Insights Into Very Late Stent Thrombosis From the Wisdom of Pathology

Percutaneous coronary intervention (PCI) with stenting is one of the most commonly performed procedures for the treatment of coronary artery disease. However, the use of bare-metal stenting has been associated with high restenosis rates and repeat PCI. This resulted in the innovation of the drug-eluting stent (DES), with controlled release of antiproliferative drugs that significantly reduced the risk of repeat revascularization.^1,2 However, concerns were raised about late stent thrombosis (ST) in randomized clinical trials of first-generation DES that were mandated by the United States Food and Drug Administration. Similarly, observational registries also reported continued increased rates of late and very late ST.^3,4 ST is a serious complication that results in significant clinical morbidity and mortality. ST has been categorized into early (ie, occurring ≤30 days), late (>30 days), and very late (>1 year) ST, according to the timing of the event relative to the index procedure. Recently, the clinical characteristics and predictors of early, late, and very late ST after DES implantation have been reported to be different.⁵ Armstrong et al reported differences in the incidence of ST by duration of implant: early ST was 7.9%; late ST was 3.8%, and very late ST was 3.6% of all patients in the CathPCI registry.⁵

In this issue of the Journal of Invasive Cardiology, Kaliyaden et al investigated “very” very late stent thrombosis (VVLST), which the authors defined as occurring more than 5 years after stent implantation.⁶ This study included 7 patients who had definite VVLST identified by angiography and all presented with acute myocardial infarction (MI) with TIMI grade 0 flow within the stented segment. All patients underwent PCI with first-generation DESs at the index procedure (4 sirolimus-eluting stents [SESs] and 3 paclitaxel-eluting stents [PESs]). Six patients were current smokers and 4 were diabetic. Two patients were taking only aspirin, while none of the patients were on clopidogrel, and 5 patients had no antiplatelet therapy at the time of VVLST. Interestingly, 3 patients discontinued dual-antiplatelet therapy (DAPT) within 14 days before the event of VVLST. Two of them had interrupted DAPT for elective surgery. 

We have previously reported that delayed reendothelialization and hypersensitivity reaction are the most important substrates of ST, especially in late and very late ST.^7,8 We investigated a total of 62 lesions from 46 human autopsy cases with first-generation DESs implanted for >30 days to determine the pathologic correlates of late and very late ST following DES implantation.⁸ Univariable logistic generalized estimating equation modeling demonstrated that the ratio of uncovered to total stent struts per section of >30% (odds ratio [OR], 9.0; 95% confidence interval [CI], 3.5-22.0) was the strongest predictor of late/very late ST.⁸ The mechanisms inducing incomplete healing by the first-generation DESs are not fully understood; however, lesion characteristics, drug used (sirolimus group of drugs or paclitaxel), total drug dose, release profile and drug distribution, and polymer biocompatibility are all important factors.

We have also compared the vascular pathologic responses of first-generation DESs following acute MI (n=17) versus those for stable angina (n=18) with duration of implant >30 days.⁹ The incidence of late/very late ST was significantly higher in patients with acute MI (7 of 17 patients; 41%) compared to those with stable angina (2 of 18 patients; 11%; P=.04). Very late ST (>1 year) was observed in 2 patients with acute MI (12%) and in none of the patients with stable angina. Morphometric analysis showed that culprit AMI sites versus stable plaque had significantly less neointimal thickness (0.04 mm vs 0.11 mm; P=.01), greater fibrin deposition (63% vs 36%; P=.01), and inflammation (35% vs 17%; P=.01), and higher prevalence of uncovered struts (49% vs 9%; P=.01). In patients with acute MI, neointimal thickness was significantly less at culprit sites as compared to non-culprit sites (0.04 mm vs 0.07 mm; P=.01), whereas this difference was not observed in patients with stable angina (0.11 mm vs 0.11 mm; P=.56). Similarly, the percentage of struts with fibrin (63% vs 52%; P=.04), struts with inflammation (35% vs 30%; P=.04), and uncovered struts (49% vs 19%; P=.02) were significantly greater at the culprit sites as compared to non-culprit sites in patients with acute MI, whereas there were no significant differences in these parameters in patients with stable angina. Vessel healing at the culprit site in AMI lesions with DES was significantly delayed compared to culprit sites in stable lesions. Therefore, it was suggested that delayed healing is an important predictor of thrombotic complications in patients treated with DES for acute MI.⁹ Moreover, we investigated vascular healing response and the mechanisms of late/very late ST in first-generation DES between SES and PES.¹⁰ The incidence of late/very late ST did not differ significantly between SES and PES (21% vs 27%; P=.47). However, differential vascular responses to the two stents (SES and PES) were observed, suggesting differences in the underlying mechanism of late/very late ST; there were localized hypersensitivity reactions, consisting of eosinophils, lymphocytes, and giant cells throughout the stented segment of SES, while late/very late ST in PES was attributed to malapposition secondary to excessive fibrin deposition on the abluminal surface. The majority of patients with hypersensitivity reaction following SES implantation died in the very late phase (>1 year) where the mean duration of implant was 649 days. One of the important pathological findings in cases with hypersensitivity reaction to SES was severe inflammation, resulting in positive remodeling and malapposition of the stent. In contrast, malapposition from excessive fibrin deposition was the primary contributor toward late/very late ST in PES, with mean implant duration of 611 days. These examples demonstrate differential pathobiological mechanisms of malapposition, while the luminal surface generally lacked endothelial cell coverage.¹⁰

More recently, the development of atherosclerotic changes within neointima termed “neoatherosclerosis” has been identified as another important mechanism of very late ST.¹¹ The incidence, character, and temporal development of neoatherosclerosis occurring within BMS and DES at autopsy were examined in a total of 299 consecutive cases (142 BMS, 157 DES [81 SES and 76 PES] cases) with 406 lesions with implant duration >30 days (197 BMS, 209 DES [103 SES and 106 PES] lesions).¹¹ Stent-related deaths from thrombosis were significantly more frequent in DES vs BMS use (20% vs 4%; P<.001), whereas restenosis as a cause of death was more frequent in BMS vs DES use (28% vs 7%; P<.001). The overall incidence of neoatherosclerosis was significantly greater in DES vs BMS use (31% vs 16%; P<.001) despite longer duration of implant for BMS. The incidence of neoatherosclerosis was also evaluated following stratification by duration of implant. For those implants with duration of 2 years or less, DES had a greater incidence of any neoatherosclerosis (29% vs 0%; P<.001), which was represented by a greater incidence of foamy macrophage clusters (14% vs 0%; P<.001) as well as fibroatheromas (13% vs 0%; P<.001). For implant durations between 2 and 6 years, the DES group still showed a higher incidence of neoatherosclerosis (41% vs 22%; P=.05). The cumulative incidence of any neoatherosclerosis with time following implantation of BMS vs SES and PES is shown in Figure 1. Neoatherosclerosis was observed more frequently and was accelerated in first-generation DES compared to BMS. A multiple logistic generalized estimating equation model identified younger age (OR, 0.963; 95% CI, 0.942-0.983; P<.001), longer duration of implant (OR, 1.028; 95% CI, 1.017-1.041; P<.001), SES usage (OR, 6.534; 95% CI, 3.387-12.591; P<.001), PES usage (OR, 3.200; 95% CI, 1.584-6.469; P=.01), and underlying unstable plaque (OR, 2.387; 95% CI, 1.326-4.302; P=.01) as independent risk factors for the development of neoatherosclerosis.¹¹ In-stent neoatherosclerosis occurs both in BMS and DES use; however, for DES implantation, it is observed more frequently at an earlier time point as compared to BMS. Moreover, formation of thin-cap fibroatheroma occurred within 2 years following DES implantation, while similar features in BMS occurred at a relatively late time point (average implant duration, 6 years). We reported ST from plaque rupture within the stent in 4 cases of BMS implantation (all >5-year duration) and in 1 case of DES implantation (SES, 23-month duration) and vulnerable plaques were identified in 3 cases of BMS implantation (all >50-month duration) and 2 cases of SES (13-month and 17-month duration) in this study. The development of neoatherosclerosis is therefore another important contributing factor for the occurrence of very late ST.¹¹

Dual-antiplatelet therapy with aspirin and an oral P2Y12 receptor blocker is the standard regimen for the prevention of thrombotic events following PCI. The optimal duration of DAPT for DES implantation is still unknown, although current guidelines from the ACCF/AHA/SCAI recommend DAPT for 12 months in patients with DES implantation.¹² These were non-emperically prescribed in the absence of evidence derived from dedicated clinical trials. Premature discontinuation of antiplatelet therapy is known to be a predictor of thrombotic events;¹³ however, the cessation of DAPT may be unexpectedly required for possible bleeding complications, unexpected surgery, etc. Recently, Kimura et al reported the influence of DAPT discontinuation as an important risk factor of ST following SES implantation at all time points including 366-548 days (2.1% vs 0.14%; P=.01) (j-Cypher Registry).¹⁴ In the same registry, cumulative incidences of surgical procedures was 0.7% at 60 days, 5.1% at 1 year, and 14.7% at 3 years.¹⁵

Second-generation DESs were developed with improved stent design and the use of more biocompatible permanent and bioabsorbable polymers as compared to first-generation DESs to overcome the problem of late ST. Meta-analyses of clinical trials have shown that the thin-strut, fluoropolymer-coated cobalt-chromium everolimus-eluting stent (CoCr EES) was associated with a lower rate of definite ST compared to other DESs and BMSs.¹⁶ The thin-strut design of the stent platform, thromboresistant properties of the fluoropolymer, and reduced polymer and drug load may contribute to the low rate of ST observed with CoCr EES.¹⁶ However, our most recent pathology report indicated that the observed frequency of neoatherosclerosis did not differ significantly between CoCr EES and first-generation DESs (CoCr EES 29%; SES 35%; PES 19%).¹⁷ Therefore, we will have to await long-term results of second-generation DESs, because it seems unlikely that progression of neoatherosclerosis with its consequences on VLST will be diminished in CoCr EES compared to first-generation DESs.

The study presented in the current issue of the Journal reports the occurrence of VVLST in the absence or cessation of antiplatelet therapy in 7 cases and highlights the substantial clinical consequences, as all patients presented with acute MI. As none of these events could be predicted, the current study reminds us that future research should be mandated to identify patients at increased risk of VVLST, since unselected prolongation of DAPT seems neither feasible nor clinically indicated in all patients. 

References

1. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346(23):1773-1780.
2. Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004;350(3):221-231.
3. Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol 2008;52(14):1134-1140.
4. Kimura T, Morimoto T, Nakagawa Y, et al. Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: five-year outcome of the j-Cypher Registry. Circulation. 2012;125(4):584-591.
5. Armstrong EJ, Feldman DN, Wang TY, et al. Clinical presentation, management, and outcomes of angiographically documented early, late, and very late stent thrombosis. JACC Cardiovasc interv. 2012;5(2):131-140.
6. Kaliyadan A, Siu H, Fischman DL, et al. “Very” very late stent thrombosis: acute myocardial infarction from drug-eluting stent thrombosis more than 5 years after implantation. J Invasive Cardiol. 2014;26(9):413-416.
7. 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(1):193-202 (Epub 2006 May 5).
8. Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation. 2007;115(18):2435-2441 (Epub 2007 Apr 16).
9. Nakazawa G, Finn AV, Joner M, et al. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study. Circulation. 2008;118(11):1138-1145.
10. Nakazawa G, Finn AV, Vorpahl M, Ladich ER, Kolodgie FD, Virmani R. Coronary responses and differential mechanisms of late stent thrombosis attributed to first-generation sirolimus- and paclitaxel-eluting stents. J Am Coll Cardiol. 2011;57(4):390-398.
11. Nakazawa G, Otsuka F, Nakano M, et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. J Am Coll Cardiol. 2011;57(11):1314-1322.
12. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation, 2011;124(23):e574-e651.
13. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293(17):2126-2130.
14. Kimura T, Morimoto T, Nakagawa Y, et al. Antiplatelet therapy and stent thrombosis after sirolimus-eluting stent implantation. Circulation. 2009;119(7):987-995.
15. Kimura T, Isshiki T, Hayashi Y, et al. Incidence and outcome of surgical procedures after sirolimus-eluting stent implantation: a report from the j-Cypher registry. Cardiovasc Interv Ther. 2010;25(1):29-39.
16. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting stents: is the paradigm shifting? J Am Coll Cardiol. 2013;62(21):1915-1921.
17. Otsuka F, Vorpahl M, Nakano M, et al. Pathology of second-generation everolimus-eluting stents versus first-generation sirolimus- and paclitaxel-eluting stents in humans. Circulation. 2014;129(2):211-223 (Epub 2013 Oct 25).

____________________________________________

From CVPath Institute, Gaithersburg Maryland.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Joner is a consultant for Biotronik and Cardionovum, and has received speaking honorarium from Abbott Vascular, Biotronik, Medtronic, and St Jude. Dr. Virmani receives research support from Abbott Vascular, BioSensors International, Biotronik, Boston Scientific, Medtronic, MicroPort Medical, OrbusNeich Medical, SINO Medical Technology, and Terumo Corporation; has speaking engagements with Merck; receives honoraria from Abbott Vascular, Boston Scientific, Lutonix, Medtronic, and Terumo Corporation; and is a consultant for 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. Dr. Yahagi reports no conflicts of interest regarding the content herein.

Address for correspondence: Renu Virmani, MD, CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD 20878. Email: rvirmani@cvpath.org