The only gamma emitter used in clinical trials for in-stent restenosis is 192Iridium (192Ir). The efficacy of intracoronary gamma radiation therapy in reducing clinical and angiographic restenosis in patients with in-stent restenosis has been established. This review is intended to give an overview of the clinical trials utilizing gamma vascular brachytherapy in patients with in-stent restenosis and give insight into the future of intracoronary radiation therapy.

In-stent restenosis (ISR) has become a major clinical problem. The rate of ISR is 7–37% of patients who undergo stent implantation and is dependent on patient characteristics, lesion morphology, and procedural technique.1 The recurrence rate after treatment for ISR varies among reported series but remains high, ranging from 50–85%, regardless of treatment modalities, including balloon angioplasty, rotational atherectomy, excimer laser ablation, and re-stenting. The diffuse pattern of ISR (> 10 mm) is associated with even higher rates of recurrence and presents a therapeutic challenge.2–4 Serial intravascular ultrasound (IVUS) studies have demonstrated that ISR results primarily from neointimal tissue hyperplasia distributed either focally or diffusely over the entire length of the stent.5,6

Recently, drug-coated stents (especially sirolimus) have shown extraordinary promise with excellent immediate angiographic and intravascular ultrasound results including the one-year follow-up data; however, their utility for ISR is unknown.7,8 Clinical feasibility studies in patients with ISR have suggested reduced post-angioplasty restenosis after gamma and beta radiation therapy.9,10 The only gamma emitter used in clinical trials for ISR is 192Iridium (192Ir). The efficacy of intracoronary gamma radiation therapy in reducing clinical and angiographic restenosis in patients with ISR has been confirmed by a number of clinical trials (Table 1). This review is intended to update and summarize the current status of clinical trials utilizing gamma vascular brachytherapy to prevent the recurrence of ISR.

Table 1

SCRIPPS (Scripps Coronary Radiation to Inhibit Proliferation Post Stenting). SCRIPPS was the first randomized trial to determine the safety and efficacy of intracoronary gamma radiation given as adjunctive therapy to stents. In this study, there were 26 of 54 patients who were randomized to receive 192Ir (8–30 Gy, dosimetry guided by IVUS) utilizing a ribbon (19–35 mm) delivered in a non-centered, closed-end lumen catheter at the treatment site (dwell time: 20–45 minutes). Only 35 patients in this cohort were patients with ISR. This study demonstrated that at 6 months, the angiographic restenosis rate was reduced with radiation (17% vs. 54%; p < 0.01). At 3 years, these results remained consistent (33% vs. 64.3%; p < 0.05). Subanalysis of the lumen diameter for patients who did not have further intervention demonstrated minimal reduction of the MLD of the irradiated segments versus control at 3 years. There were no evident clinical complications resulting from the radiation treatment, and clinical benefits were maintained at 3 years, with a significant reduction in the need for target lesion revascularization (p = 0.004). A subgroup analysis for the 35 patients with ISR has shown a 70% reduction of the recurrence rate in the irradiated group versus the placebo group.11

WRIST (Washington Radiation for In-Stent Restenosis Trial). WRIST is a series of studies that were designed to evaluate the effectiveness of radiation therapy for ISR.12 The gamma radiation in these studies is composed of ribbon with different trains of radioactive (192Ir) seeds, which are inserted manually into a closed-end lumen catheter. In the initial study, a total of 130 patients (100 patients with native coronaries and 30 patients with vein grafts) with ISR lesions (up to 47 mm in length) were blindly randomized to treatment with either placebo or 15 Gy of 192Ir at 2 mm from the source of the vessel wall. At six months, clinical and angiographic follow-up showed a dramatic reduction of the restenosis rate between the irradiated group and the control group, 19% vs. 58%, respectively (p = 0.0001). There was a 79% reduction in the need for revascularization and a 63% reduction in major adverse cardiac events (death, Q-wave myocardial infarction or target vessel revascularization) in the irradiated group compared to control. Intravascular ultrasound subanalysis demonstrated 53% of lesions from the irradiated group had increased luminal dimensions and regression of neointimal tissue at 6 months. Between 6 and 48 months, an interesting observation was noted; IRT compared to placebo patients had more target lesion revascularization (18% vs. 2%; p = 0.001) and target vessel revascularization (19% vs. 3%; p = 0.003). This likely reflects an initial freezing of neointimal growth with IRT, with diminished effectiveness over time. However, at 4-year clinical follow-up, the IRT cohort continued to have markedly lower MACE rates when compared with controls (40% vs. 65%; p = 0.005). The WRIST study is considered to be a landmark in establishing gamma radiation for the treatment of ISR.

LONG WRIST. LONG WRIST was a randomized trial involving 120 symptomatic patients with diffuse, in-stent restenotic lesions 36–80 mm (mean stent length: 70 mm) who received either a ribbon bearing 192Ir seeds or placebo seeds delivered to the target site via a noncentered, closed-lumen catheter. The radiation dosage consisted of 14–15 Gy at 2 mm distance from the center of the source. Quantitative coronary angiography at 6 months disclosed rates of restenosis of 32% in the irradiated group and 71% in the control group within the stented segment only (p = 0.0002). Rates of restenosis considering only the segment containing the lesion were 46% and 78%, respectively (p = 0.03). The 6-month rates of major adverse cardiac events were 38.3% and 61.7%, respectively (p = 0.01), with most of the significant difference accounted for by the TLR component, the rates for which were 30% and 60%, respectively (p = 0.001). The rate of late total occlusion at any time during the follow-up was 15% of irradiated patients and 6.7% of controls.

LONG WRIST HIGH DOSE. LONG WRIST High Dose was a registry of 120 patients with similar entry criteria to LONG WRIST. In comparison to LONG WRIST, a higher radiation dose was prescribed with 18 Gy delivered at 2 mm distance from the center of the source. The second 60 consecutive patients of LONG WRIST High Dose received prolonged antiplatelet therapy (clopidogrel or ticlopidine) for 6 months, instead of 1 month. Baseline clinical and angiographic details were similar in both study groups. At 6-month follow-up, major adverse cardiac events were reduced by 39% in the high-dose group (23% vs. 38%; p = 0.11) compared to LONG WRIST. Patients in the LONG WRIST High Dose group with 6 months antiplatelet therapy had a strikingly low rate of TVR (17%) and MACE (17%) compared to one month of antiplatelet therapy and the LONG WRIST groups.

IVUS analysis post-intervention and at 6-month follow-up was performed in 25 patients from LONG WRIST High Dose and in 30 IRT and 34 placebo patients from LONG WRIST.13 Stent length was longer in LONG WRIST High Dose than in placebo or treated patients in LONG WRIST (p = 0.006 and p = 0.013, respectively). At follow-up, the minimum lumen area was largest in the LONG WRIST High Dose patients (4.0 ± 1.4 mm2); areas were 2.9 ± 1.0 mm2 in IRT patients and 1.9 ± 1.1 mm2 in placebo patients in LONG WRIST (p < 0.005 for all comparisons). The clinical and serial IVUS analysis shows that IRT reduces recurrent in-stent neointimal hyperplasia in diffuse ISR lesions; furthermore diffuse lesions may require higher radiation doses and prolonged antiplatelet therapy to maintain the efficacy seen in focal lesions and minimize recurrent clinical events at 6 months.

SVG WRIST (Washington Radiation for In-Stent restenosis Trial for Saphenous Vein Grafts). SVG WRIST was a Food and Drug Administration (FDA) approved, double-blind, multicenter, randomized trial in patients post coronary bypass surgery with diffuse ISR of saphenous vein grafts (SVG). SVG WRIST was the first study to examine the effects of gamma radiation therapy on patients with ISR in bypass grafts. A total of 120 patients with diffuse ISR in SVG underwent PTCA, laser ablation or rotational atherectomy, and/or additional stents. After the intervention, a non-centered, closed-end lumen catheter was positioned at the treated site, and patients were randomly assigned to a ribbon with either 192Ir or with non-radioactive seeds both delivered by hand. Different ribbon lengths of 6, 10 and 14 seeds with a mean radiation length of 34 ± 22 mm were used to cover lesions < 47 mm in length. The prescribed radiation doses were 14 or 15 Gy to a 2 mm radial distance from the center of the source for vessels with a diameter of 4 mm and 15 Gy at 2.4 mm for vessels > 4 mm in diameter. The patients with restenosis at follow-up were eligible to receive radiation if initially randomized to placebo. The closed-end lumen catheter with either the active or the placebo seeds was delivered successfully to all patients. A mean dwell time of 21.1 ± 4.8 minutes was well tolerated in irradiated patients. At 30 days, there were no adverse events related to the radiation therapy. At 6 months, the restenosis rate was significantly lower in the irradiated group compared to control (15% vs. 43%; p = 0.004). The need for repeat intervention at the treatment site was significantly reduced by 79% in the irradiated group compared to control (10% vs. 48%; p < 0.001), and the overall major cardiac events were reduced in the irradiated group (20% vs. 55%; p < 0.001). The rate of late thrombosis in the irradiated group was 1.7% versus 6.7% in the control (p = NS), and there was no excess of edge effect in the irradiated group when compared to the control.
IVUS analysis post-intervention and at 6-month follow-up was performed. In the irradiated patients, there was no change in stent, lumen, or intimal hyperplasia (IH) area or volume, while in the control patients there was an increase in intra-stent IH area (p < 0.0001) resulting in a decrease in lumen area (p < 0.0001). Conventional treatment of ISR in bypass grafts is associated with a high recurrence rate. The SVG WRIST study demonstrated that catheter-based gamma radiation therapy for ISR in bypass grafts was safe and effective in reducing the overall restenosis rate and the need for repeat revascularization.

We examined 1,142 patients (230 in SVG and 912 in native coronaries) from the WRIST series of studies and found that gamma IRT in saphenous vein grafts had similar outcome to native coronaries with equivalent rates of angiographic restenosis (22% vs. 29%; p = NS) and target vessel revascularization (27% vs. 23%; p = NS) at 6-month follow-up.

WRIST PLUS. WRIST PLUS was driven by the late thrombosis risk seen in the early radiation trials. This was a registry of 120 patients with similar entry criteria to the WRIST protocol, but with 6 months of clopidogrel (75 mg QD) in addition to aspirin, designed to evaluate whether prolonged antiplatelet therapy would reduce late thrombotic event rates.14,15 The rate of target lesion revascularization was 21%, the rate of target vessel revascularization was 23%, and cumulative MACE was 23% at 6 months. Eight patients (5.8%) had late total occlusion at 6-month follow-up, of which 3 patients (2.5%) developed late thrombosis. When the WRIST PLUS group was compared to IRT patients in WRIST and LONG WRIST (1-month antiplatelet treatment), the strategy of prolonged antiplatelet therapy reduced the thrombosis rate (2.5% vs. 9.6%; p = 0.02), to levels seen in controls. To date, no events have been reported in 29 patients who continued taking clopidogrel. The optimal duration of clopidogrel therapy to prevent late total occlusion beyond 6 months is still unknown, which led to the inception of WRIST 12.

WRIST 12 (Washington Radiation for In-Stent restenosis Trial with 12 months of clopidogrel). WRIST 12 is a FDA-approved registry of 120 patients with diffuse ISR in native coronaries and saphenous vein grafts with lesions < 80 mm in length. Patients underwent intervention using balloon, atheroablation and/or re-stenting (38% patients), and were then treated with IRT using 192Iridium. Patients were discharged on 12 months of clopidogrel (75 mg QD) and scheduled for angiographic follow-up at 15 months. Clopidogrel was tolerated well and there was no report of leukopenia. No deaths or Q-wave myocardial infarctions were reported at 6 months, and the MACE rate was 13%. At 12 months, the group receiving 12-month prolonged antiplatelet therapy had overall 19% major adverse cardiac events and 18% of target lesion revascularization, compared to 33% and 33%, respectively, in patients who were treated with only 6 months of clopidogrel (p = 0.013 and p = 0.012, respectively), while the late thrombosis rates were 2.5% with 12 months versus 4.2% in the 6-month antiplatelet group (p = 0.72). At least 12 months of clopidogrel therapy should be recommended for patients undergoing radiation therapy for in-stent restenosis.

CURE WRIST (Compassionate WRIST). CURE WRIST is an open-label registry of patients with ISR who had at least 2 episodes of restenosis at the target lesion and are not considered good candidates for CABG or medical therapy. Patients are eligible to participate if approved by all members of a committee (interventional cardiologist, radiation oncologist and cardiac surgeon). The angioplasty procedure involves >= 1 vessel (native coronary artery or saphenous vein graft) followed by IRT with 192Iridium (14 or 15 Gy to 2 mm). At this time, a total of 173 patients have been enrolled. The mean age of the cohort is 63 ± 16 years (A total of 70% males and 45% diabetics, also 87% had previous cardiac bypass grafting). The target lesion involved a saphenous vein graft in 40% of cases; in addition, a total of 40% of patients received re-stenting. The IRT was delivered successfully in all cases with a mean source train length of 61 ± 19 mm. Six-month, one- and two-year events confirm sustainable outcomes in this refractory patient cohort who did not respond to conventional standard of care.

GAMMA-1. GAMMA-1 was a multicenter, randomized, double-blind trial studying the effects of hand-delivered 192Ir ribbon using intravascular ultrasound to guide dosimetry (dose range 8–30 Gy) in 252 patients with ISR. Six-month angiographic results revealed significant reductions in the in-stent (22% vs. 52%) and in-lesion (33% vs. 56%; p = 0.006) angiographic restenosis rates of the radiation arm versus control. Subanalysis for lesion length demonstrated a 70% reduction in the angiographic restenosis rate for lesions < 30 mm in length versus 48% for 30–45 mm lesions.16 In addition, edge effect was noted in patients who did not have enough coverage of the lesion by the radioactive seeds. Clinical events demonstrated a reduction in the TLR rate from 42% to 24%. However, the rate of death (3% versus 0.8%) and the rate of acute MI (12% versus 6%) were higher in the irradiated group versus control. These complications were related in part to the late thrombosis phenomenon.

GAMMA-2. GAMMA-2 is a registry of 125 patients who were treated for the same inclusion/exclusion criteria as GAMMA-1, but with a fixed dosimetry of 14 Gy at 2 mm from the center of the source. The treated lesions in GAMMA-2 were more heavily calcified, whereby 45% of patients required rotational atherectomy in contrast to 26% of patients in GAMMA-1. Despite the differences in lesions, the results between GAMMA-1 and -2 were remarkably similar. Both studies had similar and infrequent in-hospital adverse clinical events (2%). GAMMA-2 patients had a lower post-procedural MLD, perhaps due to increased lesion complexity and the fact that fewer stents were placed in GAMMA-2 patients, as compared to GAMMA-1. Similar to GAMMA-1, there was a 52% in-stent and a 40% in-lesion reduction in restenosis frequency. TLR was reduced by 48% and MACE was reduced by 36%. The late thrombosis rate was 4% at 270 days with only 8 weeks of antiplatelet therapy.

ARTISTIC (Angiorad Radiation Technology for In-Stent restenosis Trial In native Coronaries). ARTISTIC is a blinded, randomized trial examining the benefits of using a flexible, 30 mm 192Ir wire source in 300 patients with in-stent restenosis in native coronary arteries.17 The pilot phase of this study was recently completed and involved 26 patients at two centers, all of whom received radiation treatment. Inclusion criteria consisted of lesions < 25 mm in length with a reference vessel diameter between 2.5 and 5.0 mm and a degree of stenosis between 50–99%. Radiation was successfully delivered to 25 of 26 patients. At 6-month angiographic follow-up, low binary restenosis rates of 14% were reported with a late loss index of 0.12 and a 15% rate of MACE. A randomized study using the same system was halted after enrolling 110 patients. Preliminary results of this study demonstrated significant reduction in the angiographic restenosis rate in the irradiated arm.

INTEGRILIN WRIST. Integrilin WRIST is a single-center study of 300 patients, with randomization to a glycoprotein IIb/IIIa antagonist (Integrilin) or placebo in patients receiving gamma radiation (192Iridium) for ISR. This study specifically aims to assess the impact of Integrilin in reducing early cardiac enzyme release after percutaneous intervention with the potential for improved longer term clinical outcomes. Enrollment will be completed by mid-2002.

EDGE WRIST. EDGE WRIST is also a single-center registry, which is designed to address the question whether large margins (12 mm) from the injured segment will reduce the edge effect phenomenon. This study continues enrollment with projected completion in mid-2002. Edge restenosis maybe a limitation of intracoronary irradiation to prevent in-stent restenosis. Inadequate radiation source coverage of the injured segment, called “geographical miss,” has been proposed as a cause of edge restenosis.
We examined 506 patients from the WRIST series and found edge restenosis in 43 patients (8.5%). The majority of these lesions were focal (< 10 mm).

Event-free survival at 6 months was 85% and at 12 months 82%, which suggests encouraging outcomes after repeat intervention with conventional strategies. The coronary angiograms of 100 patients from WRIST were analyzed for edge restenosis (follow-up stenosis of >= 50% occurring £ 5 mm proximally and distally to the last seed of the radiation source) and geographic miss (injured segments not covered by the radiation source).18 Edge restenosis occurred in 10% of IRT patients and 4.7% of controls (p = NS). In patients with geographic miss, edge restenosis occurred in 21% of IRT patients and 7% of controls. In both groups (IRT and controls), late edge lumen loss was greater in IRT patients than controls (p < 0.001). A low radiation dose in the fall-off zone at the source ends in combination with vessel injury may stimulate neointimal formation. It is critical to ensure meticulous positioning of the source train in relation to the injured vessel segment in an effort to avoid edge restenosis.

RE-WRIST. Approximately one-quarter of the patients enrolled in radiation studies for ISR required repeat revascularization to the irradiated site. Re-WRIST is a 30-patient registry evaluating the safety and efficacy re-treatment with IRT in patients with refractory ISR. To meet eligibility requirements, patients had to fail an additional angioplasty after the index radiation procedure. The prescribed dose was 15 Gy to a 2 mm radial distance from the center of the source. All patients received 6 months of clopidogrel post-procedure. At present, 13 patients have been enrolled in the Re-WRIST registry. The mean age of the cohort is 65 ± 10 years (7 patients had previous CABG). The mean time interval between radiation treatments was 18 months (range 6.4–28.9) and the mean number of previous interventions to the target lesion is 4.1 ± 1.5. The radiation was delivered successfully in all patients, with no procedural or hospital complications. No clinical events have been reported to 30-day follow-up. At this preliminary stage, repeat radiation therapy appears feasible; however, clinical follow-up is needed.

Specific Observations. Specific patient subgroups, such as diabetics and patients with chronic renal failure, have traditionally had higher rates of restenosis. The WRIST trials have demonstrated that IRT for ISR reduces the chance of recurrent restenosis to rates seen in patients without these diseases, the so-called “equalizing effect” of IRT.19,20 Total occlusion of ISR lesions at entry in the WRIST studies is frequent (12%) and has a 94% successful recanalization rate with conventional percutaneous coronary intervention. Intracoronary radiation therapy for totally occluded ISR is associated with similar 6-month target vessel revascularization rates (20% vs. 20%; p = NS) outcomes to non-occlusive ISR.

Conclusions. The clinical trials of intracoronary gamma radiation therapy have demonstrated a dramatic reduction in clinical and angiographic restenosis in patients with in-stent restenosis. The encouraging results from the clinical trials have established intracoronary radiation as promising therapy for patients with in-stent restenosis, despite potential adverse effects such as edge restenosis and late thrombosis. The long-term benefits are still unclear, and potential long-term risks, such as malignancy, mandate continued judicious follow-up of all irradiated patients. While the advent of drug-coated stents has been a major advance in interventional cardiology, their application for in-stent restenosis is unknown at this time, and results of ongoing studies are awaited with anticipation. At present, it is clear that intracoronary radiation therapy remains the cornerstone therapy for in-stent restenosis.

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