Combination Antiplatelet Therapy Following Brachytherapy with Restenting: “It Ain’t Over ‘til the Fat Lady Sings”

Coronary vascular brachytherapy reduces recurrent restenosis and is a valuable adjunct to percutaneous coronary intervention (PCI) in the treatment of in-stent restenosis (level of evidence A).1–3 Although both late (6 month) coronary restenosis and the occurrence of adverse cardiovascular events are decreased by vascular brachytherapy, late (> 30 days) thrombotic occlusion is observed more frequently in irradiation (versus placebo) treated patients (Figure 1). Dr. Teirstein, a pioneer in this field, contributes an article in this issue of the Journal4 that draws attention to this potentially lethal problem but falls short in making concrete recommendations for prevention. Vascular brachytherapy is associated with a dose-dependent increase in luminal thrombus that may persist for months following treatment.5–8 In addition, brachytherapy retards re-endothelialization and vascular healing.9–11 Contrary to original dogma derived by extrapolation from painfully limited animal data, stent re-endothelialization is often not completed by 30 days but may instead require 90 days in normal individuals.12 The deployment of another coronary stent for the treatment of in-stent restenosis may further exacerbate the delay in healing and re-endothelization secondary to brachytherapy.13 Clinical factors central to the pathogenesis of late thrombosis include recurrent stenting and the discontinuation of thienopyridine therapy.13–16 Although the strategy of restenting is enticing by nature of its expedient, predictable effect on post-procedural lumen diameter, its avoidance is appropriately recommended by Teirstein.4,17 In those patients in whom further stenting is not required, six months of thienopyridine therapy See Teirstein and Reilly on pages 109–114 would appear adequate and advisable.16,17 However, in patients in whom restenting is performed, the recommendation for thienopyridine to be continued for “up to one year” may be inadequate.4 Although evidence-based support for sound recommendations in this population is lacking, anecdotal case-based experience may yield important insights that temper our long-term approach. Case Report #1. A 49-year-old male had prior deployment of two Gianturco-Roubin II stents sequentially in the proximal and mid-left anterior descending coronary at an outside institution. On May 4, 1998, at the time of gamma irradiation (Ir192, Best Industries, Gamma II trial) restenting with two 3.5 x 22 mm Crown stents (Cordis Corporation, Johnson and Johnson Interventional Systems, Miami Lakes, Florida) in sequence was performed to optimize the immediate angiographic result (Figure 2). Thienopyridine therapy was continued for 6 months, at which time protocol-driven coronary angiography demonstrated persistent coronary patency and long-term success of the brachytherapy procedure (Figure 3). Ticlopidine therapy was discontinued after follow-up angiography and the patient received aspirin monotherapy. Sixteen months after brachytherapy, the patient experienced an acute anterior wall myocardial infarction and received intravenous thrombolysis with tissue plasminogen activator. Coronary angiography performed days after thrombolysis demonstrated intraluminal filling defects consistent with residual thrombus without critical residual fixed obstruction (Figure 4). Case Report #2. A 64-year-old male underwent stent deployment in a dominant right coronary artery 6 months before presentation to our institution for in-stent restenosis. At the time of coronary brachytherapy (Ir192, Best Industries, Gamma II trial), extensive restenting was performed using high-pressure balloon post-dilatation. The immediate post-procedural result on February 8, 1999 was satisfactory (Figure 5) and protocol-driven coronary angiography at 6 months (Figure 6) demonstrated an excellent long-term result with no evidence for in-stent restenosis. Although the intent of the investigator (DJK) was to continue clopidogrel therapy indefinitely, at 31 months after brachytherapy, both clopidogrel and aspirin were discontinued because of lower gastrointestinal bleeding. Approximately 10 days after discontinuation of antiplatelet therapy, the patient experienced an acute inferior wall myocardial infarction secondary to thrombotic occlusion of the right coronary artery (Figure 7) associated with cardiogenic shock. Emergency PCI was attempted with intra-aortic balloon pump support. Discussion. Although anecdotal, these cases and other similar experiences (Ron Waksman, personal communication) suggest that patients who have extensive, complex restenting at the time of coronary brachytherapy may require thienopyridine treatment well beyond an arbitrary period of “one year”. As evidenced by the accompanying case descriptions, these patients may remain vulnerable to stent thrombosis at 16–31 months following brachytherapy. Indeed, aspirin and thienopyridine combination therapy may be required “for life”. In the absence of a reliable technique to determine adequate stent re-endothelization, perhaps an “indefinite” duration of antiplatelet therapy should be considered. Furthermore, heightened vigilance should accompany any discontinuation of antiplatelet therapy in this high-risk population. Our current approach is to hold clopidogrel for 4–5 days prior to surgical procedures and to restart clopidogrel with an oral loading dose (300 mg) on the day following surgery, if possible. Every effort should be made to limit the duration of thienopyridine discontinuation in patients who have required coronary re-restenting at the time of coronary brachytherapy. In conclusion, we concur with the recommendation of Drs. Teirstein and Reilly to avoid restenting during brachytherapy, if possible.4,17 In uncomplicated brachytherapy procedures not associated with repeat coronary stenting, combined aspirin and thienopyridine therapy should be continued for 6 months.4,16,17 In patients requiring complex or multiple restenting at the time of brachytherapy, combination antiplatelet therapy should be continued indefinitely. This recommendation appears prudent in the absence of a reliable technique to determine stent re-endothelization and/or technologies to facilitate re-endothelization in this complex subset of patients.

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