HORIZONS-AMI was a prospective dual-arm randomized trial of different antithrombotic regimens and stent types in patients with ST-segment elevation myocardial infarction. A formal intravascular ultrasound (IVUS) substudy enrolled 464 patients with baseline and 13-month follow-up at 36 centers. Of them, 318 patients with 355 lesions were evaluated for this study. Angiographic restenosis occurred in 45 of 355 lesions (12.7%). Bare-metal stent use (45.5% vs 21.2%, p <0.001) and diabetes mellitus (29.5% vs 10.9%, p <0.001) were more prevalent in patients with versus without restenosis. Postprocedure IVUS minimum lumen area (5.6 mm 2 , 5.0 to 6.1, vs 6.7 mm 2 , 6.5 to 6.9, p <0.001), minimum stent area (5.7 mm 2 , 5.1 to 6.3, vs 6.9 mm 2 , 6.6 to 7.1, p <0.001), and reference average lumen area (7.7 mm 2 , 6.8 to 8.6, vs 9.7 mm 2 , 9.3 to 10.1, p <0.001) were smaller in restenotic versus nonrestenotic lesions. By multivariable analysis, minimum stent area was an independent predictor of angiographic restenosis (odds ratio 0.75, 95% confidence interval 0.61 to 0.93, p = 0.009) in addition to diabetes, bare-metal stent use, and longer stent length. Attenuated plaque behind the stent struts had a trend to predict less binary restenosis (p = 0.07). In conclusion, a smaller IVUS minimum stent area was an independent predictor of angiographic restenosis after primary percutaneous intervention in patients with ST-segment elevation myocardial infarction, similar to patients with stable coronary artery disease.
Drug-eluting stents (DESs) decrease restenosis compared to bare-metal stents (BMSs), especially in complex patient and lesion cohorts such as diabetes mellitus, long lesions, and small vessels. Studies have demonstrated benefits of DESs in patients with acute myocardial infarction undergoing primary stent implantation. Intravascular ultrasound (IVUS) predictors of restenosis after BMS or DES implantation have been reported, but these reports have typically included patients with stable coronary artery disease. No study has examined IVUS predictors of restenosis after primary stent implantation in the setting of an acute myocardial infarction. The aim of the present study was to evaluate IVUS predictors of angiographic binary restenosis after primary stent implantation using data from the large-scale prospective multicenter Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) study. In particular, we sought to determine whether stent dimensions were predictive of restenosis in AMI lesions as they have been after stenting in stable coronary artery disease.
Methods
HORIZONS-AMI was a prospective open-label multicenter dual-arm 2 × 2 factorial randomized trial in patients with ST-segment elevation MI (STEMI) presenting <12 hours after symptom onset. Randomization arms were (1) direct thrombin inhibitor bivalirudin alone versus heparin plus a glycoprotein IIb/IIIa inhibitor (1:1 randomization), and (2) TAXUS EXPRESS paclitaxel-eluting stents versus equivalent EXPRESS BMSs (3:1 randomization). Detailed inclusion and exclusion criteria and study procedures have been reported. In patients undergoing stent randomization, 13-month angiographic follow-up was prespecified for 1,800 patients in whom acute stent implantation was successful (diameter stenosis <10% with Thrombolysis In Myocardial Infarction grade 3 flow with less than or equal to National Heart, Lung, and Blood Institute type A peri-stent dissection) and in whom neither stent thrombosis occurred nor bypass surgery was performed within 30 days. Angiograms obtained before 13 months were considered valid if restenosis was present or if the study was performed >6 months for clinical indications.
Coronary angiograms at baseline, immediately after intervention, and at follow-up were performed in ≥2 orthogonal views after intracoronary nitroglycerin and analyzed at the Angiographic Core Laboratory of the Cardiovascular Research Foundation (New York, New York) using the CMS-GFT algorithm (MEDIS, Leiden, the Netherlands). Minimum lumen diameter and average reference vessel diameter, obtained by averaging 5-mm segments proximal and distal to the target lesion location, were used to calculate diameter stenosis ([1 − minimum lumen diameter/average reference vessel diameter] × 100). In-stent analysis was confined to the stent; in-segment analysis included the stent plus 5-mm segments proximal and distal to the stent. Binary restenosis was ≥50% diameter stenosis. Qualitative analysis was done using standard published methods.
The IVUS substudy of HORIZONS was designed to compare poststent and 13-month follow-up images after successful uncomplicated stent implantation. IVUS sites were preselected based on their desire to participate in this substudy and their agreement to perform poststent and follow-up IVUS in consecutive patients in the angiographic follow-up cohort until ≥300 patients were enrolled. Allowable systems included iLab, Galaxy, or ClearView (all with Atlantis SR Pro with 40-MHz catheters, Boston Scientific, Fremont, California); or In Vision Gold with 20-MHz EagleEye catheters (Volcano Corporation, Rancho Cordova, California). Imaging was performed using motorized pullback (0.5 mm/s) to include the stent and >5-mm segments proximal and distal to the stent. IVUS studies were archived and sent to an independent treatment allocation–blinded IVUS core laboratory (Cardiovascular Research Foundation) for quantitative and qualitative analyses using validated planimetry software (EchoPlaque, INDEC Systems, Inc., Mountain View, California).
Quantitative analysis included measurement of the external elastic membrane, stent, and lumen cross-sectional areas (CSA) every 1 mm. Plaque plus media CSA was calculated as external elastic membrane minus lumen. Plaque burden was calculated as ([plaque + media/external elastic membrane] × 100). Volumes were calculated using the Simpson rule and normalized for stent and reference segment length as appropriate, but only for lesions in which motorized pullback was consistent and reliable. Reference segment measurements included the most normal-looking slice (largest lumen with least plaque) proximal and distal to the stent and the most diseased slice (smallest lumen with most plaque) proximal or distal to the stent. Focal stent expansion was minimum stent CSA divided by mean reference lumen CSA; diffuse stent expansion was mean stent CSA divided by mean reference lumen CSA. Stent symmetry was minimum divided by maximum stent diameter at the minimum stent area site.
Qualitative analysis included (1) acute stent malapposition (blood speckle behind stent struts), (2) intrastent tissue protrusion (because IVUS cannot discriminate between thrombus and plaque, “tissue protrusion” was used to include plaque and/or thrombus), (3) stent edge dissection (more than medial dissection), (4) residual edge stenosis (reference lumen CSA <4.0 mm 2 with ≥70% plaque burden ≤5 mm from a stent edge), (5) attenuated plaque (absence of ultrasound signal behind plaque without calcification), and (6) echolucent plaque (absence of ultrasound signal within plaque).
Statistical analysis was performed with SAS 9.1 (SAS Institute, Cary, North Carolina). For patient-level data categorical variables were presented as frequency and compared using chi-square statistics or Fisher’s exact test (if there was an expected cell value <5) and continuous variables were presented as median (quartiles 1 to 3) and compared using Mann–Whitney U test. For lesion-level data a generalized estimating equations approach was used to compensate for potential clustering effects of multiple lesions in the same patient and data were presented as least square means with 95% confidential intervals. To identify independent predictors of binary restenosis, clinical and IVUS variables with a p value <0.2 were entered into logistic generalized estimating equations regression model. A probability <0.05 was considered statistically significant.
Results
The formal IVUS substudy enrolled 464 patients with baseline and 13-month follow-up imaging at 36 centers. Index IVUS analysis was completed in 389 patients (58 studies did not arrive to the core laboratory and 17 were poor quality). Of them, 318 patients (355 lesions) were evaluated for this study; 13 were lost to follow-up, 12 died, and 26 did not have follow-up angiogram. We compared clinical, angiographic, and IVUS characteristics between 44 patients (45 lesions) who had angiographic binary restenosis versus 294 patients (310 lesions) who had no restenosis. Rates of binary restenosis were 13.8% per patient and 12.7% per lesion.
Baseline clinical characteristics of patients with restenosis versus without restenosis are listed in Table 1 . Diabetes mellitus (29.5% vs 10.9%, p <0.001) and BMS use (45.5% vs 21.2%, p <0.001) were more prevalent in patients with restenosis.
| Variable | Restenosis | p Value | |
|---|---|---|---|
| Yes (n = 44) | No (n = 274) | ||
| Age (years) | 62.9 (53.5–68.1) | 59.1 (50.9–68.5) | 0.30 |
| Men | 75.0% | 81.0% | 0.35 |
| Diabetes mellitus | 29.5% | 10.9% | <0.001 |
| Hypertension ⁎ | 43.2% | 53.3% | 0.21 |
| Hyperlipidemia † | 36.4% | 41.2% | 0.54 |
| Smoking | 75.0% | 65.7% | 0.22 |
| Previous myocardial infarction | 4.5% | 6.6% | 1.0 |
| Previous percutaneous intervention | 6.8% | 4.4% | 0.45 |
| Previous coronary bypass surgery | 9.1% | 3.6% | 0.11 |
| Renal insufficiency ‡ | 17.5% | 10.2% | 0.18 |
| Killip class I | 93.2% | 92.7% | 1.0 |
| Left ventricular ejection fraction (%) § | 56 (50–63) | 61 (52–68) | 0.06 |
| Interval from symptom onset to balloon (minutes) | 252 (148–514) | 207 (153–338) | 0.20 |
| Randomization to bivalirudin | 63.6% | 51.5% | 0.13 |
| Randomization to TAXUS stent | 54.5% | 78.8% | <0.001 |
| Multiple coronary vessels treated | 11.4% | 5.8% | 0.19 |
| Aspiration catheter used | 6.8% | 10.2% | 0.59 |
⁎ History of hypertension treated with medication.
† History of hyperlipidemia treated with medication.
‡ Creatinine clearance <60 ml/min as calculated at baseline by the Cockcroft–Gault equation.
§ Assessed visually on contrast left ventriculogram obtained at baseline.
Angiographic findings and procedural characteristics are presented in Table 2 . Compared to nonrestenotic lesions, restenotic lesions had a significantly smaller baseline reference vessel diameter (p <0.001), smaller postprocedure minimum lumen diameter (in segment, p <0.001; in stent, p = 0.001), more severe postintervention in-segment diameter stenosis (p = 0.006), and longer stent length (p = 0.03).
| Variable | Restenosis | p Value | |
|---|---|---|---|
| Yes (n = 45) | No (n = 310) | ||
| Target coronary artery | |||
| Left anterior descending | 45.5% | 38.5% | 0.36 |
| Left circumflex | 27.3% | 14.6% | 0.07 |
| Right | 22.7% | 45.3% | 0.07 |
| Saphenous vein graft | 4.5% | 1.6% | 0.21 |
| American College of Cardiology/American Heart Association lesion Class B2/C | 90.9% | 83.8% | 0.049 |
| Stents per vessel | 1.8 (1.5–2.1) | 1.5 (1.4–1.6) | 0.05 |
| Stent/lesion length ratio | 1.7 (1.5–1.9) | 1.6 (1.5–1.7) | 0.51 |
| Stent overlap | 95.8% | 91.0% | 0.33 |
| Stent overlap length (mm) | 2.9 (2.4–3.5) | 3.3 (2.9–3.6) | 0.35 |
| Baseline | |||
| Lesion length (mm) | 20.6 (16.7–24.5) | 17.0 (16.1–17.9) | 0.08 |
| Reference vessel (mm) | 2.7 (2.6–2.9) | 3.0 (3.0–3.1) | <0.001 |
| Minimum lumen diameter (mm) | 0.3 (0.2–0.4) | 0.4 (0.3–0.5) | 0.27 |
| Diameter stenosis (%) | 87.6 (83.1–92.2) | 86.9 (85.1–88.7) | 0.77 |
| Thrombolysis In Myocardial Infarction grade 0/1 flow | 60.5% | 53.2% | 0.48 |
| Thrombus | 70.5% | 67.6% | 0.42 |
| After intervention | |||
| Stent length (mm) | 30.6 (25.7–35.5) | 25.2 (23.9–26.5) | 0.03 |
| Minimum lumen diameter in segment (mm) | 2.2 (2.0–2.3) | 2.5 (2.4–2.5) | <0.001 |
| Minimum lumen diameter in stent (mm) | 2.6 (2.5–2.7) | 2.9 (2.8–2.9) | 0.001 |
| Diameter stenosis in segment (%) | 22.9 (19.9–25.8) | 18.6 (17.7–19.6) | 0.006 |
| Diameter stenosis in stent (%) | 5.6 (1.9–9.3) | 5.8 (4.8–6.9) | 0.91 |
| Thrombolysis In Myocardial Infarction grade 3 flow | 86.4% | 90.5% | 0.46 |
| Follow-up | |||
| Minimum lumen diameter in segment (mm) | 0.8 (0.6–0.9) | 2.3 (2.2–2.3) | <0.001 |
| Minimum lumen diameter in stent (mm) | 1.0 (0.8–1.2) | 2.5 (2.5–2.6) | <0.001 |
| Diameter stenosis in segment (%) | 71.1 (65.6–76.5) | 24.1 (22.9–25.3) | <0.001 |
| Diameter stenosis in stent (%) | 63.5 (55.2–71.8) | 15.6 (14.0–17.0) | <0.001 |
Quantitative and qualitative IVUS findings in lesions with versus without restenosis are presented in Tables 3 and 4 . Within reference segments the average lumen and external elastic membrane CSAs were smaller in restenotic versus nonrestenotic lesions. Lumen CSA was smaller at the most-diseased reference segment slice in restenotic compared to nonrestenotic lesions.
| Variable | Restenosis | p Value | |
|---|---|---|---|
| Yes (n = 45) | No (n = 310) | ||
| Reference segments | 42 | 292 | |
| Average of most normal-looking slices proximal and distal to stent edges | |||
| Average lumen area (mm 2 ) | 7.7 (6.8–8.6) | 9.7 (9.3–10.1) | <0.001 |
| Average external elastic membrane area (mm 2 ) | 12.6 (11.3–13.9) | 15.6 (14.9–16.2) | <0.001 |
| Average plaque burden (%) | 37.1 (33.1–41.2) | 36.0 (34.8–37.3) | 0.62 |
| Most diseased slice proximal or distal to stent edge | |||
| Lumen area (mm 2 ) | 5.4 (4.7–6.1) | 6.7 (6.3–7.0) | 0.001 |
| External elastic membrane area (mm 2 ) | 9.6 (8.3–10.9) | 12.2 (11.6–12.9) | 0.001 |
| Plaque burden (%) | 41.0 (36.3–45.7) | 42.6 (40.8–44.4) | 0.53 |
| Stented segments | 43 | 295 | |
| Minimum lumen area slice | |||
| Lumen area (mm 2 ) | 5.6 (5.0–6.1) | 6.7 (6.5–6.9) | <0.001 |
| Lumen area <4.0 mm 2 | 19.5% | 7.8% | 0.02 |
| Lumen area <5.0 mm 2 | 41.5% | 21.2% | 0.001 |
| Lumen area <6.0 mm 2 | 65.9% | 40.3% | <0.001 |
| Stent area (mm 2 ) | 5.9 (5.3–6.6) | 7.1 (6.8–7.3) | 0.001 |
| External elastic membrane area (mm 2 ) | 13.5 (11.4–15.5) | 15.8 (15.1–16.5) | 0.04 |
| Plaque + media area (mm 2 ) | 7.9 (6.2–9.7) | 9.1 (8.6–9.6) | 0.20 |
| Plaque burden (%) | 53.6 (49.6–57.6) | 55.2 (53.8–56.6) | 0.47 |
| Lumen symmetry | 0.86 (0.84–0.88) | 0.85 (0.84–0.86) | 0.62 |
| Minimum stent area slice | |||
| Stent area (mm 2 ) | 5.7 (5.1–6.3) | 6.9 (6.6–7.1) | <0.001 |
| Stent area <4.0 mm 2 | 19.5% | 7.5% | 0.01 |
| Stent area <5.0 mm 2 | 39.0% | 19.2% | 0.001 |
| Stent area <6.0 mm 2 | 65.9% | 36.0% | <0.001 |
| Stent symmetry | 0.88 (0.86–0.90) | 0.87 (0.87–0.88) | 0.52 |
| Volumetric analysis | 35 | 262 | |
| Stent length (mm) | 29.1 (24.2–33.9) | 26.2 (24.8–27.6) | 0.26 |
| Mean lumen area (mm 3 /mm) | 7.1 (6.4–7.8) | 8.3 (8.0–8.6) | 0.002 |
| Mean stent area (mm 3 /mm) | 7.1 (6.4–7.8) | 8.3 (8.1–8.6) | 0.001 |
| Mean external elastic membrane area (mm 3 /mm) | 14.7 (12.9–16.5) | 17.0 (16.4–17.7) | 0.02 |
| Mean plaque + media area (mm 3 /mm) | 7.9 (6.4–9.4) | 8.8 (8.4–9.2) | 0.24 |
| Plaque burden (%) | 50.5 (47.1–53.8) | 51.0 (49.9–52.0) | 0.78 |
| Stent expansion | |||
| Focal stent expansion | 78.3 (72.7–83.9) | 73.9 (72.1–75.7) | 0.14 |
| Diffuse stent expansion | 97.9 (92.0–103.7) | 89.7 (87.4–92.0) | 0.01 |
| Variable | Restenosis | p Value | |
|---|---|---|---|
| Yes (n = 45) | No (n = 310) | ||
| Reference segments | 43 | 295 | |
| Stent edge dissection | 11.1% | 6.7% | 0.61 |
| Significant residual stenosis | 8.3% | 1.8% | 0.44 |
| Stented segments | 43 | 295 | |
| Acute stent malapposition | 37.2% | 35.3% | 0.47 |
| Tissue protrusion | 62.8% | 67.9% | 0.60 |
| Attenuated plaque behind stent struts | 60.5% | 76.3% | 0.07 |
| Echolucent plaque behind stent struts | 14.0% | 21.0% | 0.31 |
| Plaque rupture behind stent struts | 2.3% | 2.7% | 0.88 |
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