Dual Antiplatelet Therapy (DAPT)

Stent thrombosis is associated with several risk factors, including inadequate antiplatelet therapy and poor therapeutic response. Among 21,009 patients who were treated with either a bare-metal stent or drug-eluting stent (DES) in the Dutch Stent Thrombosis Registry, 437 (2.1%) presented with a definite stent thrombosis [van Werkum JW et al. J Am Coll Cardiol 2009]. This included 140 cases of acute stent thrombosis, 180 subacute cases, 58 late events, and 59 very late events. The strongest predictor of stent thrombosis was inadequate antiplatelet therapy, measured as less than 30 days of clopidogrel use following stent placement (HR, 36.5; 95% CI, 8.0 to 167.8; p<0.001).

Poor response to clopidogrel also increases the risk of early stent thrombosis. Approximately 15% to 20% of patients do not respond optimally to clopidogrel, Prof. Colombo said, and 3% to 5% do not respond at all [Mega JL et al. N Engl J Med 2009]. For some patients, genetic polymorphisms that are associated with clopidogrel metabolism result in poor therapeutic response to clopidogrel. Compared with patients with the CYP2C19*1/*1 allele, those who harbor the CYP2C19*2*2 allele are significantly more likely to experience stent thrombosis despite treatment with clopidogrel (p=0.002) [Sibbing D et al. Eur Heart J 2009; Mega JL et al. N Engl J Med 2009].

Point-of-care genetic testing may help to identify patients who will have an inadequate response to clopidogrel. For patients who are identified as having a genetic polymorphism that is associated with poor clopidogrel response, antiplatelet agents, such as prasugrel and ticagrelor, provide another route for thromboprophylaxis. To avoid issues that are related with poor clopidogrel response altogether, an alternative approach involves the preferential use of prasugrel or ticagrelor in all patients who require antiplatelet therapy.

New-Generation Stents

Certain features of stents themselves also increase the risk of stent thrombosis. In the Dutch Stent Thrombosis Registry, stent-related factors that were associated with thrombosis included undersizing (HR, 13.4; 95% CI, 5.3 to 34.0; p<0.0001) and dissection (HR, 2.88; 95% CI, 1.7 to 5.0; p=0.0002).

Second-generation DES include features, such as thin struts, thin polymers, and bioabsorbable polymers, that are designed to reduce the risk of restenosis and stent thrombosis. The RESOLUTE All Comers trial evaluated the zotarolimus-eluting stent (ZES), which uses the same base stent and the same drug coating as the everolimus-eluting stent (EES) but uses a different polymer that allows a more protracted release of zotarolimus [Silber S et al. Lancet 2011]. The cumulative risk of definite and probable stent thrombosis over 2 years was similar in the EES and ZES groups (1.0% vs 1.9%; p=0.07; Figure 1). Only 3 patients in each group (0.3%) had very late (>1 year) stent thrombosis. Patients in the EES and ZES groups were equally likely to meet the composite endpoint of definite or probable stent thrombosis and any death up to 2 years (4.8% vs 4.6%; p=0.89).

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Figure 1.

RESOLUTE All Comers Trial: 2-Year Safety Outcomes.

Reproduced with permission from the Lancet. Unrestricted randomised use of two new generation drug-eluting coronary stents: 2-year patient-related versus stent-related outcomes from the RESOLUTE All Comers trial. Silber S et al. Jan 1, 2011;377(9773):1241–1247.

“Stent thrombosis has almost been conquered,” Prof. Colombo said. “Hopefully, late and very late thrombosis will be reduced by the new generation stents and possibly bioabsorbable stents,” he concluded.

While late stent thrombosis is infrequent, it remains an important concern in patients who have received coronary stents. The combination of more potent and less variable antiplatelet agents and later-generation stents provides hope for continued reductions in the rates of stent thrombosis. The optimal duration of dual antiplatelet therapy, however, remains an open question, particularly in the setting of newer-generation and bioabsorbable stents.