Late Stent Thrombosis in Brachytherapy: The Role of Long-term Antiplatelet Therapy

Percutaneous coronary intervention (PCI) has significantly changed the management of coronary artery disease. According to the American Heart Association, an estimated 539,000 percutaneous transluminal coronary angioplasty (PTCA) procedures were performed in the United States in 1998 (a 248% increase from 1987).1 The number of annual interventional procedures performed has increased by approximately 10% each year since 1997, and projections suggest the field will continue to grow. It is estimated that approximately one million PCI procedures are expected to be performed worldwide in 2001.2 Although the majority of patients undergoing PTCA experience an immediate reduction in anginal symptoms, acute complications occur in approximately 2–5% of patients and restenosis develops in approximately 30–40% within 6 months post-procedure.3,4 Various treatment options have been developed to address the limitations of PTCA. Anticoagulation with warfarin and unfractionated heparin reduces the incidence of thrombotic events, but increases the incidence of major bleeding.2,5 Mechanical maneuvers such as excimer laser coronary angioplasty, rotational atherectomy or directional atherectomy to remove the atheromatous tissue only improve outcomes in selected patients.3,6 The United States Food and Drug Administration (FDA) has approved intracoronary stenting for treatment of acute vessel closure and prevention of restenosis following PTCA. Stents have a 98% success rate acutely7 and reduce the incidence of restenosis by approximately 35–50%.3,8–11 Stents were placed in an estimated 80% of PCI procedures in the year 2000.5 This number will likely increase to 90% over the next 2 years. Stents reduce the relative risk of restenosis by reducing vessel recoil and vascular remodeling, and providing a large post-procedure luminal diameter.12 The luminal scaffolding provided by the stent may, however, increase the proliferative component of restenosis. Although the majority of problems with stents occur within 2–14 days post-procedure and are associated with subacute stent thrombosis, approximately 150,000 cases of in-stent restenosis occur annually,4,12,13 and up to 20% of stented patients show angiographic restenosis within 6 months post-intervention.7 In-stent restenosis is due almost entirely to smooth muscle hyperplasia (neointimal hyperplasia) and matrix proliferation that peaks at 1–3 months after stent deployment.12 Patient-related factors (diabetes mellitus, polymorphisms, elevated C-reactive protein and recurrent restenosis), lesion-related factors [length > 15 mm, vessel diameter size 30 days post-stenting limits this form of therapy. This article reviews the emergence of brachytherapy in the treatment of in-stent restenosis, the pathophysiology and occurrence of the complication of late stent thrombosis and the integral role of antiplatelet therapy with this new technology. Vascular brachytherapy for in-stent restenosis The major limitation of stent placement is the neointimal tissue proliferation within and adjacent to the stent as documented by intravascular ultrasound (IVUS).14 Vascular brachytherapy destroys actively dividing cells in the media and intima through damage of single- and double-stranded deoxyribonucleic acid (DNA).21–23 Beta and gamma isotopes are currently the 2 types of radiation used in brachytherapy delivery systems. Beta radiation emits electrons that penetrate only a few millimeters and requires 2–5 minutes for administration. Use of metallic stents or thick plaque material potentially restricts the effective tissue penetration of beta radiation.23,24 Gamma radiation emits photons that penetrate tissues deeply. Gamma radiation is given for 15–20 minutes and provides almost uniform delivery to all blood vessel layers and is not shielded by stents.23,24 The efficacy of brachytherapy for the treatment of in-stent restenosis has been demonstrated in clinical trials and registries (Table 1).25–30 Gamma and beta radiation has been proven effective in reducing in-stent restenosis. Angiographic restenosis 9 months following treatment is reduced by both systems.31 Results showed 14–34% restenosis rates following radiation compared with 32–72% restenosis rates seen with placebo (p Mechanisms of late stent thrombosis. Late stent thrombosis is thrombosis formation that occurs > 30 days post-intervention.22,32 The incidence of late stent thrombosis is significantly increased when brachytherapy is utilized as compared with non-radiated procedures. Late stent thrombosis may present clinically as unstable angina or myocardial infarction (MI), resulting in significant morbidity and mortality.6 Several theories exist regarding the exact mechanisms responsible for the development of late stent thrombosis post-brachytherapy.22,32 Radiation may prolong the process of healing and re-endothelialization post-intervention, thereby prolonging the presence of a thrombogenic coronary surface.32 It has been observed that monocytes, lymphocytes and macrophages commonly recruited to sites of vascular injury are reduced in thrombi present in irradiated arteries. This acellular environment may delay thrombus organization.22 By inhibiting neointimal proliferation, brachytherapy may also delay the endothelial regrowth needed to cover the stent struts,13 thereby causing stent material to remain exposed longer and thus creating an environment conducive to increased platelet recruitment33 and subsequent thrombosis.34 In addition, when healing is complete, the new endothelium may be impaired. Vasospasm and altered blood flow may contribute to thrombus development. Other theories regarding the increased incidence of late stent thrombosis include the potential presence of unhealed dissections or gradual tissue erosion around the stent, making conditions favorable for thrombus formation.22 Finally, stents themselves are inherently thrombogenic; combining their thrombogenicity with delayed re-endothelialization due to radiation may be the cause of late stent thrombosis.22,35 Late stent thrombosis in brachytherapy trials. Late stent thrombosis following brachytherapy was first observed as an incidental finding in the BETA-CATH trial. This trial evaluated the efficacy and safety of the Novoste Beta-Cath system in 1,100 patients who underwent elective PTCA or provisional stenting for single de novo or restenotic coronary artery lesions.13,24,29 All patients received aspirin and either ticlopidine or clopidogrel for 1 month. The Data Safety Monitoring Board observed a high rate (6%) of late stent thrombosis in patients randomized to receive stents. Therefore, a new randomized 452-patient study arm was added in which patients receiving new stents were treated for at least 3 months with clopidogrel or ticlopidine to evaluate the effects of prolonged combined antiplatelet therapy and brachytherapy on the occurrence of late stent thrombosis.29 Results showed that the high rate of late thrombosis in the original trial was significantly reduced by prolonged antiplatelet therapy; the radiation arm and non-radiation arm now had similar rates (1.3%) of late stent thrombosis. The BETA-CATH trial experience heightened awareness of the potential occurrence of late stent thrombosis. A review of other brachytherapy trials confirmed that there was a relationship between the development of late stent thrombosis and the use of brachytherapy.13,25–30,32,36–39 Recent and ongoing brachytherapy trials. The occurrence of late stent thrombosis appears to be related to the duration of antiplatelet therapy. Although no standard of therapy has been established in terms of duration of therapy and agent(s) of choice, late stent thrombosis seems to occur less frequently when the duration of antiplatelet therapy has been extended beyond 3 months (Table 2). In a prospective registry of 120 patients, the Washington Radiation for In-Stent Restenosis Trial Plus 6 Months of Clopidogrel (WRIST PLUS), an FDA-approved registry, evaluated the effect of antiplatelet therapy on the occurrence of late stent thrombosis after brachytherapy.38 Patients with diffuse in-stent restenosis in native coronary arteries and vein grafts underwent PCI and brachytherapy, with additional stenting done in 28.3% of patients. All patients received clopidogrel and aspirin for 6 months. Results were compared to 126 placebo (no brachytherapy) and 125 active controls (brachytherapy) from the Washington Radiation for In-stent Restenosis Trial (WRIST) and WRIST in Lesions Longer Than 36 mm (LONG WRIST) randomized gamma radiation trials for in-stent restenosis.35,38 Late thrombosis was defined as angiographic evidence of thrombosis or MI related to the treated vessel (with or without angiography) > 30 days after brachytherapy. One patient had a late thrombosis while on clopidogrel. This patient had a new stent implanted during his brachytherapy procedure. Two additional stents were implanted in the same vessel for subacute closure at day 11. Forty-seven days later, the patient developed thrombosis with a Q-wave MI. A second patient had a non-Q wave MI with angiographic evidence of thrombus on day 85. No new stent was implanted, but the patient stopped clopidogrel at day 60. Two patients had late thrombosis after the pre-specified 6-month follow-up; one presented with cardiogenic shock and Q-wave MI at day 200 and a second developed a non-Q wave MI 100 days after discontinuing clopidogrel. Neither of these patients had stents implanted as part of their initial procedure. The overall late thrombosis rate was 2.5%, which is not significantly different from the placebo controls (0.8%; p = 0.36). This thrombosis rate was a significant improvement over the late thrombosis rate of the active controls (9.6% versus 2.5%; p = 0.02) who had only received 1 month of clopidogrel therapy after radiation. The Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting III (SCRIPPS III) trial is evaluating the impact of both prolonged antiplatelet therapy and the restriction of new stent placement on the occurrence of late thrombosis.39 Five hundred patients received gamma radiation for the treatment of in-stent restenosis. New stents were placed in 22.8% of the study patients only for inadequate balloon angioplasty result or flow-limiting dissection. Patients who did not receive new stents were treated with clopidogrel for 6 months. Patients receiving new stents at the time of their radiation treatment were then treated with clopidogrel for 1 year. All patients received aspirin indefinitely. At 1 year of follow-up, there were no late thromboses. The ongoing Gamma V trial will assess the occurrence of late target lesion thrombosis after 6 months and 12 months of antiplatelet therapy in those not receiving and in those receiving new stents, respectively.40 New stent implantation. The implantation of stents as part of the brachytherapy procedure is a strong risk factor for late stent thrombosis. As mentioned above, the BETA-CATH trial recognized a 6% rate of late thrombosis in patients randomized to receive new stents.29 The 7 late thromboses in the active arm of the GAMMA I trial all occurred in patients in whom stents were implanted.26 Although late stent thrombosis is a significant concern, in each of the individual trials the number of thrombosis events was too small to draw meaningful conclusions about independent risk factors. The data from the initial SCRIPPS trial, WRIST, and GAMMA I were pooled in order to perform a multivariate analysis of the risk factors for late thrombosis.41 The events were re-adjudicated for these 3 trials; late thrombosis was defined as acute MI with angiographic evidence of thrombus or total occlusion. The pooled data from 481 patients revealed 15 late stent thromboses.41 Among the patients who did not receive a new stent, there was no difference in the late thrombosis rates between placebo and radiated patients, and this was the same as the thrombosis rate among patients in the placebo group patients who underwent stent implantation. New stent implantation was a significant risk factor for late thrombosis; twelve patients in the radiation arm who received new stents had late thrombosis, as compared with 1 patient in the placebo arm who received a stent (Figure 1).41 Antiplatelet therapy. The current trend in treatment to eliminate the risk of late stent thrombosis is, if possible, to avoid new stent placement at the time of brachytherapy and treat with aspirin and an adenosine diphosphate receptor antagonist for a longer period of time. Several clinical trials and registries have shown that combination antiplatelet therapy, most commonly aspirin and ticlopidine or aspirin and clopidogrel, acts synergistically to inhibit different sites of platelet activation and improve outcomes in stented patients.42–48 The safety and tolerability of these combination antiplatelet regimens was the focus of the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) trial.49 The combination of aspirin and clopidogrel was compared with aspirin and ticlopidine for major bleeding, neutropenia, thrombocytopenia or discontinuation for a non-cardiac event. This endpoint was reached in 4.6% of clopidogrel-treated patients versus 9.1% of ticlopidine-treated patients (p = 0.005).49 The recently completed Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial showed an early and sustained benefit in reducing the primary composite endpoint of cardiovascular (CV) death, nonfatal MI, or stroke in 12,562 patients with acute coronary syndrome without ST-segment elevation receiving clopidogrel and aspirin when compared with aspirin alone (9.3% versus 11.4%, respectively; RRR 20%; p

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