Intracoronary Radiotherapy for Restenosis
Editorial
The New England Journal of Medicine -- January 25, 2001 -- Vol. 344, No. 4
On November 3, 2000, the Food and Drug Administration (FDA) granted approval for
two devices that deliver intracoronary radiotherapy for in-stent restenosis. Given this
approval, it is possible that there will be widespread dissemination of this technique before
its safety and efficacy have been established. Before interventional cardiologists
wholeheartedly embrace this new technology, it should receive a thorough and unbiased
assessment by impartial parties. (1)
More than 500,000 percutaneous coronary revascularization procedures are performed
each year in North America. (2) Restenosis occurs in 30 to 40 percent of patients within six
months after balloon angioplasty and in 20 to 30 percent of patients after balloon
angioplasty followed by stenting. (3,4) Consequently, there are more than 150,000 cases of
restenosis each year, with an increasing number occurring in stented vessels. In an attempt
to reduce the rate of restenosis, researchers have examined a variety of medical therapies,
with limited success. (5) At the same time, investigators have pursued novel therapeutic
techniques aimed at preventing restenosis. Intracoronary radiotherapy involves treating
coronary stenoses with a radioactive source from within the artery. Two approaches include
the implantation of a radioactive stent and the catheter-based delivery of radioactive seeds.
With the first method, stents coated with radioactive isotopes are deployed at the site of the
stenosis. With the second, a "ribbon" containing radioactive seeds is placed at the site of a
coronary stenosis for a short period after percutaneous coronary revascularization.
Both beta-radiation and gamma-radiation sources have been studied. Beta radiation takes
the form of electrons, or particulate energy, and has limited tissue penetration. Most of the
therapeutic effect of beta radiation occurs 2 to 3 mm from the radioactive source. Gamma
radiation takes the form of photons and penetrates well beyond 10 mm. Indeed,
catheterization laboratories must often be reconfigured to reduce the exposure of patients
and personnel to the potentially harmful effects of gamma radiation.
To date, no randomized trials of radioactive stents in humans have been published in other
than abstract form, and only three placebo-controlled trials examining catheter-based
intracoronary radiotherapy have been published (Table 1). The Scripps Coronary Radiation
to Inhibit Proliferation Post Stenting (SCRIPPS) trial and the Washington Radiation for
In-Stent Restenosis Trial (WRIST) randomly assigned patients who underwent
percutaneous coronary revascularization for restenosis to receive either placebo or
iridium-192 (gamma radiation). (6,7,8) The Proliferation Reduction with Vascular Energy
Trial (PREVENT) (9) randomly assigned patients to receive placebo or phosphorus-32
(beta radiation). Results from these trials suggest that catheter-based intracoronary
radiotherapy reduces the rates of restenosis, but questions were also raised regarding
potential increases in the rates of myocardial infarction and late thrombosis.
Two studies that appear in this issue of the Journal are welcome additions to the limited
number of trials investigating intracoronary radiotherapy. Leon et al. (10) report the results
of the Gamma-One Trial, a multicenter study in which 252 patients were randomly assigned
to receive either placebo or iridium-192 for the treatment of in-stent restenosis. As in
previous trials, intracoronary radiotherapy caused an impressive reduction in recurrent
in-stent restenosis at six months as compared with the incidence in the placebo group. By
nine months, patients who had received intracoronary radiotherapy also had a reduction in
the composite clinical end point of death, myocardial infarction, and revascularization of the
target lesion (Table 1).
Verin et al. (11) report the results of a randomized, uncontrolled, dose-finding study in 181
patients with previously untreated coronary stenoses. Patients were randomly assigned to
receive various doses of yttrium-90 (beta radiation) after successful balloon angioplasty.
Higher doses of radiation were associated with lower rates of restenosis at six months.
There was little difference among the dose groups with respect to serious adverse cardiac
events during the first 210 days of follow-up. This is one of the first human studies to focus
on previously untreated coronary lesions rather than previously dilated lesions in which
restenosis has occurred. Little is known about intracoronary radiotherapy in this situation,
and the recent FDA approval does not include this indication.
These two articles highlight several important issues that need to be addressed before this
technology is disseminated widely. First, the total number of patients who have participated
in the published trials is small, and both clinical and angiographic follow-up have been short.
Including the data from the Gamma-One Trial, data for fewer than 600 patients in
placebo-controlled trials are available for review. Although 3-year follow-up data have
been published for the SCRIPPS trial, clinical follow-up in the other trials did not exceed 12
months.
Second, all but one of the trials used a composite clinical end point that included
revascularization of the target lesion. In each of these studies, the reduction in the
occurrence of this end point appeared to be driven entirely by the reduction in the need for
revascularization of the target lesion. Because angiography was performed routinely at 6
months in each of the trials and clinical follow-up was conducted at 9 to 12 months, the
reduction in the need for revascularization of the target lesion may well have resulted from
the protocol-mandated angiography. As has been documented in previous angiographic
trials, if cardiologists identify a restenotic lesion on protocol-mandated angiography, they
are likely to redilate it. (12)
Third, there may be an increase in the incidence of myocardial infarction after percutaneous
coronary revascularization in patients who receive intracoronary radiotherapy, possibly as a
result of late thrombosis. A review of both randomized and nonrandomized studies of
intracoronary radiotherapy found that 9 percent of the patients who received radiation had
late thrombosis, as compared with less than 2 percent of the patients who did not receive
radiation. (13) It has been hypothesized that late thrombosis is caused by the pronounced
delay in endothelialization that occurs after exposure to radiation. Current trials are
examining whether prolonged antiplatelet therapy and less repeated stenting can prevent this
complication.
Finally, intracoronary radiotherapy may be associated with a number of other
complications. Weeks to months after the administration of intracoronary radiotherapy,
restenosis may occur at the proximal and distal edges of the irradiated zones. This
phenomenon has been termed the "edge" or "candy wrapper" effect. (14) Coronary
pseudoaneurysms occurred in one study, (15) and technical problems, such as loss of
radioactive seeds or stents, may potentially occur. Secondary cancer and coronary
arteriopathy have occurred years after external-beam radiotherapy for illnesses such as
Hodgkin's disease and breast cancer. However, little is known about the likelihood of these
complications in the case of intracoronary radiotherapy, because of the small number of
clinical trials in this area that have been published and the limited follow-up data available.
Thus, many questions need to be answered before intracoronary radiotherapy receives
widespread acceptance. How safe is this technique for both patients and personnel? Which
type of radiotherapy is most effective? What is the best delivery system? What is its
long-term efficacy? Are decreased rates of revascularization of the target lesion solely a
byproduct of protocol-mandated angiography? Are we simply exchanging decreases in the
rates of restenosis for increases in the rates of myocardial infarction? Will long-term
antiplatelet therapy eliminate the problem of late thrombosis? What is the cost of this
technology? Are there any safer therapies that may supplant this technique?
Intracoronary radiotherapy is a new, exciting technology that is still in its infancy. The recent
FDA approval of two devices for intracoronary radiotherapy should not be interpreted as
carte blanche for the indiscriminate application of the technique. The FDA approval will
permit us to perform additional trials with larger numbers of patients, in different populations
of patients, and with long-term follow-up. These trials will allow us to assess whether the
clinical benefits of intracoronary radiotherapy outweigh its risks. Until this question is
answered, physicians should remain cautious in their use of intracoronary radiotherapy for
the prevention and treatment of restenosis.
Richard Sheppard, M.D.
Mark J. Eisenberg, M.D., M.P.H.
Jewish General Hospital
Montreal, QC H3T 1E2, Canada
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