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Localized Intracoronary Gamma-Radiation Therapy to Inhibit the Recurrence of Restenosis after Stenting - Gamma-One
Description:
The Gamma-One Trial was a multicenter, double-blinded randomized trial designed to test the efficacy of intracoronary gamma radiation therapy in the treatment of in-stent restenosis (ISR).
Hypothesis:
Compared to placebo, administration of intracoronary gamma radiation with iridium-192 via an intracoronary ribbon would be associated with a reduced incidence of death, myocardial infarction, and the need for repeat target lesion revascularization at nine months.
Study Design
Study Design:
Patients Enrolled: 252
Mean Follow Up: 9 months
Mean Patient Age: 58 +/- 12 (treated); 61+/- 11 (placebo)
Female: 25
Patient Populations:
Patients with history of angina and signs of myocardial ischemia, with a target lesion shorter than 45 mm long in a native coronary artery (2.75 to 4.0 mm in diameter) with >60 percent stenosis, and in which a stent had previously been implanted. Before randomization, the coronary intervention in the target lesion had to be considered by the operator to have been successful (i.e. residual stenosis in the lesion <30%).
Exclusions:
MI within preceding 72 hours; total occlusion of the vessel at the site of the ISR; intention on the part of the operator to use abciximab during the treatment of ISR; and clinically significant impairment of left ventricular function (EF<40%).
Primary Endpoints:
Composite of death, myocardial infarction, emergency CABG, and target lesion revascularization after 9 months.
Secondary Endpoints:
Binary restenosis, acute thrombosis, individual components of the composite endpoint, target vessel revascularization, and late thrombosis within 9 months.
Drug/Procedures Used:
The in-stent lesion was treated by conventional interventional techniques with re-stenting if necessary for an adequate procedural result. Intravascular ultrasonography (IVUS) was then performed to examine the treated segment and the proximal and distal reference vessels.
A dedicated radiation catheter was then inserted and a 0.076-mm (0.030-in.) ribbon containing a sealed source of iridium-192 or a similar-appearing nonradioactive ribbon (placebo) was manually inserted into the delivery catheter. The radiopaque study ribbon within the delivery catheter was positioned so that the effective dose of radiation reached vessel segments of at least 4 mm at both ends of the target lesion. The total length of the source ranged from 23 to 55 mm. Dosing was aimed at achieving 8 Gy to the IVUS-assessed target farthest from the source while ensuring that no more than 30 Gy would be delivered to the target closest to the source. Angiography and IVUS were performed a final time to assess whether additional interventional therapy was needed.
Concomitant Medications:
All patients received oral aspirin (325 mg qd) and either oral ticlopidine (250 mg bid) or oral clopidogrel (75 mg qd) for > 48 hours, whenever possible, before the index procedure. During the procedure, intravenous heparin was given to maintain an ACT >300 seconds. After the procedure, patients were treated indefinitely with oral aspirin (325 mg qd) and with either oral ticlopidine (250 mg bid) or oral clopidogrel (75 mg qd) for eight weeks.
Principal Findings:
252 patients were enrolled, and baseline characteristics were similar between groups (31% diabetics, mean lesion length 20 mm). Lesions were treated similarly prior to the study randomization. Procedural success was similar between groups, with similar acute gains in minimum lumen diameter (MLD) and other characteristics immediately after the procedure.
85% of patients underwent follow-up angiography at 6 months. The incidence of the primary endpoint of binary in-lesion restenosis was 32.4% in the radiation therapy group vs. 55.3% with placebo (p=0.01), with in-stent restenosis similarly lowered (21.6% vs. 50.5%, p=0.005). Patients in the radiation therapy group had larger in-stent MLD and smaller percent stenoses compared to patients in the placebo group, with less late loss (0.73 vs. 1.14 mm, p<0.001 for in-stent, 0.64 vs. 0.83 mm, p=0.05 for in-lesion). Treatment with radiation therapy was independently associated with a reduced incidence of angiographic restenosis in a multivariate model.
The rate of progression to the composite endpoint of death, MI, emergency CABG, and target vessel revascularization (TVR) was lower in the radiation group (28.2% vs. 43.8%, p=0.02), driven largely by lower rates of TVR. Late thrombosis (31-270 days after the procedure) was more frequent in the radiation group (5.3% vs. 0.8%, p=0.07), and there were more late myocardial infarctions in the radiation group. All patients in the radiation group with late thrombosis had stents placed during the index procedure, and no thromboses occurred in patients taking ticlopidine or clopidogrel or within one month of discontinuing these agents.
Interpretation:
In this multicenter, placebo-controlled, randomized trial of intracoronary gamma radiation for the treatment of ISR, treatment with radiation was associated with a 42% reduction in repeated revascularization of the target lesion, with lowered binary restenosis rates. These findings demonstrate the benefits of intracoronary brachytherapy in the treatment of ISR. However, these benefits were notably offset by a higher rate of late thrombosis. Among the patients with late thrombosis, however, no patients were taking dual antiplatelet therapy at the time of their event and all patients had received an additional stent at the time of the radiation therapy, suggesting that continuation of dual antiplatelet therapy beyond the recommended 8 week period and limiting the use of additional stents at the time of radiation therapy may be a way to mitigate late thrombosis.
References:
Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250-6.
Keywords: Myocardial Infarction, Coronary Restenosis, Ticlopidine, Constriction, Pathologic, Gamma Rays, Stents, Thrombosis, Coronary Vessels, Ultrasonography, Interventional, Iridium Radioisotopes, Brachytherapy, Diabetes Mellitus
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