Long-Term Follow Up of Diabetic Patients Treated with Sirolimus-Eluting Stents. An Angiographic and Three-Dimensional Intravascu
April 2006
Diabetes mellitus is associated with more aggressive coronary artery disease with almost 4 times the mortality rate and worse outcomes (including restenosis) after percutaneous coronary intervention.1–3 Stent implantation has become the percutaneous treatment of choice among patients with coronary artery disease and has improved clinical outcomes compared with balloon angioplasty, even in diabetic patients.4 However, in-stent restenosis, as well as target lesion revascularization, remain a major problem in diabetic patients treated with bare metal stents.5,6 In the last 5 years, drug-eluting stents (DES) have emerged as the most promising percutaneous device for the treatment of coronary artery disease. Building on the initial results of the first-in-man (FIM) registry,7 sirolimus-eluting stents (SES) have shown superior results in several randomized trials and large registries.8–10 Basically, SES have been shown to significantly reduce restenosis at short-term follow up (4 to 8 months) in almost all clinical conditions and lesion subsets.11–13 However, few data exist regarding the long-term inhibitory effect of sirolimus, especially in diabetic patients. The aim of this study was to use quantitative coronary angiography (QCA) and three-dimensional intravascular ultrasound (3-D IVUS) to evaluate the long-term (18 months) follow up of diabetic patients treated with SES.
Methods
Study population. From the Instituto Dante Pazzanese de Cardiologia core lab database, we selected all diabetic patients treated with SES who had per-protocol, 6-month (short term) coronary angiography and IVUS follow up. A second angiography and IVUS follow up were scheduled and performed 18 months (long term) after the index procedure. Patients were included if they had a native de novo coronary artery lesion successfully treated by a single SES, were considered to be diabetic (e.g., under medical treatment with oral hypoglycemic agents or insulin), and underwent short-term coronary angiography and IVUS. Patients with acute myocardial infarction at the index procedure, acute stent thrombosis and target lesion revascularization at short-term follow up were excluded.
Stent procedure. Percutaneous coronary intervention was performed with non-IVUS guided implantation of a Cypher™ SES (Cordis Corp, Johnson & Johnson, Miami, Florida) according to standard practice. In this cohort, all stents were 18 mm long and 2.5–3.5 mm in diameter. Patients received aspirin (325 mg/day) indefinitely and clopidogrel 75 mg/day for 60 days. Glycoprotein IIb/IIIa inhibitors were rarely used and were left at the discretion of the operator.
Angiographic and IVUS protocols. Quantitative coronary angiographic measurements were performed using dedicated software (CMS-Medis, Leiden, The Netherlands). The guiding catheter was used for calibration, and minimum luminal diameter (MLD), reference diameter (RD), and percent diameter stenosis (DS) were measured in the one projection with the “worst view.” In-stent analysis encompassed only the 18 mm-long segment covered by the stent, and the in-lesion segment was defined as the stent plus 5 mm-long segments proximal and distal to the stent edges. Short-term late lumen loss by QCA (indirect marker of neointimal proliferation) was calculated as postimplantation MLD minus short-term MLD, and long-term lumen loss as postimplantation MLD minus long-term MLD.
Quantitative IVUS measurements were performed after intracoronary administration of nitroglycerin (200 µg) at short- and long-term follow up. The imaging catheter was advanced at least 10 mm beyond the stent. Images were acquired using a commercially available imaging system (Boston Scientific Corp., Natick, Massachusetts), with 40 Mhz transducers and automated pullback at a constant speed of 0.5 mm per second. All studies were recorded on 0.5 inch (1.27 cm) high-resolution S-VHS videotape for subsequent offline analysis.
The 18 mm-long stented segment and adjacent 5 mm-long segments proximal and distal to the stent edges were examined. Cross-sectional measurements of lumen, stent and elastic external membrane (EEM) area were performed every 1 mm throughout the stent and references. Quantitative 3-D IVUS analysis [EEM volume (EEMV), stent volume (SV), and lumen volume (LV)] was performed with validated, commercially available, computer-based software (EchoPlaque, IndecSystem, Inc, Mountain View, California) using Simpson’s rule. We also calculated plaque (EEM – lumen, in the nonstented segments), neointimal hyperplasia (NIH = stent - lumen), and the percent stent obstruction (% of stent occupied by NIH), as well as the distribution of the neointima throughout the length of the stent.
One operator who was blinded to the follow-up period performed the offline QCA and 3-D IVUS analyses at both short-term and long-term follow up time points.
Statistical analysis. Continuous variables are expressed as mean ± SD and compared using the Student’s t-test, in particular, comparisons between short- and long-term follow up measurements were performed with a two-tailed paired t-test or a nonparametric test as necessary. Categorical variables were described by counts and percentages, and tested using the Fisher’s exact test. Probability values Results
Patient and lesion characteristics. Thirty-five patients met the inclusion and exclusion criteria. The short-term and long-term follow up intervals were 6.0 ± 1.0 and 18.5 ± 4.9 months after the index procedure. Baseline clinical and angiographic findings are presented in Table 1. Patient age was 63 ± 8 years; 27 (76%) patients were men, and 11 (31%) had previous myocardial infarction. The majority (85%) were noninsulin-requiring diabetic patients. The average reference vessel diameter preprocedure was 2.81 ± 0.47 mm, and the lesion length was 12.0 ± 3.5 mm. The stent-to-lesion ratio was 1.5 ± 0.5, with the majority of the treated lesions (54%) being class B2 or C according to the American College of Cardiology/American Heart Association classification. All stents were 18 mm long; 25% of the stents were 2.5 mm in diameter, 57% were 3.0 mm, and 18% were 3.5 mm. Forty-five percent (n = 15) of the lesions were predilated, and 63% (n = 22) were postdilated. The lengths of the balloons used for pre- and postdilatation were 13.64 ± 2.1 mm and 13.47 ± 2.9 mm, respectively.
QCA measurements. Quantitative angiographic data pre-intervention, postprocedure, and at short- and long-term follow up are summarized in Table 2. In the in-stent segment analysis there was a mild, though significant, decrease in MLD between postprocedure and short-term follow up. However, MLD at long-term follow-up remained essentially unchanged when compared with short-term follow up (2.69 ± 0.46 vs. 2.61 ± 0.44 mm; p = 0.5). Thus, only a very small and nonsignificant late lumen loss was observed (0.12 ± 21 vs. 0.20 ± 21 mm; p = 0.10).
In the in-lesion segment analysis we also observed no significant changes in MLD between short- and long-term follow up (2.38 ± 0.54 vs. 2.30 ± 0.62 mm; p = 0.6). There was a trend toward an increase in the in-segment late loss at long-term follow up, though it remained very small (0.05 ± 0.18 vs. 0.13 ± 0.20 mm; p = 0.09). None of the patients reached binary restenosis (diameter stenosis > 50%) at either follow-up periods.
IVUS measurements. Short- and long-term IVUS results are presented in Table 3. EEM, lumen and stent volumes remained unchanged between short- and long-term follow up periods. NIH volume at short-term follow up was very small and did not change at long-term follow up (3.7 mm3 and 4.1 mm3, respectively (p = ns). Therefore, the percent stent obstruction volume was also very small at short-term follow up, and remained virtually the same at long-term follow up (3.4% vs. 3.5%; p = ns). Figure 1 shows no significant difference on the amount of NIH according to vessel size among small, medium or large vessels at both follow-up periods.
NIH was minimal throughout the length of the stent. Moreover, the pattern of NIH distribution was quite similar at both short- and long-term follow up — almost no proliferation in the mid-stent, and slightly more at the distal and proximal parts of the stent (Figure 2). We also observed no significant changes between the two follow-up periods in the EEM, lumen and plaque volumes at both proximal and distal stent edges.
The single stent strut malapposition observed at 6 months remained unaltered at 18 months. However, there were no new cases of stent strut malapposition or aneurysm formations between the two follow-up periods.
Clinical events. There were no late major adverse clinical events. None of the patients had myocardial infarction or underwent target lesion or even target vessel revascularization at short- and long-term follow up. There were no cardiac deaths or late stent thromboses.
Discussion
The main finding of the present study is the long-term and continuous suppression of neointimal proliferation in diabetic patients treated with SES. Volumetric IVUS quantification showed minimal NIH at both short-term (6 months) and long-term (18 months) follow up in these patients. Remarkably, we did not observe early or late stent malapposition, new aneurysm formation or late stent thrombosis.
Diabetic patients are often associated with worse late prognosis after coronary intervention.1,2 Increased platelet aggregation,14 oxidation levels of low-density lipoproteins,15 procoagulant factors,16 endothelial dysfunction,17 decreased endogenous fibrinolysis18 and higher smooth muscle cell proliferation19 promote accelerated atherosclerosis. In addition, diabetics have higher rates of in-stent restenosis, mainly due to exaggerated neointimal hyperplasia,20 as well as a higher frequency of late total occlusion pattern of in-stent restenosis and its association with impaired left ventricular function and late mortality.21
DES inhibit NIH at short-term follow up (4 to 8 months) and significantly reduce in-stent restenosis compared with bare metal stents.7–10 Serial angiographic studies have shown the stability of bare stents up to 3 years after stent implantation.21,23 However, data are scarce concerning the long-term results of DES. Moreover, other antiproliferative strategies, such as radioactive stents and brachytherapy, only delay NIH suppression, leading to the so-called late catch-up phenomenon.24,25
In the diabetic subanalysis of the RAndomized study with sirolimus-eluting BX VElocity balloon-expandable stents in the treatment of patients with de novo native coronary artery Lesions (RAVEL) trial, neointimal suppression by SES was similar in diabetic and nondiabetic patients, although this study was conducted with only short-term angiographic and IVUS follow up.26 Until now, the only SES patients with long-term angiographic and IVUS follow up were those treated in the FIM registry. Four-year data from the FIM registry showed sustained suppression of neointimal hyperplasia with SES.2 However, only 6 diabetic patients (13% of the total cohort) were included in this study. In the present investigation we demonstrated sustained NIH suppression by SES in diabetic patients; there was a very low and persistent percent stent volume obstruction at both short-term and long-term follow up (3.4% and 3.5%, respectively). This was similar to those of the overall population of the FIM registry (0.4% and 6.3% at 4 and 24 months, respectively).28,29
The IVUS results of the current study contrast markedly with the typical diabetic population treated with bare stents, where the percentage of stent volume obstruction vary from 35% to as high as 50%, at both short and long-term follow up.30,31 Despite the fact that diabetics and small vessels are strong independent predictors of in-stent restenosis and target lesion revascularization, we observed the same low amount of neointimal proliferation in all vessel diameters at both follow-up periods after SES implantation. In addition, the pattern of NIH distribution throughout the length of the stent was comparable at both short- and long-term follow up and was very similar to that observed in the SIRolImUS-eluting Bx velocity balloon expandable stent trial (SIRIUS).8
In the 2-year follow-up report of the 30 patients from the FIM registry (São Paulo), in-stent long-term late loss was -0.09 ± 0.23 mm (slow-release group), and 0.28 ± 0.4 mm (fast-release group), and did not change at all compared to the earlier follow-up periods (4 months and 1 year).7,25,26 These results are in agreement with the current study where the in-stent long-term late loss was also minimal; and despite a slight, nonsignificant increase at long-term follow up, it has remained substantially low. This translated to a very low in-stent lumen loss between the two follow-up periods (0.08 mm).
There may be some concern about the apparent discrepancy between the IVUS and the QCA results of the current study. This may be explained by the different inherent methodologies of the two imaging methods: the single cross-sectional point of QCA versus the volumetric analysis of IVUS. Therefore, in some patients, there could be focal points of relatively greater late neointimal proliferation — not enough to weight the 3-D IVUS analysis, but enough to affect the MLD measured by QCA between the short- and long-term follow up periods. Nevertheless, the mean long-term QCA late loss (0.20 mm) was very small. Additionally, none of the patients reached the endpoint of binary restenosis at either follow-up time point; the maximum diameter stenosis was only 21% and 26.4% at short- and long-term follow up, respectively.
The SIRIUS diabetic substudy showed a marked reduction in the in-stent restenosis rates in patients treated with SES compared to bare metal stents.32 However, in the SES group, diabetics, especially insulin-requiring diabetics, had worst results compared with nondiabetics. This difference was mainly due to stent edge restenosis, as demonstrated by the higher rates of in-segment restenosis (35%) and in-segment late loss (0.59 mm) in the diabetic population. In our investigation QCA analysis did not show any edge effect at short-term follow up; in fact, the in-lesion late loss was lower than the in-stent late loss (0.12 mm and 0.05 mm). Importantly, our 3-D IVUS analysis also did not show any late edge effects such as an increase in plaque volume, lumen reduction or vessel shrinkage. Explanations for the discrepancy between the current study and previous reports would include stent implantation technique (i.e., full lesion coverage), better stent-to-lesion ratio, direct stenting, shorter balloons, reduced lesion complexity and risk factor modification and diabetes control. Intensive medical treatment with rigorous coronary risk factors control associated with the long-lasting inhibitory effect of SES could be the key issue in the treatment of coronary artery disease in diabetic patients.
Study limitations. The present study is a single-center experience involving a small number of patients treated early in the SES experience. Therefore, we included diabetic patients with relatively noncomplex lesions, as shown by the small lesion length and stent length, as well as the average vessel diameter. Only a few insulin-requiring diabetic patients were included.
Conclusion
The present study demonstrates the 18-month efficacy and safety of SES for the treatment of diabetic patients. This adds to the 2- and 4-year results of the FIM study with sirolimus. Further investigations with a larger number of diabetic patients, especially insulin-requiring diabetics, and longer follow-up periods are necessary to substantiate our findings.
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