Angiogenic Gene Therapy Appears Safe to Treat Stable Angina
In the Angiogenic GENe Therapy (AGENT) trial, 5 ascending doses of a replication-incapable adenovirus called Ad5 coupled to a gene for human fibroblast growth factor were administered to patients with stable angina in a double-blind, placebo-controlled trial. The results, reported in this week’s issue of Circulation, were that the single, intracoronary administration of the gene therapy was safe and well tolerated. Cindy L. Grines, MD, of the Division of Cardiology at William Beaumont Hospital in Royal Oak, Michigan, was first author on the report. Those participating came from William Beaumont Hospital, the University of Vermont, Minnesota Heart Clinic in Minneapolis, Johns Hopkins University Medical Center in Baltimore, Mount Sinai Medical Center in New York, Berlex Laboratories in Montville, NJ, the University of California at San Diego, and the Veterans Affairs San Diego Healthcare System (Circulation. 2002;105:1291–1297OpenUrl).
Adverse events reported included fever of <24 hours’ duration in 3 patients who received the highest dose and transient increases in liver enzymes in 2 patients in lower-dose groups. A total of 79 patients were enrolled in the study. Sixty patients were enrolled in 1 of 4 treatment groups and 19 were in the placebo group. The doses were delivered by one-time intracoronary infusions at ascending levels of from 3.2×108 to 3.2×1011 viral particles. Although some patients in all groups suffered worsening angina, there was no significant difference among them. One patient who received the treatment developed unstable angina 145 days after treatment. That patient died while awaiting coronary artery bypass surgery. A second treated patient experienced a transient cerebral ischemic attack at 38 days. That patient was treated by endarterectomy.
An analysis of increases in exercise time showed no significant difference among treated and untreated groups. However, when only patients with a baseline exercise time of 10 minutes or less were considered, the differences between treated and placebo patients were significant, the authors said.
The authors concluded that the study demonstrates the gene therapy is safe and points the way to new tests of the therapy.
Treatment With Azithromycin Improves Endothelial Function
Patients with coronary artery disease and evidence of Chlamydia pneumoniae infection benefited from treatment with azithromycin in a study reported in this week’s issue of Circulation by Nikhil Parchure, MRCP, Emmanouil G. Zouridakis, MD, and Joan Carlos Kaski MD, DSc, of the Department of Cardiological Sciences at St George’s Hospital Medical School in London (Circulation. 2002;105:1298–1303OpenUrl).
Infection with Chlamydia has been suspected as a trigger that can, ultimately, impair endothelial function. The 40 patients in this study all had indications of coronary artery disease and infection with Chlamydia. They were randomized to receive either azithromycin or placebo for 5 weeks. Measurements of flow-mediated dilatation of the brachial artery, E-selectin, von Willebrand factor, and C-reactive protein were all made before and after treatment.
Patients in the treatment group had improvements in the flow-mediated dilatation of the brachial artery and decreases in E-selectin and von Willebrand factor. Those in the placebo group did not show these changes. The C-reactive protein levels did not differ significantly between the groups.
The authors said they were unsure why the antibiotic had a beneficial effect on the surrogate markers for endothelial function. They said it could be from anti-chlamydial effect, the anti-inflammatory effect, a direct effect on the endothelium itself, or a combination of the three. “Further studies are needed to elucidate this issue and it would be important to also investigate the duration of the beneficial effects of azithromycin on endothelial function after discontinuation of the antibiotic therapy,” they wrote.
They also noted that although their results showed a beneficial effect on endothelial function, they could not determine whether it reduced or slowed atherosclerosis or reduced coronary events.
Clot-Busters May Increase Mortality in the Elderly
For nearly a decade, clot-busting drugs such as tissue plasminogen activator have been touted as lifesaving for people suffering from heart attacks and stroke. However, the therapy has provoked controversy as some physicians question whether the lifesaving potential is true for all groups of patients.
In the March 11, 2002, issue of the Archives of Internal Medicine, however, Stephen Soumerai, MD, Professor of Ambulatory Care and Prevention at Harvard Medical School and Harvard Pilgrim Health, and his coauthors question whether the treatment should be used across all patient classes (Arch Intern Med. 2002;161:561–568OpenUrl).
He and collaborators from his institution, Boston University School of Public Health and the University of Massachusetts Medical School, examined the records of 2659 patients with acute myocardial infarction admitted to 37 Minnesota community hospitals between 1992 and 1996. Of these, 719 were eligible for thrombolytic therapy. Sixty-three percent of the eligible patients and 14% of ineligible patients received the drugs.
Thrombolytic therapy was associated with reduced mortality among the eligible patients under the age of 80 years. However, for those over that age, there was increased mortality, the researchers noted. Patients 80 to 90 years old who received thrombolytic therapy had an estimated 40% greater risk of death in the hospital compared with patients who did not receive the thrombolytic drugs.
The drug increased the risk of death in ineligible patients who received them, regardless of their age. In the entire group ages 65 and older, the risk of death associated with thrombolytic therapy increased 4% for each year of age.
“The oldest patients, even those without contraindications to therapy, experienced an excess risk of mortality compared with untreated patients,” the authors wrote. “Findings of this study suggest a need to re-assess our approach to the use of thrombolytic therapy in the treatment of acute myocardial infarction patients older than 75 years.”
A study from John Hopkins University, published in the May 16, 2000, issue of Circulation, produced similar results: Patients over age 75 who received thrombolytic drugs were nearly 40% more likely to die within 30 days than patients not receiving the drugs (Circulation. 2000;101:2239–2246OpenUrl). Many doctors have been hesitant to prescribe thrombolytic therapy for the oldest patients with myocardial infarction, despite guidelines that strongly promote the therapy for patients of all ages, Dr Soumerai said. “Our findings, along with those of the earlier study, really seem to justify their concerns.”
Dr Soumerai said the result suggests that national guidelines on the use of drugs such as streptokinase and tissue plasminogen activator should be applied with greater selectivity and revised to maximize benefit and minimize risk.