Late-Breaking Trials at American Heart Association’s Scientific Sessions 2000
Repairing patients’ small abdominal aortic aneurysms surgically gives them no survival advantage over patients whose small aneurysms are monitored by CT scan or ultrasound every 6 months, said Frank A. Lederle, MD, who led the Department of Veterans Affairs (VA) Aneurysm Detection and Management (ADAM) Study.
Dr Lederle of the VA Medical Center in Minneapolis, Minnesota said 1136 veterans aged 50 to 79 years were enrolled at 16 VA medical centers around the country. All the veterans had aneurysms from 4 to 5.4 cm in size. Of the study participants, 99% were male, 94% were white, and 42% had coronary artery disease. He presented the results at the late-breaking clinical trials session at the American Heart Association’s (AHA) Scientific Sessions 2000 in New Orleans from November 12 through 15, 2000.
The study was designed to answer the question as to whether the surgical repair of aneurysms <5.5 cm but >4 cm was better than frequent monitoring of the aneurysms by imaging techniques. The primary end point of the study was long-term survival.
Patients were randomized to surgical repair of the aneurysm within 6 weeks of randomization or imaging surveillance using either CT scan or ultrasound every 6 months. “Our screening studies had shown that more than three-fourths of aneurysms over 4 cm were smaller than 5.5 cm and fell within the scope of our study,” said Dr Lederle. A smaller study in the United Kingdom had attempted to find the answer to the same question and found no difference between surgery and surveillance. However, he said, the operative mortality in that study was higher than the US academic norm of 3% to 5%. He said this study was designed to answer the question when there was a lower operative mortality rate.
Mean follow-up in the study was 4.8 years. By the end of the study, aneurysm repair had been performed in 92% of the study group and 61% of the surveillance group, said Dr Lederle. Repair was deferred until the aneurysm had reached 5.5 cm in size. In the surveillance group, 8.8% of the surgical repairs were done at the patient’s initiative. At 30 days, overall operative mortality was 1.8%. The mortality rate in the surveillance group was lower than that in surgery group.
There were 141 deaths among the 569 patients in the surgery group and 121 deaths in the 567 patients in the surveillance group. “The principal finding of the study was that there was no difference between the 2 groups in long-term mortality—the primary outcome,” said Dr Lederle. Deferring the repair until the aneurysm reached 5.5 cm does not increase operative mortality.
One concern had been the threat of aneurysm rupture, he said. Nine surveillance patients had rupture of their abdominal aortic aneurysms. Two of those were unexpected findings when the patient underwent elective repair. Five of the ruptures resulted in death. Two patients in the surgery group suffered ruptures. One was in a patient who had had his abdominal aneurysm repaired but died of a ruptured thoracic aneurysm.
In addition, said Dr Lederle, there were 25 sudden deaths in the surveillance group and 23 in the surgery group, “suggesting that there were not many undiagnosed rupture deaths in the surveillance group.” There was a trend that was not statistically significant toward increased mortality in the surgery group. “This was especially seen in the patients with the smallest aneurysms at entry—4 to 4.4 cm,‘ he said.
The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study demonstrated that aggressive and immediate lipid-lowering therapy in patients who have had a threatened or mild heart attack can markedly reduce cardiac events and stroke, said Gregory G. Schwartz, MD, PhD, chief of cardiology at the Denver Veterans Affair Medical Center. He and Anders G. Olsson, professor of medicine at the University of Linkoping in Sweden, reported on the results of the international trial at the AHA’s Scientific Sessions 2000 in New Orleans.
The study was designed to determine if immediate lipid-lowering therapy could reduce the risk of increasing chest pain, another heart attack, or death in the 1 to 2 million patients hospitalized annually worldwide with unstable angina or non–Q-wave myocardial infarction, said Dr Olsson. A total of 3086 patients were enrolled in the study, which was conducted at 122 centers located in 19 countries.
To be included in the MIRACL study, patients had to be diagnosed with unstable angina or mild myocardial infarction. They had to have worsening chest pain at rest or with minimal exertion within 24 hours of their hospital admission. They also had to have objective evidence of myocardial ischemia demonstrated by ECGs or elevated cardiac enzymes.
Patients were randomly assigned to treatment with the cholesterol-lowering drug atorvastatin calcium (Lipitor) at a daily dose of 80 mg or to placebo. The double-blind study lasted 16 weeks. Both groups of patients received dietary education and counseling that began within 24 to 96 hours of the acute coronary syndrome, said Dr Olsson. They also received other standard therapy.
“It is very important to note that the entry criteria for the study had no lower limit on cholesterol at entry,” said Dr Schwartz. The upper limit for cholesterol was 270 mg/dL. The baseline level of LDL cholesterol was low, at 123 mg/dL. During the course of the 16-week study, the placebo group had slight increases in cholesterol. However, in patients treated with atorvastatin, cholesterol levels dropped to an average of 72 mg/dL—40%, he said.
The trial’s end point was a combined incidence of death, heart attack, cardiac arrest, and bouts of worsening chest pain that required hospitalization on an emergency basis. These events occurred in 17.4% of the placebo patients and 14.8% of the treated group, he said. “It was a 16% relative risk reduction with atorvastatin.” The statistical significance was 0.048. In addition, there was a statistically significant reduction in each of the end points. The greatest reduction was in the worsening chest pain requiring hospitalization (26%). An unexpected finding was that strokes were reduced 50% in the atorvastatin group when compared with the subjects who received placebo.
The atorvastatin treatment was safe and well tolerated, said Dr Schwartz. There was a reversible elevation of liver function tests in 2.5% of treated patients compared with 0.6% of the placebo group. There were no documented cases of myositis.
“Patients with a threatened or mild heart attack benefit from immediate and intensive lipid-lowering therapy with atorvastatin. This treatment produces a significant reduction in recurrent cardiac events and strokes,” he said. From this, he and his colleagues concluded that “treatment with atorvastatin should be initiated in the hospital and considered irrespective of baseline cholesterol levels at the time of the acute event.”
Dr Schwartz said that starting lipid-lowering therapy immediately is important because patients who are hospitalized for an acute event are most likely to follow their physician’s recommendations. Waiting weeks or months to start treatment can reduce the likelihood that patients will follow the advice of their physicians. The MIRACL study was funded by Pfizer Inc, the manufacturer of Lipitor.
Patients with worsening chest pain or mild heart attacks are more likely to benefit from early cardiac catheterization, usually with a stent, than from early management by the best medical therapy, said Christopher Cannon, MD, an associate physician in the cardiovascular division at Brigham and Women’s Hospital in Boston. Those were the results of the Merck-sponsored Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) presented at the AHA’s Scientific Sessions 2000 in New Orleans.
The trial involved 2200 patients in 9 countries at 169 hospitals. All patients received state-of-the-art heart treatment with aspirin, heparin, β-blockers and, in many cases, cholesterol-lowering medications and the glycoprotein IIb/IIIa inhibitor tirofiban (Aggrastat). “The medical group got improved therapy over the prior trials as did the interventional group,” said Dr Cannon. Patients were then randomized to either medical treatment or the cardiac catheterization laboratory within 4 to 48 hours.
“The results, we are delighted to say, are very clear,” said Dr Cannon. “We observed a clear and significant reduction in major cardiac events at 6 months with the invasive strategy.” The combined end point was death, heart attack, or rehospitalization for worsening chest pain at 6 months.
In the early catheterization group, 15.9% of patients reached the end point. By comparison, 19.4% of the medically managed group reached the end point. Prior trials had not shown such a distinct benefit, said Dr Cannon. He believes the use of tirofiban improved the success of the angioplasty and made the invasive strategy better in this trial.
“We believe that there will need to be a large change in the practice of medicine for these patients with worsening chest pain and unstable angina, with a broader use of IIb/IIIa inhibition and early catheterization strategy,” said Dr Cannon.
In the first study to compare the effects of 2 platelet glycoprotein IIb/IIIa inhibitors, researchers compared tirofiban (Aggrastat) to abciximab (ReoPro), said Eric Topol, MD, chairman of cardiology at the Cleveland Clinic Foundation. The trial included 4812 patients at 149 hospitals in 18 countries throughout North America, Europe, and Australia who were scheduled for an interventional procedure including a stent.
In the study, 2398 patients were assigned to tirofiban and 2414 to abciximab. The end point at 30 days was death, myocardial infarction, or urgent target vessel revascularization. In the tirofiban group, 7.55% of patients reached one of the end point situations. In the abciximab group, 6.01% of patients reached the end point. Dr Topol said the difference was 26% favoring abciximab—a statistically significant finding. The study concluded that the preferred agent for coronary stenting was abciximab at the 30-day end point. In a released statement, Rick Sax, MD, senior director of clinical research at Merck Research Laboratories said, “Merck remains firm in its commitment to the use of Aggrastat when it is indicated in patients presenting to the hospital with acute coronary syndromes, including patients who subsequently go on to have an angioplasty procedure. The benefits of Aggrastat in improving outcomes in these patients were firmly established in the PRISM-PLUS study.” Merck sponsored the TARGET trial.
The addition of the angiotensin-receptor blocker valsartan (Diovan) to standard treatment for heart failure reduced all-cause mortality and morbidity in the Valsartan in Heart Failure (VAL-HeFT) trial, said principal investigator Jay Cohn, MD, professor of medicine in the cardiovascular division of the University of Minnesota Medical School in Minneapolis. However, he added, the caveat that adding valsartan to the treatment regimens of patients receiving both ACE inhibitors and β-blockers would have no beneficial effect and may even have an unfavorable effect, although the trend was not statistically significant.
The goal of the trial was determine if adding valsartan to standard treatment for heart failure would have a favorable effect on the course of the disease. “Angiotensin is thought to exert an adverse effect on the progression of heart failure and, despite the use of ACE inhibitors designed to reduce the effect of angiotensin, it is clear that angiotensin levels persist and may contribute to the progression of the disease, which remains with an unacceptable morbidity and mortality,” said Dr Cohn. The angiotensin-receptor blockers represented a new chance to block angiotensin more effectively.
The study enrolled 5010 patients on 4 continents in 300 centers. When patients entered the trial, ≈93% of them were receiving ACE inhibitors, which Dr Cohn said was about what could be seen in clinical practice. Thirty-five percent of the patients received β-blockers. This is considerably higher than that seen in private practice, he said. “Most of the patients were taking a diuretic, and two-thirds were taking digoxin.”
The patients were randomized to either valsartan or placebo. The valsartan treatment started at 40 mg twice daily and titrated up to a target dose of 160 mg twice daily if there were no adverse events. “That’s a higher dose of angiotensin-receptor blocker than is customarily used to treat hypertension,” said Dr Cohn. “It represented our goal to make sure we were blocking the angiotensin receptor throughout the 24 hours each day to achieve the desired pharmacologic effect.” Most patients achieved the target dose.
There were 2 end points: all-cause mortality and a combined end point that included all-cause mortality and morbidity that was defined as requiring hospitalization for heart failure, having a cardiac arrest from which the patient was resuscitated, or needing intravenous administration of an inotropic or vasodilator drug for progressive heart failure for at least 4 hours.
There was no difference in all-cause mortality in the 2 treatment arms, said Dr Cohn. Approximately 19% of the patients died in each treatment arm. However, when researchers analyzed the combined end point, there was a 13.3% reduction in the valsartan group. “The major component of that reduction was the decrease in hospitalization for heart failure,” he said. There was a 27.5% reduction in the need for hospitalization for heart failure in the valsartan group compared with those who did not get the drug.
The drug also had benefits in secondary end points, such as New York Heart Association class, dyspnea, edema, lung sounds, ejection fraction, and quality of life indicators. When the researchers analyzed subgroups of the population, they found that the few patients who did not receive an ACE inhibitor had a benefit that approached 45% when valsartan was added. The patients on the ACE inhibitor had a lesser benefit.
The β-blocker group had an even more dramatic reaction, he said. Patients who did not take a β-blocker benefited greatly from valsartan. Those who were taking a β-blocker and an ACE inhibitor did not have a benefit and, “in fact, the point estimate was on the adverse side of the line,” said Dr Cohn. However, Dr Cohn said reporting the finding put him on “thin ice” because he feared that it could be misinterpreted.
“The bottom line of this study is that valsartan is an effective drug to add to conventional therapy for heart failure with a little flag waving that raises the concern that perhaps being on all 3 drugs—an ACE inhibitor, a β-blocker, and an angiotensin-receptor blocker such as valsartan—may not be beneficial and could potentially have an adverse effect. We are going to do a good deal more analysis of these to determine what, if anything, that adverse trend means,” said Dr Cohn.
- Copyright © 2000 by American Heart Association