Late and very late stent thrombosis after polymer-based stent implantation in real-world

Chinese Medical Journal 2010;123(7):773-775773 Editorial

Late and very late stent thrombosis after polymer-based sirolimus- or paclitaxel-eluting stent implantation in real-world clinical practice

SHEN Wei-feng

ercutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation is superior, as opposed to bare-metal stenting, in terms of reduction of target lesion revascularization and improvement in clinical outcomes;1,2 the penetration rate of DES reached beyond 90% in routine PCI practice in China, especially with the availability of home-made polymer-based sirolimus- (Firebird, Excel or Partner) and non-polymer- based paclitaxel- (Yinyi) eluting stents.3,4 However, stent thrombosis (ST) after DES implantation remains a potentially catastrophic complication that often causes myocardial infarction or sudden death.5-11 In this issue of Chinese Medical Journal, Chen et al12 compared the incidence of late and very late ST after implantation of sirolimus- (Cypher or Cypher Select and Firebird) or paclitaxel- (Taxus or Taxus Liberte) eluting stents in a cohort of 9693 patients from Fu Wai Hospital – a tertiary referral center with the largest annual PCI volume in China. According to the Academic Research Consortium (ARC) criteria,13 ST occurred in 0.92% of patients at 1-year follow-up, which was significantly lower for Firebird stents compared with Taxus stents (0.71% vs.

1.24%, P=0.044). The rate of ST was 1.08% and 1.42% at two and three years, respectively, with no significant differences among various stent types. The annual growth rate of ST ranged approximately 0.12%–0.37%. Late and very late ST was associated with high mortality and non-fatal myocardial infarction. These observations compared favourably with previous reports of clinical practice registries with frequent off-label indications of DES, in which a constant rate of late ST of 0.6% per year for up to 3 and even 4 years after DES implantation was observed, with around 0.5% excess risk of late and very late ST with DES than with bare-metal stents.7,10

Several issues need to be addressed with regard to the predisposing factors, especially for late and very late ST. Given the unique differences between DES in specific drug, polymer, and metal backbone, there may be differences in ST. Cumulative evidence indicates that ST after DES implantation is also caused through a complex interplay among multiple clinical, angiographic or procedural, and biological factors, and is highly influenced by antiplatelet and anticoagulant treatments. In Chen and coworkers’ study,12 patients who received paclitaxel stents were more diabetic and had higher incidence of prior myocardial infarction and PCI. Diabetes is an independent risk factor for ST as a result of abnormal platelet reactivity and endothelial dysfunction despite increased neointimal hyperplasia and reduced stent malapposition (synonymous with incomplete stent apposition).7 PCI in the setting of acute coronary syndromes could predispose to ST owing to the large thrombotic burden, suboptimal stent expansion to avoid the risk of no-flow, or DES implantation on a thrombus that eventually disappears leading to stent malapposition.14 Moderate to severe renal insufficiency has been considered as a major determinant for late or very late ST.15

Certain angiographic characteristics and PCI features have been associated with ST including small vessel size, thrombotic or ulcerated lesions, bifurcations (especially during primary PCI), intermediate coronary stenosis (>50% to <70% ) proximal to the culprit lesion, long stent, stent malapposition and/or underexpansion, residual dissection, and low TIMI flow.5,9,16 Bifurcation stenting was associated with a 3.6%–3.9% ST rate, depending on whether 1 or 2 stents were implanted.5 A 1.03-fold greater ST risk for every 1-mm increase in stent length has been calculated. Acquired late stent malapposition due to regional vessel positive remodeling is observed in around 5% of patients after DES implantation by intravascular ultrasound imaging.17 The presence of late (acquired or persistent) stent malapposition may serve as a local nidus for thrombus formation by allowing fibrin and platelet deposition, and was thought to be associated with late and very late ST.18

Among biological factors, the markers of necrosis, inflammation, and high platelet reactivity on dual antiplatelet therapy have been frequently associated with ST. The unabsorbable polymer coating induces tissue factor expression,19,20 and contributes to vascular dysfunction through a pronounced production of reactive oxygen species.21 Evidence has been cumulated to indicate that impaired reendothelialization is the core

P

DOI: 10.3760/cma.j.issn.0366-6999.2010.07.001

Department of Cardiology, Ruijin Hospital, Institute of

Cardiovascular Disease, Jiao Tong University School of Medicine,

Shanghai 200025, China (Shen WF) (Email: rjshenweifeng@

https://www.360docs.net/doc/ea15312658.html,)

This work was supported by key grants from Shanghai Shen Kang

Medical High-Tech Foundation.

Chin Med J 2010;123(7):773-775 774

pathology of late and very late ST, where arterial healing

is delayed and tissue factor is continuously released, creating a local pro-thrombotic environment.22,23 Animal experiments and clinical studies have shown that drugs released from DES activate signal transduction pathways and inhibit cell proliferation. Histopathological examination of the vessel wall after DES implantation consistently reveals circumferential granulomatous inflammation consisting of macrophages, multinucleated giant cells, lymphocytes, and eosinophils adjacent to stent structs.24 Fibrin deposition within neointima and smooth muscle cell apoptosis are frequently identified beyond 6 months of implantation. Endothelial cell injury and delayed and/or incomplete endothelialization of the stent struts are also important determinants of thrombogenicity.25 Moreover, foreign bodies (stent) in the vessel wall and unhealed endothelium aggravate local inflammation and promote recruitment of inflammatory cells, which in return leads to further worsened endothelial function, favoring the occurrence of late and very late ST.

Premature discontinuation of clopidogrel treatment has been demonstrated to be the strongest factor associated with ST,26 especially at the first 6 months after DES implantation.8 On the other hand, late or very late ST may still exist despite continued clopidogrel therapy.27 It has been reported that clopidogrel results in considerable variation in the degree of platelet inhibition, with low responsiveness occurring in up to 30% of individuals. Decreased response to clopidogrel or residual platelet aggregation is associated with an increased risk of ST in patients undergoing DES-based PCI,28,29 which could be contributed by multiple clinical, cellular, and genetic factors.30 Diabetes and myocardial infarction have been independently associated with clopidogrel non- responsiveness.29 Since this agent requires two-step oxidation by the hepatic cytochrome P450 (CYP) system

to generate its active metabolite, which targets and irreversibly inhibits the P2Y12 receptor, loss-of-function polymorphism of genes responsible for the metabolism of clopidogrel (such as CYP 450 2C19) may result in ST after PCI. Currently, Sibbing et al31 have demonstrated a significantly increased risk of ST following coronary stent placement in CYP 2C19 *2 carrier status. The antiplaletet effects of clopidogrel may be also reduced with the concomitant use of several proton pump inhibitors by competitively influencing CYP 2C19 activity,32 which could possibly increase the rate of late or very late ST. Whether the new generation P2Y12 receptor antagonists such as prasugrel and ticagrelor with enhanced potency, more rapid onset, and markedly reduced response variability could favorably decrease late and very late ST after PCI with DES implantation required further investigations.30

In summary, despite low occurrence, late or very late ST

is a life-threatening complication and has emerged as a major concern after PCI with polymer-based DES implantation. Although some specific clinical, angiographic

or procedural, biological, and pharmacological factors, which predispose to drug-eluting ST, have been identified, timing of P2Y12 antagonist discontinuation, improvements in stent design which promote endothelial coverage with polymer free or absorbable DES or early disappearance of the stent scaffolding with biodegradable DES are certainly desirable. In future, long-term follow-up will be necessary to fully assess safety as well as efficacy of DES-based PCI, especially for high-risk patients.

REFERENCES

1.Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR,

O’shaughnessy C, et al. Sirolimus-eluting stents versus

standard stents in patients with stenosis in a native coronary

artery. N Engl J Med 2003; 349: 1315-1323.

2.Stone GW, Ellis SG, Cox DA, Hermiller J, O’shaughnessy C,

Mann JT, et al. A polymer-based, paclitaxel-eluting stent in

patients with coronary artery disease. N Engl J Med 2004; 350:

221-231.

3.Shen WF. Evolution of interventional cardiology in China.

Chin Med J 2009; 122: 2209-2219.

4.Shen WF. Interventional therapy of coronary artery disease in

China: retrospective and perspective. Chin Med J 2008; 121:

2336-2341.

5.Jaffe R, Strauss BH. Later and very late thrombosis of

drug-eluting stents. J Am Coll Cardiol 2007; 50: 119-127.

6.Luscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G,

Tanner FC, et al. Drug-eluting stent and coronary thrombosis.

Biological mechanisms and clinical implications. Circulation

2007; 115: 1051-1058.

7.Wenawester P, Daemen J, Zwahlen M, van Domburg R, Juni P,

Vaina S, et al. Incidence and correlates of drug-eluting stent

thrombosis in routine clinical practice. J Am Coll Cardiol

2008; 52: 1134-1140.

8.Schulz S, Schuster T, Mehilli J, Byrne BA, Ellert J, Massberg

S, et al. Stent thrombosis after drug-eluting stent implantation:

incidence, timing, and relation to discontinuation of

clopidogrel therapy over a 4-year period. Eur Heart J 2009; 30:

2714-2721.

9.van Werkum JW, Heestermans AA, Zomer AC, Kelder JC,

Suttorp MJ, Rensing BJ, et al. Predictors of coronary stent

thrombosis. The Dutch Stent Thrombosis Registry. J Am Coll

Cardiol 2009; 53: 1399-1409.

10.de la Torre-Hernandez JM, Alfonos F, Hernandez F, Elizaga J,

Sanmartin M, Pinar E, et al. Drug-eluting stent thrombosis.

Results from the Multicenter Spanish Registry ESTROFA. J

Am Coll Cardiol 2008; 51; 986-990.

11.van Werkum JW, Heestermans AA, de Korte FI, Kelder JC,

Suttorp MJ, Rensing BJ, et al. Long-term clinical outcome

after a first angiographically confirmed coronary stent

thrombosis: an analysis of 431 cases. Circulation 2009; 119:

828-834.

12.Chen JL, Gao LJ, Yang YJ, Huang JH, Qiao SB, Xu B, et al.

Comparison of the incidence of late stent thrombosis after

implantation of different drug-eluting stents in patients in the

real world: three-year follow-up results. Chin Med J 2010;

Chinese Medical Journal 2010;123(7):773-775775

123: 778-781.

13.Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van

Es GA, et al. Clinical end points in coronary stent trials. A

case for standardized definitions. Circulation 2007; 115: 2344-2351.

14.Zhang RY, Du R, Zhu ZB, Zhang Q, Hu J, LüAK, et al. Acute

coronary syndrome is an independent factor for late incomplete stent apposition after sirolimus-euting stent implantation. Chin Med J 2008; 121: 2504-2508.

15.Zhu ZB, Zhang RY, Zhang Q, Zhang JS, Hu J, Yang ZK, et al.

Moderate-to-severe renal insufficiency is a risk factor for sirolimus-eluting stent thrombosis. The RIFT study.

Cardiology 2009; 112: 191-199.

16.Montalescot G, Hulot JS, Collet JP. Stent thrombosis: who’s

guilty? Eur Heart J 2009; 30: 2685-2688.

17.Siqueira DA, Abizaid AA, Costa JDR, Feres F, Mattos LA,

Staico R, et al. Late incomplete apposition after drug-eluting

stent implantation: incidence and potential for adverse clinical

outcomes. Eur Heart J 2007; 28: 1304-1309.

18.Hassan AK, Bergheanu SC, Stijnen T, van der Hoeven BL,

Snoep JD, Plevier JW, et al. Late stent malapposition risk is

higher after drug-eluting stent compared with bare-metal stent

implantation and associates with late stent thrombosis. Eur

Heart J 2009; Epub ahead of print.

19.Steffel J, Latini RA, Akhmedov A, Zimmermann D,

Zimmerling P, Lüscher TF, et al. Rapamycin, but not FK-506,

increases endothelial tissue factor expression: implications for

drug-eluting stent design. Circulation 2005; 112: 2002-2011. 20.St?hli BE, Camici GG, Steffel J, Akhmedov A, Shojaati K,

Graber M, et al. Paclitaxel enhances thrombin-induced endothelial tissue factor expression via c-Jun terminal NH2

kinase activation. Circ Res 2006; 99: 149-155.

21.Jabs A, G?bel S, Wenzel P, Kleschyov AL, Hortmann M,

Oelze M, et al. Sirolimus-induced vascular dysfunction: increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation. J

Am Coll Cardiol 2008; 51: 2130-2138.

22.Finn A V, Joner M, Nakazawa G, Kolodgie F, Newell J, John

MC, et al. Pathological correlates of late drug-eluting stent

thrombosis: strut coverage as a marker of endothelialization.

Circulation 2007; 115: 2435-2441. 23.Chan MY, Andreotti F, Becker RC. Hypercoagulable states in

cardiovascular disease. Circulation 2008; 118: 2286-2297.

24.Wilson GJ, Nakazawa G, Schwartz RS, Huibregtse B, Poff B,

Herbst TJ, et al. Comparison of inflammatory response after

implantation of sirolimus- and paclitaxel-eluting stents in porcine coronary arteries. Circulation 2009; 120: 141-149.

25.Becker RC, Scheiman J, Dauerman HL, Spencer F, Rao S,

Sabatine M, et al. Management of platelet-directed pharmacotherapy in patients with atherosclerotic coronary artery disease undergoing elective endoscopic gastrointestinal

procedures. J Am Coll Cardiol 2009; 54: 2261-2276.

26.Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM,

Stankovic G, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents.

JAMA 2005; 293: 2126-2130.

27.Waksman R, Buch AN, Torguson R, Xue Z, Smith K, Javaid A,

et al. Long-term clinical outcomes and thrombosis rates of sirolimus-eluting versus paclitaxel-eluting stents in an unselected population with coronary artery disease (REWARDS registry). Am J Cardiol 2007; 100: 45-51.

28.Geisler T, Zurn C, Simonenko R, Rapin M, Kraibooj H, Kilias

A, et al. Early but not late stent thrombosis is influenced by

residual platelet aggregation in patients undergoing coronary intervention. Eur Heart J 2010; 31: 59-66.

29.Sibbing D, Braun S, Morath T, Mehilli J, V og W, Schomig A,

et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53: 849-856.

30.Simon DI, Parikh SA. Hunting for the “sweet spot” in P2Y12

recepor blockade. J Am Coll Cardiol 2009; 54: 1447-1449.

31.Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Dorrler K,

et al. Cytochrome P450 2C19 loss-of-function polymorphism

and stent thrombosis following percutaneous coronary intervention. Eur Heart J 2009; 30: 916-922.

32.Rassen JA, Choudhry NK, Avorn J, Schneeweiss S.

Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation

2009; 120: 2322-2329.

(Received February 2, 2010)

Edited by WANG Mou-yue and LIU Huan