Intravascular Ultrasound Findings During Episodes of Drug-Eluting Stent Thrombosis

To the Editor:Drug-eluting stents (DES) represent a breakthrough in interventional cardiology but have been unable to reduce the incidence of stent thrombosis (1–2). Delayed endothelization and late vessel remodeling might stimulate thrombus deposition and DES thrombosis especially in “real-world” situations (1–2). Therefore, a prolonged dual antiplatelet regimen has been advocated in these patients (1–2). Predisposing factors, mechanisms, and management of patients suffering episodes of DES thrombosis are not well established. Intravascular ultrasound (IVUS) provides a unique tool to optimize stent implantation, but its potential use to guide re-interventions in patients suffering DES thrombosis remains unknown. In this prospective study, we sought to assess the value of IVUS in patients suffering DES thrombosis.

Between January 2004 and June 2006, of 1,974 consecutive patients undergoing DES implantation at our institution, 26 (1.3%) experienced angiographic DES thrombosis and 12 were included in the IVUS study. Our protocol in patients experiencing stent thrombosis has been previously described (3). Briefly, any patient with a clinical suspicion of DES thrombosis was immediately brought to the cardiac catheterization laboratory. After reviewing previous coronary intervention, selected angiographic views were obtained after intracoronary nitroglycerin (0.2 mg) administration. Heparin was given as an intracoronary bolus (70 IU/kg) associated (unless contraindicated) with adjuvant glycoprotein IIb/IIIa inhibitors. The IVUS study was obtained before and after intervention (3). Intravascular ultrasound catheters with 40-MHz mechanical transducers and a 0.5-mm/s motorized pull-back device were used. Balloon angioplasty was performed, taking into account IVUS findings, to optimize procedural results. Additional stents were implanted for suboptimal results or inflow/outflow lesions. Personnel blinded to clinical and angiographic data performed qualitative and quantitative IVUS analyses (3). Malapposition was defined when at least 1 DES strut, not encompassing a side branch, was not in contact with the underlying vessel wall (3). A validated system for volumetric IVUS analysis (EchoScan, TOMTEC, Boulder, Colorado) was used for 3-dimensional reconstruction (3). Stent under-expansion was defined as minimum stent area ≤80% of mean proximal/distal reference areas. The MUSIC (Multicenter Ultrasound Stenting in Coronaries) criteria for optimal expansion were evaluated (3). Data were analyzed with the SPSS software (SPSS Inc., Chicago, Illinois); categorical variables (n, %) were compared with the Fisher exact test, and continuous data (mean ± SD) with the 2-tailed, unpaired (demographic) or paired (pre- vs. post-intervention), Student ttest. A p value <0.05 was considered statistically significant.

Table 1compares baseline characteristics of patients with and without DES thrombosis. Patients suffering from DES thrombosis were younger, more frequently smokers and treated during an acute myocardial infarction, had lower ejection fraction, and their lesions were more complex.

Of the 12 patients included in the IVUS study, 10 presented with ST-segment elevation myocardial infarction and 2 were in cardiogenic shock. Median time between DES implantation and thrombosis was 7 days, and 5 patients had late (>30 days) thrombosis. Of interest, 3 patients showed patent conventional stents in other vessels.

On IVUS (Table 2),an occlusive thrombus was seen in all patients. Most DES presented severe under-expansion, and all patients had significant inflow/outflow disease. Malapposition was detected in 6 (50%) patients (3 subacute, 3 late thrombosis), and major side branches jailed by the stent were seen in 8 (67%) patients. Optimal criteria of deployment were not present in any patient. Imaging time before intervention was 196 ± 55 s. Owing to pre-intervention IVUS findings, either larger balloon diameters (7 patients) or higher inflation pressures (9 patients) were used in all patients. A thrombectomy device was used in 4 cases, and additional stent implantation in 4. Glycoprotein IIb/IIIa inhibitors were administered in all but 1 patient. After the procedure, final DES minimal area (12 ± 4 mm²vs. 9 ± 3 mm², p = 0.008), expansion (91 ± 12% vs. 74 ± 12%, p = 0.002), and volume (491 ± 326 mm³vs. 286 ± 183 mm³, p = 0.018) significantly improved compared with pre-interventional values. After reintervention, no patient showed incomplete apposition and all but 2 patients fulfilled the MUSIC criteria. However, some residual lining thrombus could still be visualized in all patients (78 ± 48 mm³vs. 142 ± 90 mm³before intervention, p = 0.02). Before intervention, 51 ± 22% of total stent volume was occupied by thrombus, but only 17 ± 7% of stent volume had thrombus after intervention (p = 0.001).

The DES thrombosis occurred in 1 patient that had prematurely stopped clopidogrel therapy and in another patient in whom aspirin was withdrawn for noncardiac surgery, but 7 patients suffered DES thrombosis despite adequate antiplatelet therapy. Resistance to aspirin was demonstrated in 3 patients, and 1 patient had thrombocytosis. One patient with an IVUS-detected coronary aneurysm obtained complete apposition after aggressive balloon dilation; however, he died from respiratory arrest secondary to lung carcinoma. Eleven patients developed large myocardial infarctions (creatine phosphokinase 1,863 ± 1,089 IU) and were discharged 11 ± 9 days after admission.

The major findings of this study are the following: 1) an occlusive thrombus is readily visualized with IVUS in all patients with DES thrombosis; 2) most patients suffering this dreadful complication have severely under-expanded DES associated with inflow-outflow disease; 3) additional mechanical factors (malapposition, side branch exit) are common; and 4) IVUS findings might be readily used to guide and optimize results of repeated procedures.

Concerns of higher thrombosis rates have recently been raised with the widespread use of DES with expanding indications (1–2). Several studies have analyzed predisposing factors for DES thrombosis; these include premature platelet discontinuation, small final lumen diameter, acute myocardial infarction, bifurcation stenting, diabetes, renal failure, low ejection fraction, and in-stent restenosis (1–2). Our results, in the complete series of patients treated with DES, confirm the importance of clinical and angiographic factors to identify patients at higher risk for DES thrombosis.

Three previous studies have analyzed IVUS findings in patients suffering bare-metal stent thrombosis. In a large retrospective multicenter study (4), abnormal IVUS findings (under-expansion, malapposition, inflow/outflow disease, dissections, or thrombus) were detected immediately after the procedure in 94% of patients subsequently suffering stent thrombosis. Of interest, angiography failed to detect these abnormal findings. Cheneau et al. (5) retrospectively assessed post-intervention IVUS findings in 21 patients with stent thrombosis; at least 1 potential mechanical cause for thrombosis was identified in 78% of lesions. Finally, in a previous prospective study (3) we used IVUS during episodes of bare-metal stent thrombosis. Stent under-expansion, dissections, malapposition, and inflow/outflow disease were common. Notably, IVUS guidance was valuable to optimize repeated interventions.

The role of IVUS to predict DES thrombosis, however, remains controversial (6–9). Studies suggest that late malapposition is more frequently found after DES than after bare-metal stent implantation. However, in most of these studies (6–8) DES malapposition was considered to be just a pure IVUS finding without clinical repercussions. Fujii et al. (8) evaluated 15 patients experiencing DES thrombosis with IVUS. Drug-eluting stent under-expansion and residual reference segment stenosis were associated with DES thrombosis, but DES malapposition was not. Conversely, a recent report by Cook et al. (9) suggested that incomplete apposition might indeed constitute a risk factor for “very late” DES thrombosis. This finding was visualized in 10 of 13 patients (77%) with this complication. However, in these 2 previous studies (8,9) thrombus features, procedural results, and the possibility of IVUS guidance during the repeated intervention were not described.

In the current IVUS study the high rate of DES malapposition and major side branches jailed by DES is of major concern and suggests a potential pathophysiologic link with DES thrombosis. Finally, our findings underscore the critical role of IVUS to guide repeated procedures in this challenging setting. Despite the use of aggressive dilations, residual lining thrombi were uniformly detected after these rescue procedures. However, IVUS guidance led to a significant improvement in all expansion parameters.

• American College of Cardiology Foundation