Clopidogrel for Two Years after Drug-eluting Stents?

Abstract & Commentary

By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.

Source: Tanzilli G et al. Effectiveness of two-year clopidogrel + aspirin in abolishing the risk of very late thrombosis after drug-eluting stent implantation (from the TYCOON [Two-Year ClOpidOgrel Need study). Am J Cardiol. 2009;104:1357-1361.

The optimal duration for dual anti-platelet therapy (DAT) after drug-eluting stent (DES) implantation remains unknown. Based on autopsy data, DES do not endothelialize as completely or quickly as bare metal stents (BMS). Guidelines advocate prolonged DAT for DES, which is currently 12 months. However, some studies suggest there is a clinical risk of very late stent thrombosis in patients with DES, occurring > 12 months after implantation. This may be particularly true in real-world settings, where DES use in off-label settings, such as multiple stents and bifurcation lesions, may carry a higher risk of late or very late stent thrombosis than in the low-risk populations studied in the pivotal clinical trials. Whether more prolonged DAT would reduce this risk has not been systematically studied. Accordingly, Tanzili et al performed a prospective registry study of patients undergoing percutaneous coronary intervention (PCI).

Over a two-year period from 2003 to 2004, all patients undergoing uncomplicated PCI who were administered DAT were enrolled. Exclusion criteria were cardiogenic shock, use of brachytherapy, use of investigational stents, and inability to take DAT. All patients had pre-loading with aspirin 325 mg and clopidogrel 300 mg, all received intra-procedural heparin, and the use of glycoprotein IIb/IIIa inhibitors was at the operator's discretion (used in approximately 31% of cases). Post-procedure, patients receiving BMS (n = 450) received clopidogrel for one month, patients receiving DES in 2003 (173) received clopidogrel for 12 months, and patients receiving DES in 2004 received clopidogrel for 24 months; all patients received ongoing aspirin 100 mg daily. Patients were followed for four years and the primary endpoint of the study was definite or probable stent thrombosis. Secondary endpoints included cardiac death, myocardial infarction (MI), target lesion revascularization (TLR), and target vessel revascularization (TVR). Early-stent thrombosis was defined as < 30 days, late-stent thrombosis (LST) was 30 days-1 year, and very late stent thrombosis (VLST) was > 1 year from the index procedure.

Baseline demographics were well matched between all groups (BMS, DES with 12-month DAT, DES with 24-month DAT). More bifurcation lesions were treated in the 24-month group, but otherwise angiographic and procedural variables were similar.

Stent thrombosis occurred most frequently in patients treated with DES and 12 months DAT. Total stent thrombosis occurred in 0.7%, 3% and 0.4% in the BMS, DES with 12-month DAT and DES with 24-month DAT respectively (p = 0.02). This was primarily due to increased VLST in the 12-month DAT group (0%, 2% and 0% in the BMS, DES with 12-month DAT and DES with 24-month DAT respectively, p = 0.03). No cases of stent thrombosis were seen after two years in any group. However, between 1-2 years after the index procedure, patients who stopped clopidogrel after 12 months had a 2% rate of stent thrombosis. Notably, self-reported compliance with DAT was 96%-98% at the end of the DAT period. There was no difference between the groups in cardiac mortality. Patients receiving BMS had higher TLR and TVR as expected, but there was no difference between the DES patients receiving 12-month DAT and those receiving 24-month DAT. The authors conclude that a two-year dual anti-platelet regimen with aspirin and clopidogrel can prevent the occurrence of very late stent thrombosis after PCI with DES.

Commentary

As more long-term data emerge regarding DES and the risk of stent thrombosis, registry data are important in generating new hypotheses that can then be formally tested in prospective, randomized, controlled trials. This interesting dataset from Tanzilli and colleagues suggests that VLST occurs in approximately 2% of patients in the second year following DES implantation if clopidogrel is ceased at one year, as is the current recommendation. Several important factors require comment. Firstly, the rate of VLST is higher than reported in other series. It is not clear in what clinical context these VLST events occurred, such as the perioperative setting, which may confound the data. Secondly, we are not told which DES were used, and the stent thrombosis rates differ between stent types. Finally, the small numbers and non-randomized nature of the study makes this hypothesis-generating, and we should not change clinical practice on the results of a single registry alone. However, the suggestion that extending the DAT duration to 24 months reduces hard clinical end-points is intriguing and worthy of further study. Their demonstration of no stent thrombosis events from two years to four years of follow-up after ceasing clopidogrel underscores the long-term safety of DES in current real-world clinical practice.