Long-term Angiographic and Clinical Outcome After Percutaneous Transluminal Coronary Angioplasty and Intracoronary Radiation Therapy in Humans
Background Ionizing radiation has been shown to reduce neointimal formation after balloon angioplasty in experimental models of restenosis. This study was designed to evaluate the feasibility, safety, and effectiveness of intracoronary radiation therapy (ICRT) after percutaneous transluminal coronary angioplasty (PTCA) for preventing restenosis in human coronary arteries.
Methods and Results Twenty-one patients (22 arteries) with unstable angina underwent standard balloon angioplasty. ICRT was performed with the use of an 192Ir source wire that was hand delivered to the angioplasty site. Angiographic follow-up was performed at 24 hours, between 30 and 60 days, and at 6 months. Angioplasty was successful in 19 of 22 lesions, and insertion of the radioactive source wire was successful at all treated sites. Angiographic study at 24 hours demonstrated early late loss of the luminal diameter from 1.92±0.55 to 1.40±0.27 mm. Between 30 and 60 days, repeat angiography demonstrated total occlusion in 2 arteries, a new pseudoaneurysm in 1 artery, and significant dilatation at the treatment site in 2 additional vessels. At ≥6 months’ follow-up, all remaining arteries (n=20) maintained patent, with a mean lumen diameter of 1.65±0.8 mm. The calculated late lumen loss was 0.27±0.56 mm, and the late loss index was 0.19. Clinical events at 1 year included myocardial infarction in 1 patient, repeat angioplasty to the treated site in 3 patients, and persistent angina in 7 patients.
Conclusions These preliminary results demonstrate that ICRT after coronary intervention is feasible and is associated with an acceptable degree of complications and lower rates of angiographic restenosis indexes.
Prevention of restenosis after successful PTCA remains the greatest therapeutic challenge in interventional cardiology. Experimental and pathological studies have described restenosis as a healing response to vascular injury that primarily involves formation of a cellular neointima and late vascular remodeling.1 2 3 4 The effective use of endovascular irradiation to prevent intimal proliferation in animal models of balloon arterial injury has been demonstrated in preclinical studies. Use of a high-energy γ-emitter (192Ir) before or after overstretch balloon injury significantly reduced neointimal formation when measured 2 to 4 weeks after injury. This benefit was seen with doses ranging from 14 to 25 Gy directed to the vessel wall and was maintained at 6 months’ follow-up.7 8 9 Results of clinical studies with endovascular 192Ir radiation in
restenotic stented femoral arteries have indicated low restenosis rates in ≤6 years of follow-up.10
The purposes of this study were to evaluate the feasibility and safety of a system to deliver ICRT after balloon angioplasty in human subjects and to study the short- and long-term angiographic and clinical results of such therapy.
All experimental protocols were approved by the ethics and academic review boards of Miguel Perez-Carrefio and Centro Medico Hospitals, Caracas, Venezuela. Informed consent was obtained in each case.
Patients and Lesion Characteristics
From July 1994 through January 1995, ICRT after PTCA was attempted in 17 men and 4 women (22 total arteries; 1 patient had the procedure in both the left circumflex artery and the RCA). The average age of the patients was 52 years (range, 34 to 73 years). The majority of patients had presented with unstable angina (class 2 to 4) with at least one high-grade stenotic lesion that required PTCA. The majority of lesions (17 of 22 lesions; 77.3%) were de novo lesions. Two patients received stents in addition to the planned PTCA and ICRT: a Gianturco-Roubin stent for acute closure after balloon angioplasty before ICRT and a stent for severe acute recoil after PTCA and ICRT. One patient was treated with ICRT for Palmaz-Schatz in-stent restenosis, and 1 additional patient underwent a rotational atherectomy ablation before ICRT.
All treated lesions were in native coronary arteries: 11 in the left anterior descending artery, 7 in the RCA, and 4 in the left circumflex artery. The majority (19 of 22; 86.4%) of the lesions were type B according to the American Heart Association/American College of Cardiology lesion classification. The mean of the reference vessel diameter was 2.96±0.49 mm (range, 1.8 to 4.0 mm), and the MLD before angioplasty was 0.51±0.26 mm. The MLD after intervention was 1.92±0.55 mm. Angiographic follow-up was performed after administration of intracoronary nitroglycerin at 24 hours in 18 patients and between 30 and 60 days in 12 patients; 19 patients had late angiographic follow-up at ≥6 months. Arteriograms were consistently obtained in the same projections. The quantitative angiographic measurements were read by independent observers according to a method validated by the core laboratory at Emory University in Atlanta, Ga.11 We calculated late loss, defined as Postprocedure MLD−MLD at Follow-up, and late loss index, defined as Late Loss/Acute Gain, where Acute Gain=Postprocedure MLD−MLD Before PTCA.
The radiation system used in this study consisted of a 4F, noncentered, monorail delivery catheter and a 3-cm 192Ir line source with either a 0.018 or 0.014 in diameter fixed to a wire of a similar caliber. After the catheter was placed in position, the 192Ir wire was hand delivered through the catheter to the treatment site. The treatment time was calculated on the basis of the activity of the source (range, 529 to 982 mCi), the prescribed dose, and a distance of 1.5 mm from the center of the source (the prescription point). The initial activity of the source was determined with the use of a well chamber calibrated for a 192Ir wire. The dose rate at different depths was measured with the use of thermal luminescent dosimeter chips at various distances from the wire. The mean treatment time was 580±226 seconds (range, 164 to 929 seconds). The prescribed dose for the first 9 patients (10 arteries ) was 25 Gy using the 0.0180-in wire; in 11 patients, the prescribed dose was 20 Gy; and in 1 patient, it was 18 Gy using the 0.014-in wire. The reference lumen diameter was estimated by the operator during the procedure, and the dose calculations were performed at that time on the basis of this estimation.
After determination by the core laboratory of the true luminal diameters of the treated vessels, the actual dose delivered to the luminal surface of the vessel was recalculated (assuming the catheter was positioned in the center of the artery) with the use of a standard, commercial treatment-planning system. The mean actual dose at the luminal surface of the treatment site was consistently higher than the prescribed dose and was calculated to be 35.6±11.1 Gy (range, 19.5 to 55 Gy for all arteries), whereas the mean dose at the reference vessel diameter was 23.3±7.5 Gy (range, 11.1 to 42.9 Gy). Because a noncentered system was used in this trial, it is likely that vessels that were treated with 25 Gy received even higher doses of up to a maximum of 92.5 Gy when the catheter was lying against the vessel lumen surface, whereas the contralateral wall of those locations received a minimum dose of 7.2 Gy in larger arteries.
All procedures were performed with the use of an 8F guiding catheter system and a conventional balloon angioplasty technique. After the PTCA balloon was removed, the delivery catheter was inserted to fully cover the angioplasty site. A dummy (nonradioactive) wire was advanced within the catheter to the angioplasty site to ensure free insertion of the radioactive wire. The dummy wire was then removed, and the radioactive wire was advanced and positioned at the angioplasty site by both fluoroscopic control and distance measurement. After the radiation treatment, the radioactive wire was removed and placed in a shielded container. Intracoronary nitroglycerin was given, and a final angiogram was taken immediately after the procedure. In the event of acute recoil, an additional balloon dilation was performed. All patients were treated with heparin for 24 hours and discharged 48 to 72 hours after the procedure. After discharge, all patients were treated with aspirin and warfarin for a period of 3 months to reduce the risk of thrombosis that may occur due to a possibility of delayed reendothelialization.
Radiation Protection Considerations
Special safety precautions were taken during the procedure. The sources were transported in a shielded box and were manipulated only with the use of long forceps. Shielding included leaded glass goggles, a thyroid shield, and two fluoroscopy aprons. The handling of the source was shared among three operators. Total handling time of the radioactive wire was <1 minute per artery, and the calculated exposure of radiation to a single operator who performed these 22 radiation procedures was 2 mSv.
All data were recorded on standardized forms, entered into a computerized database, and expressed as proportions or as mean±SD. Given the lack of a concurrent group of nonirradiated patients, the only comparison that was tested was the postprocedural MLD versus the MLD at 24 hours and at follow-up, for which the paired ttest was used. All tests of significance were two-tailed, and values of P<.05 were considered to indicate statistical significance.
Angioplasty was successful (percent residual diameter stenosis <50%) in 19 of 22 sites (86.4%). However, ICRT was successfully delivered to all treated sites. All patients tolerated the radiation therapy, with none of the patients developing ischemia, arrhythmia, or any other major complication during the procedure, and none of the radiation treatments were interrupted. One patient developed coronary spasm after the radiation treatment that was refractory to intracoronary nitroglycerin but resolved after prolonged balloon inflation. The mean MLD after the procedure was 1.92±0.55 mm, and the mean residual percent diameter stenosis after the procedure was 34±13%. All treated arteries undergoing 24-hour angiography were patent except 1 that sustained subacute thrombosis in a bifurcated site (without resulting in acute myocardial infarction or creatine phosphokinase elevation). This patient underwent successful angioplasty to both the thrombosed branch and the radiation-treated site. Early luminal loss was demonstrated in the treated arteries at 24 hours with a reduction of the MLD from 1.92±0.55 to 1.40±0.27 mm, leaving a mean residual percent diameter stenosis of 45±10% (P<.001). All patients were free from in-hospital major cardiac events such as myocardial infarction, bypass surgery, or death. The first 9 patients (10 arteries) who were treated with a higher dose of 25 Gy had a repeat angiogram between 30 and 60 days after the procedure. Two of these patients, although asymptomatic, had total occlusion at the treated site at 30 and 38 days, respectively, without evidence of recent myocardial infarction on their ECG. One of these patients had a total occlusion before the initial angioplasty and radiation treatment. The other patient had severe dissection during the angioplasty procedure before the radiation treatment. One patient developed a small pseudoaneurysm-like appearance at the treatment site immediately after the procedure that was pronounced at 6 months. Another patient (Patient 2 in the Table⇓) who underwent uncomplicated PTCA to the proximal left anterior descending coronary artery developed pseudoaneurysm at the treatment site at 60 days that was enlarged at 8 months. (Fig 1⇓). This patient remained asymptomatic and refused bypass surgery. The actual dose calculated for this patient was 38.5 Gy delivered to a distance of 1.5 mm from the source, and because the radiation was delivered by a noncentering delivery system, it is likely that the vessel wall at the treated site received up to 92 Gy. Two other vessels (the RCA and left circumflex artery) that were treated with 25 Gy (patient 7 in the Table⇓) showed vessel dilatation and irregular appearance at early (right coronary artery) and late follow-up (left circumflex artery) (Fig 2⇓).
The angiographic follow-up in this study ranged between 6 and 14 months (average, 8±1.9 months) (Table⇑). Except for the two subacute occlusions at 30 days, all of the remaining arteries studied were patent, with a mean luminal diameter at last follow-up of 1.65±0.8 mm and a mean residual stenosis of 41±24%, similar to the postangioplasty result (P=.2). The calculated late loss for the entire cohort was 0.44±0.7 mm, whereas the late loss after excluding the two patients with total occlusions was 0.27±0.56 mm, and the late loss index was 0.19±0.4. An example of a case with a negative late loss at 14 months with site dilatation is shown in Fig 2⇑. MLD at late follow-up demonstrated negative late loss in 10 of the 22 arteries (Table⇑). At 8±1.9 months, angiographic binary restenosis (>50% diameter stenosis) occurred in 6 (27.3%) of the 22 treated lesions. At the 12-month clinical follow-up, the survival rate free of myocardial infarction, bypass surgery, or revascularization of the target lesion was 80.9%. Clinical events recorded included a myocardial infarction in one patient (with a patent artery at the treated site), repeat angioplasty in three patients (one of these to a new site), and persistent angina in seven patients. None of the patients or the medical personnel developed complications or illnesses that could be related to the effects of the radiation procedure.
This study describes the first human ICRT trial and is among the first to report clinical and angiographic follow-up of >6 months’ duration. The study demonstrated that intracoronary irradiation after standard balloon angioplasty using a catheter-based system is feasible and can be performed with a low and acceptable incidence of procedural or in-hospital adverse events.
Freedom from myocardial infarction, bypass surgery, or revascularization of the target lesion at 1 year was 80.9%, similar to the value of 80.5% in the stent group at 6 months in the STRESS trial12 and higher than that reported in several balloon angioplasty studies.13 14 Radiation as an adjunct therapy to intracoronary stenting was suggested as an ideal combination because radiation has been shown to be very effective at suppressing the neointimal proliferation seen with stent placement, in which the stent prevents vessel contraction (unfavorable remodeling).7 16 However, the results seen here with radiation alone, negative late loss in 10 arteries, and a late loss index of 0.19 raise the possibility of favorable remodeling after ICRT and the question of the need for intracoronary stenting after adequate balloon angioplasty for prevention of late constriction (Fig 3⇓).
The lack of a consistent effect after ICRT may be related to the inhomogeneity of dosing due to the lack of centering and inaccurate dose calculations performed in this study. The error in dosing was a result of failure to estimate an accurate vessel size. This can be prevented in the future by using either on-line quantitative coronary angiography or intravascular ultrasound and a centered delivery system.
Another potential concern is the presence of total occlusion at two treated sites at 30 and 38 days’ angiographic follow-up. Although one of these patients had a totally occluded artery before ICRT and the other had severe dissection at the time of the angioplasty, this may be a result of delayed reendothelialization. Therefore, ICRT may require a more intense anticoagulation protocol.
Six of the 10 arteries that were treated with higher doses of 25 Gy developed angiographic complications (total occlusions in 2 and pseudoaneurysm and arterial dilatation in 4 vessels). It is possible that some areas of these vessels could have been exposed to two to three times the intended dose due to the noncentered catheter. Although the irregularity and pseudoaneurysm were seen immediately after the procedure in 2 of these patients, it is possible that the radiation at these high doses interferes with the wound-healing process, and this could suggest an upper limit of vessel wall integrity and tolerance to likely toxic doses for this therapy after balloon angioplasty. In contrast, it is possible that the contralateral wall of larger arteries received lower doses than are required for therapy, which may explain the lack of consistency in the effectiveness of the treatment in this cohort.
The hand-loading delivery system used in this study is limited in effectively shielding 192Ir by standard lead aprons, thus exposing the medical personnel to additional radiation exposure, especially when high activities are used. Additional studies can minimize these problems by using a remote afterloading device to deliver the source and a radiation shield to block exposure to personnel.
The importance of this trial primarily lies in demonstrating that ICRT for prevention of restenosis is feasible and free of any unexpected acute complications. This limited experience without a concurrent nonirradiated group does not allow us to comment definitively on the efficacy of this approach. Preliminarily, it appears that ICRT may inhibit late luminal loss due to either inhibition of neointima formation or by promotion of favorable remodeling. Larger randomized studies are needed to determine whether ICRT will be proven effective in reducing clinical events after PTCA.
Selected Abbreviations and Acronyms
|ICRT||=||intracoronary radiation therapy|
|MLD||=||minimal lumen diameter|
|PTCA||=||percutaneous transluminal coronary angioplasty|
|RCA||=||right coronary artery|
We thank Jorge Saucedo, MD, Alexandra Lanski, MD, and Jeff Popma, MD, for their consultation in reviewing the angiograms.
- Received March 7, 1997.
- Revision received June 16, 1997.
- Accepted June 16, 1997.
- Copyright © 1997 by American Heart Association
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