Background：
Patients who receive percutaneous transluminal coronary angioplasty (PTCA) are often haunted by restenosis of the target vessel within 6 months. Intracoronary irradiation has been shown to alter the luminal narrowing response after balloon angioplasty.
Methods:
The Taiwan Radiation in Prevention of Post-Pure Balloon Angioplasty Restenosis-I (TRIPPER-I) study evaluated the feasibility, safety, and 6-month angiographic restenosis with intracoronary irradiation after pure balloon angioplasty (POBA) of de novo and post-POBA restenotic lesions in native coronary arteries using a self-centering b-emitter rhenium-188 (Re-188)-filled balloon.
Results:
Forty patients received 14 Gy at a 0.5-mm tissue depth with a Re-188 solution-filled perfusion balloon catheter, and 25 control patients received 5-min inflation with a perfusion balloon catheter. There were no procedural complications or in-hospital or 30-day major adverse cardiac events. Six-month angiographic follow-up was performed on 39 Re-188 (97.5%) and 25 control patients (100%). The restenosis rate was 49% in the Re-188 and 56% in the control groups (p=0.62). The composite end-points of death, myocardial infarction, and target-vessel revascularization were 40% in the Re-188 group and 36% in the control group (p=0.80).
Conclusions:
Catheter-based radiotherapy after POBA of de novo and post-POBA restenotic lesions with a Re-188-filled balloon is feasible but was ineffective in reducing target lesion restenosis with a dose of 14 Gy delivered at a 0.5-mm tissue depth in this study.
(Chang Gung Med J 2003;26:98-106)

Key words:
angioplasty, restenosis, coronary artery disease, brachytherapy.

METHODS

Study design
This was a prospective, non-randomized, single-center study approved by the Ethics Committee of our institution and Ministry of Health authorities. The Re-188 isotope was produced at the Institute of Nuclear Energy Research and delivered once every 1-2 weeks to our hospital for intracoronary brachytherapy. Patient enrollment to either the radiation or control group was dependent on the availability of the Re-188. There was no attempt to match the control group with the irradiation group. Between August 1999 and August 2000, 40 study and 25 control patients were enrolled in the study. At the time of registration, patients were evaluated by a radiation oncologist and interventional cardiologist. Risks and benefits were discussed with the patients. Patients willing to provide written informed consent were enrolled in the study. The criteria for enrollment were an age of 50 years or older, clinically indicated balloon angioplasty of a native coronary artery (either de novo or post-POBA restenotic lesions), target lesion with a reference vessel of between 2.5 and 3.5 mm in diameter, and lesion length ?5 mm. Patients were excluded if the POBA procedure was not successful, the final angiographic residual stenosis was greater than 30% by on-line quantitative coronary analysis (QCA), a stent had been implanted, there was angiographic evidence of a thrombus in the target lesion, or the patient was pre-menopausal, had previous thoracic therapeutic radiation, advanced renal failure (creatinine greater than 3.0 mg/dl), left ventricular ejection fraction < 25%, evolving myocardial infarction within 72 hours, or had used thrombolytic or GpIIb/IIIa inhibitors within the previous 48 hours. At 1 and 6 months after the procedure, telephone contact with the patient, an outpatient visit, or chart check was employed to record the recurrent ischemic symptoms, death, target vessel myocardial infarction, or requirement for revascularization of the treated vessel. All patients were admitted to the hospital at around 6 months post-procedure for repeat coronary angiography.
The primary end point of the study was the angiographic restenosis rate at 6 months after the procedure. The secondary end points were the following major adverse cardiac events: death, myocardial infarction, coronary artery bypass surgery, and percutanoeus intervention in the target vessel.

Procedure
Patients were pretreated with 100 mg/day aspirin. An intravenous or intracoronary bolus of 10,000 IU heparin was administered prior to the placement of a 0.014-inch guidewire into the target coronary artery. POBA balloon sizes were chosen by visual estimation or QCA of the reference vessel diameters. Gradual increments of the POBA balloon pressures or sizes were made to achieve a less than 30% residual stenosis by on-line QCA. The involved lesion was successfully treated if the residual stenosis was less than 30% according to on-line QCA. After the successful POBA, media-to-media measurements at the index study were obtained by intravascular ultrasonography (IVUS) to determine the radiation dose. The IVUS study was only intended for vessel sizing, not for determination of the adequacy of the POBA. No further intervention was performed for an unsatisfactory post-POBA result, such as dissection or small minimal luminal diameter (MLD), according to the IVUS study. Irradiation and control procedures were carried out after successful POBA without stenting or use of any other devices. A Lifestream perfusion balloon dilatation catheter (Advanced Cardiovascular Systems, Santa Clara, CA) was used in both the Re-188 and control groups to deliver the irradiation and diluted contrast, respectively. The size of the perfusion balloon for the delivery of the Re-188 isotope was within ±0.5 mm of the reference vessel diameter by IVUS. The balloon was prepared by applying negative pressure with an empty 10-ml syringe via a 3-way valve. The Re-188-filled leaded glass syringe was connected to the balloon by the 3-way valve. The entire proximal balloon inflation structure was then embedded in a Lucite shield. The balloon was positioned to cover the target lesion and match the approximate position of the previous angioplasty balloon. A tiny amount of Re-188 solution (without contrast) was injected into the 10-ml empty syringe on the other side of the 3-way valve in order to eliminate the small amount of air present in the system. The balloon was manually inflated with the Re-188 solution at an approximate inflation pressure of 3 atm. Cineangiograms were taken with contrast injections to verify the position and full expansion of the balloon (Fig. 1). The irradiation did not cover the precise length of the vessel exposed to barotrauma from the POBA balloon plus a proximal and distal edge zone. After irradiation, the balloon catheter, guidewire, 10-ml syringe, 3-way valve, and the Re-188-filled syringe were placed in a plastic bag and immediately placed into a lead-shielded container for decay.
Radiation source and dosimetry
Re-188 has a maximum transition energy of 2.13 MV, mean beta ray energy of 0.77 MV, and physical half-life of 17 hours. The carrier-free liquid Re-188 was obtained as sodium perrhenate prior to use by elution of a tungsten-188/Re-188 generator and was concentrated to 50-209 mCi/ml.
Media-to-media measurements of the vessel size at different sites of the target vessel, approximately 5 mm proximal and distal to the lesion, and at the lesion, were obtained by IVUS after successful POBA with the use of a 3.2-Fr. catheter. The vessel size data, the length and nominal size of the perfusion balloon catheter, and the activity of the Re-188 were used to calculate the irradiation (dwell) times to deliver 14 Gy to a tissue depth of 0.5 mm. This corresponded to a dose of 28 Gy at the surface of the balloon. The computer treatment-planning program was provided by Columbia University (New York, NY, USA).

Quantitative coronary angiography
Angiographic measurements were done with the on-line image system of a Philips 5000 catheterization laboratory machine. Image calibration was performed with a contrast-filled catheter. The external diameter of the catheter was used as the calibration standard. Coronary MLD and the degree of stenosis (percentage of the diameter) were measured from coronary end-diastolic-matched frames in the single worst view obtained before dilation, at the end of the procedure, and during follow-up angiography 6 months later (or earlier if there were recurrent symptoms). Restenosis was defined as the presence of stenosis of more than 50% of the luminal diameter by on-line QCA at follow-up in a vessel with less than 30% residual stenosis immediately after POBA.

Statistical analysis
Statistical analyses of frequency counts were performed with the use of chi-square test or Fisher's exact test for small samples, and the means were compared using the 2-sample t-test. All tests were 2-sided. Values were reported as the mean±SD. Differences were considered statistically significant at p<0.05.

RESULTS

Between August 1999 and August 2000, 65 patients were enrolled in the study; 40 were assigned to the Re-188 group and 25 to the control group. Baseline clinical and angiographic characteristics were similar between the 2 groups (Tables 1, 2). In the Re-188 group, the prescribed dose of 14 Gy at a 0.5-mm tissue depth was successfully delivered to all patients with Re-188 via a Lifestream perfusion dilatation balloon catheter. The average specific activity of the Re-188 was 108.7±45.0 (range, 50-209) mCi/ml. The mean dwell time for the irradiated group was 440±214s, while the dwell time for the control group was 300s. The treatment was given in a single inflation cycle in all patients. No adverse effects of delivering the radiation were observed. All patients were maintained on 100 mg/day aspirin indefinitely; none of them took clopidogrel or ticlopidine in addition to aspirin after the procedure. There were no deaths, myocardial infarctions, or reinterventions by the 30-day follow-up.
The baseline, post-procedure, and 6-month QCA results showed that the post-procedure reference vessel diameter (Re-188 vs. the control; 2.89± 0.31 vs. 3.13±0.45 mm; p=0.01) and MLD (Re-188 vs. control; 2.32±0.31 vs. 2.58±0.44 mm; p=0.01) of the Re-188 group were significantly smaller than the control group (Tables 3, 4). Angiographic follow-up data were obtained at 6 months in all patients in the control group (100%) and 39 of the 40 patients in the Re-188 group (97.5%). One patient in the Re-188 group refused follow-up angiography and remained asymptomatic 18 months after the procedure. The mean time to angiographic follow-up was 5.8±2.0 months in the Re-188 group and 6.4±1.9 months in the control group. On the follow-up angiographic examination, there was total occlusion of the vessel in 3 of 39 patients who had had irradiation and 1 of 25 control patients (7.7% vs. 4%, p=0.55). Of the 3 patients in the irradiated group with an occlusion, 2 presented with unstable angina (at 2 and 4 months after the procedure, respectively). One patient in the irradiated group and 1 patient in the control group had silent total occlusions of the target vessel, which were discovered at the 6-month angiographic examination. Angiographic restenosis either within the lesion or at its marginal segment (5 mm beyond the approximate proximal or distal location of the previous angioplasty balloon) was observed in 49% of patients in the Re-188 group, compared with 56% of those in the control group (p=0.57). Restenosis limited to the marginal segment only occurred in 1 patient in the Re-188 group; 97% of the instances of restenosis in the Re-188 group were due to renarrowing of the target lesion.
Subgroup analyses with reference vessel diameters of < 3.0 mm and ?3.0 mm, and de novo and post-POBA restenotic lesions were performed (Table 5). The Re-188 group had significantly more vessels with a reference vessel diameter < 3.0 mm (Table 5). Six-month target lesion angiographic restenosis occurred in 11 of the 24 lesions (46%) with a reference diameter < 3.0 mm in the Re-188 group, and 6 of the 8 lesions (75%) with a reference diameter < 3.0 mm in the control group (p=0.23). In the de novo lesions, the 6-month angiographic restenosis rates of the Re-188 and control groups were 47% (15 of 32 lesions) and 50% (10 of 20 lesions), respectively. In the post-POBA restenotic lesions, the 6-month angiographic restenosis rates of the Re-188 and control group were 57% (4 of 7 lesions) and 80% (4 of 5 lesions), respectively (p=0.58).
Clinical events
Clinical follow-up data were obtained for all patients at a mean of 12.3±3.8 months in the Re-188 group and 12.6±3.1 months in the control group (Table 6). One patient in the Re-188 group sustained a myocardial infarction on day 46. Angiographic examination showed a tight stenosis at the target lesion. The patient was then treated with stent implantation. Two patients in the Re-188 group, who had total occlusion of the vessel, subsequently underwent bypass surgery. There were no other myocardial infarctions, bypass surgeries, or deaths. Twelve patients in the Re-188 group underwent a percutaneous coronary intervention of the target lesion (7 received stent implantation and 5 underwent POBA) at the 6-month follow-up visit. One patient had a percutaneous intervention of the target vessel 8 months later. In this patient, the stenotic lesion was at the marginal segment of the previous lesion, and it was surmised that the new lesion site had probably been traumatized by the inflated balloon during the POBA procedure. Target vessel revascularization was required in 15 of the 40 patients in the Re-188 group (37.5%) and 9 of the 25 patients in the control group (36%). The number of patients who reached the composite clinical end points did not significantly differ between the Re-188 and control groups (40% vs. 36%, p=0.80).
DISCUSSION

The TRIPPER-I was a study of radiotherapy using a self-centering b-emitter Re-188 solution-filled balloon in patients undergoing POBA of the native coronary artery (either de novo or post-POBA restenotic lesions) without stent implantation. Randomization in this study was impossible due to the limited supply of the Re-188 isotope. Hence, a contemporaneous control group was collected. The study demonstrates that intracoronary irradiation with 14 Gy at a 0.5-mm tissue depth delivered by a Re-188 solution filled balloon was ineffective in reducing 6-month target lesion restenosis and the composite end-points of death, myocardial infarction, and target-vessel revascularization. The main cause of restenosis after irradiation in this study was intralesional stenosis. In contrast, edge stenosis was the main cause (61%) of restenosis after irradiation in the ECRIS-1 trial conducted by Hoeher et al. using the same isotope (Re-188) delivered at 15 Gy at a 0.5-mm tissue depth.(15) In that study, 68% of their patients underwent stent implantation, and the restenosis rate was significantly higher in the irradiated group as compared to the control group. The low intralesional restenosis rate might have been due to the effect of the stent itself. The lack of an effect might be attributed to the low irradiation dose used in both our TRIPPER-1 study and the EndoCoronary Rhenium Irradiation Study (ECRIS)-1 trial. In the ECRIS-2 trial, the irradiation dose was increased to 22.5 Gy at a 0.5-mm tissue depth delivered by a balloon > 10 mm longer than the segment traumatized by the preceding angioplasty to avoid a geographic miss. The interim analysis revealed a marked reduction in the restenosis rate.(15)
Data from animal studies and clinical trials show a wide therapeutic window and a minimum therapeutic dose. In order to deliver the optimal dosimetry, the target cells and treatment dose have to be determined. The intended target cells for irradiation in intravascular brachytherapy are not clearly identified. Smooth muscle cells originating from the adventitia and progenitor cells originating from the media have been suggested to play a role in the restenosis process.(16-18) Nevertheless, the media will be treated when the adventitia is targeted. However, multiple factors like the dose gradient of the isotopes, the location and volume of the residual plaque, and the presence of calcification or stenting have to be taken into account to determine the treatment dose. Based on animal studies, treatment doses of different isotopes using various delivery systems have been prescribed in clinical trials. The pre- determined effective dose was not effective in our trial due to the fact that the over-stretched normal coronary artery of the porcine model differs from heavy plaque-loaded lesions (mean percent of stenosis was 80%±6%) of the coronary arteries in our patients. The presence of plaque or calcium in the vessel walls might lead to the attenuation or absorption of the dose causing treatment under-dosing. Although it is ideal to have a uniform dose delivered to the vessel wall, the eccentricity of the residual plaque in the vessel wall might render the various centering devices ineffective in providing true centering.
Smaller vessels have been associated with a high rate of restenosis. In our trial, lesions with a reference vessel diameter < 3.0 and ?3.0 mm in the Re-188 group had 46% and 53% restenosis rates, respectively. Lesions with a reference vessel diameter of < 3.0 mm in the placebo group had a 75% (6 of 8 lesions) restenosis rate compared with 46% (11 of 24 lesions) in the Re-188 group (a 39% reduction; p=0.23). Although, the difference in the restenosis rate in vessels of < 3.0 mm in diameter was not statistically significant, the decrease in the restenosis rate as compared to the control group might have been due to the closer proximity of the intended target for irradiation in smaller vessels.
Several randomized clinical trials focused on in-stent restenosis using iridium-192 and showed a remarkable reduction in the restenosis rate.(12,19,20) Recently, the US FDA approved 2 devices for the delivery of intracoronary radiation after effective percutaneous intervention of in-stent restenosis. Ongoing randomized clinical trials of intracoronary brachytherapy for de novo and restenotic lesions not previously stented and not stented during the procedure might expand the currently approved indications.
Animal studies have shown that radiation can induce thrombosis.(21,22) Intracoronary brachytherapy for patients with in-stent restenosis is associated with a high rate of late total occlusion (> 30 days after the procedure).(23) This phenomenon is more pronounced after restenting. In our study, 3 of 39 (7.7%) Re-188 patients had late total occlusion, 2 of whom suffered unstable angina and 1 of whom had a silent occlusion. There was only 1 silent late occlusion among the 25 patients (4%) in the placebo group. This was not statistically significant. However, adjunct antiplatelet therapy with ticlopidine or clopidogrel in patients receiving intracoronary brachytherapy after POBA might be needed to prevent this potentially disastrous complication.

Study limitations
The patient population in this study was small. Although it was a placebo-controlled study, it was not randomized. Trends were seen but not were significant by the tests employed. This could indicate a true lack of difference, an insufficiently large sample tested, or another variable of difference between the 2 groups. The study was limited to 6-month follow-up. Further follow-up is required to ensure that the safety of the procedure observed is maintained over time.

Conclusions
Catheter-based radiotherapy after POBA of de novo or post-POBA restenotic lesions with a Re-188-filled balloon is feasible, but was ineffective in reducing target lesion restenosis with a dose of 14 Gy delivered at a 0.5-mm tissue depth in this study.

Acknowledgements

Supported in part by a grant from the Chang Gung Memorial Hospital Medical Center and a grant from the Institute of Nuclear Energy Research, Taiwan, R.O.C. The authors appreciate the efforts of the catheterization laboratory staff, Mr. Wei-Dih Chang and Ms. Yui-Jiao Liao. We thank the contributions of Mr. Ching-Jen Liu and the personnel of the Institute of Nuclear Energy Research for assistance with the delivery of the isotope and the procedures. We are indebted to Howard Amols, PhD, Cheng-ShinWuu, PhD, and Judith Weinberger, MD, PhD for their generosity in providing the computer software for dwell time calculations and their enthusiasm in offering technical assistance to conduct the study.

REFERENCES

1. Chokshi SK, Meyers S, Abi-Mansour P. Percutaneous transluminal coronary angioplasty: ten years experience. Prog Cardiovasc Dis 1987;30:147-210.
2. Califf RM, Fortin DF, Frid DJ, Harlan WR 3rd, Ohman EM, Bengtson JR, Nelson CL, Tcheng JE, Mark DB, Stack RS. Restenosis after coronary angioplasty: An overview. J Am Coll Cardiol 1991;17:2B-13B.
3. Holmes DR Jr, Vliestra RE, Smith HC, Vetrovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF, Detre KM. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from the PTCA registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1984;53:77C-81C.
4. Popma JJ, Califf RM, Topol EJ. Clinical trials of restenosis after coronary angioplasty. Circulation 1991;84:1426-36.
5. Hermans WRM, Rensing BJ, Strauss BH, Serruys PW. Prevention of restenosis after percutaneous transluminal coronary angioplasty: The search for a "magic bullet." Am Heart J 1991;122:171-87.
6. Mak KH, Topol EJ. Clinical trials to prevent restenosis after percutaneous coronary revascularization. Ann N.Y. Acad Sci 1997;811:255-84.
7. Wiedermann JG, Marboe, Amols H, Schwartz A, Weinberger J. Intracoronary irradiation markedly reduces neointimal proliferation after balloon angioplasty in swine: persistent benefit at 6-month follow-up. J Am Coll Cardiol 1995;25:1451-6.
8. Waksman R, Robinson KA, Crocker JR, Gravanis MB, Cipolla GD, King SB III. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine. Circulation 1995;91;1533-9.
9. Verin V, Popowski Y, Urban P, Belenger J, Redard M, Costa M, Widmer MC, Rouzand M, Nouet P, Groh E, Schwager M, Kurtz JM, Rutishauser W. Intra-arterial b-irradiation prevents neointimal hyperplasia in a hypercholesterolemia rabbit restenosis model. Circulation 1995;92: 2284-90.
10. Waksman R, Robinson KA, Crocker JR, Wang C, Gravanis MB, Cipolla GD, Hillstead RA, King SB III. Intracoronary low-dose b-irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation 1995;92:3025-31.
11. Condado JA, Waksman R, Gurdiel O, Espinosa R, Gonzalez, Burger b, Villoria G, Acquatella H, Crocker I, Seung K, Liprie S. Long term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 1997;96:727-32.
12. Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Morris N, Leon MB, Tripuraneni P. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336:1697-703.
13. King SB III, Williams DO, Chougule P, Klein L, Waksman R, Hilstead R, Macdonald J, Anderberg K, Crocker IR. Endovascular b-radiation to reduce restenosis after coronary balloon angioplasty. Results of the beta energy restenosis trial (BERT) Circulation 1998;97:2025-30.
14. Makkar R, Whiting J, Li A, Honda H, Fishbein M, Knapp FF, Hausleiter J, Litvack F, Eigler NL. Effects of b-emitting 188Re balloon in stented porcine coronary arteries. An Angiographic, intravascular ultrasound, and histomorphometric study. Circulation 2000;102:3117-23.
15. Hoeher M, Woehrle J, Wohlfrom M, Grebe O, Hanke H, Kochs M, Reske SN, Kotzerke J. Intracoronary b-irradiation with liquid Rhenium-188 to prevent restenosis following coronary angioplasty. Result from the randomized ECRIS-1 trial. Circulation 2000;102: Suppl II:II-750. Abstract.
16. Austin GE, Ratliff NB, Hollman J, Taibei S, Philip DF. Intimal proliferation of smooth muscle cells as an explanation for recurrent coronary stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1985;6:569-75.
17. Liu MW, Roubin GS, King SB III. Restenosis after coronary angioplasty: potential biologic determinants and role of intimal hyperplasia. Circulation 1989;79:1374-87.
18. Karas SP, Gravanis MB, Santolan Ec, Robinson KA, Anernerg KA, King SB III. Coronary intimal proliferation after balloon injury and stenting in swine: an animal model of restenosis. J Am Coll Cardiol 1991;20:467-74.
19. Waksman R, White RL, Chan RC, Bass BG, Geirlach L, Mintz GS, Satler LF, Mehran R, Serruys PW, Lansky AJ, Fitzgerald P, Bhargava B, Kent KM, Pichard AD, Leon MB. Intracoronary g-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000;101:2165-71.
20. Leon MB, Teirstein PS, Moses JW, Tripuraneni P, Lansky AJ, Jani S, Wong SC, Fish D, Ellis S, Holmes DR, Kerieakes D, Kuntz RE. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250-6.
21. Vodovotz Y, Waksman R, Kim WH, Bhargava B, Chan RC, Leon M. Effects of intracoronary radiation on thrombosis following balloon over-stretch injury in the porcine model. Circulation. 1999;100:2527-33.
22. Salame M, Lampkin J, Mulkey P, Verheye CS, Hillstead RA, Crocker IR, Chronos NAF, King SB, Robinson KA. Effects of endovascular irradiation on platelet recruitment at the site of balloon angioplasty in pig coronary arteries. J Am Coll Cardiol. 1999;33:44A. Abstract.
23. Waksman R, Bhargava B, Mintz G, Mehran R, Lansky AJ, Satler LF, Pichard AD, Kent KM, Leon MB. Late total occlusion after intracoronary brachytherapy for patients with in-stent restenosis. J Am Coll Cardiol 2000; 36:65-8.

From the Section of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Kaohsiung; 1Institute of Nuclear Energy Research, Taoyuan; 2Department of Radiation Oncology, Chang Gung Memorial Hospital, Kaohsiung.
Received: Aug. 12, 2002
Accepted: Nov. 22, 2002
Address for reprints: Dr. Stephen Wan Leung, Department of Radiation Oncology, Yuan's General Hospital. 136, Swei Road Section 4, Kaohsiung, Taiwan, R.O.C.
Tel.: 886-7-3351121 ext. 1651
Fax: 886-7-3319997