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(Circulation. 1999;99:3090-3091.)
© 1999 American Heart Association, Inc.
Cardiovascular News |
Many Cardiologists Still Unsure of Electron Beam Computed Tomography's Benefit as a Screening Tool
The role of electron beam computed tomography (EBCT) or ultrafast CT in screening populations of asymptomatic, healthy people remains unclear, said leaders at the American College of Cardiology's 48th Scientific Sessions meeting (March 7–10, 1999) in New Orleans, La. Robert O'Rourke, MD, professor of cardiology at the University of Texas Medical School at San Antonio, said a joint committee of the American Heart Association and the American College of Cardiology is writing a consensus document on the technology's role in diagnosis of coronary artery disease, but he doubts that such a document will recommend screening.
Although O'Rourke said he could not reveal the contents of the proposed statement, which is still under discussion, "the way we are thinking in relationship to it is that it is not a test that is useful in finding which patients need coronary angiography." The data are not in, and there is controversy.
EBCT combines an electron gun and a stationary tungsten target to dramatically decrease the time taken to scan the coronary arteries. A scan can usually be made while the patient holds his or her breath. It is so fast that the motion of the heart does not skew the image received. Areas of calcification in the arteries are viewed on the scan. Proponents of the technique say such calcification has a positive correlation with atherosclerosis.
"I think it's important to state that there is certainly no reason to use EBCT in unselected patients who are frequently self-referred in the states where that is allowed; it leads to additional testing. Now, I don't want to the throw the baby out with the bathwater, because that would be inappropriate," said O'Rourke. "It is a very sophisticated instrument that lots of scientists have spent lots of time in developing, but let me say this, as I have said to my critics: if the water gets too high, the baby drowns."
The technique is helpful in identifying coronary stenosis in patients with atypical chest pain, said Robert Detrano, MD, professor of cardiology at the University of California at Los Angeles. "Our major concern is with people who have low risk," he said.
Even with people who have a family history of heart disease, other risk factors tend to predict cardiac events better than the calcium score, said Detrano. "I don't see any reason to scan everyone with a family history," he said.
O'Rourke said his committee is struggling with the issue of which patients should undergo EBCT. The calcium detected is unequivocally a mark of atherosclerosis, he said. However, the relationship between calcium and atherosclerosis differs with age and among individuals. He said the committee is unsure which patients should have additional tests after receiving a positive, high calcium score after EBCT. Such procedures are often costly for patients, who may end up having no detectable coronary artery stenosis, he said.
He said third-party payers such as Blue Cross/Blue Shield are also struggling with that issue. The staff of Blue Cross/Blue Shield has decided that a positive or negative score on EBCT does not yet provide good information about whether asymptomatic patients need coronary angiography.
In an attempt to determine the value of EBCT in asymptomatic patients, Axel Schmermund, MD, from the department of cardiology at the University Clinic in Essen, Germany, compared coronary arteries from 28 patients younger than 50 years of age who had died of sudden coronary death with 16 age-matched control patients who had died of noncardiac problems. Although the extent of atherosclerotic plaque was less than usually seen in older patients, it was much greater than that found in the age-matched controls, said Schmermund. Similarly, there was more calcified plaque in the sudden death patients than in the control subjects, he said. "Calcification as a measure of the overall extent of atherosclerotic plaque disease did separate the 2 groups," he said. "It might be helpful to examine the extent of calcification to predict the increased risk of sudden coronary death."
S. Lewis Meyer, president and chief executive officer of California-based Imatron, a company that makes the ultrafast CT machines, said, "We have to be careful about using the word `screening.'" Rather, he said, a technique such as ultrafast CT is best used in a population "that would have a reasonable chance of having the disease."
Cardiologists tell Meyer that the test is best used in men over the age of 40 and under the age of 65 or 70 years and in women in their late 40s until age 70. Combine that population group with 1 other risk factor, "and I would say that the experts who deal with EBCT would strongly disagree with O'Rourke's comments about screening," said Meyer. He said that a large percentage of people in those age groups have atherosclerosis that is not well predicted by standard risk factors.
Data suggest that the calcified portion of accumulated plaque represents 20% of all plaque, Meyer said. "It is a surrogate measure of total plaque burden. We are not ready for scanning every American male over the age of 21. We want to focus the technology on a population base where there is a reasonable probability of a positive result."
Meyer pointed to 2 studies in the New England Journal of Medicine. One showed EBCT's usefulness in monitoring the effectiveness of cholesterol-lowering drugs. The other compared ultrafast CT with conventional coronary angiography. The researchers concluded that diagnosis of high-grade stenosis and occlusions of the coronary arteries seems superior to other noninvasive techniques.
"The real challenge ought to be treating the disease in the [blood] vessel wall," said Meyer. "It should be finding people who should be treated and treating them." Meyer sees EBCT as a preventive tool that can be used to alert people to their risk of heart disease early and encourage them to change their lifestyles to save their lives.
Whatever the method of diagnosis, researchers know that they need to find new ways of treating cardiovascular disease. As Timothy Henry, MD, of Hennepin County Medical Center in Minneapolis, Minn, said, "We are seeing an increasing number of patients who are still alive after heart attacks. There is a larger and larger group of patients with significant chest pain and limited activities for whom there is no good invasive alternative. That's where the urgency in this field comes from."
Gene Therapy for Angiogenesis
One promising new technique is revascularization, or therapeutic angiogenesis. However, the first large randomized trial of the technique with vascular endothelial growth factor (VEGF) had disappointing results, according to Henry, who was principal investigator of the double-blind trial that compared VEGF with placebo. A total of 178 patients were enrolled in the study: 63 in the placebo group, 56 in a low-dose VEGF group, and 59 in a high-dose group. Henry and his collaborators administered VEGF directly into the heart in a 20-minute infusion and combined that with 4-hour intravenous infusions on days 3, 6, and 9 of the study. Patients who received the low dose directly in the coronaries also received low-dose IV treatments later. The same was true of the high-dose group, said Henry.
The preliminary end point of the trial was the 60-day exercise time. Other measurements that have yet to be correlated include 120-day exercise time and quality-of-life indicators, including classification of angina. Nuclear perfusion scans will be used to look at heart function, as well as perfusion and stress. There were 2 deaths in the placebo group and none in the treatment groups, said Henry. Three patients in the placebo group developed cancer, and 1 developed abnormal retinopathy. None of the patients in the treatment groups developed either problem. There was no difference among the groups in numbers of hospital admissions or myocardial infarctions. Exercise times increased 43 seconds in the placebo group, 26 seconds in the low-dose VEGF group, and 32 seconds in the high-dose VEGF group. There was a significant improvement in angina class in all 3 groups, he said.
"While these results are not exactly what we hoped for, I do think there will be ongoing interest and excitement in this area," said Henry. "There is a large group of people with no other alternative. I believe this field is based on sound science. It is based on the natural growth factors that work in our body."
The trial is important in a rapidly developing field in which there have no been no controlled studies, Henry said. He hopes that future results from the study will tell scientists if they are measuring the right things and giving the right drug. A major question is whether to give the protein or the gene. "The way to get there is to do trials with placebo," he said. "There is a prominent effect of placebo" in this trial.
Jeffrey Isner of Tufts Medical School in Boston, Mass, said the results can be interpreted in at least 3 ways. "One interpretation could be that despite lots of previous work in animal models, therapeutic angiogenesis does not work. I think that would be a gross and erroneous interpretation of this work.
"A second interpretation would be that this particular trial has not yet shown favorable results, perhaps because of the route of administration employed, the dose employed, and the frequency of treatments or the choice of agent. VEGF is not the only angiogenic growth factor. The third interpretation would be that this clinical trial addresses a question that has been hotly debated over the last several years: what would work better, the protein or the gene? In this case, the recombinant protein was administered intracoronary and then IV. It has a short circulating half-life and may be taken up by the tissues, remaining bioavailable. It is a very different approach from gene therapy. The gene continues to express or make the protein over a period of 2 to 3 weeks with low systemic concentrations in the blood but high concentrations locally," said Isner, a pioneer in angiogenic therapy for heart disease.
"One interpretation is that given at this dose and this way, the protein may not be as effective as the gene," said Isner. He said his group tried a gene-therapy approach because we knew we could manufacture DNA for a limited trial in our institute. "We have used it in over 70 patients now," he said.
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