applied to a clinical disease.”
COPPA II Study
The Clinical Outcomes from the Prevention of Post-operative Arrhythmia (COPPA) II study determined that at a moderate dose of 675 mg, the drug propafenone can reduce the incidence of postoperative atrial fibrillation to 12.4%, but use of the drug accomplished no reduction in length of stay, according to Peter Kowey, MD, of the Main Line Health Heart Center at Lankenau Hospital and Institute for Medical Research in Wynnewood, Pa.
At the lower dose of 450 mg, 22.5% of the patients who received the drug had atrial fibrillation, compared with 22.7% in the placebo group. “It doesn’t appear to make a whole lot of difference to patients in terms of morbidity,” said Dr Kowey.
The study was undertaken because between 30% and 50% of CABG patients suffer atrial fibrillation immediately after the surgery. “It is associated with significant morbidity and has a significant financial burden associated it with it because it prolongs length of stay,” he said. β-Blockers can reduce postoperative atrial fibrillation by ≈50%. Dr Kowey’s study was an attempt to determine if the drug propafenone could reduce the problem further if it were given over a short period of time.
A total of 293 patients were enrolled in the study at 7 sites. The double-blind study involved placebo or propafenone, given daily at doses of 450 and 675 mg, respectively. Treatment with oral medication was started within 24 hours of surgery and was continued for the duration of hospitalization, to a maximum of 15 days. The study end point was 5 minutes of atrial fibrillation. In addition to the study drug or placebo, 93% of patients received digoxin and 84% received β-blockers. “The high dose of propafenone was protective because only 12.4% of the propafenone high dose group reached end point arrhythmia,” said Dr Kowey.
Eric Prystowsky, MD, of Indianapolis, Ind, said, “We don’t know what happened to patients afterwards. If you just did nothing, within 6 weeks, usually more than 90% of patients are back in regular rhythm.” As designated discussant for the study, he said, “We know nothing about whether the patient is feeling better. . . The take-home message is, don’t prophylax atrial fibrillation patients. Get them on β-blockers if they develop atrial fibrillation. Don’t procrastinate. Make a decision. Start them on anticoagulation and send them home with good rate control.”
The Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) study found no advantage to the use of the drug tranilast in reducing the frequency of major adverse cardiovascular events in patients who had undergone a successful percutaneous coronary intervention (PCI).
David R. Holmes, Jr, MD of the Mayo Clinic, said, “It was a negative trial.” The double-blind, randomized, placebo-controlled, 9-month trial enrolled 11 488 patients during 1999 and 2000. Patients were assigned to 5 different groups: tranilast in a daily dose of 300 or 450 mg, given for 1 or 3 months, or placebo. When the data were analyzed, however, researchers found no difference in the occurrence of death, myocardial infarction, or target vessel–driven revascularization during the 9 months after initial PCI.
Dr Holmes said it is possible that the study used the wrong doses or the wrong timing, duration, or route of administration, but he also acknowledged, “. . .maybe it just doesn’t work.” He said that there is discussion underway of testing the drug as a stent coating in Japan. The trial does, however, provide a large database of information about patients undergoing PCI in different countries and under different conditions, which could be used by researchers in the future as they plan new studies of other drugs or techniques, according to Dr Holmes.
Patrick Serruys, MD, of the Thorax Center in Rotterdam, the Netherlands, said, “We are dealing with a mega-mammoth trial that cost more than $100 million, and at the end of the day, we have nothing.” In part, he said, the fault was in trying to design the trial to meet the US Food and Drug Administration’s requirement of major adverse cardiovascular events as end points. Doing that and attempting to determine the optimum length of drug administration means that researchers end up with >11 000 patients in their studies. Dr Serruys agreed, however, that the study had created a large library of PCI data that could be invaluable in the future.
The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial found that left ventricular assist devices (LVADs) (in particular, the Thoratec VE Heartmate) lengthened and improved the quality of lives of patients with congestive heart failure when compared with those who received optimal medical management. The study, which was undertaken to determine if LVADs could be used as permanent implants rather than as bridges to heart transplants, involved 22 centers and 129 patients, said Eric Rose, MD, Chairman of the Department of Surgery at Columbia College of Physicians and Surgeons, New York, NY, and the study’s principal investigator.
The study’s designers had hoped to reduce mortality by one third over 2 years compared with medically managed patients, according to Dr Rose. The patients were severely ill. They were classified as New York Heart Association Class IV and had an extremely low ejection fraction.
In the study, 68 patients were assigned to the LVAD group, and 61 were assigned to the medical group. After 1 year, 52.1% of the LVAD group survived, whereas only 24.7% of the medical group survived. At 2 years, 22.9% of the LVAD group and 8.1% of the medically treated group were alive. However, the relative risk of serious adverse events, including bleeding, infection, and device malfunction, was 2.35 times greater in the LVAD group. Measures of quality of life favored the LVAD group.
“Of 1000 patients treated with the LVAD, 270 lives would be saved,” said Dr Rose. He could not, however, predict exactly what the cost of implanting the LVAD would be in the future. He predicted that Medicare would cover the costs of the procedure, leading private insurers to follow suit.
Sharon Hunt, MD, professor of cardiovascular medicine at Stanford University School of Medicine, Stanford, Calif, said the trial demonstrated that the LVAD can accomplish the task for which it was initially envisioned. “The LVAD was never envisioned to be used as it has,” she said. “It was meant as an alternative to biological replacement of the heart. Its use as a bridge has proved it is an invaluable tool in extending lives of a number of patients. It is a natural progression to begin using the devices for the purpose for which they were designed. They can prolong life. REMATCH is a landmark report.”
“One of the best things about REMATCH is that it defines a class of heart failure patients who will not survive without LVAD,” said Dr O.H. Frazier, Director of Cardiovascular Research at the Texas Heart Institute. He and his institution in Houston, Tex, participated in the study.