(Circulation. 2007;115:2379-2381.)
© 2007 American Heart Association, Inc.
Editorial |
From the Cardiovascular Research Foundation, New York, NY.
Correspondence to Gary S. Mintz, MD, 611 Pennsylvania Ave, SE No. 386, Washington, DC 20003. E-mail gsm18439{at}aol.com
Key Words: Editorials remodeling stents thrombosis ultrasonics
| Introduction |
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Article p 2426
During every phase of percutaneous coronary intervention, intravascular ultrasound (IVUS) has provided important insights into the mechanisms of success and reasons for failure. In this issue of Circulation, Cook et al1 continue this tradition by reporting the IVUS findings in 13 patients who developed stent thrombosis >1 year after DES implantation. They concluded, "Incomplete stent apposition is highly prevalent in patients with very late stent thrombosis after DES implantation, suggesting a role in the pathogenesis of this adverse event."
| What Is Incomplete Stent Apposition? |
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| When and How Often Does ISA Occur, and What Is Its Mechanism? |
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Acute ISA is mostly technique dependent and can occur after implantation of any type of stent. Acute ISA can resolve or persist; acute and persistent ISA can increase, remain stable, or decrease in size. It is not clear why some ISA resolves and some persists. However, acute and persistent ISA after DES implantation is associated with less neointimal hyperplasia compared with acute ISA that resolves spontaneously.7,8 Although reendothelialization is below the resolution of IVUS, it is interesting to speculate that acute and persistent ISA also may be associated with reduced reendothelialization compared with acute and resolved ISA.
Late ISA, ISA detected at follow-up, can be late and acquired (occurring between implantation and follow-up) or acute and persistent as noted above. The mechanisms of late and acquired ISA are either positive remodeling (an increase in vessel dimensions) without an equal amount of peristent plaque or intimal hyperplasia growth so that the vessel pulls away from the stent (the most common mechanism) or plaque or thrombus dissolution so that a gap forms between the stent and the vessel wall (primarily in patients presenting with acute coronary syndromes).813 Although late and acquired ISA can occur after BMS implantation, brachytherapy treatment of BMS restenosis, radioactive stent implantation, and DES implantation, the exact underlying pathological mechanism responsible for positive remodeling remains unknown. Late and acquired ISA is a continuum from 1 malapposed stent strut to aneurysm formation.14 The frequency of late ISA appears to be greater after DES compared with BMS implantation depending on DES type, but it is less clear that the gaps between stent and vessel wall are larger after DES compared with BMS implantation, although aneurysm was rare in the BMS era. Like acute and persistent ISA, late and acquired ISA (whether after BMS or DES implantation) also is associated with less neointimal hyperplasia and presumably reduced reendothelialization.810 There are only 2 reports of patients with late ISA who underwent a second follow-up IVUS study; for the most part, ISA in these patients either remained stable or regressed during the second follow-up period.14,15
| What Is the Diagnostic Accuracy of IVUS in Detecting ISA? |
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| How Predictive Is ISA for Late Stent Thrombosis? |
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None of the patients with late stent thrombosis had baseline IVUS; therefore, it was not possible to differentiate acute and persistent ISA from late and acquired ISA. However, this may not be as important as the size of the stentvessel wall gaps or the underlying pathology.
Late ISA was present in 10 of 13 late stent thrombosis patients and measured 8.3±7.5 mm2 in maximum cross-sectional area (range, 2 to 24 mm2), with 9 of 10 late stent thrombosis patients having a gap of
4 mm2. To put this in perspective, the average late ISA area in the stent thrombosis patients in the study by Cook et al was great than the average minimum stent area in these patients. Furthermore, this average late ISA area was twice the size of the average late ISA of the 21 control patients (4.0 mm2), the average late ISA area of the 7 slow-release and 10 moderate-release patients in the TAXUS-II trial (5.1 mm2 and 3.4 mm2, respectively), and the average late ISA area of 85 DES-treated patients reported by Hong et al8 (3.0 mm2)none of whom had late sequelae. These were not subtle findingscases of malapposition likely to be missed by IVUS and requiring more advanced intracoronary imaging techniques; they represented the extreme end of the spectrum, with 3 of 10 having frank aneurysms (lumen [stent+ISA] area >50% larger than the proximal reference), similar to the 2 patients reported by Feres et al16 who developed late stent thrombosis after follow-up IVUS detected marked late and acquired ISA.
What of the other 3 patients? One had a minimum stent area of 5.0 mm2, and the other 2 had no IVUS-detectable explanation for late thrombosis. It is possible that ISA was missed because thrombus formation obscured the stentvessel wall gap.
It has long been speculated that underexpansion and malapposition have a synergistic effect on stent thrombosis. Thus, the authors calculated a stent expansion index, dividing the minimum stent area by the reference lumen area, to show that stent expansion was less in late stent thrombosis patients compared with control subjects. Does this make sense? No, not in the conventional sense in which stents were underexpanded at implantation and underexpansion was detected only at follow-up. In fact, minimum stent area was similar between stent thrombosis and control patients. Instead, positive remodeling (increase in vessel dimensions), which was responsible for late and acquired ISA, probably affected the reference segments, causing an increase in vessel and lumen dimensions and artificially reducing the expansion index. This highlights the diffuse nature of this positive remodeling in these patients. It is not known whether a mere mismatch between an adequate absolute minimum stent area and a larger reference lumen area (rather than true underexpansion) contributes to stent thrombosis. However, the findings of Cook et al suggest a lessening of the impact of mechanical stent implantation problems on late stent thrombosis compared with acute/subacute stent thrombosis.1 Only 3 of 13 of late stent thrombosis patients had "real" stent underexpansion, a minimum stent area <5.0 to 5.5 mm2 (a common criterion for DES underexpansion6,17,18), fewer than have been reported with IVUS studies of acute/subacute thrombosis.
| Does ISA in and of Itself Cause Late Stent Thrombosis? |
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| Is This an Argument for Routine Use of IVUS? |
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| What Next? |
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40% of patients in RAVEL,20 15% of patients in SIRIUS,12 and 20% of patients in an integrated analysis of TAXUS-IV, V, and VI. Paired (postintervention and follow-up) IVUS, necessary to detect late and acquired ISA, was done in even fewer patients. Among these multicenter studies, there were <100 patients with late ISA, and only half of them had late and acquired ISA. The single-center study by Hong et al8 alone contained 133 patients with late ISA, 82 of whom had late and acquired ISA. Importantly, none of these studies reported late stent thrombosis in any late ISA patient either at the time of detection or during subsequent clinical follow-up, although the size of the ISA was similar to that in the control group in the study by Cook et al. The report by Cook et al1 raises as many questions as it answers. It is possible to conceive of a study that would answer some of these questions: baseline (blinded) IVUS, routine IVUS follow-up with randomization of late ISA patients to additional stent expansion versus no intervention, and subsequent clinical follow-up with IVUS imaging of patients presenting with late events. Given the relative infrequency of each event, the difficulty in collecting comprehensive data (particularly the required IVUS data), the "modest" reported size of late ISA in large prospective studies, and the protracted follow-up that would be necessary, the number of patients and the time course would be daunting. For now, we must rely on important observations such as the study performed by Cook and colleagues that provide insights into this clinical problem, and the question of whether identifying and treating late ISA will reduce late stent thrombosis remains unanswered.
| Acknowledgments |
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Dr Mintz is a member of the speakers bureau for Boston Scientific Corp and is a consultant for and shareholder of Volcano Corp.
| Footnotes |
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| References |
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