Veronique L. M. A. Coen

Late Coronary Occlusion After Intracoronary Brachytherapy

BACKGROUND Intracoronary brachytherapy appears to be a promising technology to prevent restenosis. Presently, limited data are available regarding the late safety of this therapeutic modality. The aim of the study was to determine the incidence of late (>1 month) thrombosis after PTCA and radiotherapy. METHODS AND RESULTS From April 1997 to March 1999, we successfully treated 108 patients with PTCA followed by intracoronary beta-radiation. Ninety-one patients have completed at least 2 months of clinical follow-up. Of these patients, 6.6% (6 patients) presented with sudden thrombotic events confirmed by angiography 2 to 15 months after intervention (2 balloon angioplasty and 4 stent). Some factors (overlapping stents, unhealed dissection) may have triggered the thrombosis process, but the timing of the event is extremely unusual. Therefore, the effect of radiation on delaying the healing process and maintaining a thrombogenic coronary surface is proposed as the most plausible mechanism to explain such late events. CONCLUSIONS Late and sudden thrombosis after PTCA followed by intracoronary radiotherapy is a new phenomenon in interventional cardiology.

Geometric Vascular Remodeling After Balloon Angioplasty and β-Radiation Therapy: A Three-Dimensional Intravascular Ultrasound Study

BACKGROUND Endovascular radiation appears to inhibit intimal thickening after overstretching balloon injury in animal models. The effect of brachytherapy on vascular remodeling is unknown. The aim of the study was to determine the evolution of coronary vessel dimensions after intracoronary irradiation after successful balloon angioplasty in humans. METHODS AND RESULTS Twenty-one consecutive patients treated with balloon angioplasty and beta-radiation according to the Beta Energy Restenosis Trial-1.5 were included in the study. Volumetric assessment of the irradiated segment and both edges was performed after brachytherapy and at 6-month follow-up. Intravascular ultrasound images were acquired by means of ECG-triggered pullback, and 3-D reconstruction was performed by automated edge detection, allowing the calculation of lumen, plaque, and external elastic membrane (EEM) volumes. In the irradiated segments, mean EEM and plaque volumes increased significantly (451+/-128 to 490.9+/-159 mm(3) and 201.2+/-59 to 241.7+/-74 mm(3); P=0.01 and P=0.001, respectively), whereas luminal volume remained unchanged (250.8+/-91 to 249.2+/-102 mm(3); P=NS). The edges demonstrated an increase in mean plaque volume (26.8+/-12 to 32. 6+/-10 mm(3), P=0.0001) and no net change in mean EEM volume (71. 4+/-24 to 70.9+/-24 mm(3), P=NS), resulting in a decrease in mean luminal volume (44.6+/-16 to 38.3+/-16 mm(3), P=0.01). CONCLUSIONS A different pattern of remodeling is observed in coronary segments treated with beta-radiation after successful balloon angioplasty. In the irradiated segments, the adaptive increase of EEM volume appears to be the major contributor to the luminal volume at follow-up. Conversely, both edges showed an increase in plaque volume without a net change in EEM volume.

β-Particle–Emitting Radioactive Stent Implantation A Safety and Feasibility Study

Background—This study represents the Heart Center Rotterdam’s contribution to the Isostents for Restenosis Intervention Study, a nonrandomized multicenter trial evaluating the safety and feasibility of the radioactive Isostent in patients with single coronary artery disease. Restenosis after stent implantation is primarily caused by neointimal hyperplasia. In animal studies, b-particle‐ emitting radioactive stents decrease neointimal hyperplasia by inhibiting smooth muscle cell proliferation. Methods and Results—The radioisotope 32 P, a b-particle emitter with a half-life of 14.3 days, was directly embedded into the Isostent. The calculated range of radioactivity was 0.75 to 1.5 mCi. Quantitative coronary angiography measurements were performed before and after the procedure and at 6-month follow-up. A total of 31 radioactive stents were used in 26 patients; 30 (97%) were successfully implanted, and 1 was embolized. Treated lesions were in the left anterior descending coronary artery (n512), the right coronary artery (n58), or the left circumflex coronary artery (n56). Five patients received additional, nonradioactive stents. Treated lesion lengths were 13 64 mm, with a reference diameter of 2.9360.47 mm. Minimum lumen diameter increased from 0.8760.28 mm preprocedure to 2.8460.35 mm postprocedure. No in-hospital adverse cardiac events occurred. All patients received aspirin indefinitely and ticlopidine for 4 weeks. Twenty-three patients (88%) returned for 6-month angiographic follow-up; 17% of them had in-stent restenosis, and 13% had repeat revascularization. No restenosis was observed at the stent edges. Minimum lumen diameter at follow-up averaged 1.8560.69 mm, which resulted in a late loss of 0.9960.59 mm and a late loss index of 0.5360.35. No other major cardiac events occurred during the 6-month follow-up. Conclusions—The use of radioactive stents with an activity of 0.75 to 1.5 mCi is safe and feasible. (Circulation. 1999;100:1684-1689.)

Residual Plaque Burden, Delivered Dose, and Tissue Composition Predict 6-Month Outcome After Balloon Angioplasty and β-Radiation Therapy

BACKGROUND Inhomogeneity of dose distribution and anatomic aspects of the atherosclerotic plaque may influence the outcome of irradiated lesions after balloon angioplasty (BA). We evaluated the influence of delivered dose and morphological characteristics of coronary stenoses treated with beta-radiation after BA. METHODS AND RESULTS Eighteen consecutive patients treated according to the Beta Energy Restenosis Trial 1.5 were included in the study. The site of angioplasty was irradiated with the use of a beta-emitting (90)Sr/(90)Y source. With the side branches used as anatomic landmarks, the irradiated area was identified and volumetric assessment was performed by 3D intracoronary ultrasound imaging after treatment and at 6 months. The type of tissue, the presence of dissection, and the vessel volumes were assessed every 2 mm within the irradiated area. The minimal dose absorbed by 90% of the adventitial volume (D(v90)Adv) was calculated in each 2-mm segment. Diffuse calcified subsegments and those containing side branches were excluded. Two hundred six coronary subsegments were studied. Of those, 55 were defined as soft, 129 as hard, and 22 as normal/intimal thickening. Plaque volume showed less increase in hard segments as compared with soft and normal/intimal thickening segments (P<0.0001). D(v90)Adv was associated with plaque volume at follow-up after a polynomial equation with linear and nonlinear components (r = 0.71; P = 0.0001). The multivariate regression analysis identified the independent predictors of the plaque volume at follow-up: plaque volume after treatment, D(v90)Adv, and type of plaque. CONCLUSIONS Residual plaque burden, delivered dose, and tiss composition play a fundamental role in the volumetric outcome at 6-month follow-up after beta-radiation therapy and BA.

High dose rate brachytherapy for the palliation of malignant dysphagia

BACKGROUND AND PURPOSE High dose rate (HDR) brachytherapy is a commonly used palliative treatment for esophageal carcinoma. We evaluated the outcome of HDR brachytherapy in patients with malignant dysphagia. MATERIAL AND METHODS A retrospective analysis over a 10-year period was performed of 149 patients treated with HDR brachytherapy, administered in one or two sessions, at a median dose of 15Gy. Patients were evaluated for functional outcome, complications, recurrent dysphagia, and survival. RESULTS At 6 weeks after HDR brachytherapy, dysphagia scores had improved from a median of 3 to 2 (n=104; P<0.001), however, dysphagia had not improved in 51 (49%) patients. Procedure-related complications occurred in seven (5%) patients. Late complications, including fistula formation or bleeding, occurred in 11 (7%) patients. Twelve (8%) patients experienced minor retrosternal pain. Median survival of the patients was 160 days with a 1-year survival rate of 15%. Procedure-related mortality was 2%. At follow-up, 55 (37%) patients experienced recurrent dysphagia. In 34 (23%) patients a metal stent was placed to relieve persistent or recurrent dysphagia. CONCLUSION HDR brachytherapy is a moderately effective treatment for the palliation of malignant dysphagia. The incidence of early major complications is low, however, persistent and recurrent dysphagia occur frequently, and require often additional treatment.

Outcome from balloon induced coronary artery dissection after intracoronary beta radiation

OBJECTIVE To evaluate the healing of balloon induced coronary artery dissection in individuals who have received β radiation treatment and to propose a new intravascular ultrasound (IVUS) dissection score to facilitate the comparison of dissection through time. DESIGN Retrospective study. SETTING Tertiary referral centre. PATIENTS 31 patients with stable angina pectoris, enrolled in the beta energy restenosis trial (BERT-1.5), were included. After excluding those who underwent stent implantation, the evaluable population was 22 patients. INTERVENTIONS Balloon angioplasty and intracoronary radiation followed by quantitative coronary angiography (QCA) and IVUS. Repeat QCA and IVUS were performed at six month follow up. MAIN OUTCOME MEASURES QCA and IVUS evidence of healing of dissection. Dissection classification for angiography was by the National Heart Lung Blood Institute scale. IVUS proven dissection was defined as partial or complete. The following IVUS defined characteristics of dissection were described in the affected coronary segments: length, depth, arc circumference, presence of flap, and dissection score. Dissection was defined as healed when all features of dissection had resolved. The calculated dose of radiation received by the dissected area in those with healed versus non-healed dissection was also compared. RESULTS Angiography (type A = 5, B = 7, C = 4) and IVUS proven (partial = 12, complete = 4) dissections were seen in 16 patients following intervention. At six month follow up, six and eight unhealed dissections were seen by angiography (A = 2, B = 4) and IVUS (partial = 7, complete = 1), respectively. The mean IVUS dissection score was 5.2 (range 3–8) following the procedure, and 4.6 (range 3–7) at follow up. No correlation was found between the dose prescribed in the treated area and the presence of unhealed dissection. No change in anginal status was seen despite the presence of unhealed dissection. CONCLUSION β radiation appears to alter the normal healing process, resulting in unhealed dissection in certain individuals. In view of the delayed and abnormal healing observed, long term follow up is indicated given the possible late adverse effects of radiation. Although in this cohort no increase in cardiac events following coronary dissections was seen, larger populations are needed to confirm this phenomenon. Stenting of all coronary dissections may be warranted in patients scheduled for brachytherapy after balloon angioplasty.

Three-Dimensional Intravascular Ultrasound Assessment of Noninjured Edges of β-Irradiated Coronary Segments

BackgroundThe “edge effect,” late lumen loss at the margins of the treated segment, has become an important issue in the field of coronary brachytherapy. The aim of the present study was to assess the edge effect in noninjured margins adjacent to the irradiated segments after catheter-based intracoronary &bgr;-irradiation. Methods and ResultsFifty-three vessels were assessed by means of 3-dimensional intravascular ultrasound after the procedure and at 6- to 8-month follow-up. Fourteen vessels (placebo group) did not receive radiation (sham source), whereas 39 vessels were irradiated. In the irradiated group, 48 edges (5 mm in length) were identified as noninjured, whereas 18 noninjured edges were selected in the placebo group. We compared the volumetric intravascular ultrasound measurements of the noninjured edges of the irradiated vessels with the fully irradiated nonstented segments (IRS, n=27) (26-mm segments received the prescribed 100% isodose) and the noninjured edges of the vessels of the placebo patients. The lumen decreased (6 mm3) in the noninjured edges of the irradiated vessels at follow-up (P =0.001). We observed a similar increase in plaque volume in all segments: noninjured edges of the irradiated group (19.6%), noninjured edges of the placebo group (21.5%), and IRS (21.0%). The total vessel volume increased in the IRS in the 3 groups. No edge segment was subject to repeat revascularization. ConclusionsThe edge effect occurs in the noninjured margins of radiation source train in both irradiated and placebo patients. Thus, low-dose radiation may not play an important role in this phenomenon, whereas nonmeasurable device injury may be considered a plausible alternative explanation.

Endovascular brachytherapy in coronary arteries: the Rotterdam experience

Purpose: The use of endovascular coronary brachytherapy to prevent restenosis following percutaneous transluminal coronary angioplasty (PTCA) began in April 1997 at the Department of Interventional Cardiology of the Thoraxcenter at the University Hospital of Rotterdam. This article reviews the more than 250 patients that have been treated so far.Methods and Materials: The Beta-Cath System (Novoste), a manual, hydraulic afterloader with 12 90Sr seeds, was used in the Beta Energy Restenosis Trial (BERT-1.5, n=31), for compassionate use (n=25), in the Beta-Cath System trial (n=27) and in the Beta Radiation in Europe (BRIE, n=14). Since the Beta-Cath System has been commercialized in Europe, 57 patients have been treated and registered in RENO (Registry Novoste). In the Proliferation Reduction with Vascular Energy Trial (PREVENT), 37 patients were randomized using the Guidant-Nucletron remote control afterloader with a 32P source wire and a centering catheter. Radioactive 32P coated stents have been implanted in 102 patients. In the Isostent Restenosis Intervention Study 1 (IRIS 1), 26 patients received a stent with an activity of 0.75-1.5 µCi, and in the IRIS 2 (European 32P dose response trial), 40 patients were treated with an activity of 6-12 µCi. In two consecutive pilot trials, radioactive stents with non-radioactive ends (cold-end stents) and with ends containing higher levels of activity (hot-end stents) were implanted in 21 and 17 patients, respectively.Results: In the BERT-1.5 trial, the radiation dose, prescribed at 2 mm from the source train (non-centered), was 12 Gy (10 patients), 14 Gy (10 patients) and 16 Gy (11 patients). At 6-month follow-up, 8 out of 28 (29%) patients developed restenosis. The target lesion revascularization rate (TLR) was 7 out of 30 (23%) at 6 months and 8 out of 30 (27%) at 1 year. Two patients presented with late thrombosis in the first year. For compassionate use patients, a restenosis rate (RR) of 53% was observed. In the PREVENT trial, 34 of 37 patients underwent an angiographic 6-month follow-up. The doses prescribed at 0.5 mm depth into the vessel wall were 0 Gy (8), 28 Gy (9), 35 Gy (11) and 42 Gy (8). TLR was 14% in the irradiated patients and 25% in the placebo group. One patient developed late thrombosis. In the IRIS 1 trial, 23 patients showed an RR of 17% (in-stent). In the IRIS 2 trial, in-stent restenosis was not seen in 36 patients at 6-month follow-up. However, a high RR (44%) was observed at the stent edges.Conclusions: The integration of vascular brachytherapy in the catheterization laboratory is feasible and the different treatment techniques that are used are safe. Problems, such as edge restenosis and late thrombotic occlusion, have been identified as limiting factors of this technique. Solutions have been suggested and will be tested in future trials.

Comparison of brachytherapy strategies based on dose-volume histograms derived from quantitative intravascular ultrasound.

PURPOSE We present in this paper the comparison, by simulation, of different treatment strategies based either on beta- or gamma-sources, both with and without a centering device. Ionizing radiation to prevent restenosis is an emerging modality in interventional cardiology. Numerous clinical studies are presently being performed or planned, but there is variability in dose prescription, and both gamma- and beta-emitters are used, leading to a wide range of possible dose distributions over the arterial vessel wall. This paper discusses the potential merits of dose-volume histograms (DVH) based on three-dimensional (3-D) reconstruction of electrocardiogram (ECG)-gated intravascular ultrasound (IVUS) to compare brachytherapy treatment strategies. MATERIALS AND METHODS DVH describe the cumulative distribution of dose over three specific volumes: (1) at the level of the luminal surface, a volume was defined with a thickness of 0.1 mm from the automatically detected contour of the highly echogenic blood-vessel interface; (2) at the level of the IVUS echogenic media-adventitia interface (external elastic lamina [EEL]), an adventitial volume was computed considering a 0.5-mm thickness from EEL; and (3) the volume encompassed between the luminal surface and the EEL (plaque + media). The IVUS data used were recorded in 23 of 31 patients during the Beta Energy Restenosis Trial (BERT) conducted in our institution. RESULTS On average, the minimal dose in 90% of the adventitial volume was 37 +/- 16% of the prescribed dose; the minimal dose in 90% of the plaque + media volume was 58 +/- 24% and of the luminal surface volume was 67 +/- 31%. The minimal dose in the 10% most exposed luminal surface volume was 296 +/- 42%. Simulations of the use of a gamma-emitter and/or a radioactive source train centered in the lumen are reported, with a comparison of the homogeneity of the dose distribution. CONCLUSIONS It is possible to derive DVH from IVUS, to evaluate the dose delivered to different parts of the coronary wall. This process should improve our understanding of the mechanisms of action of brachytherapy.

External beam radiation therapy to prevent anastomotic intimal hyperplasia in prosthetic arteriovenous fistulas: results of a randomized trial

External beam irradiation has a documented effect on intimal hyperplasia reduction. However, it did not result in less reinterventions or stenoses after radiation treatment of the venous anastomosis in polytetrafluoroethylene dialysis access.