Prolonged Antiplatelet Therapy to Prevent Late Thrombosis After Intracoronary γ-Radiation in Patients With In-Stent Restenosis
Washington Radiation for In-Stent Restenosis Trial Plus 6 Months of Clopidogrel (WRIST PLUS)
Background—Intracoronary γ-radiation reduces recurrent in-stent restenosis. Late thrombosis (>30 days after radiation therapy) is identified as a serious complication. The Washington Radiation for In-Stent Restenosis Trial (WRIST) PLUS, which involved 6 months of treatment with clopidogrel and aspirin, was designed to examine the efficacy and safety of prolonged antiplatelet therapy for the prevention of late thrombosis.
Methods and Results—A total of 120 consecutive patients with diffuse in-stent restenosis in native coronary arteries and vein grafts with lesions <80 mm underwent percutaneous coronary transluminal angioplasty, laser ablation, and/or rotational atherectomy. Additional stents were placed in 34 patients (28.3%). After the intervention, a closed-end lumen catheter was introduced into the artery, a ribbon with different trains of radioactive 192Ir seeds was positioned to cover the treated site, and a dose of 14 Gy to 2 mm was prescribed. Patients were discharged with clopidogrel and aspirin for 6 months and followed angiographically and clinically. All patients but one tolerated the clopidogrel. The late occlusion and thrombosis rates were compared with the γ-radiation–treated (n=125) and the placebo patients (n=126) from the WRIST and LONG WRIST studies (which involved only 1 month of antiplatelet therapy). At 6 months, the group receiving prolonged antiplatelet therapy had total occlusion and late thrombosis rates of 5.8% and 2.5%, respectively; these rates were lower than those in the active γ-radiation group and similar to those in the placebo historical control group.
Conclusions—Six months of clopidogrel and aspirin and a reduction in re-stenting for patients with in-stent restenosis treated with γ-radiation is well tolerated and associated with a reduction in the late thrombosis rate compared with a similar cohort treated with only 1 month of clopidogrel and aspirin.
Treatment of in-stent restenosis (ISR), especially when diffuse (>10 mm length), is challenging, and the recurrence rate is high (30% to 70%), regardless of the technique.1 Four randomized studies of intracoronary radiation using 192Ir have demonstrated a reduction in angiographic late loss, binary restenosis, and need for target lesion and target vessel revascularization compared with controls.2 3 4 5
Late total occlusion (LTO) and thrombosis (>30 days after intervention and radiation therapy) are serious complications of intracoronary radiation, with reported rates between 6% and 15%, especially after the placement of new stents.6 7 8 Preclinical studies demonstrated a relationship between radiation dose, platelet recruitment, and thrombus formation.9 10
Clopidogrel, an antiplatelet agent, proved to be effective in the reduction of subacute thrombosis when given with aspirin for 30 days after intracoronary stenting.11 In the present study, we (1) report a prospective registry examining the effectiveness of clopidogrel and aspirin for 6 months in reducing the incidence of LTO and thrombosis after catheter-based γ-radiation for patients with ISR and (2) compare the results with the active and placebo control groups from the Washington Radiation for In-Stent Restenosis Trial (WRIST) and WRIST in Lesions Longer than 36 mm (LONG WRIST) randomized trials using γ-radiation for diffuse ISR and only 1 month of antiplatelet therapy.
This clinical trial involved an Investigational Device Exemption granted by the Food and Drug Administration and was approved with informed consent by the Institutional Review Board. The study was designed as a prospective registry in 120 consecutive patients who presented with symptoms of angina with ISR in a native artery or vein graft. The control groups were the active γ-radiation (n=125) and the placebo groups (n=126) of the WRIST and the LONG WRIST studies, pooled together for comparison with the patients in the current study. Entry criteria included a diameter stenosis ≥50%, vessels 2.5 to 4.0 mm in diameter, and lesion length <80 mm with successful primary treatment (<30% residual stenosis without complications). Major exclusion criteria included recent (<72 hours) acute myocardial infarction (MI), ejection fraction <20%, angiographic thrombus, and/or allergy to antiplatelet therapy. Patients underwent intervention using a balloon, laser ablation, or rotational atherectomy. Additional stenting was discouraged; however, 34 lesions (28.3%) were re-stented for edge dissections or suboptimal angiographic results.
In WRIST PLUS, patients were treated with clopidogrel 300 mg loading before the intervention and with 75 mg/d for 6 months; in WRIST and LONG WRIST, clopidogrel or ticlopidine 250 mg/d was given for 30 days.
Radiation System and Dosimetry
After the intervention, a closed-end lumen catheter was introduced into the artery, and a ribbon with different trains of radioactive 192Ir seeds (6, 10, 14, 17, 19, and 23 seeds) was delivered by hand and positioned to cover the treated site. All seeds were equal in length (3 mm separated with a 1 mm space) and had a mean specific activity of 25.3±3.5 mCi. The prescribed radiation dose was 14 Gy to a 2 mm radial distance.
Study End Points and Data Analysis
The primary clinical end points were late thrombosis and the composite clinical events of death, MI, and target lesion revascularization at 6 months. Secondary angiographic end points were LTO, binary restenosis, and late loss (mm). An independent angiographic core laboratory analyzed the results. Angiographic binary restenosis (at 172±47 days) was defined as ≥50% diameter stenosis within the stent plus its edges (<5 mm). LTO was defined angiographically, and a minimum lumen diameter of 0 mm was imputed. Late thrombosis was defined as angiographic evidence of thrombus or presence of MI related to the treated vessel >30 days after the radiation. An independent committee adjudicated all events. Continuous variables were expressed as mean±SD; categorical data were expressed as percentages. Student’s t test was used to compare continuous variables; χ2 statistics or Fisher’s exact test was used to compare categorical values. Any variable significantly associated with the primary end points (P<0.20) was included in a stepwise logistic regression analysis.
A total of 120 patients (71 men; aged 61.1±11.5 years) with recurrent ISR were enrolled. Clinical characteristics included diabetes (39%), hypertension (69%), hyperlipidemia (86%), prior MI (46%), and current smokers (10%); these characteristics were similar to those in the historical control groups, and all patients but one tolerated the clopidogrel. Procedural details and the angiographic results are shown in Table 1⇓. Only one patient developed thrombosis on clopidogrel; this patient received a new stent at the time of the radiation, was found to have subacute closure at day 11 and had 2 additional stents implanted in the same vessel at that time, and 47 days later developed thrombosis with Q-wave MI. All the other patients in this cohort with late thrombosis or total occlusion did not receive new stents during the radiation treatment. One patient stopped the clopidogrel at 60 days and had a non–Q-wave MI with evidence of angiographic thrombosis on day 85. Two other patients who completed 6 months of clopidogrel with a patent artery presented with late thrombosis. One developed Q-wave MI and cardiogenic shock at day 200, and another developed non–Q-wave MI 100 days after cessation of the clopidogrel. Five more patients presented with angiographic LTO without events.
At the 6-month follow-up, irradiated patients in WRIST PLUS had an incidence of major adverse coronary events of 23.3% (28 of the 120 patients) versus 32.0% (40 of 125 patients; P=0.13) in patients from WRIST and LONG WRIST (Table 2⇓). Angiographic follow-up detected overall rates of 5.8% and 2.5% for LTO and late thrombosis, respectively, in patients treated with 6 months of clopidogrel. These rates are similar to those in the placebo group (1.6% and 0.8%) and lower than those in the active control group (13.6% and 9.6%) treated with 1 month of antiplatelet therapy (Figure⇓). The duration of antiplatelet therapy did not influence the binary restenosis and the late loss indices in the irradiated groups who were on antiplatelet therapy for 6 months versus 1 month of treatment (26% versus 27% and 0.58 mm versus 0.46 mm, respectively). No independent predictors of late thrombosis were identified. Radiation therapy was predictive of freedom from 6-month major adverse coronary events (odds ratio, 0.20; 95% confidence interval, 0.10 to 0.38; P<0.001).
Clinical trials using intracoronary radiation with the administration of antiplatelet therapy for <2 months have reported high rates of LTO and late thrombosis varying from 6% to 14%.6 7 8 The present trial indicates that prolonged antiplatelet therapy (6 months) after γ- radiation in patients treated for ISR reduces the rate of LTO and late thrombosis compared with similar historical controls. Only one patient developed late thrombosis on clopidogrel, and the overall thrombosis rate was similar to that of the placebo group in the randomized γ-radiation trials. In previous analyses, we determined that additional stenting was a strong correlate for late thrombosis.6 The reduction of re-stenting in this registry (28.3% versus 56% of historical active controls; P<0.001) could also contribute to the overall lower rate of late thrombosis.
LTO without clinical events could be related to a different mechanism of action, such as progression of the disease that leads eventually to occlusion. Interestingly, none of the patients with LTO without events had additional stent implantation, and the rate of LTO without events did not differ between the short versus the long-term antiplatelet therapy groups (4.0% versus 3.3%; P=NS).
The effectiveness of γ-radiation in reducing recurrent ISR was comparable to that reported in other γ-radiation trials.2 3 4 5 This study did not detect differences in the restenosis rate between our patients and the radiated controls. Thus, clopidogrel does not contribute to a further reduction of the restenosis rate, and its main role is to prevent late thrombosis. Prolonged clopidogrel therapy (3 to 6 months) was associated with comparable late thrombosis rates in studies for ISR that used β-emitters (START [Stents and Radation Therapy] used 90Sr/Y and INHIBIT [Intimal Hyperplasia Inhibition with Beta In-Stent Trial] used 32P).12 In these trials, the rates of late thrombosis were 0.5% and 1.8%, respectively.
Finally, the 2 late thrombotic events that occurred after the 6 months of clopidogrel treatment while patients continued to take aspirin raise the question of whether 6 months of antiplatelet therapy will be enough to eradicate this phenomenon.
The encouraging results of the current study suggest that prolonged antiplatelet therapy after intracoronary radiation and reducing re-stenting during intervention for patients with ISR result in a reduction of late thrombosis rates to background levels that are similar to those seen in patients treated without radiation. The optimal duration of clopidogrel beyond 6 months is still unknown and will require further investigation.
Dr Waksman serves as a consultant to several restenosis prevention, radiation device companies.
- Received January 16, 2001.
- Revision received March 15, 2001.
- Accepted March 29, 2001.
- Copyright © 2001 by American Heart Association
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