MI, myocardial infarction; CABG, coronary artery bypass graft; NR, not reported. ap < 0.05.
trials with medicating stents coated with substances such as paclitaxel and sirolimus are underway.
Brachytherapy prevents restenosis by decreasing intimal hyperplasia and cellular proliferation within treated segments of atherosclerotic coronary arteries. In November 2000, the Food and Drug Administration (FDA) approved two sources of radiation for the prevention of recurrent ISR. The first utilizes y radiation (photons) emitted from an iridium-192 source; the second utilizes b radiation (electrons) emitted from yttrium-90 or phosphorous-32 sources. Radiation is delivered via a "ribbon", which is temporarily introduced into the coronary artery by a catheter-based delivery. Radioactive stents are presently being studied as an alternative delivery system.
y Radiation has been studied in three randomized controlled trials (127-129). The protocols of these trials involved recruitment of patients with optimal angiographic results after combinations of PTCA, RA, ELCA, and DCA for ISR, randomization to either adjunctive y radiation or placebo, and routine post-PCI care with thienopyridines (clopidogrel or ticlopidine) and aspirin. Gp IIb/IIIa inhibitors were contraindicated. The SCRIPPS Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS) trial (127) recruited patients with restenoses of any kind, whereas the Washington Radiation for In-Stent Restenosis Trial (WRIST) (128) and the GAMMA-ONE (129) trials targeted only patients with ISR. GAMMA-ONE was the only multicenter trial. Results from each trial were compelling. Restenosis rates were decreased by 42-68%, and TLR rates were decreased by 43-73%. Important caveats to these results were found, however. Although composite end points including death, MI, TLR, CABG, and thrombosis were improved, the difference was almost entirely accounted for by the decrease in TLR, a variable likely influenced by the protocol-driven follow-up angiography (130). Furthermore, in WRIST, there was an increase in TVR (7.6%) and TLR (9.3%) in mo
6-12 in the treatment group, suggestive of the possibility that radiation delayed the recurrence ISR rather than prevented it. There was also a trend towards the increase in late thrombotic events in the treatment group (9.2 vs 3.5% at 12 mo, p = NS). In GAMMA-ONE, late thromboses were also more common in the irradiated group (5.3 vs 0.7%, p = 0.07). All events occurred in patients who had received new stents at the time of irradiation and had discontinued thienopyridine therapy for more than 1 mo. The conclusion of the authors of the GAMMA-ONE trial was that y radiation would not be a viable option for the subset of patient who had received a new stent in the context of treatment for ISR, until the issue of late thrombosis was resolved.
Following this study, the Washington Radiation for In-Stent Restenosis Trial plus 6 mo of clopidogrel (WRIST-PLUS) trial treated 120 patients with ISR with intracoronary y radiation, but extended clopidogrel therapy to 6 mo. Repeat stenting was discouraged but allowed (28.3% received new stents) (131). The primary end point of this study was the occurrence of late thrombosis, as well as the combined end point of death, MI, and TLR at 6 mo. Control groups were historical from the WRIST study. Outcomes for WRIST-PLUS were similar to the placebo arms of the historical controls, and better than the irradiated results of the controls, in terms of late total occlusion and late thrombosis. This important finding indicates that a strategy of reduced new stent placement and long-term clopidogrel therapy effectively removed all of the increased late thrombotic side-effects of y radiation. Notably, the FDA advises against the use of new stents with y radiation, but recommends 1 yr of antiplatelet therapy in that context (132).
b Radiation confers several practical advantages over y radiation: decreased radiation exposure to patient, medical personnel, and environment; decreased procedure time; and obviated need for catheterization laboratory redesign. The Beta Energy Restenosis Trial (BERT) was a pilot trial that treated 21 patients with b radiation from a Sr/Y90 source and found no in-hospital or 30-d morbidity or mortality (133). Restenosis rate was lower than expected at 15%, and late loss index was also low. This motivated three random-ized-controlled trials (RCTs): Stents and Radiation Therapy (START) (134); Proliferation Reduction with Vascular Energy Trial (PREVENT) (135); and BETA-WRIST (136). START was the largest of the three, randomizing 476 patients to b radiation or placebo. Stent use was discouraged and only occurred in 21% of cases. Thienopyridine therapy was administered for 90 d. In 8 mo of follow-up, no late thromboses occurred, and restenosis rate was 14% in the treatment group vs 41% in the placebo group. A recent dose-finding study was performed in patients with de novo lesions (137). The largest dose given (18 gy) was found to actually increase luminal size on angiographic follow-up, and the overall restenosis rate across doses was 16%. As the authors note, a randomized clinical trial comparing a strategy of stentless PCI plus radiation vs PCI with stent for the prevention of restenosis is needed.
Stent-based delivery systems for medication appear to be a viable option for local medication to prevent restenosis (138). Animal models suggested that antimitotic agents might be beneficial in decreasing the proliferative and hyperplastic response to endothelial damage (139). At present, only sirolimus (Rapamune)-coated stents have had any human experience in the U.S. Sirolimus' FDA-approved indication is as an immune-modulator to prevent rejection in patients with renal transplants. Mechanistically, it binds to an intracellular protein and up-regulates p27, leading to cell-cycle arrest. It has been shown to inhibit human smooth muscle cell proliferation in vitro (140). In a pilot trial, 30 patients with angina pectoris were randomized to receive fast-release or slow release sirolimus-coated stents, and were studied with IVUS immediately postprocedure and at 4 mo. Patients took daily aspirin and clopidogrel for 60 d. Clinical follow-up was also performed at 8 mo. Angiographic results were impressive: intimal hyperplasia was 10.7% by IVUS (141) compared to historic IVUS controls of 19-48%, and there was essentially no late lumen loss or edge-effect. At 8 mo, there were no clinical events (MI, death, TLR, TVR, cerebrovascular accident [CVA], stent thromboses). The effects were seen with both formulations.
Paclitaxel, the antineoplastic agent used in certain malignancies such as breast, has a different mechanism of action. It binds microtubules and polymerizes them, making them unstable, thereby arresting the cell cycle. Elegant animal models have demonstrated that stents eluting paclitaxel are promising in their ability to prevent neointimal hyperplasia and proliferation (139). Their impact on human coronary arteries is yet to be determined.
Photophoresis is an immunomodulatory treatment, in which patients are phlebotomized, and their blood is separated into leukocyte-poor blood, which is returned to the patient, and leukocyte-rich plasma, which is exposed to uv light in the presence of a photo-activated substance such as methoxsalen, which covalently binds DNA, cell surface molecules, and cytoplasmic components in the exposed leukocytes prior to being returned to the patient. Reinfused the T-cell response is modulated. A small pilot RCT of methoxsalen photophoresis in the prevention of restenosis was recently reported (142). Seventy-eight patients being treated with single-vessel angioplasty were randomized to photophoresis or control. Patients were followed clinically for 6 mo including routine exercise treadmill testing (ETT). Clinical restenosis rates were significantly lower in the treatment group compared to the control group (8 vs 27%, p = 0.04).
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