Author + information
- Received October 31, 2000
- Revision received May 14, 2001
- Accepted June 4, 2001
- Published online September 1, 2001.
- Seong-Wook Park, MD, PhD, FACC∗,* (, )
- Myeong-Ki Hong, MD, PhD∗,
- Dae Hyuk Moon, MD, PhD†,
- Seung Jun Oh, PhD†,
- Cheol Whan Lee, MD∗,
- Jae-Joong Kim, MD, PhD∗ and
- Seung-Jung Park, MD, PhD, FACC∗
- ↵*Reprint requests and correspondence: Dr. Seong-Wook Park, Departments of Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong, Songpa-gu, Seoul, 138-736, Korea
This study was done to evaluate the feasibility and efficacy of beta-radiation therapy with a rhenium-188–mercaptoacetyltriglycine (188Re-MAG3)-filled balloon after rotational atherectomy for diffuse in-stent restenosis (ISR).
Rotational atherectomy has been shown to be safe and efficient for the treatment of ISR, but the recurrence rate is still high. Intracoronary beta-irradiation after rotational atherectomy may be a reasonable approach to prevent recurrent ISR.
Fifty consecutive patients with diffuse ISR (length >10 mm) in native coronary arteries underwent rotational atherectomy and adjunctive balloon angioplasty, followed by beta-irradiation using a 188Re-MAG3–filled balloon catheter. The radiation dose was 15 Gy at a depth of 1.0 mm into the vessel wall.
The mean lengths of the lesion and irradiated segment were 25.6 ± 12.7 mm and 37.6 ± 11.2 mm, respectively. Radiation was delivered successfully to all patients, with a mean irradiation time of 201.8 ± 61.7 s. No adverse event, including myocardial infarction, death or stent thrombosis, occurred during the follow-up period (mean 10.3 ± 3.7 months), and nontarget vessel revascularization was needed in one patient. The six-month binary angiographic restenosis rate was 10.4%, and the loss index was 0.17 ± 0.31.
Beta-irradiation using a 188Re-MAG3–filled balloon after rotational atherectomy is safe and feasible in patients with diffuse ISR, and it may improve their clinical and angiographic outcomes. Further prospective, randomized trials are warranted to evaluate the synergistic effect of debulking and irradiation in patients with diffuse ISR.
Intracoronary stenting reduces restenosis, as compared with balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA]). However, in-stent restenosis (ISR) develops in a significant proportion of patients, particularly in those with multiple or long stents. In-stent restenosis remains an important clinical problem, because the recurrence rate is high with repeat PTCA, especially in diffuse ISR (1,2). Previous studies have shown that rotational atherectomy may improve the long-term clinical outcome in patients with diffuse ISR, but the incidence of major adverse cardiac events (MACE) is still high (3–5). Recently, several studies have demonstrated the efficacy of local gamma- or beta-irradiation in patients with ISR (6–8). The major advantage of beta-irradiation is its low penetration depth, thus minimizing the radiation exposure to the patient and the operator and decreasing the potential damage to the adjacent normal tissue. However, the rapid fall-off of radiation dose within 2 mm may be associated with an inhomogeneous dose delivery to the target tissue, especially in the vessel with very eccentric atheromatous plaque. Intracoronary irradiation using a radioactive solution-filled balloon is a simple and inexpensive method to deliver radiation to the vessel wall. With only a few modifications, it can be applied to coronary arteries, even those with a large diameter or angulated arterial segments. In addition, the dose distribution is uniform, without the aid of centering devices (9). Rhenium-188 (188Re) is a beta-emitting radionuclide with a short half-life of 17 h and other suitable physicochemical properties, and it acts as a therapeutic radioisotope (9). The purchase of a tungsten-188 (188W)/188Re generator enables daily milking of high activity of 188Re solutions for several months.
We presumed that beta-irradiation with 188Re after effective rotational atherectomy may improve the delivery of an optimal radiation dose to the target tissue, which could translate into improvement in the patient’s long-term clinical outcome. The purpose of this study was to evaluate the feasibility and efficacy of intracoronary beta-radiation therapy with a 188Re-mercaptoacetyltriglycine (MAG3)–filled balloon after rotational atherectomy in patients with diffuse ISR (R4registry).
Fifty consecutive patients with diffuse ISR were prospectively evaluated at the at Asan Medical Center between March 1999 and February 2000. Inclusion criteria were diffuse ISR (lesion length >10 mm, diameter stenosis >50%) in a native coronary artery with angina, demonstrable myocardial ischemia and written, informed consent. Exclusion criteria were acute myocardial infarction (MI) within 72 h, poor renal function (serum creatinine >3.0 mg/dl), pregnancy, contraindication to antiplatelet therapy and concomitant serious disease with expected survival of <2 years. In patients with multiple ISR, only one lesion was treated with radiation therapy. Additional new stent implantation was strongly discouraged, although not contraindicated. During the study period, rotational atherectomy and adjunct balloon angioplasty without radiation therapy were successfully performed in nine patients with diffuse ISR who refused to join this study. Our Institutional Review Board approved this study.
Radiation delivery system, dosimetry and procedure
The radiation system was a 188Re-MAG3–filled angioplasty balloon. Rhenium-188 is a high-energy beta-emitter with a maximal energy of 2.12 MeV that is available daily as 188Re-perrhenate solution from the 188W/188Re generator (Oak Ridge National Laboratory, Oak Ridge, Tennessee) and has a half-life of 17 h. Highly concentrated (3.7 to 11.1 GBq/ml) 188Re-MAG3solution was prepared from 188Re-perrhenate and MAG3(Technescan, Mallinckrodt Medical, St. Louis, Missouri), using the synthesizer developed at our institution (10), which is a compressed air–driven, semi-automated, shielded system. Rhenium-188–MAG3was purified and concentrated by C18Sep-Pak cartridges to the desired radioactivity and volume, and then it was mixed with ionic contrast agent (Hexabrix, Guerbet, France) to make a final iodine concentration to 20% (vol/vol). To minimize the operator’s exposure to radiation, a syringe with 1.5 ml of 188Re-MAG3was shielded with a beta-and gamma-shielding syringe holder (10-mm acryl and 20-mm lead). The isotope-containing syringe with the shielding syringe holder was put inside a plastic box to avoid possible radioisotope contamination of the operating table (Fig. 1). Before this clinical trial, we performed a detailed dosimetric study using the Monte Carlo simulation method. Attenuation due to iodine contrast media, the balloon and the guide wire was considered in this simulation model. The overall dose reductions caused by the presence of the central lumen of the balloon, balloon wall and contrast medium were 5.6%, 7.7% and 9.1% at the 3.0-mm diameter balloon surface for 10%, 20% and 30% of contrast media in the 188Re solution, respectively. Dose rates at 1.0 mm from the surface of a balloon filled with 3.7 GBq/ml of 188Re and 20% Hexabrix were 1.65, 1.98, 2.26 and 2.51 Gy/min for a 2.5-, 3.0-, 3.5- and 4.0-mm diameter balloon, respectively. We also performed experimental dosimetric studies using the GafChromic (Agfa Co.) film and tissue equivalent phantoms for balloons of 2.5, 3.0, 3.5 and 4.0 mm in diameter. The average difference between measured and calculated radial doses around the balloon was 6.6% for distances at 0.5 to 1 mm from the balloon surface. From the dosimetric data, the irradiation time was calculated to deliver 15 Gy at a depth of 1.0 mm into the vessel wall from the balloon–artery interface, depending on the size of the balloon and the actual radioactivity of 188Re-MAG3solution. Radiation exposure to the operator was <5 μSv per treatment.
All patients were pretreated with aspirin (200 mg/day), ticlopidine (500 mg/day) and cilostazol (200 mg/day) for two days. Ticlopidine was given for one month, but aspirin and cilostazol were administered for more than six months after irradiation. Rotational atherectomy and adjunctive PTCA were performed to obtain an optimal angiographic result (diameter stenosis <20%). Coronary angiograms were obtained at each step to determine the actual segment treated with atherectomy and PTCA. The long conventional balloon (30 and 40 mm in length; Boston Scientific Corporation, San Jose, California), which was the same kind of balloon used for the dosimetric study, was selected for irradiation to cover the proximal and distal uninjured margin of at least 5 mm. For long ISR (>30 mm) that could not be covered by a single long balloon, manual stepping was permitted, with minimal overlapping. The 188Re-MAG3–filled syringe and conventional in-deflator device were connected to the balloon by three-way valves (Fig. 1). After complete removal of air from the balloon, 188Re-MAG3solution was introduced into the balloon manually. Inflation of the balloon was maintained with the nominal inflation pressure of 6 atm. Fractionation was allowed in case of severe angina or significant hemodynamic changes. After irradiation, the whole system was removed and brought to the Department of Nuclear Medicine for decay.
Quantitative coronary angiography (QCA)
Coronary angiograms were analyzed by two experienced angiographers using an on-line QCA system (ANCOR version 2.0, Siemens, Germany). Angiographic measurements were made during diastole after intracoronary nitroglycerin administration, using the guiding catheter for magnification calibration. Single matched views with the worst diameter stenosis were compared.
Intravascular ultrasound (IVUS) imaging
Preradiation, postradiation and follow-up IVUS studies were performed in identical fashion in 44 of 50 patients, using a commercially available system (Boston Scientific Corporation/ Cardiovascular Imaging System, Inc., San Jose, California). With this system, the transducer was withdrawn automatically at 0.5 mm/s to perform the imaging sequence. The cross-sectional area (CSA) measurements of the external elastic membrane (EEM), lumen, plaque plus media by IVUS have been reported previously (11,12). The EEM CSA (representing total arterial CSA) was measured by tracing the leading edge of the adventitia. The plaque plus media CSA (representing atherosclerotic plaque) was calculated as the EEM CSA minus the lumen CSA. Plaque burden was measured as the plaque plus media CSA divided by the EEM CSA. The intimal hyperplasia (IH) CSA was measured as the stent CSA minus the lumen CSA, and percent IH CSA as 100 × (IH CSA/stent CSA). The proximal and distal reference segments and irradiated segments were assessed quantitatively.
Primary and secondary end points
All patients were evaluated clinically during an office visit at one, three and six months, and then every four months after radiation therapy. Repeat coronary angiography and IVUS were performed at six months after irradiation, or earlier if clinically indicated. Major adverse cardiac events, including death, nonfatal MI and repeat revascularization, were evaluated. The primary end point was the occurrence of any MACE during the follow-up period. Myocardial infarction was diagnosed when cardiac enzymes were elevated threefold or greater, with chest pain lasting >30 min or with the appearance of new electrocardiographic changes. The secondary end point was the angiographic incidence of restenosis (diameter stenosis >50%) and a loss index by QCA. Intravascular ultrasound variables were also analyzed.
The results are presented as the mean value ± SD or number (%) of patients. Serial changes of continuous variables were compared by repeated measures analysis of variance and a multiple comparisons procedure with the Bonferroni correction. A p value <0.05 was considered statistically significant.
In-hospital outcomes and procedural results
Fifty consecutive patients (42 men, 55.7 ± 9.0 years old) underwent successful radiation therapy after rotational atherectomy and adjunctive balloon angioplasty. Their clinical characteristics were unstable angina in 66% and stable angina in 34%. Their risk factors included hypertension in 38%, diabetes mellitus in 26%, hypercholesterolemia in 24% and current smoking status in 62%. Eight patients (16%) had an old MI, and seven patients (14%) had experienced at least one intervention for recurrent ISR. The mean left ventricular ejection fraction was 60.2 ± 6.8%. The mean burr size of rotational atherectomy was 2.06 ± 0.21 mm, and the burr/artery ratio was 0.72 ± 0.09. Adjunctive balloon angioplasty was performed in all patients to obtain optimal angiographic results, with a mean balloon/artery ratio of 1.23 ± 0.20. No patient received additional new stent implantation. The maximal inflation pressure was 9.1 ± 3.8 atm. The mean lengths of the lesion and irradiated segment were 25.6 ± 12.7 mm and 37.6 ± 11.2 mm, respectively. The mean irradiation time was 201.8 ± 61.7 s. Fractionation was needed in six patients, and stepping of a 30-mm balloon was done in seven patients. No procedure-related complications or in-hospital MACE occurred.
Primary and secondary end points
At a mean of 10.3 ± 3.7 months of clinical follow-up, MACE had occurred in one patient (2%); repeat revascularization was needed because of aggravation of stenosis at the ostium of the left main coronary artery, which was not related to the previous irradiation. Death, MI or stent thrombosis did not occur in any patients during the follow-up period. Angiographic follow-up was done in 48 patients (follow-up up rate of 96%) at 5.8 ± 1.7 months after irradiation. The quantitative angiographic results are shown in Table 1. An example of a 6-month follow-up angiogram after radiation therapy is shown in Figure 2. Binary angiographic restenosis occurred in five patients; thus, the overall angiographic restenosis rate was 10.4%. The remaining two patients who refused angiographic follow-up were free of angina. The late loss index was 0.17 ± 0.31. The pattern of restenosis included two focal ISRs and three edge restenoses (one in the proximal and two in the distal edge), with a mean of 57.2 ± 5.2% lumen diameter stenosis. These patients with recurrent restenosis, however, did not undergo a further coronary intervention because they had either mild angina (n = 3) or absence of a perfusion abnormality on the thallium perfusion single-photon emission computed tomographic image (n = 2). Fractionation or stepping of the radiation balloon was not associated with any clinical events or late angiographic aneurysm formation.
The IVUS findings are shown in Table 2. There was no significant difference in stent CSA, lumen CSA, IH CSA or percent IH CSA between the post-radiation and follow-up studies. In 19 (43%) of 44 lesions, the minimal in-stent lumen CSA at six-month follow-up was larger than that immediatly after irradiation.
This study is the first to indicate the feasibility and safety of intracoronary beta-irradiation combined with rotational atherectomy to prevent recurrent ISR in patients with diffuse ISR.
Comparison with previous studies
Because this study was based on a registry, the effectiveness of beta-irradiation with 188Re-MAG3after atherectomy may not be conclusive. The incidences of MACE and angiographic restenosis at six months, however, were at least similar to or lower than those of other trials of irradiation or rotational atherectomy alone. Considering the long lesion length (25.5 ± 12.7 mm) in this study, the angiographic restenosis of 10.4% and the loss index of 0.17 are very encouraging. In the previous rotational atherectomy trial of ISR, the rates of repeat ISR and target vessel revascularization were 28% and 26%, respectively, at a mean follow-up of 13 ± 5 months (3). In another study, the incidences of one-year MACE after rotational atherectomy for diffuse ISR were 5% for death, 2% for Q-wave MI and 28% for overall target lesion revascularization (4). Previous clinical trials with radiation therapy for ISR showed six-month MACE and angiographic restenosis rates as follows: Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting (SCRIPPS): MACE in 19% and restenosis in 17% (6); gamma-Washington Radiation for In-Stent Restenosis Trial (WRIST): target vessel revascularization in 26.2% and restenosis in 19% (7); and beta-WRIST: target vessel revascularization in 34% and restenosis in 22% (8).
The clinical results of radiation therapy with liquid 188Re for human coronary stenosis were first reported by Höher et al. (13). They demonstrated the technical feasibility and safety of the liquid isotope-filled balloon system in 100% of patients treated, but the restenosis rate (46%) and the late loss index (0.57 ± 0.57) at six months were relatively high. There are many differences between this study and ours in terms of the methodologic aspects. First, the study population is different. Höher et al. (13)included de novo lesions, whereas our study included solely ISR. Second, the use of rotational atherectomy and optimal balloon angioplasty before irradiation in the current study may have favorably influenced the late angiographic and clinical outcomes. Rather, aggressive balloon dilation strategy (mean balloon/artery ratio of 1.23 ± 0.20) was applied according to the IVUS findings, which was not associated with significant complications. The radiation dose was also different between the two studies: 15 Gy at 0.5 mm (Höher et al.) versus 15 Gy at a depth of 1 mm into the tissue. However, it is not clear whether the difference in the radiation dose made a significant difference in the outcomes, considering the different target lesions (i.e., de novo vs. ISR) The presence of a stainless-steel stent is known to reduce the radiation dose by 4% to 14%, depending on the design and structure of the stent (14). In addition to the differences described earlier, the use of a contrast agent to fill the radiation balloon needs to be considered. Insertion of a radiopaque contrast medium allows fluoroscopic verification of complete inflation of the balloon at the exact segment that is being treated. The radiation dose immediately adjacent to an air bubble was shown to be 30% lower than that for a filled balloon (15). Höher et al. (13)did not assess the complete filling of the radioisotope without air bubbles at the time of irradiation, although it was demonstrated in their in vitro studies. Furthermore, 16 of 28 patients required radiation dose fractionation, which might have increased the chance of air inclusion in the balloon. In this regard, we believe that the addition of a contrast medium to the liquid isotope is essential for intracoronary radiation therapy using a 188Re-filled balloon. Recently, Fox and Henson (16)reported the fractional dose correction values for 33% of the contrast medium in saline, using the point kernel method. A dose reduction of 7.4% at 0.02 mm from the 3.2-mm diameter balloon surface was comparable to our previous result of 6.5% dose reduction at the surface of a 3.0-mm diameter balloon filled with 30% contrast medium.
Clinical applications and safety issue
There are many advantages to using a liquid 188Re-filled angioplasty balloon for radiation therapy. This method can be applied to vessels of various sizes and at the angulated segment, without significant technical difficulty. Technical failure was absent in the present study. Besides versatile application and technical feasibility, there is a theoretical advantage of uniform dose distribution of radiation, because centering is not an important issue with this method. The potential disadvantages of this method would be radiation exposure to the patient in case of balloon leakage and contamination of the operating table during the procedure. The risk of contamination with an isotope in the catheterization laboratory, however, can virtually be eliminated with the use of a safety box and careful handling of the radiation source. Highly concentrated liquid 188Re-MAG3(3.7 to 11.1 GBq/ml) was used in this study to shorten the balloon inflation time and to obviate the need for dose fractionation, which may increase the chance of air inclusion in the balloon. Only six patients (12%) needed fractionation of the radiation dose. For the safety of the patients, in case of balloon rupture, an in vivo experiment with a whole-body scan was performed in pigs before the human trial. After intracoronary injection of 370 MBq of 188Re-MAG3solution, rapid urinary excretion of 188Re-MAG3was confirmed, with no significant isotope activity in other organs in 60 min. The absorbed dose in the whole body was 0.01 mGy/MBq. Rhenium-188–MAG3was first introduced in intracoronary radiation therapy because of its rapid renal excretion, which facilitates its removal from the body in case of balloon rupture (9). Previous studies have demonstrated that 188Re-labeled MAG3has the lowest internal radiation dose among three 188Re radiopharmaceutical agents, in case of balloon rupture, because of its rapid renal excretion (17). If radiation therapy is performed using liquid 188Re-MAG3of 11.1 GBq/ml and a balloon catheter of 3.0 mm in diameter and 30 mm in length, 2.35 GBq 188Re-MAG3would be released from the balloon in the event of balloon rupture. This radioactivity would result in a whole-body absorbed dose of 25.6 mGy, which is equivalent to only 1/100 of the minimal tolerance dose of bone marrow (2,500 mGy) (17). In this study, we synthesized highly concentrated 188Re-MAG3by using an automated synthesis system to minimize radiation exposure to personnel who are involved in the routine preparation (10). The preparation of 188Re-MAG3by using the automated system was simple, as well as reproducible in obtaining high radiolabeling yields >95%. The total preparation time was <30 min.
Edge restenosis has been an important issue associated with radiation therapy, especially with radioactive stents (18). The pathophysiology of the edge effect may be the result of vessel wall injury concomitant with low-dose radiation at the edges of the irradiated area (“geographic miss”) (19). In the current study, the incidence of edge restenosis was 6%, which was much lower than that in previously reported studies. Höher et al. (13)reported a high incidence (35%) of edge restenosis, in which the length of the radiation balloon was the same as that of the dilation balloon. The use of a long balloon or stepping of the balloon for irradiation in the current study may have reduced the incidence of edge restenosis. Although every effort was made to irradiate the proximal and distal uninjured margin at least 5 mm, post hoc detailed angiographic analysis revealed that geographic miss was present in 55.6% of treated margins. The three patients with edge restenosis also had geographic miss. The results of this and previous studies indicate that the radiation balloon should be sufficiently longer than the injured segment to avoid geographic miss (“the longer, the better”).
Intravascular ultrasound findings
The effect of irradiation on the intimal hyperplasia was evaluated with serial IVUS studies. The small, nonsignificant changes of percent IH CSA within the stent (35% after radiation to 40% at follow-up) during the follow-up period are believed to be the result of excellent inhibition of neointimal hyperplasia formation by irradiation, which could result in the maintenance of a widely patent lumen at follow-up. The findings of the current study were similar to the results of IVUS analysis in the beta-WRIST trial involving ISR (20). Furthermore, in 19 (43%) of 44 lesions with IVUS follow-up, the minimal in-stent lumen CSA at follow-up was larger than that after irradiation. This finding suggests that the regression of neointimal tissue within the stent occurred by means of irradiation during the follow-up period. A similar finding was also noticed in 53.2% of the lesions with radiation in WRIST trial (7).
Late thrombosis is a valid concern after radiation therapy. The rate of late total occlusion has been reported to be up to 10% (21). In this study, there has been no late occlusion until now. Plausible explanations may be avoidance of new stent implantation and continued administration of aspirin and cilostazol for more than six months. Cilostazol has been demonstrated to have an antithrombotic efficacy similar to that of ticlopidine and to reduce restenosis rate after PTCA (22,23). The antiproliferative effect of cilostazol might have possibly contributed, in part, to the low incidence of restenosis in the current trial. The beneficial effect of long-term use of cilostazol after radiation therapy needs to be determined.
The results are based on a registry data. Because of the lack of a control group, we could not prove the efficacy of beta-irradiation after rotational atherectomy in patients with diffuse ISR. The number of study patients is relatively small. The real beneficial effect of atherectomy before beta-irradiation should be evaluated in prospective, randomized clinical trials including a large number of patients. Regarding the safety of beta-irradiation combined with rotational atherectomy, our study is limited to the procedural results and six-month follow-up. However, there was no increased incidence of MACE in patients who passed six months of follow-up. Longer term clinical follow-up results will be reported in the future. Finally, in many cases, IVUS evaluation was done before the intervention to select the appropriate size of the atherectomy burr and dilation balloon, which could have influenced the selection of devices. It remains to be determined whether an angiography-guided approach would result in similar angiographic and clinical outcomes.
Radiation therapy with beta-emitting 188Re-MAG3after rotational atherectomy is technically feasible and safe for diffuse ISR. The six-month clinical event rates and angiographic restenosis rates were low. The results of this study suggest that beta-irradiation using 188Re-MAG3combined with rotational atherectomy may be a viable therapeutic modality for patients with diffuse ISR. Further prospective, randomized studies comparing beta-irradiation plus atherectomy with beta-irradiation alone need to be done to elucidate the role of debulking for radiation therapy in diffuse ISR.
☆ This work was supported by grant no. 1999-2-206-001-3 from the Interdisciplinary Research Program of the KOSEF.
- cross-sectional area
- external elastic membrane
- intimal hyperplasia
- in-stent restenosis
- intravascular ultrasound
- major adverse cardiac events
- myocardial infarction
- percutaneous transluminal coronary angioplasty
- quantitative coronary angiography
- Received October 31, 2000.
- Revision received May 14, 2001.
- Accepted June 4, 2001.
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