CLINICAL RESEARCH
Intracoronary brachytherapy after stenting de novo lesions in diabetic patients
Results of a randomized intravascular ultrasound study
Manel Sabaté, MD*,*,
Gela Pimentel, MD*,
Carlos Prieto, BSc*,
JoséMaría Corral, MD*,
Camino Bañuelos, MD*,
Dominick J. Angiolillo, MD*,
Fernando Alfonso, MD*,
Rosana Hernández-Antolín, MD*,
Javier Escaned, MD*,
Panayotis Fantidis, MD*,
Cristina Fernández, MD*,
Antonio Fernández-Ortiz, MD*,
Raúl Moreno, MD* and
Carlos Macaya, MD*
* San Carlos University Hospital, Madrid, Spain
Manuscript received August 8, 2003;
revised manuscript received February 6, 2004,
accepted February 10, 2004.
* Reprint requests and correspondence: Dr. Manel Sabaté, Servicio de Cardiología, Hospital Clínico San Carlos, Plaza Cristo Rey s/n, 28040 Madrid, Spain.
msabate.hcsc{at}salud.madrid.org
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Abstract
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OBJECTIVES: We studied the efficacy of intracoronary brachytherapy (ICB) after successful coronary stenting in diabetic patients with de novo lesions.
BACKGROUND: Intracoronary brachytherapy has proven effective in preventing recurrences in patients with in-stent restenosis. However, the role of ICB for the treatment of de novo coronary stenoses remains controversial.
METHODS: Ninety-two patients were randomized to either ICB or no radiation after stenting. Primary end points were in-stent mean neointimal area (primary end point of efficacy) and minimal luminal area of the entire vessel segment (primary end point of effectiveness), as assessed by intravascular ultrasound at six-month follow-up. Quantitative coronary angiography analysis was performed at the target, injured, irradiated, and entire vessel segments.
RESULTS: At follow-up, the in-stent mean neointimal area was 52% smaller in the ICB group (p < 0.0001). However, there was no difference in the minimal luminal area of the vessel segment (4.5 ± 2.4 mm2 vs. 4.4 ± 2.1 mm2). Restenosis rates increased progressively by the analyzed segment in the ICB group: target (7.1% vs. 20.9%, p = 0.07), injured (9.5% vs. 20.9%, p = NS), irradiated (14.3% vs. 20.9%, p = NS), and vessel segment (23.8% vs. 25.6%, p = NS). At one year, 1 cardiac death, 6 myocardial infarctions (MIs) (3 due to late stent thrombosis), and 10 target vessel revascularizations (TVRs) (6 due to the edge effect) occurred in the ICB group, whereas in the nonradiation group, there were 11 TVRs and no deaths or MIs.
CONCLUSIONS: Intracoronary brachytherapy significantly inhibited in-stent neointimal hyperplasia after stenting in diabetic patients. However, clinically this was counteracted by the occurrence of the edge effect and late stent thrombosis.
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Abbreviations and Acronyms
| | CK | = creatine kinase | | ICB | = intracoronary brachytherapy | | IVUS | = intravascular ultrasound | | MACE | = major adverse cardiac events | | MI | = myocardial infarction | | MLD | = minimal luminal diameter | | NIH | = neointimal hyperplasia | | QCA | = quantitative coronary angiography | | TLR | = target lesion revascularization | | TVR | = target vessel revascularization |
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Diabetes mellitus, a major risk factor for atherosclerosis, is commonly affecting patients (up to 25%) referred for percutaneous or surgical treatment of coronary artery disease (1,2). In particular, after percutaneous coronary interventions, diabetic patients have higher mortality, restenosis rates, and also disease progression at different sites (3,4), as compared with nondiabetics. Intracoronary brachytherapy (ICB) has emerged as an effective technique to prevent recurrences in patients treated for in-stent restenosis (5–9). Besides, diabetics remain as one of the subgroups of patients with in-stent restenosis that benefits most from ICB (10–12). However, the role of ICB to prevent restenosis after percutaneous coronary intervention in de novo coronary lesions remains controversial (13–16). We sought to investigate whether ICB is effective in preventing restenosis after stenting de novo coronary stenoses in patients with diabetes mellitus.
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Methods
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Study design.
This was a single-center, prospective, randomized, unblinded, controlled trial. The primary objective of this study was to assess the efficacy of intracoronary beta-radiation on neointimal proliferation inhibition after coronary stent implantation in diabetic patients assessed by intravascular ultrasound (IVUS) at six-month follow-up. The trial complied with the provisions of the Declaration of Helsinki regarding investigations involving human subjects and was approved by the medical ethics committee of our institution. Written, informed consent was obtained from all patients. All events were judged by an independent committee that was unaware of the treatment allocation group.
Patient selection.
Patients were eligible for the study if they were identified as non–insulin-dependent or insulin-dependent diabetics, according to a World Health Organization report (17). Besides, patients had to be receiving pharmacologic (insulin or hypoglycemic agents) treatment for at least one month before the procedure. Patients with signs and/or symptoms of ischemia and de novo significant coronary stenoses were included. Target lesions had to be amenable for stenting, ICB, and IVUS imaging. The reference diameter had to be between 2.5 and 4 mm, as visually assessed, and the lesion length had to be <35 mm. Randomization was performed by a computer-generated code after the coronary stenting was considered successful according to angiographic (residual stenosis after stenting <15% of the luminal diameter) and IVUS criteria (complete apposition of the stent throughout its entire length, minimal luminal area >80% of reference segment luminal area, and absence of complications such edge dissections). There was a sub-randomization according to the type of diabetes mellitus (insulin- or non–insulin-dependent). Main exclusion criteria included a history of chest radiation, injured segment >45 mm during percutaneous coronary intervention, myocardial infarction (MI) within the preceding 72 h, stenoses located in a saphenous vein graft or internal mammary artery, and use of debulking techniques during the procedure.
From February 2001 to April 2002, 92 patients were enrolled in this trial and randomly assigned (46 in each group) to receive or not receive beta-radiation after successful stenting. The sample size was calculated for a difference of 30% in the mean in-stent neointimal hyperplasia (NIH) area between the groups (estimated for a mean NIH area of 2.2 mm2 in the nonradiation group vs. 1.5 mm2 in the radiation group), with a standard deviation of 1.5, alpha error of 0.05, and beta error of 0.20, as well as 10% missing values during follow-up.
Procedural details.
All patients were taking aspirin (100 to 250 mg) and received intravenous heparin (100 IU/kg) before the procedure. If the duration of the entire procedure exceeded 30 min, the activated clotting time was measured and intravenous heparin was given to maintain it above 250 s. The percutaneous coronary intervention was performed according to standard clinical practice. Abciximab was administered at the discretion of the operator. To ensure successful stent implantation, IVUS analysis was performed immediately afterward. Intracoronary nitrates (0.2 mg nitroglycerin) were systematically administered before IVUS. A 2.6-F, 40-MHz IVUS catheter (CVIS, Atlantis plus, Boston Scientific, Sunnyvale, California) was advanced distal to the treated site. A continuous, motorized pullback at a speed of 0.5 mm/s was carried out. This was followed by an electrocardiographically (ECG)-gated pullback at a step size of 0.2 mm. Both pullbacks were performed from the most distal part of the target vessel that was suitable for placing the IVUS probe up to the ostium of the artery. After successful stenting, patients were randomized to receive radiation or not. Radiation was performed by means of the Guidant Galileo Intravascular Brachytherapy System (Guidant Corporation Vascular Intervention, Houston, Texas), which uses the 27-, 32-, or 52-mm-long centering balloon catheters, with nominal diameters of 2.5, 3.0, and 3.5 mm (18). Patients allocated to radiation received 20 Gy at 1 mm beyond the luminal diameter. Prescription was based on the average of the luminal diameters at the proximal and distal reference segments, as assessed by IVUS. Positioning of the centering balloon was performed after stenting, trying to ensure complete coverage of the injured segment and a minimum of 5 mm at both margins to avoid geographic miss (19). For those patients not randomized to radiation, no sham source was used, and the procedure ended after IVUS imaging. An antiplatelet regimen included 100 to 250 mg aspirin indefinitely and a 300-mg loading dose of clopidogrel, followed by 75 mg/day for one month in the control group or for one year in the radiation group. At six-month angiographic follow-up, further IVUS analysis of the treated segment was performed.
Definitions.
Death was reported as cardiac or noncardiac death. Q-wave MI was defined as the development of new, pathologic Q waves in two or more ECG leads, with postprocedural creatine kinase (CK) levels of twice the upper limit of normal (<190 U/l) and CK-MB levels above normal. Non–Q-wave MI was defined as an elevation of postprocedural CK levels of twice the upper limit of normal, with CK-MB above normal. Device success was defined as the attainment of residual stenosis <15% by quantitative coronary angiography (QCA) and the successful delivery of the radiation device. Procedural success was defined as device success without in-hospital major adverse cardiac events (MACE), including death, MI, or emergency coronary artery bypass graft surgery or repeat angioplasty. Target vessel revascularization (TVR) was defined as revascularization within the treated vessel, and target lesion revascularization (TLR) as revascularization within the irradiated plus edge segment on follow-up angiography. All TLR/TVRs required a significant stenosis and objective evidence of ischemia related to the restenotic artery before treatment. Late stent thrombosis was defined as the occurrence of stent thrombosis beyond one month-follow-up (20). A geographic miss was defined as injured coronary segments receiving low-dose radiation (19). Two independent analysts reviewed all cine films to assess the incidence of geographic miss. A coronary aneurysm was defined as coronary dilation 1.5 times the reference diameter considered as normal on the follow-up angiogram. Late stent malapposition was defined as the presence of unapposed stent struts at follow-up IVUS analysis in the absence of such stent malapposition at the index procedure.
IVUS analysis.
Postprocedural and follow-up IVUS studies were analyzed by an independent core laboratory (University of Florida Health Science Center, Jacksonville, Florida), which was blinded to the treatment protocol. Volumetric analysis of the treated segment was performed from the three-dimensional reconstruction derived from the ECG-gated image acquisition and digitization (EchoScan, Tomtec, Munich, Germany), followed by the automated contour detection system for quantitative analysis of the lumen, stent, plaque, and total vessel area and volumes (Fig. 1). This method has been extensively validated in vitro and in vivo (21–23). To define the reference segments to be analyzed at the core laboratory (stented and vessel segments), two strategies were followed: in the ICB group, the stent was identified in the longitudinal view, and the vessel segment (irradiated plus edges) was defined by the recognition of angiographic anatomic landmarks noted during positioning of the centering catheter in the longitudinal view from IVUS. In the control group (no sham source), the stent was also identified on the longitudinal view, and the vessel segment was defined as that which, when centered on the stent, included the length of the hypothetically needed radiation catheter plus 5 mm both edges. This method made the entire vessel segments comparable between groups (mean length of vessel segment in the ICB group 37 ± 4 mm vs. 36 ± 6 mm in the control group, p = NS). In the event of total occlusion at follow-up, it was imputed that the entire volume of the stent was completely filled with NIH.
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Figure 1 Cross-sectional (A and A') and longitudinal (B and B') intravascular ultrasound images of a coronary segment immediately after treatment and at follow-up. Luminal, plaque, and total vessel function curves are represented in the bottom charts (C and C'). In this example, a marked increment of intra-stent neointimal hyperplasia is shown.
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QCA analysis.
Quantitative coronary angiography was done with the CMS-GFT system (Medis, Leiden, the Netherlands). Angiographic parameters of restenosis were analyzed within the target, injured, irradiated, and total analyzed segment to include the edges, according to a previously validated methodology (24). A lumen of 0 mm was imputed if a total occlusion was present at follow-up. The binary restenosis rate was defined as  50% diameter narrowing at follow-up within the segment subject to analysis. Acute gain was defined as the change in minimal luminal diameter (MLD) of the analysis segment from before to after the procedure. Late loss was defined as the change in MLD from the final procedure to the follow-up angiogram. Proximal and distal edges were defined as being 5 mm from the radiated segment.
Study end points and follow-up.
The primary end point was double: in-stent mean neointimal area at six-month follow-up (primary end point of efficacy) and minimal luminal area of the entire vessel segment (primary end point of effectiveness). The rationale behind the use of both IVUS-assessed primary end points is first to evaluate the full therapeutic effect of brachytherapy under ideal conditions of a randomized trial (efficacy). Secondly, the impact of the treatment in the "real world" of everyday clinical practice (effectiveness) is measured in the entire vessel segment, where both desired and undesired effects (geographic miss, edge effect, or late thrombosis) may occur. Secondary end points included angiographic parameters of restenosis as assessed by QCA at six-month follow-up: in-stent late loss as a secondary end point of efficacy, vessel segment MLD as a secondary end point of effectiveness, and binary restenosis rate; MACE, including death, MI, and TVR at 30 days and 6, 12, and 13 months; and development of complications such as aneurysm formation, stent thrombosis, edge effect (geographic miss), and late stent malapposition. Clinical follow-up was scheduled at 1, 6, 12, and 13 months (one month after clopidogrel withdrawal).
Statistical analysis.
Statistical analysis was performed by the SPSS-PC program. Continuous variables are expressed as the mean ± SD. Categorical variables are expressed as percentages. The efficacy and effectiveness of therapy were assessed by comparing both primary end points between groups. Continuous variables were compared by means of the Student t test. Categorical variables were compared by means of the chi-square test or Fisher exact test when at least 25% of values showed an expected frequency <5. A two-tailed value of p < 0.05 was considered statistically significant.
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Results
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Baseline and procedural characteristics.
Baseline clinical characteristics were comparable between groups (Table 1). Target coronary vessels were well balanced between groups, as well as the main procedural variables (Table 2). Device success was achieved in 100% of cases.
In-hospital and one-month results.
Procedural success was achieved in 89 (96.7%) of 92 patients. Two patients allocated to the ICB group presented with a non–Q-wave MI, with raise in CK up to 400 U/l and 900 U/l, respectively. This was related to side-branch occlusion during the procedure. Another patient had a noncardiac death four days after stenting and brachytherapy due to hemorrhagic shock. None of patients from the nonradiation arm presented with MACE during hospitalization. No additional MACE occurred during the one-month follow-up in either group.
Results of IVUS.
Quantitative volumetric analysis of the stented segment is presented in Table 3. At follow-up, the in-stent luminal volume was significantly larger in the ICB group, at the expense of a significant reduction in NIH volume (Table 3, Fig. 2). The in-stent mean neointimal area (primary end point of efficacy) showed a 55% relative reduction within irradiated stents (1.04 ± 1.6 mm2 vs. 2.30 ± 1.6 mm2, p = 0.0005). In the same way, the percentage of in-stent volume obstruction was significantly lower in the ICB group (13 ± 22% vs. 26 ± 16% in nonradiated group, p = 0.002). However, the minimal luminal area of the entire segment (primary end point of effectiveness) was comparable between groups (4.5 ± 2.4 mm2 vs. 4.4 ± 2.1 mm2, p = NS) due to a relocation of this cross-sectional area to distant segments from the target site in the ICB group. By IVUS, one true aneurysm was identified at follow-up in an irradiated stent edge inducing proximal late stent malapposition without clinical consequences.
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Figure 2 Change in total vessel volume (TVV), plaque volume (PV), and luminal volume (LV) at the stented segment from post-treatment to follow-up between groups. Open bars = control group; shaded bars = brachytherapy group.
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Results of QCA.
The QCA data in the four prespecified coronary segments are presented in Table 4. Angiographic parameters were significantly better in the ICB group when target and injured segments were analyzed. However, these differences were no longer significant in the entire segment (irradiated plus edges), mimicking the phenomenon evidenced by IVUS. Similarly, the restenosis rate progressively increased from the target to entire segments in the irradiated group, whereas it remained almost invariable in the nonradiated group (Fig. 3). Cumulative frequency distribution curves of the MLD demonstrated the discrepancy between target and entire segment analyses (Figs. 4 and 5). The geographic miss phenomenon was detected in four patients (4.3%). All of them presented with the edge effect at follow-up.
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Figure 3 Absolute reduction in restenosis rates in the four prespecified coronary segments between groups. Open bars = control group; shaded bars = brachytherapy group.
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Figure 4 Cumulative frequency distribution curves of MLD between groups at the target segment. By comparison, using the Student t test, the mean MLD at follow-up (F/U) became significant between groups (p > 0.0001).
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Figure 5 Cumulative frequency distribution curves of minimal luminal diameter between groups at the vessel segment. By comparison, using the Student t test, the mean minimal luminal diameter at follow-up (F/U) was no longer significant between groups.
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Six-month and one-year clinical follow-up results.
Clinical follow-up was performed in 100% of patients at six months and one year. Six-month angiographic follow-up was performed in 91.3% of patients receiving radiation and 93.4% of patients not receiving radiation. Reasons for missing angiographic follow-up included death in two patients (one cardiac and one noncardiac), MI before follow-up in two patients, and refusal in the remaining three patients. Overall, there were no statistical differences between groups in the number of MACE at follow-up (Table 5). However, they differ qualitatively between groups. All cases of MACE in the control group were caused by TVR secondary to in-stent restenosis. Conversely, MACE in the ICB group included cardiac death (n = 1), MI (n = 6), and the edge effect (n = 6). Also, TVR secondary to restenosis purely located within the stent occurred only in three irradiated patients (7.1%). The three patients presenting with Q-wave MI showed stent thrombosis related to clopidogrel withdrawal. Reasons for clopidogrel withdrawal included urgent gastrointestinal surgery in one patient and a referral physician's decision in the other two patients. Furthermore, two non–Q-wave MIs were periprocedural (see earlier text). The third one occurred at five months. The patient presented with unstable angina and subsequently developed an increase in CK up to 500 U/l. The patient experienced a severe proximal and distal edge effect not related to geographic miss. At 13-month follow-up (one month after clopidogrel withdrawal), there was no additional MACE in either group.
Clinical results according to type of diabetes.
The primary end points derived from IVUS between diabetes types are presented in Table 6. Overall, no major differences in response to treatment were encountered between insulin- and non–insulin-dependent diabetics. On QCA and parallel to what occurred in the entire population, it appears there was a treatment effect at the target segment, which faded away when the entire vessel segment was analyzed (restenosis rates at target, injured, irradiated, and vessel segments in insulin-dependent diabetics: 20% vs. 0%, 20% vs. 0%, 20% vs. 7.7%, and 26.7% vs. 23.1% [nonradiation vs. ICB group], p = NS for all comparisons; non–insulin-dependent diabetics: 21.4% vs. 10.3%, 21.4% vs. 13.8%, 21.4% vs. 17.2%, and 25% vs. 24.1% [nonradiation vs. ICB group], p = NS for all comparisons). Moreover, clinical events were equally distributed between diabetes type both at six months and one year.
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Discussion
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This is the first randomized trial involving ICB in diabetic patients with de novo coronary stenoses. This study demonstrated that ICB may be successfully delivered after stenting and is able to significantly reduce the degree of in-stent neointimal proliferation at follow-up, as compared with conventional stent implantation alone. Thus, the primary end point of efficacy, which evaluated the full therapeutic potential of this technique, showed a significant reduction of in-stent NIH leading to a restenosis rate of only 7% within the target segment. The degree of inhibition of NIH proliferation observed in our study is comparable to that of previous randomized trials of ICB, where relative reductions of 65% in mean in-stent NIH were evidenced (5,6). Furthermore, a similar inhibitory effect has been demonstrated in a recent IVUS substudy from the TAXUS-II trial (25). At six-month follow-up, both the TAXUS-SR (0.7 ± 0.9 mm2) and the TAXUS-MR (0.6 ± 0.8 mm2) groups showed a significant reduction in mean NIH, compared with the bare-metal stent (1.9 ± 1.5 mm2, p < 0.001).
Besides, our results are concordant to those obtained in subanalyses of diabetics treated with ICB from in-stent restenosis trials (10–12), in which radiation was particularly beneficial. In a recent subanalysis from the WRIST series (11), diabetics treated with ICB showed a 76% reduction in binary restenosis rate, compared with placebo, and, as in our study, this benefit applied for both insulin- and non–insulin-dependent diabetics. In another substudy from the Gamma-1 trial (12), the antirestenosis effect of iridium-192 was larger for diabetic patients than for nondiabetic patients: the absolute in-lesion restenosis rate was reduced by 40% for diabetics and 16% for nondiabetics.
However, this potent inhibitory effect within the stent was clinically counteracted by the occurrence of edge restenosis and late stent thrombosis. Besides, three events not related to the radiation procedure (two non–Q-wave MIs and one noncardiac death) occurred in the ICB group.
In this regard, the combination of ICB and stenting of de novo coronary stenoses has been discouraging in most previous trials (13–16). The Dose Finding Study (13) demonstrated a very low restenosis rate (3.9%) in patients treated with balloon angioplasty and allocated to the highest prescribed dose group (18 Gy at a tissue depth of 1 mm). However, in this study, those patients receiving a stent had a poor outcome due to high rates of stent occlusion (14.3%) and angiographic restenosis (20%). Similarly, in the BRIE Registry (14), late loss was significantly worse in patients receiving a coronary stent with respect to those treated with conventional balloon angioplasty (0.37 vs. 0.12 mm, p = 0.009). The BRIDGE trial (15) randomized 100 patients with de novo coronary stenoses to direct stenting or direct stenting plus ICB. Similar to our results, a significant 50% reduction in in-stent late loss was observed with ICB, but this was not accompanied by any clinical benefit due to the occurrence of the edge effect and late thrombosis. The Beta-Cath trial (R. E. Kuntz, unpublished data, 2001) also failed to demonstrate any clinical benefit of ICB as compared with placebo due to the edge effect. Recently, the ECRIS trial (16) demonstrated that intracoronary beta-irradiation with a rhenium-188–filled balloon catheter efficiently reduced restenosis and revascularization rates in patients with de novo (71%) and restenotic lesions. Both the Beta-Cath and BRIE trials were designed with the use of short radiation sources (30-mm Novoste Beta-rail source), before full knowledge of the concept of geographic miss in interventional cardiology (19). In contrast, both in the BRIDGE (15) and in the current study, special care in trying to avoid both geographic miss (use of long sources) and late thrombosis (prolonged dual-antiplatelet regimen) was taken. Interestingly, the ECRIS trial did reduce the occurrence of the edge effect in de novo stenoses (6%) by using an irradiation balloon catheter that exceeded at least 5 mm at each side from the traumatized area (16).
The edge effect was involved in six of 10 TVRs in the ICB group and was mostly related to geographic miss. Overall, this phenomenon was confirmed by independent analysis in four patients (4.3%), but all of them eventually presented with a clinically relevant edge effect. Geographic miss, however, was not demonstrated in the other two patients with the edge effect in whom long enough sources were used to cover the entire injured segment plus margins. In such patients, injury at a distance not evident on angiography or a source-induced injury cannot be ruled out.
In our trial, 6.5% of ICB patients presented with late stent thrombosis, as compared with 0% in the control arm. This increased rate of thrombosis mimics that of historical series (20,26), although it is clearly higher than that found in recent studies employing a long-term, dual-antiplatelet regimen (aspirin and thienopyridines) (16,27). In our study, late thromboses were associated in all cases with clopidogrel withdrawal as these occurred five and seven days after drug withdrawal. The rate of compliance with the dual-antiplatelet regimen in our trial was 93.4%, which was high above that of other trials designed to evaluate the efficacy of long-term use of clopidogrel (28,29). In particular, in the CREDO trial (28) and CURE trial (29), 63% and 78.9% of patients enrolled completed the full one-year course of the study drug, respectively. On the other hand, none of the remaining patients presented with stent thrombosis after clopidogrel withdrawal at 12 months.
This experience has shed light on the potential and limitations of this technique and may represent a rationale for the correct use of new antirestenotic devices, such as drug eluting stents, which also exhibit a potent in-stent antiproliferative effect.
Study limitations.
This is a single-center trial with a small size population. Although this study is well powered for the primary end point derived from IVUS, the relatively small size impedes one from drawing any definitive conclusion about the clinical data, as the study was not powered to detect clinical differences between the two groups.
In order to assess the effectiveness of the technique, this trial is not blinded (no sham source was introduced in control subjects). However, the measure of the primary end points by IVUS analysts, who were blinded to the treatment allocation, makes the study well validated for both the efficacy and effectiveness evaluation. For obvious reasons, QCA analysis was not blinded. However, these secondary end points derived from QCA corroborated the results of the primary end points derived from a blinded IVUS evaluation.
Finally, this trial evaluated a cohort of diabetic patients amenable to being treated with conventional stenting, IVUS, and ICB. Thus, these results cannot be extrapolated to the entire population of diabetics with more complex coronary stenoses not suitable for stenting, IVUS analysis, or ICB with current sources. As a matter of fact, this cohort of patients represents 25% of diabetic patients treated with angioplasty in our institution during the recruitment period.
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Footnotes
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This study was awarded by the 2001 Basic and Clinical Investigation Grant of the Spanish Society of Cardiology and the FIS Grant 2001 01/0539.
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