In-Stent Pseudo-Restenosis Due to an Organized Thrombus Six Months after Implantation of a Sirolimus-Eluting Stent

Case Presentation. An 82-year-old female with several coronary risk factors was referred to our hospital for management of angina pectoris. She had undergone unsuccessful primary angioplasty for inferior myocardial infarction 7 years earlier, with complete occlusion of the right coronary artery (RCA). The long occlusion of the middle and distal RCA was opened a few days later, and two 3.5 x 13 mm and 3.0 x 28 mm bare-metal stents (BMS), respectively, were implanted. However, new, progressively restenotic lesions developed proximally and distally to the original BMS, and 3 and 9 months after her initial referral, the patient underwent balloon dilatation and deployment of a 3.0 x 18 mm proximal and a 3.5 x 25 mm distal BMS, respectively. Approximately 5 months later, coronary angiography revealed recurrent diffuse in-stent restenosis (Figure 1A), which was treated with 3 sirolimus-eluting Cypher™ stents (Cordis Corp., Miami, Florida). We deployed 3.5 x 23 mm, 3.5 x 23 mm and 3.0 x 28 mm stents proximally to distally in the middle and distal segments of the RCA without gaps between the stents. Each stent was postdilated at pressures ranging between 18 and 22 atm. The final angiography confirmed the achievement of satisfactory results (Figure 1B). Retrograde collateral perfusion from the left anterior descending artery to an occluded posterior descending branch of the RCA was observed. Examination of the treated lesion with an Atlantis SR 40 MHz intravascular ultrasound (IVUS) catheter (Boston Scientific Corp., Natick, Massachusetts) confirmed the proper expansion and close apposition of the stents to the vessel, no gaps between the stents and 7.9 mm² proximal, 6.6 mm2 middle and 5.2 mm2 distal minimal stent areas. The patient was treated with aspirin, 200 mg daily, since 1994, as well as ticlopidine, 200 mg daily, since drug-eluting stent (DES) implantation, uninterruptedly.
Follow-up coronary angiography was performed 6 months later in order to examine the status of the stented vessel. It showed a focal stenosis in the distal RCA (Figure 1C). IVUS revealed the presence of solid material in the area where the stents had been properly expanded and completely apposed to the vessel (Figure 2). Continuity and uniform distribution of the struts were confirmed. However, the entire lesion was contained within the 2-layer overlap of the BMS and DES, near the 3-layer overlap of 2 DES and 1 BMS. The lesion surface was rugged and its echo density within the stents, though somewhat heterogeneous, did not show the characteristic speckle of a fresh thrombus. Therefore, this lesion was attributed to common intimal hyperplasia and was dilated with a 3.0 x 15 mm Quantum™ Maverick^® balloon (Boston Scientific) at 8 atm (Figure 1D). After dilatation, a new hazy area was observed distal to the site of dilatation (Figure 1E) from which we sampled a 5.9 x 3.5 mm elastic, yellowish fragment with an aspiration device (T-VAC, Nipro, Tokyo) (Figure 3A). Satisfactory angiographic results were obtained after further balloon dilatation at 6 atm (Figure 1F). On pathological examination, the specimen was an organized thrombus consisting mainly of fragmented, shapeless erythrocytes (Figure 3B). Its surface was covered with a membrane penetrated by cells derived from smooth muscle (Figures 3 C and D), suggesting that it had developed ≥2 weeks before the last coronary angiogram.

How Would You Treat This Patient?

Dean J. Kereiakes, MD, FACC
Medical Director, The Heart Center of Greater Cincinnati and
The Lindner Research Center at The Christ Hospital
Cincinnati, Ohio

This patient was originally treated for chronic total right coronary artery occlusion with bare-metal stent (BMS) deployment. It is unclear whether the patient subsequently experienced 1 or 2 BMS in-stent restenosis events which were treated by percutaneous coronary intervention (PCI) without additional stent deployment. Finally, this patient was treated with extensive (74 mm) Cypher stent deployment including multiple segments of DES overlap. Thus, specific segments of the right coronary artery received coverage with 3 stents (BMS + Cypher stent overlap). Although IVUS was utilized to optimize the DES procedure, no information is provided on periprocedural adjunctive pharmacotherapy. Elective angiography performed 6 months following DES deployment demonstrates an apparent focal high-grade obstruction within the DES stented segment. Although re-endothelialization of both Taxus^®(Boston Scientific) and Cypher stents appears to occur over a relatively short time frame in normal porcine coronary arteries, it has become increasingly evident that following deployment in human coronary arteries, there may be delayed and or incomplete healing/endothelial coverage. This phenomenon appears to be particularly evident in segments of DES overlap. Incomplete healing and endothelial coverage has been demonstrated both angioscopically^1,2 and pathologically.³ By serial angioscopic evaluation, the presence of thrombus within the stented coronary segment appears more frequent following DES compared with BMS, and is significantly increased in the presence of yellow plaque.² The fact that the aspirated thrombus in the present case appeared to be days to weeks old is not surprising. In fact, the majority of thrombi aspirated in cases of native vessel (no prior stent) acute myocardial infarction are days to weeks old.⁴ Following extensive Cypher stent deployment, the present patient received oral therapy with aspirin 200 mg and ticlopidine 200 mg daily. This dose of ticlopidine appears low and is likely to be inadequate to achieve high levels of platelet inhibition. In fact, the currently prescribed standard daily dose of clopidogrel (75 mg) was chosen, as it provides a roughly similar degree of platelet inhibition to what is achieved following administration of ticlopidine 250 mg orally twice daily. In addition, there is marked individual variability in responsiveness to clopidogrel therapy. Following a 300 mg oral clopidogrel load and 75 mg daily, the average inhibition of platelet aggregation in response to 5 µM ADP is approximately 40% with a range of 20–80%. It has been estimated that 15–31% of patients undergoing PCI are “resistant” or “nonresponders” to clopidogrel. Recent data are available which link reduced responsiveness to clopidogrel with adverse clinical events following PCI including stent thrombosis.^5–7 Once thrombus was aspirated during the current PCI procedure, I would have administered intravenous abciximab based on its specific pharmacokinetic and pharmacodynamic properties which include its tapered effect over time following discontinuation and receptor redistribution. In addition, abciximab has a more potent antithrombin effect than other GP IIb/IIIa inhibitors, possibly mediated by dual (aVb3 and GP IIb/IIIa) receptor blockade. I would have administered an oral clopidogrel loading dose of ≥600 mg, despite the fact that the patient was receiving daily thienopyridine therapy,⁸ and I would consider the administration of clopidogrel 75 mg twice daily for at least 6 weeks. Preliminary results from three ongoing studies suggest that a 150 mg daily dose of clopidogrel provides a greater degree and more uniform level of platelet inhibition. Finally, “triple-drug” antiplatelet therapy following coronary stenting with the addition of cilostazol (in combination with aspirin and clopidogrel/ticlopidine) has been associated with a reduction in stent thrombosis and major adverse cardiovascular events.⁹ Novel platelet P2Y12 receptor inhibitors on the near horizon include prasugrel and AZD 6140, which provide more potent and uniform (less interindividual variability) platelet inhibition as well as a marked reduction in the prevalence of resistance. I believe that the keys to long-term success in the present case lie not only in the use of IVUS and high-pressure balloon postdilatation to optimize DES deployment during the procedure, but also in the choice of periprocedural and long-term adjunctive pharmacotherapy. Patients such as the one described in the present report will predictably have delayed/incomplete endothelial stent coverage and should be treated accordingly.¹

Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FACP
Associate Director
Cleveland Clinic Cardiovascular Coordinating Center Staff
Cardiac, Peripheral, and Carotid Intervention
Associate Professor of Medicine
Department of Cardiovascular Medicine
Cleveland Clinic Foundation
Cleveland, Ohio

This is a fascinating case of an organized thrombus found incidentally 6 months after a complex DES implantation. Each of the management steps in this patient’s care seems reasonable and appropriate. The finding, however, of an incidental asymptomatic organized thrombus 6 months after DES implantation does raise a number of potential concerns. Before considering those, the first point that deserves some discussion was the initial indication for the procedure. The patient presented with a myocardial infarction and had an unsuccessful attempt at primary angioplasty. A few days later, the RCA occlusion was opened and 2 BMS were implanted. While this was a perfectly reasonable treatment strategy, in the absence of angina or ischemia, it is not clear that this “open artery” approach is necessarily warranted, given the recent findings of the Occluded Artery Trial (OAT).
The patient subsequently received 2 additional BMS. Diffuse in-stent restenosis later developed, which was treated with 3 DES. While it is not unreasonable to treat BMS restenosis with DES, I favor treating the first bout of stent restenosis with balloon angioplasty. In fact, I will often treat the second and even third bout of stent restenosis with balloon angioplasty. While this is a less effective solution for recurrent restenosis, sometimes restenosis does “burn itself out”. Yes, this approach does increase the risk for needing repeat percutaneous procedures, but I really do try to avoid the situation of having a “stent sandwich.” The risk of stent thrombosis does increase in this situation, in particular when DES are added to the mix. In situations where recurrent stent restenosis needs to be treated with DES, I favor postdilatation to a high pressure with a noncompliant balloon, followed by IVUS interrogation to ensure appropriate apposition and sizing.
The dose of ticlopidine used in this study is common in Japan due to concerns of higher rates of bleeding when more established doses are used in the Japanese population — however, it should be noted that these lower doses really do not have the same prospective validation in large numbers of patients that the more standard dosing regimens do. In this particular case, the follow-up angiogram was performed 6 months after the complex DES procedure. There is no mention of any ischemia or angina, so this must have been done as a screening procedure after a complex stent implantation. I think this approach is reasonable after certain complex stenting procedures such as left main stenting or perhaps the case illustrated here, though caution must be employed before too liberally performing routine follow-up coronary angiography, as it does certainly raise the risk of repeat target vessel revascularization without any clear evidence of improving patient outcome. Interestingly, the follow-up angiogram in this case revealed what appeared to be focal restenosis. We are not given the details of periprocedural antithrombotic therapy, but apparently after the balloon inflation, there was a distal hazy area that was aspirated and found on pathological examination to be an organized thrombus. I agree with the IVUS assessment that was performed here, as well as with the balloon angioplasty and subsequent aspiration procedure when the embolic complication occurred. The pathological examination suggested that this was an older thrombus and not due to an intraprocedural complication. This does raise the concern that when there are multiple layers of stent, especially with polymer and potentially drug coatings, the risk for thrombus formation increases. It is of particular concern that this situation may have arisen in the context of the patient being on both aspirin and ticlopidine. Assuming that the patient was compliant and that the dosing was appropriate, this leads one to wonder how frequently this may occur if we did routinely perform angiography and IVUS in these situations. While DES are highly effective in the treatment of BMS restenosis, this case does support at least a degree of caution before adding too many layers to a stent sandwich.

David F. Kong, MD, AM, FACC, FSCAI
Assistant Professor of Medicine
Divison of Cardiovascular Medicine
Duke University Medical School
Durham, North Carolina

The patient is an 82-year old female with an RCA infarct treated initially with BMS and subsequent in-stent restenosis treated with SES. Commendably, the operators employed meticulous technique during their stent deployment, using frequent IVUS examination to confirm stent apposition. This is particularly important where multiple layers of stent are involved. Long stented segments and multiple layers of stent struts have been associated with impaired endothelialization.^1,2
It appears the six-month follow-up angiogram was performed purely electively, as opposed to being prompted by recurrence of angina or some clinical event. The aspirated sample is very interesting. One hypothesis for late thrombosis is that there is continual deposition of clot on exposed areas of the stent. The presence of both hyperplastic intima and old erythrocytes indicates that several simultaneous processes are occurring. Unlike some late thrombosis specimens,³ there is no evidence of active inflammation in the aspirated sample. It is unclear from the specimen which is the adluminal surface; some of the hyperplastic tissue may have been stimulated by the initial BMS implantation. I speculate that there was some negative remodeling during the interval period which prompted subacute, nonocclusive thrombus.^4–6 This thrombus was in the process of healing at the 6-month angiogram. Balloon dilatation shifted this material, expressing it beyond the end of the stent. This is speculative, because the long-term biology of DES remains poorly understood, particularly for DES implanted for in-stent restenosis.
Aspiration of the mass was appropriate, given its haziness. I would be content to leave this vessel as a balloon dilatation result. Any adjunctive therapy (such as laser, brachytherapy or atherectomy) would increase the degree of endothelial injury. At this juncture, repeat stenting with BMS or DES is also unfavorable — adding more metal will not improve matters.
Future re-look angiography should be triggered by recurrent symptoms. We recently learned from the OAT trial that stable patients who have PCI 3 to 28 days following acute myocardial infarction (as was performed in this patient) have no statistically significant advantage in major cardiovascular events compared to medical therapy over an average of 3 years.⁷ Consequently, if the patient (or the operators!) now have a diminished appetite for repeat revascularization procedures, a trial of optimal medical therapy would be reasonable.
Although the patient was on an ADP inhibitor continuously, the experience of Antonio Colombo and colleagues suggests that late thrombotic events may still occur, even in the presence of compliance with ADP inhibition. Clopidogrel has only recently become commercially available within Japan, and this accounts for the long-term ticlopidine therapy administered to the patient. Although it is unusual to perform platelet aggregation studies routinely, they may help guide dosing of ADP antagonists in this particular patient. The optimum duration of dual antiplatelet therapy after DES implantation remains unknown. Given the evidence of subacute thrombosis at 6 months, dual antiplatelet therapy should be continued for at least another year in this patient, if not longer.

References (D.J. Kereiakes)

1. Kotani J, Awata M, Nanto S, et al. Incomplete neointimal coverage of sirolimus-eluting stents: Angioscopic findings. J Am Coll Cardiol 2006;47:2108–2011.
   
2. Ovabu J, Ueda Y, Oqasawara N, et al. Angioscopic evaluation of neointima coverage: Sirolimus drug-eluting stent versus bare metal stent. Am Heart J 2006;152:1168–1174.
   
3. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: Delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193–202.
   
4. Rittersma SZ, Van der Wal AC, Koch KT, et al. Plaque instability frequently occurs days or weeks before occlusive coronary thrombosis: A pathological thrombectomy study in primary percutaneous coronary intervention. Circulation 2005;111:1160–1165.
   
5. Gurbel PA, Bliden KP, Guver K, et al. Platelet reactivity in patients and recurrent events post-stenting: Results of the PREPARE POST-STENTING study. J Am Coll Cardiol 2005;46:1820–1826.
   
6. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: Results of the CREST study. J Am Coll Cardiol 2005;46:1827–1832.
   
7. Hochholzer W, Trenk D, Bestehorn HP, et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006;48:1742–1750.
   
8. Kastrati A, Von Bekerath N, Joost A, et al. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation 2004;110:1916–1919.
   
9. Lee SW, Park SW, Hong MK, et al. Triple versus dual antiplatelet therapy after coronary stenting: Impact on stent thrombosis. J Am Coll Cardiol 2005;46:1833–1837.

References (D.F. Kong)

1. Finn AV, Kolodgie FD, Harnek J, et al. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 2005;112:270–278.
2. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: Delayed healing and late thrombotic risk. J Am Coll Cardiol 2006;48:193–202.
3. Virmani R, Guagliumi G, Farb A, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: Should we be cautious? Circulation 2004;109:701–705.
4. Mintz GS, Shah VM, Weissman NJ. Regional remodeling as the cause of late stent malapposition. Circulation 2003;107:2660–2663.
5. Nakatogawa T, Hibi K, Furukawa E, et al. Impact of peri-stent remodeling on in-stent neointimal proliferation in acute myocardial infarction. Am J Cardiol 2004;94:769–771.
6. Degertekin M, Regar E, Tanabe K, et al. Evaluation of coronary remodeling after sirolimus-eluting stent implantation by serial three-dimensional intravascular ultrasound. Am J Cardiol 2003;91:1046–1050.
7. Hochman JS, Lamas GA, Buller CE, et al. for the Occluded Artery Trial Investigators. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med 2006;355:2395–407.