The aim of this study was to evaluate the vascular response after everolimus-eluting stent (EES) implantation in the SPIRIT III Japan Registry (JAPAN) compared to EES implantation in the SPIRIT III United States (USA) trial using serial intravascular ultrasound (IVUS) analysis. Data were obtained from the JAPAN and the randomized EES arm of the USA trial. Serial (postprocedure and 8-month follow-up) IVUS analysis was available in 199 lesions (JAPAN 82, USA 117) of 183 patients (JAPAN 73, USA 110). Although no difference was observed in vessel size in the reference segment between the 2 groups, postprocedure minimum lumen area and stent volume index were significantly greater in the JAPAN arm (minimum lumen area 5.8 ± 2.2 vs 5.1 ± 1.5 mm 2 , p = 0.03; stent volume index 7.0 ± 2.4 vs 6.3 ± 1.7 mm 3 /mm, p = 0.03). Postprocedure incomplete stent apposition (ISA) was less frequently observed in the JAPAN arm (15.9% vs 33.3%, p = 0.006), possibly related to higher maximum balloon pressure and/or more postdilatation without excess tissue prolapse or edge dissection. In the JAPAN arm, percent neointimal obstruction and maximum percent cross-sectional narrowing were significantly lower at 8-month follow-up (percent neointimal obstruction 3.5 ± 4.2% vs 6.8 ± 6.4%, p = 0.0004). Late acquired ISA was infrequent in the 2 arms. In conclusion, comparative IVUS analysis between the JAPAN and USA arms showed more optimal stent deployment in the JAPAN arm as evidenced by the lower incidence of postprocedure ISA and larger minimum lumen area after the procedure. Moreover, there was less neointimal hyperplasia in patients with EES implants from the JAPAN arm compared to the USA arm.
Optimal stent deployment remains an important issue in the drug-eluting stent era. Optimal deployment is associated with lower incidences of restenosis and stent thrombosis. Due to variation in available medical resources and device usage, stent implantation strategies may significantly differ among different health care systems. SPIRIT III was the first clinical trial of drug-eluting stents concurrently conducted in Japan and the United States of America using the same inclusion/exclusion criteria. The aim of the present study was to evaluate the vascular response after everolimus-eluting stent (EES) implantation in the SPIRIT III Japan Registry (JAPAN) compared to EES implantation in the SPIRIT III USA (USA) trial using serial intravascular ultrasound (IVUS) analysis.
Methods
The SPIRIT III trial was a prospective, multicenter, randomized, single-blind, controlled clinical trial in which patients with de novo native coronary artery lesions were randomized in a 2:1 ratio to receive the polymer-based EES (XIENCE V; Abbott Vascular, Santa Clara, California) or the polymer-based paclitaxel-eluting stent (TAXUS EXPRESS ; Boston Scientific Corp., Natick, Massachusetts) at US institutions. The JAPAN was a prospective, multicenter, nonrandomized registry to evaluate the safety and efficacy of the polymer-based EES (XIENCE V) in 88 consecutive Japanese subjects at 12 sites in Japan. All subjects in the 2 trials were screened using the same inclusion/exclusion criteria and study procedure. In this IVUS study, data were derived from the JAPAN arm and the EES arm in the USA trial. The study was approved by the institutional review board at each participating center, and consecutive, eligible patients signed written informed consent. For this trial, EESs were available in 2.5-, 3.0-, 3.5-, and 4.0-mm diameters and in 8-, 18-, and 28-mm lengths. Multiple stent use was allowed as needed at an operator’s discretion.
In the JAPAN study, the protocol recommended that patients receive aspirin (≥80 mg/day) for >5 years and ticlopidine (200 mg/day) for ≥3 months. In the USA study, the protocol recommended that patients receive aspirin (≥80 mg/day) indefinitely and clopidogrel (75 mg/day) for ≥6 months.
IVUS was performed after the procedure and at 8 months after stent implantation. IVUS procedure was performed in standard fashion using automated motorized pullback (0.5 mm/s) with commercially available imaging systems (40-MHz IVUS catheter from Boston Scientific Corp. or 20-MHz IVUS catheter from Volcano Corp., Rancho Cordova, California). IVUS analysis was done in an independent core laboratory at Stanford University (Cardiovascular Core Analysis Laboratory, Stanford, California). Incomplete stent apposition (ISA) was defined as ≥1 stent strut clearly separated from the vessel wall with evidence of blood speckles behind the strut not associated with any side branches. ISA was classified as “persistent,” “resolved,” or “late acquired.” All images were reviewed by 2 independent observers, and adjudication of opinion was based on consensus of these observers. Volumetric IVUS analysis was performed using commercially available software (echoPlaque, Indec Systems Inc, Santa Clara, California). Vessel, stent, lumen, and neointimal volumes were computed for the stented segment and stent margins 5 mm distal and proximal to the stent. Volume index (volume/length) was calculated for the vessel, lumen, plaque, stent, and neointima. Percent neointimal obstruction was calculated as neointimal volume divided by stent volume to assess overall degree of neointimal proliferation throughout the stented segment. Cross-sectional narrowing (percentage) was defined as neointimal area divided by stent area to assess the most severe impact of neointima on luminal encroachment.
Data are presented as mean ± SD or frequency. Statistical analysis was performed using StatView 5.0 (SAS Institute, Cary, North Carolina). For continuous variables, comparisons between the JAPAN and USA were performed with 2-tailed unpaired t test and comparisons between baseline and follow-up were done by paired t test. Categorical variables were compared using chi-square or Fisher’s exact test. Significance was assumed at a p value <0.05.
Results
Serial IVUS analysis was available in 199 lesions (JAPAN 82, USA 117) of 183 patients (JAPAN 73, USA 110). Patient characteristics for the 2 groups showed that the JAPAN arm was significantly older, had lower body mass index, smaller waist circumference, less hypercholesterolemia, less unstable angina, and less family history of coronary artery disease than the USA arm ( Table 1 ). Lesion characteristics and procedural outcomes are presented in Table 2 , with lesion types, lesion lengths, and reference vessel diameters being comparable between the 2 arms. Although postdilatation was at an operator’s discretion in the trial, it was more frequently performed in the JAPAN arm. In addition, maximal balloon pressure was significantly higher in the JAPAN arm.
| Variable | JAPAN | USA | p Value |
|---|---|---|---|
| (n = 73) | (n = 110) | ||
| Age (years) | 68.6 ± 8.0 | 62.6 ± 10.2 | <0.0001 |
| Men | 69.9% | 72.7% | 0.67 |
| Body mass index (kg/m 2 ) | 23.7 ± 2.8 | 30.0 ± 6.0 | <0.0001 |
| Waist circumference (cm) | 84 ± 8 | 105 ± 15 | <0.0001 |
| Total cholesterol (mg/dl) | 171 ± 28 | 171 ± 45 | 0.92 |
| High-density lipoprotein cholesterol (mg/dl) | 46 ± 11 | 41 ± 13 | 0.01 |
| Triglyceride (mg/dl) | 125 ± 50 | 177 ± 138 | 0.002 |
| Diabetes mellitus | 31.5% | 26.4% | 0.45 |
| Hypertension | 69.9% | 71.8% | 0.78 |
| Hypercholesterolemia | 47.9% | 70.0% | 0.003 |
| Current smoker | 20.5% | 26.4% | 0.46 |
| Unstable angina pectoris | 5.5% | 18.2% | 0.02 |
| Previous myocardial infarction | 12.3% | 19.1% | 0.29 |
| Previous percutaneous coronary intervention | 21.9% | 32.7% | 0.15 |
| Previous coronary bypass | 2.7% | 9.1% | 0.12 |
| Family history of coronary artery disease | 4.1% | 38.2% | <0.0001 |
| Variable | JAPAN | USA | p Value |
|---|---|---|---|
| (n = 82) | (n = 117) | ||
| Target coronary artery | |||
| Left anterior descending/left circumflex/right | 37%/23%/40% | 40%/23%/37% | 0.85 |
| Lesion type | |||
| A/B1/B2/C | 9%/25%/50%/16% | 7%/31%/37%/25% | 0.22 |
| Angiographic features | |||
| Lesion length (mm) | 13.9 ± 5.0 | 15.1 ± 6.0 | 0.14 |
| Reference vessel diameter (mm) | 2.8 ± 0.5 | 2.7 ± 0.5 | 0.41 |
| Procedural outcomes | |||
| Mean stent length (mm) | 22.6 ± 9.6 | 23.4 ± 8.5 | 0.56 |
| Mean stent diameter (mm) | 3.1 ± 0.5 | 3.1 ± 0.4 | 0.30 |
| Maximum predilatation balloon pressure (atm) | 10.0 ± 2.9 | 10.3 ± 3.0 | 0.45 |
| Maximum stent implantation balloon pressure (atm) | 13.0 ± 2.6 | 13.8 ± 2.5 | 0.03 |
| Frequency of postdilatation | 65.9% | 48.7% | 0.02 |
| Maximum postdilatation balloon pressure (atm) | 17.9 ± 2.7 | 15.7 ± 3.3 | 0.0003 |
Table 3 presents the results of qualitative analysis performed. Postprocedure ISA was significantly less frequently observed in the JAPAN arm than in the USA arm, whereas no differences were observed in edge dissection or intraluminal tissue between groups. Calcium-associated ISA was comparable between the 2 arms (JAPAN 2.4% vs USA 3.4%). There were 3 late-acquired ISA cases (JAPAN 1, USA 2). In a subgroup analysis of patients who received postdilatation (Japan 54 vs USA 57), postprocedure ISA remained significantly less in the JAPAN arm (JAPAN 20.4% vs USA 38.6%, p = 0.04).
| Variable | JAPAN | USA | p Value |
|---|---|---|---|
| (n = 82) | (n = 117) | ||
| Dissection | 2 (2.4%) | 2 (1.7%) | 0.72 |
| Proximal edge/distal edge | 0/2 | 1/1 | |
| Intraluminal tissue prolapse | 14 (17.1%) | 24 (20.5%) | 0.54 |
| Incomplete stent apposition | |||
| After procedure | 13 (15.9%) | 39 (33.3%) | 0.006 |
| Persistent | 12 (14.7%) | 24 (20.5%) | |
| Proximal edge/stent body/distal edge | 8/3/1 | 13/7/4 | |
| Resolved | 1 (1.2%) | 15 (12.8%) | |
| Proximal edge/stent body/distal edge | 1/0/0 | 10/2/3 | |
| Late acquired | 1 (1.2%) | 2 (1.7%) | 0.78 |
Serial volumetric analysis was available in 141 cases (JAPAN 70, USA 71; Table 4 ). All parameters (vessel, plaque, and lumen volume) after the procedure and follow-up were comparable between arms in either reference segment. Although no difference was observed in vessel size in the adjacent reference segments between the 2 arms, postprocedure minimum lumen area (JAPAN 5.8 ± 2 vs USA 5.1 ± 1.5 mm 2 , p = 0.03) and stent volume index (JAPAN 7.0 ± 2.4 vs USA 6.3 ± 1.7 mm 3 /mm, p = 0.03) were significantly greater in the JAPAN arm ( Table 5 ). Similarly, percent neointimal obstruction and maximum percent cross-sectional narrowing were significantly lower at 8-month follow-up in the JAPAN arm ( Table 5 ), with the distribution of percent neointimal obstruction and maximum percent cross-sectional narrowing being shifted to the left compared to those in the USA arm ( Figure 1 ). The number of cases with >1 pullback IVUS run was higher in the JAPAN arm (31.4% vs 16.9%).
| Variable | JAPAN (n = 70) | p Value | USA (n = 71) | p Value | ||
|---|---|---|---|---|---|---|
| After Procedure | Follow-up | After Procedure | Follow-up | |||
| Proximal adjacent segments | ||||||
| Vessel volume index (mm 3 /mm) | 14.6 ± 4.6 | 14.3 ± 4.6 | 0.28 | 14.3 ± 4.0 | 13.9 ± 4.2 | 0.06 |
| Plaque volume index (mm 3 /mm) | 6.9 ± 2.8 | 6.9 ± 2.9 | 0.90 | 6.9 ± 2.6 | 6.8 ± 2.7 | 0.72 |
| Lumen volume index (mm 3 /mm) | 7.7 ± 3.1 | 7.3 ± 2.8 | 0.11 | 7.3 ± 2.4 | 6.9 ± 2.4 | 0.04 |
| Distal adjacent segments | ||||||
| Vessel volume index (mm 3 /mm) | 9.9 ± 4.2 | 10.3 ± 4.5 | 0.04 | 10.0 ± 3.4 | 10.1 ± 3.6 | 0.71 |
| Plaque volume index (mm 3 /mm) | 4.3 ± 2.3 | 4.5 ± 2.7 | 0.10 | 4.3 ± 2.2 | 4.3 ± 2.2 | 0.99 |
| Lumen volume index (mm 3 /mm) | 5.5 ± 2.3 | 5.7 ± 2.3 | 0.25 | 5.8 ± 2.1 | 6.0 ± 2.7 | 0.16 |
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