Intracoronary β-Radiation Therapy Inhibits Recurrence of In-Stent Restenosis
Background—Intracoronary γ-radiation therapy reduces recurrent in-stent restenosis (ISR). This study, BETA WRIST (Washington Radiation for In-Stent restenosis Trial) was designed to examine the efficacy and safety of the β-emitter 90-yttrium for the prevention of recurrent ISR.
Methods and Results—A total of 50 consecutive patients with ISR in native coronaries underwent percutaneous transluminal coronary angioplasty, laser angioplasty, rotational atherectomy, and/or stent implantation. Afterward, a segmented balloon catheter was positioned and automatically loaded with a 90-yttrium, 0.014-inch source wire that was 29 mm in length to deliver a dose of 20.6 Gy at 1.0 mm from the balloon surface. In 17 patients, manual stepping of the radiation catheter was necessary for lesions >25 mm in length. The radiation was delivered successfully to all patients, with a mean dwell time of 3.0±0.4 minutes. Fractionation of the dose due to ischemia was required in 11 patients. At 6 months, the binary angiographic restenosis rate was 22%, the target lesion revascularization rate was 26%, and the target vessel revascularization rate was 34%; all rates were significantly lower than those of the placebo group of γ-WRIST.
Conclusions—β-Radiation with a 90-yttrium source used as adjunct therapy for patients with ISR results in a lower-than-expected rate of angiographic and clinical restenosis.
The treatment of in-stent restenosis (ISR), especially when diffuse (>10 mm in length), is challenging, and the recurrence rate is high (30% to 70%), regardless of the technique used.1 2 3 Randomized studies of intracoronary γ-ionizing radiation (Ir-192) have demonstrated a reduction in angiographic late loss, binary restenosis, and the need for target lesion revascularization and target vessel revascularization compared with controls.4 5 Preclinical studies using β-emitters demonstrated a reduction of neointima formation in stented arteries in the porcine model.6 7 Clinical feasibility studies have suggested that β-emitters reduce postangioplasty restenosis.8 9 In the present study, we report a prospective registry examining the effectiveness and safety of intracoronary catheter-based radiation treatment of ISR, and we compare the results with the placebo control from the Washington Radiation for In-Stent restenosis Trial (WRIST), a randomized trial of γ-radiation treatment of ISR.
This clinical trial involved an Investigational Device Exemption granted by the Food and Drug Administration, and it was approved by the Institutional Review Board and the Radiation Safety Committee at the Washington Hospital Center. Informed consent was obtained from all patients. The study population was 50 patients who had symptoms of angina and native artery ISR. Entry criteria included a diameter stenosis >50%, vessels 2.5 to 4.0 mm in diameter, and lesion length <47 mm, with successful (<30% residual stenosis without complications) primary treatment. Exclusion criteria included recent (<72 hours) acute myocardial infarction (MI), ejection fraction <20%, angiographic thrombus, and multiple lesions in the same vessel.
Radiation Delivery System, Dosimetry, and Procedure
The β-radiation system used a 90-yttrium pure β-emitter with maximum energy of 2.28 Mev, a half-life of 64 hours, and an initial activity of ≈130 mCi. The source was a flexible, 0.014-inch wire that was 29 mm in length and was secured between the distal and proximal tungsten markers for accurate positioning. The source wire was delivered into a centering balloon-closed end-lumen catheter 30 mm in length with 4 interconnected-segmented balloons 2.5 to 4.0 mm in diameter (Schneider-Europe AG). The afterloader (Sauerwein Isotopen-Technique Germany) automatically advanced the source to the target and computed the dwell time on the basis of activity, prescription dose, and balloon size. The prescribed dose was 20.6 Gy to a distance of 1.0 mm from the surface of the inflated balloon. The dose rate varied from 16.0 to 5.6 Gy/min. The maximum calculated dose to the vessel wall was 38 Gy. Focal ISR was treated with balloon dilatation (n=3). Diffuse lesions were treated either with excimer laser angioplasty (n=5) or rotational atherectomy (n=27) followed by balloon dilatation. Additional stents (n=18) were used to optimize final results or to cover edge dissections.
The centering catheter was selected on the basis of vessel size and was placed to cover the treatment segment. The catheter was connected to the afterloader, and the segmented balloons were inflated with 5 cc of CO2 to avoid the shielding of β-rays by contrast. For lesions >25 mm in length (n=17), the balloon catheter was positioned in 2 steps, with an overlap of ≤2 mm at the stented segment to cover the lesion and the edges. The calculated dose at the overlapped area did not exceed 70 Gy to the vessel wall. After the radiation treatment, the source was automatically redelivered back to the afterloader, and an angiogram and IVUS study documented the final result. Patients were discharged on a daily dose of clopidogrel 75 mg or ticlopidine 500 mg, given for a month.
Primary and Secondary End Points
The primary end point was the cumulative composite clinical outcome (major adverse clinical events [MACE]) of death, MI, and repeat target lesion revascularization at 6 months. Secondary angiographic end points were restenosis, late loss (in millimeters), and loss index (late loss/acute gain). Quantitative coronary angiographic analysis was performed using the cardiovascular measurement system (Medis [The Netherlands]). Angiographic binary restenosis (at 172±47 days) was defined as <50% diameter stenosis. A minimum lumen diameter of 0 mm was imputed in the presence of a total occlusion. Lesions extending <5 mm proximal and distal to the radiated segment were identified for target lesion revascularization and any lesions beyond these margins for target vessel revascularization.
Intravascular ultrasound (IVUS) analysis (motorized transducer pullback) was performed both at baseline and follow-up. Volumes were calculated from planar measurements that were performed at every 1-mm axial length.
An external committee independently adjudicated all events in a blinded fashion. Results are expressed as mean±1SD. The sample size of 50 patients was selected (80% power and 95% confidence) to demonstrate a 50% reduction in MACE when compared with the control group of the native coronary arteries from the WRIST study.5 Student’s t test was used to compare continuous variables; χ2 statistics or Fisher’s exact test was used to compare categorical values.
A total of 50 patients (30 men and 20 women aged 60±10 years) with ISR were enrolled in the study. Clinical characteristics included diabetes (24%), hypertension (73%), hyperlipidemia (86%), current smokers (18%), prior MI (55%), and prior procedures to the treated site (1.46±0.46). Angiographic results are shown in Table 1⇓. All patients had acute angiographic success without complications. The average size of the centering balloon was 3.15±0.45 mm in diameter, and the mean dwell time was 3.0±0.9 minutes; fractionation of the radiation treatment due to ischemia was necessary in 11 of the 50 patients. Radiation exposure at the patient chest was 7.0±0.8 miliRam/h and at bedside, 0.07±0.01 mR/h. No procedural or in-hospital adverse events or complications related to the radiation existed at 30 days.
At the 6-month follow-up (Table 2⇓), MACE had occurred in 17 of the 50 patients (34%). Angiographic follow-up was performed in 42 patients (Figure 1⇓). ISR (confined to the borders of the stent) was present in 9 of 41 patients (22%), but in-lesion restenosis (extending >5 mm proximal and distal to the irradiated segment) existed in 14 of 41 patients (34%). MACE and angiographic restenosis were significantly lower in the treated group than in the control group (from WRIST); these values were 34% versus 66% (P>0.01) and 34% versus 72% (P>0.01), respectively.
IVUS follow-up was performed in 25 patients. Intimal hyperplasia volume increased by 16±30 mm3, and minimum lumen area decreased by only 1.0±1.4 mm2. These indices are significantly different from the values in the control group (56±55 mm3 and 2.0±1.7 mm2; P>0.01 and P=0.02, respectively).
Late total occlusion (2 to 6 months) after the procedure was detected in 5 patients, 4 of whom presented with clinical events. Two had non-Q-wave MI and 2 had unstable angina.
Multivariant analysis detected β-radiation as the only predictor for the reduction of angiographic restenosis (odds ratio, 0.17; 95% confidence intervals, 0.059, 0.494; P<0.01) and cardiac events (odds ratio, 0.28; 95% confidence intervals, 0.111, 0.705; P<0.01).
Prior clinical trials with β-emitters demonstrated lower indices of late loss and loss index after angioplasty in de novo lesions. The present trial is the first to indicate the feasibility and effectiveness of intracoronary β-radiation to prevent recurrent ISR. Because this study was based on a registry, the effectiveness of β-radiation was inferred from a comparison with recurrence rates in control groups from similar studies (Scripps Coronary Radiation to Inhibit Proliferation Post Stenting [SCRIPPS], 55%4 ; WRIST, 62%5 ; GAMMA1, 55%5a; and from the angioplasty [52%] versus rotablation [65%] study for the treatment of diffuse restenosis [ARTIST]). The restenosis rates (in-stent and at the edge) in our study, although slightly higher, were similar to those reported in γ-WRIST (Figure 2⇓). The rapid fall of the dose and the potential shielding of the β-radiation by the stent10 required a higher prescribed dose in the current trial than in the γ trials. However, the centering catheter allowed us to provide a uniform dose to the vessel wall (35 Gy). This dose was less than the recorded dose of a non-centered γ-source (47 Gy), for a similar dose prescribed to the adventitia. Overlapping the source to treat longer lesions did not increase complications. A major limitation of the technique is the high rate of late thrombosis that occurred, especially when additional stents were placed (4 of 18 patients [22%] versus 1 of 32 patients [3%] without additional stents, which is similar to rates reported in other studies using β- and γ-emitters).11
This study was not a randomized, placebo-controlled study, and it is limited to 6 months of follow-up. Although the inclusion/exclusion criteria were identical to those of γ-WRIST, the placebo group had some increased risk for restenosis, such as longer lesion length and smaller reference vessel diameter. However, multivariate analysis detected β-radiation as the only predictor for a reduction of angiographic restenosis and clinical events.
The encouraging results of the current study suggest that intracoronary β-radiation using 90-yttrium may be a viable therapeutic option for patients with ISR. These findings should be corroborated in randomized clinical trials.
This study was supported by the Cardiovascular Research Foundation and, in part, by Scimed, Boston Scientific.
Reprint requests to Dr Ron Waksman, Washington Hospital Center, 110 Irving St, NW, Suite 4B-1, Washington, DC 20010.
The principal investigator, Dr Ron Waksman, serves as a consultant to several device companies, including the sponsors of this study.
- Received December 30, 1999.
- Revision received February 22, 2000.
- Accepted February 22, 2000.
- Copyright © 2000 by American Heart Association
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