CLINICAL STUDY
The effect of intracoronary radiation for the treatment of recurrent in-stent restenosis in patients with diabetes mellitus
Luis Gruberg, MD**,
Ron Waksman, MD, FACC**,*,
Andrew E. Ajani, MD**,
Han-Soo Kim, MD**,
R. Lawrence White, MD
,
Ellen E. Pinnow, MS**,
Lowell F. Satler, MD, FACC**,
Augusto D. Pichard, MD, FACC**,
Kenneth M. Kent, MD, PhD, FACC** and
Joseph Lindsay, Jr, MD, FACC**
* Cardiovascular Research Institute, Washington Hospital Center, Washington, DC, USA
Washington Cancer Center, Washington Hospital Center, Washington, DC, USA
Manuscript received August 13, 2001;
revised manuscript received March 5, 2002,
accepted March 27, 2002.
* Reprint requests and correspondence: Dr. Ron Waksman, Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010.
ron.waksman{at}medstar.net
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Abstract
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OBJECTIVES: The purpose of this study was to examine the effect of intracoronary radiation therapy (IRT) in diabetic patients with in-stent restenosis (ISR).
BACKGROUND: Diabetic patients are at an increased risk for restenosis, repeat revascularization procedures and late mortality after percutaneous coronary interventions and stenting. Intracoronary radiation therapy, utilizing both gamma and beta-emitters, has been shown to reduce the rate of ISR.
METHODS: The study group consisted of 749 consecutive patients with ISR who were treated with either IRT or placebo in randomized trials and registries at our center. Diabetic patients (252 radiation and 51 placebo) were compared with nondiabetic patients (371 radiation and 75 placebo).
RESULTS: In-hospital outcomes were similar between diabetic and nondiabetic patients treated with and without radiation. At six-month clinical and angiographic follow-up, there was a significant reduction in the binary restenosis (63.8% vs. 15.7%, p < 0.0001), target lesion revascularization (66.7% vs. 17.6%, p < 0.0001) and target vessel revascularization (TVR) (70.6% vs. 22.9%, p < 0.0001) rates in diabetic patients treated with radiation compared to placebo. Comparisons between the placebo arms detected a trend towards higher restenosis (63.8% vs. 48.4% p = 0.13) and TVR (70.6% vs. 56.0%, p = 0.14) in diabetic versus nondiabetic patients. In contrast, diabetic and nondiabetic patients treated with IRT experienced similar restenosis (15.6% vs. 10.7% p = 0.33) and TVR (22.9% vs. 28.2% p = 0.41) rates.
CONCLUSIONS: In diabetic patients with ISR, intracoronary radiation significantly reduced the recurrence of ISR compared to placebo. Additionally, similar rates of restenosis and revascularization procedures were achieved in irradiated diabetic and nondiabetic patients. In view of these results, IRT should be considered as a valuable therapeutic alternative in all diabetic patients with ISR.
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Abbreviations and Acronyms
| | CABG | | coronary artery bypass graft surgery | | CI | | confidence interval | | DM | | diabetes mellitus | | ITDM | | insulin-treated diabetes mellitus | | IRT | | intracoronary radiation therapy | | ISR | | in-stent restenosis | | NITDM | | noninsulin-treated diabetes mellitus | | PCI | | percutaneous coronary interventions | | TLR | | target lesion revascularization | | TVR | | target vessel revascularization | | WRIST | | Washington Radiation for In-Stent restenosis Trial |
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Patients with diabetes mellitus (DM) referred for percutaneous coronary intervention (PCI) constitute one of the greatest challenges for the interventional cardiologist. These patients are usually older, female and sicker with more frequent comorbid conditions, such as hypertension, hyperlipidemia and more advanced cardiovascular disease, as manifested by multivessel coronary artery disease and congestive heart failure (1). Restenosis continues to be the major limitation of PCI, particularly in patients with DM. Restenosis rates after balloon angioplasty in diabetic patients can be very high (up to 63%) (1–3), and although stenting has been shown to decrease these rates, patients with DM continue to have significantly higher restenosis rates and clinical events following PCI (4–9).
Intracoronary radiation therapy (IRT), utilizing both gamma- and beta-emitting sources, is a novel catheter-based procedure that has demonstrated a reduction in restenosis rates and the need for revascularization procedures in a broad range of patients with ISR, as documented in multiple, randomized, double-blind trials (10–12). The objective of this report was to analyze the efficacy of IRT in patients with DM and compare the outcomes of IRT and placebo in diabetic versus nondiabetic patients.
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Methods
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The Washington Radiation for In-Stent restenosis Trials (WRIST) are a series of studies designed to assess the benefit of IRT with either gamma- or beta-emitters in both native coronary arteries and saphenous vein grafts for the treatment of ISR. Details of these trials (SVG-WRIST, WRIST, High dose and Long WRIST, Compassionate USE, Plavix-WRIST and Beta WRIST) have been published previously (10–13). All of these trials were sponsored by an Investigational Device Exemption granted by the Food and Drug Administration and approved by the Institutional Review Board and Radiation Safety Committee at the Washington Hospital Center. These studies were monitored by an external data and safety monitoring board, and clinical events were reviewed by an independent committee. Informed consent was obtained from each patient before enrollment into the study. All patients underwent coronary intervention via the transfemoral approach with conventional catheter-based systems according to current guidelines (14). Weight-adjusted heparin dosage was administered during the procedure in order to maintain an activated clotting time of 250 to 300 s and was routinely discontinued at the end of the procedure. Patients received aspirin 325 mg at least 24 h before the procedure and continued indefinitely afterwards. Patients were treated concomitantly with either ticlopidine 250 mg twice daily or clopidogrel 75 mg a day for four weeks. Of this cohort, 120 patients were treated with clopidogrel for six months. Glycoprotein IIb/IIIa inhibitors were not used in these protocols. Patients were followed clinically at 30 days and at 6 and 12 months.
Study population.
Between February 1997 and February 2000, a total of 749 patients with ISR in their native coronary artery or saphenous vein grafts were treated with either IRT or placebo following conventional intervention. Device selection, including atheroablative devices (rotational and directional atherectomy or excimer laser angioplasty) or additional stents, was left at the discretion of the operator. In this cohort, 402 patients underwent randomization and 307 were treated in open registries, 303 patients had DM, 252 were treated with IRT and 51 were randomized to the placebo arm. Of the 446 nondiabetic patients, 371 were treated with IRT and 75 were randomized to placebo. Comparisons were made between the radiation and placebo-treated groups in the diabetic and nondiabetic population and between diabetic and nondiabetic patients. Angiographic entry criteria included a diameter stenosis 
50% within the stented area in vessels 2.5 to 5.0 mm in diameter in patients who underwent successful angioplasty (<30% residual diameter stenosis in the absence of complications). Patients with a recent myocardial infarction (<72 h), left ventricular ejection fraction <20%, prior irradiation to the chest, angiographic evidence of thrombus or multiple lesions in the target vessel were excluded from the studies.
Diabetes mellitus: definitions.
Patients were prospectively classified as diabetic if they were treated with oral hypoglycemic drugs or insulin or if they had a previous history of elevated fasting glucose (140 mg/dl) on at least two separate occasions. According to the type of treatment, patients were classified at the time of the initial procedure into three categories: 1) diet only; 2) noninsulin-treated diabetes mellitus (NITDM) (patients treated with oral hypoglycemic drugs and diet, but without insulin); and 3) insulin-treated diabetes mellitus (ITDM) (patients treated with insulin, irrespective of other therapy).
Radiation delivery and dosimetry.
For gamma radiation, a 192-Iridium source train was delivered into a noncentering end-lumen catheter. The prescribed dose was either 14 or 15 Gy to a distance of 2.0 mm from the surface of the source for vessels between 2.5 and 4.0 mm or 15 Gy to a distance of 2.4 mm for vessels >4.0 mm in diameter. Maximal dose to the near wall was 
55 Gy, whereas the minimum dose to the far wall was 7.3 Gy. For beta radiation, a 90-strontium pure beta-emitter source was delivered into a centering balloon end-lumen catheter. The prescribed dose was 20.6 Gy to a distance 1.0 mm from the surface of the inflated balloon. The dose rate varied from 16.0 to 5.6 Gy/min.
quantitative coronary angiographic analysis.
Quantitative coronary angiographic analysis was performed by two independent core laboratories blinded to the treatment protocols, using the Cardiovascular Measurement System (MEDIS, Leiden, The Netherlands), as described previously (10–13). Angiographic binary restenosis at follow-up was defined as 50% diameter narrowing within the stent and in the segment that included the stent plus its edges (5 mm at each end). Total occlusion was considered to have a 100% diameter stenosis.
Statistical analysis.
The study population was analyzed in three separate ways. First, patients were grouped by the presence or absence of DM. Second, patients were grouped based on whether they had received actual radiation treatment or had been part of the placebo control group (n = 126). Third, the population of diabetic patients was subgrouped by the treatment modality into ITDM and NITDM patients. Data are presented as mean ± SD. For continuous variables, comparisons between the two groups were made with the Student t test and for categorical values by the chi-square or Fisher exact test. Multivariate logistic analysis with backward regression was used to model independent predictors of restenosis and target vessel revascularization (TVR). Variables included in the model were age, gender, diabetes, hypertension, lesion length, postprocedural minimal lumen diameter and each one of the different trials in order to assess the exact contribution of these factors on restenosis rates. Statistical analysis was performed with SAS software (SAS Institute, Cary, North Carolina). A p value <0.05 was considered statistically significant.
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Results
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The baseline clinical characteristics of the 749 patients enrolled in the radiation trials for ISR are presented in Table 1. Although there were no significant differences between patients assigned to IRT or placebo in either the diabetic or the nondiabetic groups, diabetic patients had more clinical characteristics that have been associated with a worse outcome, including a significantly higher percentage of women, hypertension and lower left ventricular ejection fraction than patients without DM. Angiographic and procedural characteristics are shown in Table 2. Diabetic patients had a trend towards more long, diffuse ISR, although of borderline statistical significance (p = 0.09), whereas nondiabetic patients in the placebo arm had a lower percentage of vein graft lesions and total occlusions (TIMI flow 0 to 1) (p = 0.08) and a higher percentage of ostial lesions compared to nondiabetic patients treated with radiation or to diabetic patients (p = 0.002) (15).
The results of quantitative coronary angiography analysis are summarized in Table 3. Baseline and postprocedural vessel lumen dimensions were smaller in diabetic patients than in nondiabetics. In-hospital outcomes were similar between the groups, with 100% procedural success in all groups and similar death, myocardial infarction and repeat angiography rates. The contribution of each one of the different trials to the pooled results and the TVR rates for each trial are shown in Table 4. On multivariate analysis, only lesion length was an independent predictor of TVR (OR = 1.02; 95% confidence interval [CI] = 1.01 to 1.04, p = 0.01) and target lesion revascularization (TLR) (OR = 1.03; 95% CI = 1.01 to 1.05, p = 0.01).
Diabetes group: radiation versus placebo.
Clinical events at six-month follow-up are depicted in Table 5 and Figures 1 to 3 . Restenosis rates were reduced by 76% in diabetic patients treated with radiation, compared to those patients in the placebo arm of the study (p < 0.0001) (Fig. 1). Rates of TLR and TVR were also significantly reduced in comparison to the placebo arm (Figs. 2 and 3). Higher revascularization rates, especially TVR, than restenosis rates can be attributed to edge effect, operators biased to treat borderline lesions (<50% stenosis) and progression of disease in these patients. Non-TVR rates were similar in the radiation and the placebo arms (11.8% vs. 7.8%, p = 0.62). Mortality rates were similar between the two groups, as were the rates of late total occlusion. There was a higher rate of myocardial infarction in IRT-treated patients, which could be attributed to a surprisingly low rate of non–Q-wave myocardial infarction in the placebo group. Major adverse cardiac events (death, myocardial infarction and repeat revascularization) were significantly lower in patients treated with intracoronary radiation, 25.3% versus 70.6%, p < 0.0001, compared to placebo.
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Figure 1 Binary restenosis rates at six-month angiographic follow-up between patients treated with intracoronary radiation versus patients randomized to the placebo arm. White bars= placebo; black bars= radiation.
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Figure 2 Target lesion revascularization rates at six-month follow-up in patients treated with intracoronary radiation and patients randomized to the placebo arm. White bars= placebo; black bars= radiation.
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Figure 3 Target vessel revascularization rates at six-month follow-up in patients treated with intracoronary radiation and patients randomized to the placebo arm. White bars= placebo; black bars= radiation.
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Irradiated arm diabetic versus nondiabetic patients.
As shown in Table 5 and Figures 1 to 3, event-free survival (freedom from death, myocardial infarction and repeat revascularization) was 74.7% in the diabetic group compared to 70.7% in the nondiabetic group (p = 0.20). Mortality rates were low and similar between diabetic and nondiabetic patients, 3.7% versus 2.4% (p = 0.38), respectively. Rates of TLR by either balloon angioplasty or coronary artery bypass graft surgery (CABG) were also similar between the two groups, although there was a trend towards a higher rate of TVR by CABG in nondiabetic patients treated with radiation, 9.8% versus 5.7% in diabetics treated with radiation (p = 0.09). Late total occlusion rates were also similar between the two groups, 5.3% versus 6.2% (p = 0.62), respectively. At the six-month angiographic follow-up, late lumen loss was 0.51 ± 0.75 mm for diabetic patients compared with 0.48 ± 0.75 for nondiabetic patients (p = 0.81) treated with radiation and the late loss index was 0.68 ± 0.75 compared to 0.52 ± 1.17 (p = 0.33), respectively.
placebo arm: diabetic versus nondiabetic patients.
During the performance of these trials, 126 patients underwent randomization to the placebo arm (no radiation); 38% (n = 51) of them had DM. Nondiabetic patients in the placebo arm had smaller vessel lumen diameters at the lesion site before the procedure than did nondiabetic patients treated with radiation (Table 3). This was corrected with the intervention and resulted in a significantly greater acute gain in this group of patients (1.02 ± 0.49 versus 1.22 ± 0.57, p = 0.01), respectively. At six-month angiographic follow-up, diabetic patients treated with placebo had a trend toward higher restenosis rates (63.8% vs. 48.4%, p = 0.13), TLR rates (66.7% vs. 54.7%, p = 0.20) and TVR rates (70.6% vs. 56.0%, p = 0.14) compared to nondiabetic patients, respectively. Late total occlusion rates were similar between the two groups.
ITDM versus NITDM.
Analysis of the data based on the type of diabetes revealed similar event-free survival, 74.1% in the ITDM versus 76.7% in NITDM patients treated with IRT (p = 0.64), and similar restenosis rates at six-month angiographic follow-up, 14.1% and 17.1%, respectively (p = 0.62). Both groups had comparable rates of TLR, 19.6% versus 17.1%, respectively (p = 0.46), although more ITDM patients underwent TLR by coronary artery bypass graft surgery (8.0%) compared with NITDM patients (2.3%) (p = 0.04). Late total occlusion rates were higher in ITDM patients (8.0% vs. 3.0%, p = 0.08).
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Discussion
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This study used pooled data to compare the in-hospital and six-month clinical and angiographic outcomes of diabetic and nondiabetic patients who underwent IRT for the prevention of recurrence of ISR in the WRIST studies. Diabetic patients randomized to the placebo arm had a trend towards higher event rates, including restenosis, TLR and TVR, compared with nondiabetic patients also randomized to the placebo arm, as shown in previous studies, although statistical significance was not reached for any parameter. In this cohort, diabetic patients had smaller vessel dimensions at baseline and at the end of the procedure and a trend towards more diffuse type of ISR. Despite this, there were no differences in the TLR and TVR rates or the restenosis rates at six-month angiographic follow-up in the radiation group when compared with the nondiabetic group. Comparison by treatment modality (radiation vs. placebo) detected a 76% reduction in the restenosis rates in diabetic patients treated with radiation, a 74% reduction in TLR rates and a 68% reduction in TVR rates, which was slightly higher (not significantly) than the reduction achieved in nondiabetic patients and in previous radiation trials (11,12).
These results warrant several comments. First, the percutaneous treatment of ISR with conventional methods is associated with high failure rates in both diabetic and nondiabetic patients. Second, IRT for the prevention of recurrence of ISR significantly reduced restenosis and revascularization procedures in diabetic patients. The pronounced reduction in event rates in the diabetic patients is underscored by the increased recurrence of adverse events seen in the placebo group. Third, diabetic patients respond to intracoronary radiation in a similar fashion as nondiabetic patients treated with intracoronary radiation, which equalizes the outcome of nondiabetic and diabetic patients. Finally, when diabetic patients were compared according to therapeutic regimen, patients with ITDM and NITDM had similar event-free survival, mortality, revascularization procedures and restenosis rates, although there was a higher incidence of TLR by bypass surgery in the ITDM group of patients compared with NITDM patients. Previous studies have shown that patients with ITDM have a higher incidence of in-hospital mortality, higher TLR rates and significantly lower event-free survival when compared with patients with NITDM (5,16,17). Late total occlusion due to late thrombotic events (>30 days after the index procedure), one of the main complications of intracoronary radiation (18,19), was not encountered more frequently in diabetic patients compared with nondiabetic patients, despite previous reports that have shown a trend toward higher rates of subacute stent thrombosis in diabetic patients who undergo stenting (5–16). The trend toward a higher incidence of late total occlusion in ITDM patients suggests that diabetic status may play an important role in terms of progression of the disease, which may lead to a higher incidence of late total occlusion in this subset of patients. Given the very small number of patients, this sort of analysis is clearly hypothesis-generating.
Stent-based delivery of sirolimus has recently been shown to be feasible and effective in reducing in-stent neointimal hyperplasia by inhibiting cellular proliferation (20). Although the use of drug-eluting stents in the diabetic population may decrease the proportion of diabetic patients with ISR and alter the management of coronary revascularization, the performance of this stent in diabetic patients is not yet known.
study limitations.
The present study was a retrospective analysis of pooled data obtained from a heterogeneous group of patients who were enrolled in registries and randomized clinical studies. Therefore, the results and conclusions are subject to the limitations inherent in all such reports. The current analysis is limited to patients undergoing intervention for ISR, and the results cannot be generalized to the entire diabetic population that undergo PCI. Comparing results among the randomized and nonrandomized trials, taking into account different types of lesions, different types of patients and different types of radiation into a pooled analysis, may be somewhat imprecise. Finally, the relatively small number of patients in the placebo arm, especially during the analysis by treatment regimen, is clearly hypothesis-generating and may lead us to incur a type II statistical error.
Clinical implications.
Patients with DM referred for PCI constitute one of the greatest challenges faced by the interventional cardiologist in the present era. In view of the results obtained in this study, IRT should be considered as a valuable therapeutic alternative in all diabetic patients with ISR, and needs confirmation in a randomized, controlled setting.
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Footnotes
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Dr. Waksman is a consultant to several device companies in the field of radiation for the prevention of restenosis.
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Abstract
Methods
