(Circulation. 2001;103:e9030.)
© 2001 American Heart Association, Inc.
50th Annual Scientific Sessions of the American College of Cardiology
Angiogenesis Results Positive
Treatment with the angiogenesis-promoting fibroblast growth factor 2 (FGF-2), given intra-arterially, increased exercise tolerance in patients with intermittent claudication in a study presented by Robert J. Lederman, MD, of the National Heart, Lung and Blood Institute at the 50th Annual Scientific Sessions of the American College of Cardiology, March 18 through 21, 2001, in Orlando, Florida.
The study involved 190 patients who were randomized to 1 of the following 3 groups: a single 30-µg/kg dose of FGF-2, two 30-µg/kg doses of FGF-2 given 30 days apart, and placebo. The study, which was called the Therapeutic Angiogenesis with FGF-2 For Intermittent Claudication (TRAFFIC), measured the patient’s peak walking time at baseline and at 90 days. Dr Lederman was at the University of Michigan in Ann Arbor at the time that this study was done.
At 90 days, placebo patients increased their walking time
0.6 minutes, which is 
14% over baseline, indicating a strong
placebo effect in the trial. Patients who received a single dose of the
protein increased their walking time 1.77 minutes, which is a 34%
increase over baseline, and the double-dose group walked 1.54 minutes
longer, which is a 20% increase. Dr Lederman said the increase was
statistically significant for both treatment groups. "But double is
not better than single," he said, a result that was surprising.
However, the trial does prove the value of this agent in improving the
treadmill performance of these patients.
In contrast to Dr Lederman’s study, the Angiogenic Gene Therapy Trial for Stable Angina (AGENT) involved the transfer of a gene using a viral vector, said Cindy Grines, MD, of William Beaumont Hospital in Royal Oak, Michigan, who presented her study during a press conference at the cardiology meetings. "This is the first placebo-controlled, randomized, double-blind study of gene therapy delivered by an intracoronary means into the heart," said Dr Grines.
A total of 60 of the 79 patients in her study received the treatment, which involved the administration of an adenovirus expressing FGF-4. Patients in the active treatment arm received 5 ascending doses of FGF-4 delivered by gene transfer using the inactivated form of the adenovirus.
"The active group showed a substantial improvement over the placebo arm," Dr Grines said. "But there is a substantial placebo effect. You need to insist on a double-blind, randomized trial when dealing with something like angina. "
Dr Grines said patients improved significantly from baseline in exercise tests. One concern was the effect that preexisting antibodies to the adenovirus would have on patient response to the therapy. "We found that patients with low antibody titers had a greater response, with a >30% increase in ejection fraction compared with patients with higher baseline titers."
The importance of this study was that patients and investigators did not know what the patients were getting: treatment or placebo, said Dr Grines. This was a significant difference from other studies of angiogenesis in patients with this problem.
"This issue is like anything else," said Valentin Fuster, MD, PhD, of the Mount Sinai Medical Center in New York City, who moderated the session. "Three years ago, there were isolated cases presented showing that angiogenesis is working, but everyone knew what the patient was receiving. We said that people needed to do more trials. We have the first 2 trials showing that there is promise in what was at that time an opening door. We have a larger number of patients, longer follow-up, and different methods of delivery." He said that evaluating the potential for stimulating angiogenesis to treat hearts will be proven over a long period of time with many studies taking place.
MIRACLE Study Proves Value of Cardiac Resynchronization as Therapy in Heart Failure
"Cardiac resynchronization therapy has emerged as a promising new treatment for chronic heart failure," said William Abraham, MD, chief of the division of cardiovascular medicine at the University of Kentucky in Lexington. The Multicenter InSync Randomized Clinical Evaluation (MIRACLE) was a randomized, double-blind, controlled trial to assess cardiac resynchronization therapy in patients with heart failure. The trial used atrial-synchronized biventricular pacing to achieve its effect.
Dr Abraham noted that "previous studies were encouraging but limited by small numbers of patients, poorly controlled study designs, or their unblinded natures." This was the first randomized, double-blind trial to assess the therapy. All patients had the cardiac resynchronization device implanted, but the device was turned off in patients randomized to the placebo group. All patients were in New York Heart Association (NYHA) class III or IV.
Of the 244 patients who had completed the first 6 months of the study by December 7, 2000, studies showed that 60% of those in the resynchronization group had improved their NYHA class by at least 1, compared with 34% of those in the control group. The treatment group also improved at rates significantly higher than those of the placebo group in terms of quality of life and the length of a 6-minute hall walk, said Dr Abraham.
CAPRICORN Bolsters Use of ß-Blockers in Patients With Left Ventricular Dysfunction After Acute Myocardial Infarction
The use of the ß-blocker carvedilol in the treatment of patients who have left ventricular dysfunction after acute myocardial infarction resulted in a 29% reduction of the combined end point of death or recurrent myocardial infarction, said Henry J. Dargie, MD, of the University of Glasgow in presenting results from the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. This result was particularly significant now, when patient treatment involves the use of ACE inhibitors, anti-thrombolytics, and invasive therapy, said Dr Dargie.
In the study, 1959 patients with a proven myocardial infarction and a left ventricular ejection fraction <40% were randomly assigned to receive either drug or placebo. There were 151 deaths in the placebo group and 116 in the carvedilol group. Recurrent myocardial infarctions were 41% lower and deaths were 23% lower in the treatment group. "CAPRICORN filled a gap between the treatment of patients with chronic heart failure and the patients in the Cardiac Care Unit," said Dr Dargie.
COPERNICUS Analysis Shows Value of ß-Blocker in Treatment of Patients With Severe Heart Failure
The use of ß-blockers in patients with advanced heart failure has not previously been well studied, said Milton Packer of Columbia University’s College of Physicians and Surgeons in New York City. The design of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial randomized 2289 patients with an at-rest ejection fraction <25% to receive carvedilol or placebo in addition to other therapy for heart failure.
Patients were followed for 29 months when the study was stopped by its monitoring committee because of a marked reduction of mortality in the treatment group. Mortality was reduced 35% in the treatment group. In addition, said Dr Packer, there was a 20% reduction in hospitalizations for patients in the treatment group. They also spent 27% fewer days in the hospital and required fewer treatments for heart failure.
Estimates are that only 15% to 20% of heart failure
patients receive ß-blocker treatment, although experts think that the
number should be 80%. "We really hope that these data will have a
significant effect on the perception that physicians have about
ß-blockers and heart failure. We hope it will heighten the mandate
for the use of these drugs in patients across the entire spectrum of
this disease," Dr Packer said.
Tezosentan Represents New Class of Drugs for Treatment of Acute Decompensated Heart Failure
The drug tezosentan, an intravenous dual endothelin-receptor antagonist, had a positive effect on cardiac index and pulmonary capillary wedge pressure when given at doses of 50 or 100 mg per hour for 24 hours to patients with acute decompensated heart failure, said Craig Pratt, MD, of Baylor College of Medicine in Houston.
"The results were that pump function was dramatically improved and pulmonary capillary wedge pressure was reduced, reducing breathlessness or dyspnea," said Dr Pratt. A total of 292 patients were randomized to receive tezosentan at 1 of the 2 doses or placebo intravenously for 24 hours. Patients were excluded if systolic blood pressure was <85 mm Hg or if they had an acute coronary syndrome or percutaneous transluminal angioplasty within the past 7 days.
The treatment groups had a positive change in the cardiac index from baseline at 6 hours and the change was maintained for 24 hours during the treatment for 6 hours after. Similar positive effects were seen for secondary end points such as pulmonary artery pressure and pulmonary and systemic vascular resistance. There were no dose-related decreases in arterial pressure and no changes in heart rate.
"Tezosentan is one of an exciting new class of drugs that improves hemodynamics, reduces dyspnea, and improves patient outcome," said Dr Pratt.
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