CLINICAL STUDY: INTERVENTIONAL CARDIOLOGY
The outcome of percutaneous coronary intervention in patients with In-Stentrestenosis who failed intracoronary radiation therapy
Andrew E. Ajani, MBBS*,
Ron Waksman, MDFACC*,*,
Edouard Cheneau, MD*,
Dong-Hun Cha, MD*,
Scott McGlynn, MD*,
Marco Castagna, MD*,
Rosanna C. Chan, MD ,
Lowell F. Satler, MDFACC*,
Kenneth M. Kent, MDFACC*,
Augusto D. Pichard, MDFACC*,
Ellen Pinnow, MS* and
Joe Lindsay, MDFACC*
* Division of Cardiology, Washington Hospital Center, Washington, D.C., USA
Washington Cancer Institute at the Washington Hospital Center, Washington, DC, USA
Manuscript received June 24, 2002;
revised manuscript received October 25, 2002,
accepted November 1, 2002.
* Reprint requests and correspondence: Dr. Ron Waksman, Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, D.C. 20010, USA.
ron.waksman{at}medstar.net
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Abstract
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OBJECTIVES: This study reports the outcome of patients who failed intracoronary radiation therapy (IRT) for the treatment of in-stent restenosis (ISR).
BACKGROUND: Intracoronary radiation therapy has demonstrated a reduction in the recurrence rate of restenosis for patients with ISR. However, 10% to 30% of these patients require repeat intervention to the irradiated site.
METHODS: Of 961 patients who were assigned to gamma or beta radiation for the treatment of diffuse ISR, we evaluated the outcome of 282 (29%) consecutive patients who failed IRT and compared them with the 679 (71%) patients who had successful IRT. For patients who failed radiation, the mean time to the first target vessel revascularization (TVR) was 173 ± 127 days after the index procedure and the total duration of follow-up was 494 ± 304 days.
RESULTS: Patients who failed IRT were younger (60 ± 10 vs. 63 ± 11 years, p = 0.002) and had a higher incidence of restenting (51% vs. 41%, p = 0.003). The majority (55%) of the restenotic lesions after IRT failure were focal ( 10 mm), with a mean lesion length of 11.9 ± 1.9 mm. Of the 257 patients who had subsequent TVR after failed IRT, 68 (26%) underwent coronary artery bypass grafting and 189 (74%) underwent percutaneous coronary intervention using balloon in 61%, restenting in 26%, atheroablation in 11%, and the cutting balloon in 2% of cases. At six months, 6% of patients died, 1% had Q-wave MI, 17% had repeat TVR, and the overall rate of major adverse cardiac events was 21%.
CONCLUSIONS: The predominant angiographic pattern of lesions in patients who failed IRT is focal restenosis, with these lesions responding well to conventional revascularization methods.
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Abbreviations and Acronyms
| | CABG | | coronary artery bypass grafting | | IRT | | intracoronary radiation therapy | | ISR | | in-stent restenosis | | MACE | | major adverse cardiac events | | MI | | myocardial infarction | | PCI | | percutaneous coronary intervention | | TLR | | target lesion revascularization | | TVR | | target vessel revascularization | | WRIST | | Washington Radiation for In-Stent restenosis Trial |
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Restenosis after stent implantation can be predicted by a number of variables, including vessel size, post-procedural percent diameter stenosis, and stent length (1,2). In-stent restenosis (ISR) represents a clinical entity of striking magnitude, and is likely to become more prevalent as coronary stenting continues its widespread application (3). Intracoronary radiation therapy (IRT) using both gamma and beta emitters has demonstrated a reduction in the recurrence rate of restenosis for patients with ISR of native coronary arteries and saphenous vein grafts (4–9). However, 10% to 30% of these patients require repeat intervention to the irradiated site, which occurs either within the stented segment or involves edge restenosis (10). Although the rate of recurrent restenosis after IRT has been established, the nature of this restenotic process (i.e., focal vs. diffuse, in-stent vs. edge) has been inadequately characterized. In addition, factors that predict radiation failure are unknown. The aim of this study was to report clinical and angiographic outcomes of patients who failed IRT, defined as patients who required repeat target vessel revascularization (TVR) after IRT (either by percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]), or patients with subsequent total occlusion at the irradiated lesion who were managed medically.
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Methods
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Selection of patients.
We analyzed 961 consecutive patients enrolled in the Washington Radiation for In-Stent restenosis Trial (WRIST) series of radiation trials for ISR using gamma and beta emitters at the Washington Hospital Center between February 1997 and March 2001. These trials were designed to test the effectiveness of IRT as an adjunctive treatment to the conventional intervention of ISR. The study population included patients treated with IRT who had completed at least six months of clinical follow-up.
All studies involved an Investigational Device Exemption granted by the Food and Drug Administration, and were approved by the Institutional Review Board and the Radiation Safety Committee at the Washington Hospital Center. Informed consent was obtained for all patients. All clinical events were independently adjudicated by an external committee.
The inclusion criteria for the initial IRT index procedure included ISR, lesion diameter stenosis >50% in the presence of angina or inducible ischemia on functional testing, reference vessel diameter 2.5 to 5.0 mm, lesion length <80 mm, and successful primary coronary intervention. Exclusion criteria included acute myocardial infarction (MI) within 72 h of the index procedure, left ventricular ejection fraction <20%, angiographic visible thrombus, multiple coronary lesions, and previous coronary or chest radiation therapy.
Procedural protocol
Before the percutaneous coronary artery or saphenous vein graft intervention, an angiogram and an intravascular ultrasound study were performed to determine lesion length and vessel size. Percutaneous intervention was performed with conventional or cutting balloon dilation, excimer laser, rotational atherectomy, and/or re-stenting. In preparation for IRT treatment, the patient was further sedated, with the activated clotting time maintained at >300 s with intravenous heparin.
The gamma (192-Iridium) and beta (90-Yttrium) IRT treatments in the WRIST studies have been previously described (4,6). Accurate positioning of the source train was documented by angiography; at least 4-mm overlap of normal segments on each end of the ISR was employed to limit edge restenosis. A radiation oncologist was responsible for handling the radiation source, a radiation physicist was integral in dose calculation, and a radiation safety officer ensured that adequate safety precautions were undertaken during the radiation dwelling period.
A final angiogram was performed, and if required, further intervention was undertaken to optimize the final results. Routine post-PCI care included cessation of heparin, early sheath removal, and, in addition to aspirin, antiplatelet therapy with either ticlopidine 250 mg orally twice daily or clopidogrel 75 mg daily for one to six months (depending on the study protocol).
Study end points
Target lesion revascularization (TLR [site of the injured and irradiated segment at the index procedure]) and TVR (any part of the treated vessel including the site of the initial injured and irradiated segment) consisted of repeat PCI or CABG, driven by clinical signs of ischemia in the presence of angiographic restenosis.
The specific focus of this study was to analyze the efficacy of repeat revascularization procedures after failed IRT. This was defined as the need for TVR at any time period beyond the index radiation procedure or patients with total occlusion of the target lesion on routine follow-up angiography who were managed medically. The need for additional TVR was also analyzed, including the time interval between interventions and the type of revascularization strategy performed (PCI or CABG). Major adverse cardiac events (MACE) were defined as death, Q-wave MI, or TVR. Late total occlusion was defined as angiographically documented total occlusion at the lesion site at least 30 days after the index IRT procedure.
Angiographic analysis
The Washington Hospital Center angiographic core laboratory performed quantitative angiography using the CMS-GFT system (Medis, Leiden, Netherlands). Angiographic analysis was performed on the angiogram of patients requiring percutaneous reintervention of the target lesion, and a comparison was made to the angiogram of the index procedure. The minimal luminal diameter was determined for the total analyzed segment (5 mm proximal and distal to the irradiated segment). The reference vessel diameter and pre- and post-procedural diameter stenoses after the intervention were calculated. Edge restenosis was defined as a follow-up diameter stenosis  50% of the reference vessel diameter within 5 mm of the proximal or distal irradiated zone.
Statistical analysis
In comparing patients who failed radiation with those who did not, continuous variables were expressed as means ± SD and categorical data were expressed as percentages. Student t test was used to compare continuous variables; chi-square statistics or Fisher exact test was used to compare categorical values. A stepwise logistic regression analysis was performed to determine independent predictors of radiation failure. The variables used in this analysis included the following: index procedure variables; type of radiation (gamma or beta); age; gender; hypertension; diabetes; history of smoking; hypercholesterolemia; history of MI; history of CABG; history of PCI; unstable angina; multivessel disease; pre- and post-minimal luminal diameter; lesion length; reference vessel diameter; left ventricular ejection fraction; coronary vessel treated; and the initial treatment strategy, which included balloon angioplasty alone, excimer laser coronary angioplasty, rotational atherectomy, or restenting. Independent variables were expressed as odds ratio (OR) with 95% confidence intervals (CI). A value of p < 0.05 was considered statistically significant.
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Results
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Characteristics of study population.
A total of 961 consecutive IRT patients (mean follow-up 494 ± 304 days) were analyzed, and 282 (29%) IRT failure patients were identified (Fig. 1). The baseline characteristics of patients are displayed in Table 1. Of the IRT failures, 25 patients had total occlusion at the irradiated site and were managed medically (4 patients in this group had subsequent percutaneous laser myocardial revascularization therapy). The majority, 257 (91%), underwent TVR (mean time to first TVR was 173 ± 127 days after the index procedure).
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Figure 1 Study population defined by outcome after intracoronary radiation therapy (IRT). CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention; TVR = target vessel revascularization.
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Of the total cohort, 911 patients (95%) were enrolled in gamma radiation trials for ISR and 50 patients (5%) received beta radiation for ISR (Table 2). Twenty-nine percent of patients receiving gamma radiation failed, and 30% of patients receiving beta radiation failed (p = NS). Patients who failed IRT were younger (60 ± 10 vs. 63 ± 11 years, p = 0.002) and more likely to have required restenting at the index procedure (51% vs. 41%, p = 0.003), compared with patients who had successful IRT. A total of 74 patients (26% of 282) had angiographic late total occlusion diagnosed at the time of IRT failure. Late thrombosis (late total occlusion with a clinical event) was identified in 28 of these patients, i.e., 38% of the late total occlusion population.
In-hospital outcomes for first TVR after failed radiation therapy
The procedural success rate of the first TVR after failed radiation therapy was 96% for patients treated with PCI. Sixty percent of patients required TLR at the time of IRT failure. No coronary perforations were identified, and 14% of patients had a post-procedural creatine kinase rise to 3 times baseline. There were no in-hospital deaths or Q-wave MI, and 4% of patients underwent repeat in-hospital PCI.
In patients who underwent TVR with PCI, conventional balloon angioplasty was used in 61% of patients, restenting in 26%, atheroablation (rotablation or excimer laser) in 11%, and cutting balloon in 2%.
Angiographic results for first TVR after failed radiation therapy
Quantitative coronary angiography performed on the PCI for first TVR after failed radiation therapy demonstrated that the majority of recurrent ISR lesions were relatively short, with a mean lesion length of 11.9 ± 1.9 mm (Table 3). Fifty-five percent of these restenotic lesions were focal (10 mm). Analysis of diffuse lesions at index IRT revealed a 50% reduction in lesion length at subsequent first TVR after failed IRT (28.5 ± 13.5 mm at index IRT vs. 14.4 ± 7.5 mm at time of TVR for IRT failure, p < 0.001). Edge restenosis was identified as the site of failure in 18% of cases. Thirty-two patients of the IRT failure group who had TVR (12% of 257 patients) had total occlusion ISR at the index procedure, 8 (25%) of whom returned with total occlusion at the time of IRT failure.
The reference vessel diameter of the radiation failures was 2.65 ± 0.49 mm, and the pre- and post-intervention minimal luminal diameter were 0.86 ± 0.74 mm and 1.87 ± 0.43 mm, respectively. The diameter stenosis improved from 67 ± 27% preintervention to 20 ± 15% post-intervention.
Late outcomes of radiation failure patients
Of the 257 patients who required TVR, 68 (26%) underwent CABG and 189 (74%) underwent PCI. Additional TVR was required in 3% of patients in the CABG group and 32% of patients in the PCI group (mean period between first and second TVR was 152 ± 108 days).
At six months follow-up after IRT failure of 282 patients, 15 patients (5%) died and 3 patients (1%) sustained a Q-wave MI (Table 4). The etiology of the 15 deaths are as follows: 4 late thromboses (all patients had ceased clopidogrel at the time of the clinical event), 5 MI (distribution consistent with non-irradiated vessel), 5 congestive cardiac failures, and 1 major ischemic stroke. Twenty-six patients required TLR (9%), 47 (17%) required TVR, and the overall MACE rate was 21%.
The only independent predictor of IRT failure on multivariate analysis was restenting at the index IRT procedure (OR 1.54, CI 1.15 to 2.06, p = 0.035).
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Discussion
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The principal findings of this study include the following: 1) the rate of failed IRT was 29% (of 961 patients) at a mean follow-up of 494 ± 304 days; 2) in patients failing IRT, the majority (91%) underwent repeat TVR; 3) in the majority of these cases, PCI was the preferred method of revascularization (74% overall), and in these cases, conventional balloon dilation was used most frequently (61%); 4) the predominant pattern of recurrence was focal restenosis (55%), with an overall mean lesion length of 11.9 ± 1.9 mm; 5) edge restenosis was detected in 18%; 6) at six months follow-up after confirmed IRT failure, the rate of subsequent TVR was 17% and MACE was 21%; 7) the rate of recurrent TVR was 32% in patients with radiation failure treated with repeat PCI (mean time interval between first and second TVR of 152 ± 108 days); and 8) restenting was an independent predictor of failed IRT.
The etiology of failed IRT is poorly understood. One explanation may be underdosing. A subset of patients may require a higher radiation dose than prescribed by conventional protocols. In Long WRIST High Dose (11) (18 Gy delivered at 2 mm), the six-month TVR rate was 17% compared with 33% in irradiated patients of Long WRIST (11) ([15 Gy at 2 mm], p < 0.001). Moreover, intravascular ultrasound analysis in the same cohorts showed that despite longer ISR lesions, Long WRIST High Dose had a greater minimum lumen area (4.0 ± 1.4 mm2) compared with the irradiated patients of Long WRIST (2.9 ± 1.0 mm2, p < 0.005) (11).
A second explanation for IRT failure is late thrombosis, which has recently been reported to be controlled with prolonged antiplatelet therapy (12). Thirdly, inadequate coverage of the treated lesions with radiation may lead to geographic miss; a cause of recurrence at the edge of the radiation field known as edge effect (10). Specific analysis for "geographic miss" was not performed in this study, although it has been previously shown in the first (original) WRIST (65 patients from this cohort) to be a confounding contributor to radiation failure (10). Eighteen percent of cases requiring repeat TVR after IRT were due to edge restenosis, an entity that remains poorly understood. Edge restenosis may be related to the radiation source train not fully covering the injured segment (a combination of injury and low-dose IRT) (13). A longer radiation source train has been proposed to ensure that the injured vessel is suitably irradiated. However, in the START 40/20 trial, the rate of TVR was not reduced by lengthening the source train (40 mm) compared with the IRT patients of START (14).
In the cohort of IRT failures who underwent TVR, conventional balloon angioplasty was favored among a variety of treatment strategies available for the treatment of ISR. Balloon angioplasty has traditionally been preferred for focal lesions, and atheroablation therapy has been preferred for diffuse ISR lesions (15–17). Restenting has been used to treat edge dissection and to prevent tissue prolapse in an attempt to optimize final luminal area. Despite theoretical advantages, no approach has proved superior, and the recurrence rate of ISR without IRT remains high (>50%), whichever technique is used. In patients receiving adjunctive IRT for ISR, the device used did not influence clinical outcomes (18). The cutting balloon has gained popularity for ISR with recent reports of less late loss and reduced restenosis, although it has not been tested with IRT (19). The cutting balloon limits "watermelon" seeding and thus potentially reduces balloon injury length.
This study reflects a contemporary series of IRT patients spanning over four years. The highest percentage of IRT failures per study was found in the earliest trials such as WRIST (43%) and Long WRIST (53%). In this period of time, significant advances have been made in the understanding of IRT, particularly the need for prolonged antiplatelet therapy, the need for longer source trains, avoidance of restenting, and the benefits of higher dosing (10,12). Although we did not control for these factors in the current study, they appear to have contributed to the reduced failure rate seen in Long WRIST High Dose (27%) and WRIST 12 (20) (17%).
The type of emitter (gamma or beta) did not influence IRT failure in our cohort. This observation is interpreted with caution as this study was not designed to assess differences in emitters, and the number of patients in the beta cohort was relatively small.
In terms of treatment guidelines, we now believe it is essential to limit restenting at the time of index radiation, to ensure an adequate radiation treatment margin, and to administer at least 12 months antiplatelet therapy (clopidogrel) in addition to aspirin. The role of drug-eluting stents for this population remains ill-defined.
Study limitations.
This study has the inherent limitations of a retrospective design. However, the data were collected prospectively and adjudicated independently. The majority of patients enrolled in radiation trials had routine angiographic follow-up. We estimate that approximately 10% to 15% of patients had TVR performed on angiographic criteria (oculo-stenotic reflex of the operator), not driven by cardiac symptoms or functional testing, which may have overestimated the true failure rate.
Conclusions
Our initial experience with IRT for ISR suggests a failure rate of 29%. The predominant angiographic pattern of these lesions is focal, responding well to conventional revascularization methods (PCI and cardiac bypass grafting). We anticipate that the implementation of various therapeutic modifications associated with the radiation procedure (e.g. dosing, antiplatelet therapy) will further reduce the need for TVR in this complex patient population.
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Abstract
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