Introduction

Percutaneous revascularization has revolutionized the management of patients across the spectrum of coronary artery disease, from chronic stable angina through to acute coronary syndromes (ACS). Drug-eluting stents greatly reduced the risk of in-stent restenosis compared with bare-metal stents (or balloon angioplasty) ; however, stent thrombosis that occurred with these stents was often related to delayed endothelialization . This relatively rare but serious complication of stent implantation created near-paranoia in the media and in the cardiology community, with reported rates of mortality for patients with stent thrombosis of up to 45% .

This review will explore the clinical burden and pathology of stent thrombosis in relation to the timing of an event, with a focus on the underlying role of thrombin in the fundamental process, and will reassess recent developments in antithrombotic therapy to reduce the risk of stent thrombosis.

Clinical burden and pathology of stent thrombosis

According to a recent article by Claessen et al. , the incidence of stent thrombosis up to 1 year post-stenting appears to be similar for bare-metal and drug-eluting stents, quoted as ranging from approximately 0.6% to 3.3%. However, there is some suggestion of higher rates of very late stent thrombosis with drug-eluting stents compared with bare-metal stents. In a 5-year follow-up study from the Netherlands of patients enrolled in the Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction with ST-segment Elevation (PASSION) trial, there was a trend towards a higher incidence of definite or probable very late stent thrombosis (> 1 year) in patients receiving paclitaxel-eluting stents compared with bare-metal stents (3.5% vs 1.1%, respectively; P = 0.06), reaching statistical significance for definite very late stent thrombosis (3.3% vs 0.7%; P = 0.04) . Another long-term US study in patients with ST-elevation myocardial infarction ( n = 1640) reported incidence rates of stent thrombosis (definite, probable or possible) of 2.7% (0–30 days), 5.2% (at 1 year) and 8.3% (at 5 years) during the drug-eluting stenting period (2003–2009) , although these high rates may reflect the high-risk population included in this analysis. Drug-eluting stenting was also the only significant independent predictor of very late stent thrombosis (hazard ratio [HR] 3.77, 95% confidence interval [CI] 1.81–7.88; P < 0.001). Interestingly, a recent meta-analysis by Palmerini et al. suggested that the incidence of the Academic Research Consortium defined definite stent thrombosis with a second-generation everolimus-eluting stent was significantly lower than with first-generation stents (paclitaxel, sirolimus and zotarolimus eluting, pooled data: 0.5% vs 1.3%, respectively; relative risk 0.38; 95% CI 0.24–0.59; P < 0.0001). Similar results were reported for Academic Research Consortium defined definite or probable stent thrombosis (relative risk 0.46, 95% CI 0.33–0.66; P < 0.0001).

The occurrence of stent thrombosis varies depending on a host of clinical patient characteristics, the type of stent used, and the type of adjunctive pharmacotherapy used acutely and chronically to prevent these events ( Fig. 1 ). The patients profiled as having an increased risk of stent thrombosis include those with common comorbidities such as diabetes , renal dysfunction and previous myocardial infarction ; patients with multiple stents implanted, especially those of long length and narrow diameter ; and patients with poor compliance to medical therapy, including dual antiplatelet therapy (DAPT; aspirin plus a P2Y ₁₂ inhibitor) . Additionally, the specifications of various stents, including stent strut thickness, type and thickness of the polymer coating, and the antiproliferative therapy required, have also been linked to an increased risk of stent thrombosis .

Factors associated with stent thrombosis.

Despite relatively low incidence rates of stent thrombosis, the case-fatality rate with stent thrombosis remains high. One-year mortality rates of approximately 10–25% in patients with stent thrombosis have been reported . More recently, the findings from an analysis of data from the US Veterans Affairs Clinical Assessment, Reporting and Tracking (CART) programme of patients undergoing angiography for diagnosis and treatment of stent thrombosis have been published . In the 656 patients identified, there was an unadjusted 30-day mortality risk of 13% in those with early stent thrombosis, decreasing to 6% in those with late stent thrombosis and 3% with very late stent thrombosis.

The event that instigates stent thrombosis differs depending on the time frame of an event. In the acute or subacute time frames (< 30 days), the most common cause is related directly to the stent implantation, including suboptimal stent deployment, untreated edge dissections or high thrombus burden at the time of stent implantation . Incomplete stent apposition to the vessel wall (also referred to as stent malapposition) has a major role in the development of stent thrombosis ; this is known to occur when the stent diameter is significantly smaller than the vessel wall diameter, and is most common in patients with high thrombotic burden, including those undergoing primary percutaneous coronary intervention (PCI). This may also occur if the vessel wall is heavily calcified or irregular, or if significant discrepancies exist between stenosed and adjacent areas . In these circumstances, the risk of stent thrombosis is similar between patients receiving bare-metal stent and drug-eluting stent implantations .

Late and very late stent thromboses are most frequently related to inadequate or delayed re-endothelialization , stent malapposition or fracture , or hypersensitivity reactions to the polymers coating the metallic stent . First-generation drug-eluting stents caused substantial positive remodelling or peri-stent aneurysm formation, increasing the risk of stent thrombosis . Additionally, stent thrombosis can occur as a result of incomplete endothelialization of the stented vessel wall, leading to exposed stent struts . Although bare-metal stents exhibit complete re-endothelialization within 6 months, first-generation drug-eluting stents have been shown to fail to re-endothelialize fully even several years post-implantation . Through all of these phases, patient compliance and/or resistance to antithrombotic and pharmacological therapy have a role . In addition, “new” atherosclerotic plaques can also form over time in stented arteries, which may subsequently rupture, causing a stent thrombosis .

Although the exact pathology of in-stent thrombus formation remains unclear, from a cellular perspective it is thought to be similar to the process of thrombus formation in ACS, which leads to an occlusive or sub-occlusive thrombus. The initial event in coronary thrombosis is usually disruption of the atherosclerotic plaque, which exposes thrombogenic material to the circulating blood, resulting in platelet activation and the formation of a platelet thrombus . Thrombin is generated through simultaneous activation of the coagulation cascade by disruption of the plaque, contributing to the stabilization of the initially loose platelet clot by generating cross-bound fibrin within the thrombus. With its additional role as a strong platelet activator, thrombin is a key mediator in thrombosis. The final product of this sequence of events is a stable thrombus consisting of aggregated platelets and fibrin . In-stent thrombi are composed of a combination of platelets and fibrin, suggesting that a similar “dual pathway” sequence of events–platelet activation and thrombin generation–is involved in their formation .

Antithrombotic therapy for the prevention of stent thrombosis

The design and outcomes of various key clinical trials for secondary prevention in patients with recent ACS involving DAPT and direct oral anticoagulants are summarized in Table 1 . Although research and expert opinion continues to assess the optimal duration of DAPT, guidelines recommend DAPT with aspirin and a P2Y ₁₂ receptor blocker to prevent stent thrombosis after an ACS for 1 year . The discussion regarding the optimal duration of DAPT following ACS and the effect of the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS–TIMI 54) and the Dual Antiplatelet Study (DAPT) are beyond the scope of this manuscript .

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