Sirolimus-Eluting Stent Thrombosis Several Years after Clopidogrel Discontinuation

Despite meta-analyses showing either similar rates or only slightly increased rates of stent thrombosis in patients with a drug-eluting stent (DES),^1–5 clinicians remain concerned about the risk of late stent thrombosis in these patients. It is a uncommon phenomenon that rarely occurred in the previous bare-metal stent era. Late stent thrombosis, with its new set of proposed standard definitions from the Academic Research Consortium (ARC), is now a real clinical problem, regardless of what the initial clinical trials or industry-sponsored postmarketing registries show. Almost every interventional cardiologist can relate to at least one (or more) catastrophic case(s). Recently, reports of these cases have been labeled as more and more remote from the initial stent implantation. Some are referring to very-late stent thrombosis.⁶ Because of the growing number of reports, the FDA (U.S. Food and Drug Administration) has recommended that dual antiplatelet therapy be continued for 12 months in patients who are not at high risk of bleeding, with the acknowledgement that the optimal duration of clopidogrel treatment remains undefined.⁷

We are reporting on a case of “very-very” late stent thrombosis that occurred 43 months post-implantation. We believe this represents the most delayed reported thrombosis following sirolimus-eluting stent implantation, which might not have been preventable using even the latest FDA recommendations.

Case Presentation. A 39-year-old male presented with an anterior myocardial infarction (MI) in June 2003. Primary PCI was performed on the mid left anterior descending artery (LAD). The lesion was treated with a 3.0 x 18 mm Cypher stentCordis Corp., Miami, Florida), and balloon angioplasty was performed on the moderate-sized jailed diagonal (Figures 1–3). The patient’s hospital course was uneventful. His ejection fraction was 40% with apical akinesis. He was discharged on 325 mg of aspirin, 75 mg of clopidogrel, as well as a 3-month courseof warfarin. Clopidogrel was discontinued at 12 months. He did well for years, until his recent presentation.

In January 2007, the patient (now 43 years old ) presented in cardiogenic shock with an acute anterior MI. He was again taken immediately to the catheterization laboratory. There was an acute stent thrombosis in the proximal-mid LAD. The patient required endotracheal intubation on the table for agitation and hemodynamic instability. The lesion was easily crossed with an IQ wire (Boston Scientific Corp., Natick, Massachusetts) and predilated using 2.0 x 15 mm and 2.5 x 15 mm Maverick balloons (Boston Scientific). The lesion was stented with a Liberté 3.0 x 20 mm bare-metal stent (Boston Scientific) because of thrombogenecity. The diagonal was coming at a 90-degree angle and was jailed during the procedure. Abxicimab infusion was started and 600 mg of clopidogrel was administered. The postinterventional course was complicated by severe epistaxis, for which abxicimab had to be stopped. The patient slowly recovered and was extubated several days after the initial event. The echocardiogram revealed an ejection fraction of 45%, with apical hypokinesis. He was discharged home on life-long clopidogrel.

Discussion

The Cypher stent was introduced in January 2003, and the Taxus stent in September 2003 in Canada. Although DES penetration never reached the trend in the United States, both stents became the gold standard, especially in young patients with long LAD lesions, as described in this report. This patient was our 33rd patient to receive a DES. At the time, the issue of late stent thrombosis was basically unheard of. In this case, clopidogrel was given for 1 year, which at the time was 4 times the recommended duration. This patient was maintained on an aggressive and appropriate medical regimen for secondary prevention, and nothing in his follow-up course could have predicted such a dramatic event occurring more than 3 and a half years postintervention.

We believe reporting such cases of exceptionally late stent thrombosis is of utmost importance. It gives the interventional community an idea of “real-life” cases of stent thrombosis in patients where DES might have been implanted as off-label use. Over the years, we have had the impression that certain lesion subgroups not represented in the initial trials might have the most antirestenotic benefit (very long lesions, small vessels and bifurcations). The decreased risk of restenosis has proven true, but the cardiology community encountered an unexpected outcome that was not even suggested by preclinical studies. The FDA has recently clearly stated that off-label use is associated with increased risks of both early and late stent thrombosis, as well as death or MI.⁷ We are now faced with a large number of patients who received these stents and for whom long-term benefit, in terms of mortality, is put into question. The issue of chronic de-endothelialization post-DES implantation is unresolved. Even whether long-term or lifelong dual antiplatelet therapy counterbalances the risks of having exposed unendothelialized stent struts is unknown. Unfortunately, the FDA has not addressed the question pertaining to patients who have already stopped their dual antiplatelet therapy for several years. Should all of these patients return to the use of ADP receptor antagonists, even with the inherent bleeding risk involved?⁸

In our practice, we have seen several of these very late stent thromboses. We believe this is a problem that is currently underreported. Two reasons that the incidence of late thrombosis is higher in real-life patients compared to trial patients may be that they are often sicker and their lesions are more complex. The use of routine intravascular ultrasound peri-PCI is less frequently performed because of costs and time issues. As a consequence, we have significantly reduced our use of DES, especially in off-label situations. In our current practice, we maintain our DES population on life-long clopidogrel until further data are available on the long-term safety of aspirin-only therapy. Whether patients such as those in this report who have discontinued their clopidogrel in the past should be put back on the drug remains unknown. This is a question that pertains to millions of patients worldwide and an answer is urgently needed.

References

1. Spaulding C, Daemen J, Boersma E, et al. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007;356:989–997.

2. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel- eluting coronary stents. N Engl J Med 2007;356:998–1008.

3. Lagerqvist B, James SK, Stenestrand U, et al. Long-term outcomes with drugeluting stents in Sweden. N Engl J Med 2007;356:1009–1019.

4. Mauri L, Hsieh W, Massaro JM, et al. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med 2007;356:1020–1029.

5. Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents. N Engl J Med 2007;356:1030–1039.

6. Bhatia V, Kachru R, Kaul U. Very late stent thrombosis after implantation of drug-eluting stent. JAPI 2006;54;879–880.

7. Farb A, Boam AB. Stent thrombosis redux — The FDA perspective. N Engl J Med 2007;356:984–987.

8. Peters RJG, Mehta SR, Fox KAA, et al. for the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: Observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003;108:1682–1687.