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Dr. Erik C. L Grove
Prof. Steen Dalby Kristensen,
DES have largely solved the problem of restenosis but both bare-metal stents (BMS) and DES induce platelet adhesion, activation and thrombus formation. Effective dual anti-platelet therapy with aspirin and clopidogrel should be continued for 12 months after the intervention with DES.Gradually, stents are covered with endothelial cells that do not induce thrombus formation, and the need for platelet inhibition decreases - but aspirin should be continued life-long.Patients, however, can have high platelet reactivity or low-responsiveness to anti-platelet therapy. In the future, individualised therapy might partly be based on measurement of the intensity of platelet inhibition.
For several years restenosis was the Achilles’ heel of coronary artery stenting by limiting long-term efficacy. Introduction of drug eluting stents (DES) reduced this problem dramatically (1,2). Recently, studies have indicated that this reduction in restenosis might have been obtained at the expense of a higher incidence of stent thrombosis, particularly late stent thrombosis. This supposition has reignited a debate about the mechanisms of stent thrombosis especially in relation to DES.
The incidence of stent thrombosis has been reported in a number of studies most of which have found an incidence of 0.5-2 %, but despite being a quantitatively minor problem, stent thrombosis has a major clinical impact owing to a high risk of myocardial infarction and death. Thus, mortality due to stent thrombosis has been reported to be as high as 45 % (3).
A new standard definition of stent thrombosis was recently proposed by an Academic Research Consortium (ARC) in order to make it possible to compare the true rates of stent thrombosis across different trials and registries (4). The ARC is composed of clinical investigators, industry representatives and regulators including the Food and Drug Administration, and the definition categorises stent thrombosis according to the level of documentation and timing.
• Definite or confirmed event (symptoms suggestive of an acute coronary syndrome and angiographic or pathologic confirmation of stent thrombosis) • Probable event (unexplained death within 30 days or target vessel myocardial infarction without angiographic confirmation of stent thrombosis) • Possible event (any unexplained death after 30 days) Based on the elapsed time since stent implantation stent thrombosis can be classified as: • Early (0-30 days post stent implantation) • Late (>30 days) • Very late (>12 months) Often, early stent thrombosis is further subdivided into acute (<24 hours) and subacute (1-30 days) events.
- Both bare-metal stents (BMS) and DES induce platelet adhesion, activation and thrombus formation and, therefore, effective anti-platelet therapy is mandatory for some time after stent implantation. Gradually, stents are covered with endothelial cells that do not induce thrombus formation, and the need for platelet inhibition decreases.
- Cytotoxic drugs used in DES in order to reduce smooth muscle cell growth after coronary intervention also inhibit this endothelialisation (5).
- Futhermore, sirolimus and paclitaxel induce expression of tissue factor in the stented lesion causing activation of the coagulation system.
- The polymers used to load these drugs may cause inflammation in the coronary artery characterized by infiltration of eosinophilic cells in the vessel wall suggestive of hypersensitivity reaction and this might also contribute to a prothrombotic environment (5).
Procedure -and lesion- related parameters: • use of multiple stents • small vessel diameter • coronary dissection • geographic miss • slow flow • long lesions • stent malapposition • underexpansion of the stent • stent design (strut thickness and polymer type) • bifurcation lesions
Patient characteristics: • diabetes • Acute Coronary Syndromes (especially STEMI) • left ventricular dysfunction • renal failure • advanced age • high platelet reactivity
Anti-platelet therapy: • inadequate intensity of therapy (i.e. non-dual platelet inhibition or insufficient dose) • non-compliance • premature cessation of anti-platelet therapy
Platelets have a pivotal role in thrombus formation including stent thrombosis and, thus, an optimal anti-platelet therapy is of crucial importance in the prevention of stent thrombosis.
High platelet reactivity is a risk factor for thrombotic events.
Relative low-responsiveness to anti-platelet therapy (often referred to as drug resistance) is associated with ischemic cardiovascular events such as unstable angina, myocardial infarction, and cardiac death.
Furthermore, it has been shown that high post-interventional platelet reactivity and incomplete inhibition of the P2Y12 platelet receptor are risk factors for subacute stent thrombosis (6,7). An impaired response to anti-platelet therapy with aspirin has been reported in patients suffering stent thrombosis (8).
Thus, measuring the effect of anti-platelet therapy might prove valuable in determining the optimal treatment for the individual patient. However, currently no golden standard or guidelines on such measurements exist.
Dual anti-platelet therapy with aspirin and clopidogrel must be continued for a longer time period after implantation of DES than after BMS implantation, and treatment for 12 months is usually recommended.
Aspirin should be continued life-long. Clinically, there is a temporal link between cessation of dual anti-platelet therapy and the occurrence of stent thrombosis (9), and recently presented registry data indicate that some patients might benefit from prolonged dual anti-platelet therapy (10,11).
However, dual anti-platelet therapy for more than 12 months has not been tested in clinical trials and is, therefore, currently not recommended, because long-term dual anti-platelet therapy is associated with an increased risk of bleeding complications (12). The challenge is to find the optimal balance in order to achieve the lowest possible risk of stent thrombosis without subjecting patients to an unnecessary risk of bleeding complications.
Stents coated with new cytotoxic drugs and polymers may have different properties in terms of affecting endothelialisation, vascular inflammation and induction of tissue factor activity. Coating with NO-donors may decrease platelet adhesion and aggregation. Stents coated with CD34-antibodies may capture circulating endothelial progenitor cells and may be able to prevent thrombosis by increasing and accelerating endothelial coverage. Furthermore, development of biodegradable stents might also be a way to decrease the incidence of late and very late stent thrombosis.
Anti-thrombotic therapy is likely to be optimised with the development of new more efficient anticoagulants and anti-platelet drugs with a lower risk of bleeding complications. Patients and health personnel should be informed about the risk associated with premature cessation of therapy.
Development of new tests able to assess platelet inhibition may identify patients with a reduced benefit from aspirin or clopidogrel and may make it possible to further individualise and optimize anti-platelet therapy.
The risk of stent thrombosis has been a known complication after PCI for quite a long time and might be increased after implantation of DES. The issue of in-stent thrombus formation, therefore, has attracted great attention once again.
Though evidence remains inconclusive, some studies indicate that the incidence of late and very late stent thrombosis is increased after DES implantation.
Importantly, it is unknown whether very late stent thrombosis is a time limited phenomenon and, thus, the problem might increase, if events continue to accrue over time.
As a consequence, large-scale clinical trials with long-term follow-up as well as mechanistic studies are highly warranted. Currently, it is not known whether very late stent thrombosis is prevented with an extended course of dual anti-platelet therapy.
Certainly, the issue of stent thrombosis emphasizes the importance of careful patient selection and individualised therapy which, in future, might partly be based on measurement of the intensity of platelet inhibition.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban HE, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. 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. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349(14):1315-1323. 3. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293(17):2126-2130. 4. Food and Drug Administration. Circulatory System Devices Panel Meeting. 2006. 5. Luscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, Virmani R. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation 2007;115(8):1051-1058. 6. Gurbel PA, Bliden KP, Guyer K, Cho PW, Zaman KA, Kreutz RP, Bassi AK, Tantry US. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005;46(10):1820-1826. 7. Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, Tantry US. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005;46(10):1827-1832. 8. Wenaweser P, Dorffler-Melly J, Imboden K, Windecker S, Togni M, Meier B, Haeberli A, Hess OM. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 2005;45(11):1748-1752. 9. Pfisterer M, Brunner-La Rocca HP, Buser PT, Rickenbacher P, Hunziker P, Mueller C, Jeger R, Bader F, Osswald S, Kaiser C. Late clinical events after clopidogrel discontinuation may limit the benefit of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents. J Am Coll Cardiol 2006;48(12):2584-2591. 10. Eisenstein EL, Anstrom KJ, Kong DF, Shaw LK, Tuttle RH, Mark DB, Kramer JM, Harrington RA, Matchar DB, Kandzari DE, Peterson ED, Schulman KA, Califf RM. Clopidogrel use and long-term clinical outcomes after drug-eluting stent implantation. JAMA 2007;297(2):159-168. 11. Michael Maeng, Lisette O.Jensen, Anne Kaltoft, Per Thayssen, Hans H.Hansen, Morten Bøttcher, Jens F.Lassen, Lars R.Krusell, Lars Pedersen, Klaus Rasmussen, Knud N.Hansen, Søren P.Johnsen, Henrik T.Sørensen, Leif Thuesen. Stent thrombosis after implantation of drug-eluting or bare metal coronary stents in Western Denmark. Presented at the ACC Congress, March. 2007. 12. Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354(16):1706-1717.
Dr Erik C. L. Grove, MD & Steen D. Kristensen, MD, DMSc, FESC Aarhus University Hospital, Skejby, Denmark
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