Two-Year Intravascular Ultrasound Observations in Diabetic Patients Treated with Single and Double Dose Sirolimus-Eluting Stents

ABSTRACT: Background. Diabetes has been reported as an independent predictor of restenosis after drug-eluting stent implantation. The purpose of this study was to assess the long-term impact of increased drug dose in sirolimus-eluting stents (SES) on neointimal hyperplasia (NIH) in diabetic patients using volumetric intravascular ultrasound analysis. Methods. The 3D trial is a multicenter, prospective, randomized, feasibility study of double-dose (280 µg/cm2) or conventional single-dose (140 µg/cm2) SES for the treatment of de novo coronary lesions in diabetic patients. To evaluate long-term efficacy, complete serial volumetric analyses (baseline, 6-month and 2-year follow up) were performed in 39 diabetic patients (17 single-dose, 22 double-dose). Each volume was divided by stent length to acquire volume index, expressed as mm3/mm. Percent neointimal volume was calculated as (neointimal volume/stent volume) x 100 at follow up. Results. Volumetric analysis showed similar results over time between the 2 stent groups (p = NS for all). At 2-year follow up, minimal increases in NIH area and percent NIH were observed in both groups, which translated into a decrease in lumen volume index compared to baseline (p < 0.05 for all). No late-acquired incomplete stent apposition was observed in either group. Conclusions. The current single dose of sirolimus in SES is effective in inhibiting NIH in diabetic patients up to 2 years. In this patient subset, double-dose SES did not confer additional NIH suppression at 2-year follow up compared to conventional single-dose SES.
J INVASIVE CARDIOL 2008;20:411–416

Key Words: diabetes mellitus; ultrasonics; stents; plaque

Diabetes mellitus has been associated with a higher rate of in-stent restenosis and less-optimal clinical outcomes following bare-metal stent implantation.1,2 Although sirolimus-eluting stents (SES) significantly reduced neointimal hyperplasia,3,4 several studies have reported that diabetes is still an independent predictor of restenosis following SES implantation.5–7 The broad therapeutic window of sirolimus8 raises a question as to whether an increased drug dosage on SES can confer additional benefit in neointimal hyperplasia reduction in this patient subset. The 3D trial is a multicenter, prospective, feasibility study of diabetic patients randomized to double-dose (280 µg/cm2) or conventional single-dose (140 µg/cm2) SES. The aim of our study was to assess the long-term impact of double-dose SES on inhibition of NIH formation compared to conventional single-dose SES in diabetic patients using serial intravascular ultrasound (IVUS) quantitative analyses.

Methods

Study population and protocol. This trial was a randomized feasibility study of double- or single-dose sirolimus-eluting Bx Velocity ® balloon-expandable stent for the treatment of diabetic patients with de novo native coronary artery lesions. The target vessel was between ≥ 2.5 mm to ≤ 3.5 mm in diameter and the lesion length was < 30 mm by visual estimation. Patients were randomly assigned (1:1) to receive either the double-dose (280 µg/cm2) or the conventional single-dose (140 µg/cm2) sirolimus-eluting Bx Velocity® stents (SES) (Cordis Corp., Miami Lakes, Florida). Patients were excluded if they had: 1) unprotected left main disease; 2) Q-wave or non-Q-wave myocardial infarction within the preceding 24 hours; 3) a target lesion in the ostium, a saphenous vein graft, in-stent restenosis or a bifurcation lesion including a side branch > 2.5 mm in diameter; 4) a thrombus-containing lesion; 5) left ventricular ejection fraction < 30%; 6) totally occluded vessel; 7) impaired renal function (creatine > 2.0 mg/dL); or 8) allergies to aspirin, clopidogrel or ticlopidine. All patients provided written informed consent prior to the procedure using a form approved by the local ethics committee.

IVUS Imaging and Analysis. IVUS examinations were scheduled post procedure, 6 months, and 2 years after stent implantation. A single-element mechanical transducer (30 MHz or 40 MHz IVUS catheter, Boston Scientific Corp., Natick, Massachusetts) with console was used. All ultrasound images were analyzed by an independent core laboratory.

IVUS images were analyzed with commercially available software (echoPlaque, Indec Systems, Mountain View, California) as previously described.9 In brief, the following values were obtained: lumen volume index (LVI), stent volume index (SVI), plaque volume index [PVI], vessel volume index [VVI] and neointimal volume index (NIVI) (expressed as mm3/mm). Percent neointimal volume (%NIV) was calculated as the ratio between the neointimal volume and stent volume x 100. To evaluate longitudinal NIH distribution, available cases with a 23 mm single SES were selected and NIH was measured every 1 mm (23 subsegments) within the stent in each case. Incomplete stent apposition (ISA) was defined as previously described.10

Statistical analysis. Statistical analysis was performed with StatView 5.0 software (SAS Institute Inc., Cary, North Carolina). Quantitative data are presented as mean ± standard deviaion, and qualitative data are presented as frequencies. Continuous variables were compared using the Student’s t-test, and categorical data were compared by the chi square test or Fisher’s exact test. A two-way analysis of variance (ANOVA) with one repeated-measures factor was performed for evaluation of the interactions between dose difference (single dose and double dose) and time course (post procedure, 6-months and 2-year follow up). Bonferroni correction was used for post hoc analysis within the time course. Simple linear regression analysis was performed to evaluate the correlation between post-procedure minimal stent area (MSA) and follow-up minimal lumen area (MLA). To identify predictors of MLA at 2-year follow up, univariate and multivariate linear regression analyses were used in all patients. Statistical significance was assumed at a value of p < 0.05.

Results

Patient and lesion characteristics. Fifty-six patients were enrolled in the double-dose diabetes (3D) study and randomly assigned to single-dose or double-dose SES. Of these, 14 patients did not undergo follow-up IVUS examination at 6 months or 2 years after SES implantation, and 3 patients had incomplete image acquisition or inadequate image quality. Thus, serial volumetric IVUS analysis was available for 39 patients (17 single-dose SES, 22 double-dose SES) whose demographic information is listed in Table 1. There were no significant differences regarding baseline clinical and angiographic characteristics between the entire patient group and the selected patients group (data not shown). The frequency of insulin-required treatment in this sample was 24% in the single-dose group and 32% in the double-dose group (p = NS).

Serial volumetric IVUS results. Serial IVUS data are shown in Table 2. There was no significant interaction effect between the two stent groups (p = NS), indicating that the patterns of change in all parameters over time did not differ by drug dose. Moreover, during the follow-up period, all IVUS data at each time point did not differ between the single- and double-dose groups (p = NS). In the two groups, NIVI showed a minimal increase from 6 months to 2 years, resulting in a minimal increase in %NIV within the stent. These differences were statistically significant (p < 0.05 for all). Over time, significant changes in LVI and MLA were observed (p < 0.01 and p < 0.05, respectively). While the VVI within the stent was decreased in the double-dose group (p = 0.04), the single-dose group showed a trend toward decreased VVI between 6 months and 2 years (p = 0.17). Neither SVI nor PVI was significantly different (p = NS) in the two groups. At the proximal and distal edges, the mean VVI, PVI and LVI was not different between the two stent groups at any time during IVUS follow up (post procedure, 6 months and 2 years; p = NS) (Table 2).

Post-procedure MSA and follow-up MLA. Regression analysis demonstrated a significant positive correlation between post-procedure MSA and follow-up MLA at 6 months after SES implantation in both groups (single dose: r = 0.87, p < 0.0001; double dose: r = 0.95, p < 0.0001). Moreover, at 2-year follow up, this significant positive correlation was still maintained (single dose: r = 0.92, p < 0.0001; double dose: r = 0.86, p < 0.0001) (Figure 1). A multivariate linear regression model was used to determine independent predictors of MLA at 2-year follow up. Variables including angiographic reference vessel diameter, stent size, prior myocardial infarction, hyperlipidemia, left anterior descending artery lesion and postprocedural MSA, LVI, VVI, PVI in the proximal and distal edges (all with p < 0.1 in univariate analysis) were tested in this model. Of these, the sole independent predictor of MLA at 2-year follow up was post-procedure MSA (p = 0.012; coefficient = 0.628; 95% CI = 0.154–1.102).

Incomplete stent apposition. Persistent ISA was observed from 6 months to 2 years after deployment in 1 patient (5.9%) for the single-dose group and in 2 patients (9.1%) for the double-dose group. No late-acquired ISA was observed during the 2-year follow-up period in either stent group (Table 3).
Subsegmental analysis of longitudinal neointimal distribution. Thirty-two patients (13 for single-dose and 19 for double-dose) treated with a 23 mm single SES were acceptable for serial NIH analysis at every 1 mm (23 subsegments) within the stent at 6-month and 2-year follow up (Figure 2). During this interval, there was minimal increase in NIH (0.12 ± 0.11 to 0.24 ± 0.27 mm3/mm; p = 0.06 for single dose and 0.10 ± 0.11 to 0.27 ± 0.28 mm3/mm; p = 0.008 for double dose, respectively). At 2-year follow up, both stent groups showed greater NIH at proximal and distal stent edges (p < 0.05). However, the amount of NIH in each subsegment did not differ between the two stent groups (p = NS).

Discussion

The major findings of this study are: 1) SES were highly effective in inhibiting NIH in diabetic patients; 2) the double-dose SES did not confer additional NIH suppression; 3) final stent dimension after the procedure was an independent predictor of MLA; 4) no late-acquired ISA was observed; and 5) the unique distribution pattern of NIH characterized by accumulation at stent edges was sustained up to 2 years’ follow up.

Dose response in SES. The dose-response effect of SES has been studied in preclinical models. The rabbit iliac model showed a dose-dependent response in reducing NIH formation between two different doses (64 µg vs. 196 µg/stent),11 whereas a relatively constant degree of NIH suppression was observed from 6 µg to 1200 µg/stent in the porcine coronary model. In the human model, only limited data are currently available. In the REDOX trial (Evaluation of Two Reduced Sirolimus Doses on the BX VELOCITY Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary Artery Lesions), the two reduced doses (70% and 45% of sirolimus single dose) were equally effective in NIH suppression throughout 12 months after stenting.12 Despite different baseline characteristics, the amount of NIH in the current study was similar to that in the REDOX trial, confirming a wide therapeutic window of sirolimus.

In this clinical trial, there was no difference in the amount of neointimal volume between the different dose groups, with the % neointimal volume being 4.0% in single-dose and 4.2% in double-dose SES at 2-year follow up. Several possible explanations should be considered. First, the degree of neointimal suppression seen in the single-dose SES cohort was similar to that of non-diabetics in previous SES studies.4,13 Therefore, the assumption that neointimal volume would be further reduced if an SES with increased drug dose were used might have been inadequate. Second, the study may have been underpowered, with a study sample too small to support the hypothesis. Third, the resolution of IVUS may not have been high enough to show the difference in this small amount of neointimal growth. The reasons for the failure to demonstrate a significant difference, however, remain unclear from this study. 

Previous long-term IVUS studies for neointimal hyperplasia. In bare-metal stents (BMS), serial IVUS studies have demonstrated that NIH progression is mainly observed during the first 6 months, whereas NIH regression most likely occurs beyond 6 months to 1 or 2 years after stenting.14–16 This finding was supported by a 3-year angioscopic study.17 A human postmortem study demonstrated that less cellularity and an increase in type I collagen contributed to NIH regression beyond 18 months after BMS implantation.18 Compared to BMS, drug-eluting stents (DES) have shown dramatic NIH reduction in de novo coronary artery lesions after stenting. The 2-year IVUS study from the TAXUS II trial showed persistent dose-dependent NIH suppression after paclitaxel-eluting stents (PES) implantation compared to BMS implantation.19 In this study, an increase in NIH area was observed in both the slow- and moderate-release groups, whereas NIH regression occurred in the BMS group between 6 months and 2 years. Another long-term serial IVUS study reported findings 2 years and 4 years after implantation from the first-in-man experience with SES. The 2-year %NIV was 6.3% in the fast-release group and 7.5% in the slow-release group, with minimal change up to 4 years (9.1% vs. 5.7%, respectively).20,21 Thus, initial lumen dimension within the stent was sustained throughout 2–4 years after SES implantation. Although the current study enrolled only diabetic patients, the amount and percent NIH volume is similar to the aforementioned studies. Because a delayed arterial healing process may occur in DES, it is an open question whether this minimal NIH formation may eventually lead to clinically relevant events. Thus, longer serial IVUS analyses are warranted to better evaluate this issue. Another IVUS observation after DES implantation is the area change outside of the stent. In SES, one study demonstrated negative remodeling of the plaque behind the stent struts up to 4 years after implantation.19 In PES, there is a trend toward an increase in the outside area of the stent at 6 months and subsequent regression between 6 months to 2 years.14 The similar tendency of the change outside of the stent was observed in the current study, suggesting that the remodeling pattern outside of the stent may be different between the initial 6 months and later follow up (2–4 years) after implantation. To clarify whether this phenomenon is due to drug effect will require long-term IVUS studies involving a large patient population.

The final stent dimension after the procedure was an independent predictor of and was highly correlated with follow-up MLA out to 2 years. Several IVUS studies have shown that post-procedure MSA is an important predictor of in-stent restenosis or clinical outcomes at follow up in both BMS and DES.22–25 However, most studies reported relatively short follow-up periods in low-risk patients. This study demonstrated the impact of post-procedure MSA on long-term follow-up MLA, even in high-risk diabetic patients.

Incomplete stent apposition. The absence of diabetes may represent an independent predictor of late-acquired ISA after DES implantation.13,26 It is speculated that exaggerated NIH formation during the healing process seen in diabetes may compensate for the gap between stent struts and the vessel wall after stenting. In the current study, 3 patients with persistent ISA (ISA was observed post procedure and at 6-month follow up) were found without adverse vascular response, and no patients had late-acquired ISA at 2-year follow up.

Longitudinal neointimal distribution. Serial IVUS analyses provide precise representation of NIH amount and its distribution throughout the length of the stents. In BMS, NIH area occupied 30–40% of the stent volume and its distribution was fairly even within the entire stent length.27 Recent DES studies have shown a minimal amount of NIH within the stent but the distribution pattern varied between different drugs.25,28,29 SES showed a unique pattern of NIH characterized by accumulation at the stent edges, particularly at the proximal edge,28,29 whereas zotarolimus-eluting stents exhibited less accumulation of NIH at the stent edges than at the mid-body of the stent.29 Regarding NIH distribution within the stent, most IVUS studies report follow up 6–8 months after stenting. The current study demonstrated NIH distribution in SES at 6-month and 2-year follow up. Although there was minimal increase in NIH from 6 months to 2 years after implantation, the percent NIH volume within the stent was < 10%, with a distribution pattern similar to previous studies at each time point. Furthermore, this pattern did not differ between double-dose and single-dose SES. Because most of sirolimus release theoretically occurs within 30 days,20 it is worth noting that the distribution pattern of NIH at 6 months was sustained up to 2 years after stenting, even in diabetic patients. Whether an accumulation of NIH is likely to occur at both stent edges remains unclear. The possible explanations of this phenomenon include uneven drug concentration distribution at the stent edges compared to the mid-body,30 the possibility of inevitable injury at the stent edges during stent deployment and changes in shear stress distribution at the stent edges after stenting.31

Study limitations. The small number of patients in the current study limits the ability to evaluate the efficacy of increased drug dose in SES. The frequency of insulin-requiring patients was relatively low in both stent groups, which limits evaluation of the effect of insulin supplementation on study results. The findings of this article were derived from the patients who were able to receive IVUS at follow up, potentially leading to a risk for selection bias. Finally, the current study enrolled only diabetic patients, thus the SES efficacy on NIH formation between diabetics and non-diabetics at 2-year follow up cannot be evaluated.

Conclusions

Findings from this IVUS analysis of the 3D trial demonstrate that the current single dose of SES is effective in inhibiting NIH in diabetic patients. Compared to conventional single-dose SES, a double dose did not confer additional NIH suppression at 2-year follow up. For long-term adequate lumen patency, final stent dimension post procedure is still an important predictor for diabetic patients treated with SES.