BACKGROUND: Intracoronary brachytherapy appears to be a promising
      technology to prevent restenosis. Presently, limited data are available
      regarding the late safety of this therapeutic modality. The aim of the
      study was to determine the incidence of late (>1 month) thrombosis after
      PTCA and radiotherapy. METHODS AND RESULTS: From April 1997 to March 1999,
      we successfully treated 108 patients with PTCA followed by intracoronary
      beta-radiation. Ninety-one patients have completed at least 2 months of
      clinical follow-up. Of these patients, 6.6% (6 patients) presented with
      sudden thrombotic events confirmed by angiography 2 to 15 months after
      intervention (2 balloon angioplasty and 4 stent). Some factors
      (overlapping stents, unhealed dissection) may have triggered the
      thrombosis process, but the timing of the event is extremely unusual.
      Therefore, the effect of radiation on delaying the healing process and
      maintaining a thrombogenic coronary surface is proposed as the most
      plausible mechanism to explain such late events. CONCLUSIONS: Late and
      sudden thrombosis after PTCA followed by intracoronary radiotherapy is a
      new phenomenon in interventional cardiology

Cervinka, P.

Coen, V.L.M.A. (Veronique)

Costa, M.A. (Marco)

Giessen, W.J. (Wim) van der

Kay, I.P. (Ian Patrick)

Levendag, P.C. (Peter)

Ligthart, J.M.R. (Jürgen)

Sabaté, M. (Manel)

Serrano, P. (Pedro)

Serruys, P.W.J.C. (Patrick)

Erasmus University Digital Repository

ISSN: 1524-4539 Copyright © 1999 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online72514Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 1999;100;789-792 CirculationLevendag and Patrick W. Serruys Cervinka, Jurgen M. R. Ligthart, Pedro Serrano, Veronique L. M. A. Coen, Peter C. Marco A. Costa, Manel Sabaté, Wim J. van der Giessen, I. Patrick Kay, Pavel Late Coronary Occlusion After Intracoronary Brachytherapy http://circ.ahajournals.org/cgi/content/full/100/8/789located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/static/html/reprints.htmlReprints: Information about reprints can be found online at    journalpermissions@lww.comStreet, Baltimore, MD 21202-2436. Phone 410-5280-4050. Fax: 410-528-8550. Email: Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, 351 West Camden   http://circ.ahajournals.org/subsriptions/Subscriptions: Information about subscribing to Circulation is online at  at SWETS SUBS SERVICE on October 23, 2006 circ.ahajournals.orgDownloaded from Late Coronary Occlusion AfterIntracoronary BrachytherapyMarco A. Costa, MD; Manel Sabate´, MD; Wim J. van der Giessen, MD, PhD; I. Patrick Kay, MBChB;Pavel Cervinka, MD; Jurgen M.R. Ligthart, BSc; Pedro Serrano, MD; Veronique L.M.A. Coen, MD;Peter C. Levendag, MD, PhD; Patrick W. Serruys, MD, PhDBackground—Intracoronary brachytherapy appears to be a promising technology to prevent restenosis. Presently, limiteddata are available regarding the late safety of this therapeutic modality. The aim of the study was to determine theincidence of late (.1 month) thrombosis after PTCA and radiotherapy.Methods and Results—From April 1997 to March 1999, we successfully treated 108 patients with PTCA followedby intracoronary b-radiation. Ninety-one patients have completed at least 2 months of clinical follow-up. Of thesepatients, 6.6% (6 patients) presented with sudden thrombotic events confirmed by angiography 2 to 15 months afterintervention (2 balloon angioplasty and 4 stent). Some factors (overlapping stents, unhealed dissection) may havetriggered the thrombosis process, but the timing of the event is extremely unusual. Therefore, the effect of radiationon delaying the healing process and maintaining a thrombogenic coronary surface is proposed as the most plausiblemechanism to explain such late events.Conclusions—Late and sudden thrombosis after PTCA followed by intracoronary radiotherapy is a new phenomenonin interventional cardiology. (Circulation. 1999;100:789-792.)Key Words: thrombosis n angioplasty n radioisotopesThrombotic occlusion after PTCA is associated withincreased morbidity and mortality rates.1 Current tech-niques of stenting followed by antiplatelet therapy havedramatically reduced the incidence of this event to ,1.5%.2,3See p 780Intracoronary radiation is a promising new therapy toprevent restenosis. Recent randomized trials demonstrateda reduction in the restenosis rate and maintenance ofbenefits up to 2-year follow-up.4 – 6 Presently, limited dataare available regarding long-term safety after intracoro-nary brachytherapy.5,7 Although subacute thrombosis hasbeen reported after radiotherapy,4,8 –9 the incidence of latethrombotic events has not been determined.The aim of this study was to document the incidence oflate (.1 month) thrombotic events after elective PTCAfollowed by intravascular radiotherapy.Methods and ResultsFrom April 1997 to March 1999, 108 consecutive patientswere successfully treated with catheter-based intracoronaryb-radiation at the Thoraxcenter (Rotterdam, The Nether-lands). The Medical Ethical Committee approved the use ofradiation therapy and informed consent was obtained fromevery patient. All patients presented with stable anginapectoris and single vessel disease. Brachytherapy was per-formed using the Beta-Cath system (Novoste Corporation)10(n576 patients, 32 stents and 44 balloon angioplasty [BA]),or the Guidant intravascular brachytherapy system (GuidantCorporation Vascular Intervention)11 (n532 patients, 13Stents and 19 BA). BA and stenting were performed accord-ing to standard techniques. Intravascular ultrasound (IVUS)was performed after radiation with a mechanical ultrasoundcatheter (CVIS, Boston Scientific). Off-line quantitative cor-onary angiography was performed using CAAS system (PieMedical Imaging BV). Six-month angiographic and IVUSfollow-up was scheduled in all patients.All patients were discharged without complications. Ninety-one patients completed at least 2-month clinical follow-up. Weobserved 1 case of subacute thrombosis occurring 15 days afterstenting. This patient received an 18-mm long stent (postdilatedat 10 atm) with optimal IVUS result. Ticlopidine withdrawal (12days after stenting) was the plausible explanation of thrombosisin this case.Six patients (6.6%) presented with sudden late throm-botic coronary occlusion. Two of them were treated withBA and the remaining 4 received an additional stent afterradiation. Their clinical characteristics are summarized inReceived May 10, 1999; revision received June 12, 1999; accepted June 24, 1999.From Thoraxcenter (M.A.C., M.S., W.J.v.d.G., I.P.K., P.C., J.M.R.L., P.S., P.W.S.), Dijkzigt University Hospital, and Daniel den Hoek CancerCenter (V.L.M.A.C., P.C.L.), Rotterdam, The Netherlands.Correspondence to Prof Patrick W. Serruys, Head of the Department of Interventional Cardiology, University Hospital Dijkzigt-ThoraxcenterBd418, Dr. Molewaterplein,40 –3015GD Rotterdam, The Netherlands. E-mail serruys@card.azr.nl© 1999 American Heart Association, Inc.Circulation is available at http://www.circulationaha.org789Brief Rapid Communicationthe Table. No clinical or anatomic characteristic appearedto be related to these events.In patient 1, overlapping 9- and 32-mm NIR stents(Medinol Ltd) were optimally implanted as assessed byIVUS. Patients 2 and 3 (BA) showed type B dissectionswithout compromising flow postprocedure. Patients 4and 5 both received a Multilink 25-mm stent (AdvancedCardiovascular Systems/Guidant), and patient 6 received aNIR 16-mm stent with optimal angiographic results. Stentpatients were discharged on aspirin (250 mg/d) and ticlo-pidine (250 mg BID for 15 days in patients 3 and 4, and for30 days in cases 5 and 6). BA patients received aspirinalone.Patient 1 was readmitted with ventricular fibrillation 2months after the procedure, whereas, patients 2, 5, and 6sustained inferior myocardial infarctions (MI) between 2.5and 3 months after the treatment. The irradiated segmentwas occluded at 6-month angiogram in patients 1 and 2(Figure 1). Thrombotic occlusion was successfully treatedby primary angioplasty in patients 5 and 6.In patient 3, the 6-month IVUS control revealed apersistent (unhealed) submedial dissection (Figure 2) withno signs of restenosis. Nine months later, this patientsustained a posterolateral MI which was treated withthrombolytics. Two weeks after this treatment, an angio-gram performed because of recurrent angina showed theocclusion in the irradiated area. Similarly, the 6-monthIVUS control of patient 4 showed no neointimal hyperpla-sia. Four months after control, she had a stroke and aspirinwas replaced by acenocoumarol. Ten days later, shesustained an anterior MI. The thrombotic occlusion in thetreated site was confirmed by angiography.DiscussionProgression to total occlusion after BA is a stable process inthe general nonirradiated population which occurs in approx-imately 4% of patients, leading to a MI in ,0.5%.12 Incontrast, our study shows a high incidence (6.6%) of throm-botic clinical events 2 to 15 months after PTCA andbrachytherapy.Coronary dissection after BA is associated with abruptclosure; however, type B dissections (NHLBI classifica-tion), as observed after BA in our patients, have not beenrelated to thrombotic events.13 The normal healing process,present after dissections, may be impaired after intracoro-Clinical and Angiographic VariablesVariables 1 2 3 4 5 6Age, y 57 58 49 73 52 62Sex Male Female Male Female Female FemalePre-procedureTarget vessel LCX RCA LCX LAD RCA RCAType of lesion B B B A A BRD, mm 2.5 2.8 2.67 2.66 2.84 2.6MLD, mm 0.9 1.12 0.64 1.09 0.65 0.55DS, % 66 60 76 60 77 78Lesion length, mm 13 15 18 11.2 9.6 9.7ProcedureBrachytherapy system Beta-Cath Guidant Beta-Cath Beta-Cath Beta-Cath Beta-CathSource length, mm 30 27 30 30 30 30Prescribed dose, Gy 12* 35† 12* 14* 18* 14*Stent/angioplasty Stent Balloon Balloon Stent Stent StentTotal stent length, mm 41 25 25 16PostprocedureDissection/type No Yes/B Yes/B No No NoMLD, mm 2.47 2.07 2.15 2.4 2.34 2.4DS, % 21 26 21 9.5 17 7Clinical success Yes Yes Yes Yes Yes YesFollow-upEvent VF Inferior MI Postlateral MI Anterior MI Inferior MI Inferior MITime, mo 2 3 15 10 3 2.5Antiplatelet medication Yes Yes Yes No Yes YesAssociated factors Long stent Dissection Dissection at 6-mo Aspirin withdrawal No NoLCX indicates left circumflex artery; RCA, right coronary artery; LAD, left anterior descending artery; RD, reference diameter; MLD,minimal lumen diameter; DS, diameter stenosis; VF, ventricular fibrillation; and MI, myocardial infarction.*At 2 mm from the source; †at 0.5 mm into the vessel wall.790 Circulation August 24, 1999nary radiation.14 Whether unhealed dissections, as demon-strated in patient 3, is related to late thrombosis remains tobe elucidated in a larger population. Further, the necessityof stenting mild dissections without compromising flowafter radiotherapy should be investigated.The mean time of subacute thrombosis after stenting isapproximately 5 to 6 days.2,3 In a recent study, subacutethrombosis occurred within the first 24 hours in 86% ofpatients treated with aspirin and ticlodipine for 14 days,with no case of thrombotic events occurring after 15days.15 Colombo et al reported only 2 cases (0.6%) ofthrombosis occurring 2 to 6 months after stenting.2 Incontrast, in our study, 4 patients receiving a stent (8.8%)experienced thrombosis late after radiation.Experimentally, reendothelialization after injury takes.4 weeks to be completed.16 However, the clinical pre-sentation of subacute thrombosis infrequently occurs laterthan 15 days after stenting,15 when the reendothelializationprocess may still be incomplete. Delayed reendotheli-alization as a trigger mechanism of late stent thrombosisafter antineoplastic therapy has been hypothesized previ-ously.17 Farb et al reported incomplete endothelialization 3months after placement of b-radioactive stent.18 Neverthe-less, the same group showed no differences regardingendothelial cell growth between radioactive and controlstents in another experimental model.19 Further studiesshould address the timing of stent reendothelializationafter brachytherapy to determine its role on the pathogen-esis of late thrombosis.Although multiple stents have been related to subacutethrombosis,20 the significance of multiple stent implanta-tion (patient 1) on late thrombotic phenomena has not beendemonstrated.The use of intracoronary b-radiation is a commonfeature in our patients. However, the judgment of whetherradiation is the key factor in the pathogenesis of latethrombosis should await the analysis of ongoing trials.Concomitantly, the benefit of prolonged antiplatelet ther-apy with the combination of aspirin, clopidogrel, orticlopidine should be considered.LimitationsOur patients were included in well-controlled b-radiationstudies with similar baseline characteristics and inclusioncriteria (lesion length ,15 mm, treatment of single vessel).However, 2 different systems to deliver b-radiation wereused.In addition, it is not possible to rule out the naturalhistory of coronary disease as a cause of late thrombosis.However, the incidence of total occlusion in the generalnonirradiated population is much lower than that observedin our study. In fact, the incidence of late thromboticevents would be even higher if, in the interest of complete-ness, we waited for 1-year follow-up in the total patientpopulation.Finally, whether late thrombosis is a generic complica-tion of intracoronary radiotherapy or is restricted to the useof b-sources cannot be extrapolated from our findings.Figure 1. Patient 1. A, Preprocedureangiography shows a significant lesion inthe mid-third of left circumflex artery. B,Radioactive source placed in treated site.C, Postprocedure angiography and IVUSimages show an optimal result (arrow-heads). D, At 2 months, the proximal partof stent appeared occluded.Costa et al Late Thrombosis After Brachytherapy 791References1. De Feyter PJ, de Jaegere PP, Serruys PW. Incidence, predictors, andmanagement of acute coronary occlusion after coronary angioplasty. AmHeart J. 1994;127:643–651.2. Colombo A, Hall P, Nakamura S, Almagor Y, Maiello L, Martini G,Gaglione A, Goldberg SL, Tobis JM. Intracoronary stenting withoutanticoagulation accomplished with intravascular ultrasound guidance.Circulation. 1995;91:1676 –1688.3. Wilson SH, Rihal CS, Bell MR, Velianou JL, Holmes DR Jr, BergerPB. Timing of coronary stent thrombosis in patients treated withticlopidine and aspirin. Am J Cardiol. 1999;83:1006 –1011.4. Teirstein PS, Massullo V, Shirish J, Popma JJ, Mintz GS, Russo RJ,Schatz RA, Guarnieri EM, Steuterman S, Morris NB, Leon MB,Tripuranemi P. Catheter-based radiotherapy to inhibit restenosis aftercoronary stenting. N Engl J Med. 1997;336:1697–1703.5. Teirstein PS, Massullo V, Shirish J, Russo RJ, Cloutier DA, SchatzRA, Guarnieri EM, Steuterman S, Sirkin K, Norman S, Tripuranemi P.Two-year follow-up after catheter-based radiotherapy to inhibit cor-onary restenosis. Circulation. 1999;99:243–247.6. Waksman R, White LR, Chan RC, Porrazo MS, Bass BG, Satler LF,Kent KM, Geirlach LM, Mehran R, Murphy MRM, Mintz GS, LeonMB. Intracoronary radiation therapy for patients with in-stent reste-nosis: 6-month follow-up of a randomized clinical study. Circulation.1998;98(suppl I):I-651. Abstract.7. Condado JA, Saucedo JF, Caldera C, Proctor B, Fadoul M, WalksmanR. Two years angiographic evaluation after intracoronary 192 iridiumin humans. Circulation. 1997;96(suppl I):I-220. Abstract.8. Condado JA, Waksman R, Gurdiel O, Espinosa R, Gonzalez J, BurgerB, Villoria G, Acquatella H, Crocker IR, Serung KB, Liprie SF.Long-term angiographic and clinical outcome after percutaneoustransluminal coronary angioplasty and intracoronary radiation therapyin humans. Circulation. 1997;96:727–732.9. King SB III, Williams DO, Chougule P, Klein L, Waksman R,Hillstead R, Macdonald J, Anderberg K, Crocker IR. Endovascularb-radiation to reduce restenosis after coronary balloon angioplasty:results of the beta energy restenosis trial (BERT). Circulation. 1998;97:2025–2030.10. Hillstead RA, Johnson CR, Weldom TD. The Beta Cath® system. In:Waksman R, Serruys PW, eds. Handbook of Vascular Brachytherapy.London, UK: Martin Dunitz Ltd.; 1998:41–51.11. Raizner AE, Calfee RV. The Guidant intravascular brachytherapysystem. In: Waksman R, Serruys PW, eds. Handbook of VascularBrachytherapy. London, UK: Martin Dunitz Ltd; 1998:53–58.12. Rozenman Y, Gilon D, Welber S, Sapoznikov D, Wexler D, Lotan C,Mosseri M, Weiss AT, Hasin Y, Gotsman MS. Total coronary arteryocclusion late after successful coronary angioplasty of moderatelysevere lesions: incidence and clinical implications. Cardiology. 1994;85:222–228.13. Huber SM, Mooney JF, Madison J, Mooney MR. Use of morphologicclassification to predict clinical outcome after dissection from coro-nary angioplasty. Am J Cardiol. 1991;68:467– 471.14. Meerkin D, Bonan R, Joyal M, Tardif JC. Intracoronary beta radiationeffects on dissection resolution. J Am Coll Cardiol. 1999;33(supplA):48A. Abstract.15. Berger PB, Bell MR, Hasdai D, Grill DE, Melby S, Holmes DR Jr.Safety and efficacy of ticlopidine for only 2 weeks after successfulintracoronary stent placement. Circulation. 1999;99:248 –253.16. van der Giessen WJ, Serruys PW, Beusekom HMM, van Woerkens LJ,van Loon H, Soei LK, Strauss BH, Beatt KJ, Verdouw PD. Coronarystenting with a new, radiopaque, balloon-expandable endoprosthesisin pigs. Circulation. 1991;83:1788 –1798.17. Smith SC, Winters KJ, Lasala JM. Stent thrombosis in a patientreceiving chemotherapy. Cathet Cardovasc Diagn. 1997;40:383–386.18. Farb A, Tang A, Virmani R. The neointima is reduced but endothe-lialization is incomplete 3 months after 32P B-emitting stentplacement. Circulation. 1998;98(suppl I):I-779. Abstract.19. Laird JR, Carter AJ, Hufs WM, Hoopes TG, Farb A, Nott SH, FischellRE, Fischell DR, Virmani R, Fischell TA. Inhibition of neointimalproliferation with low-lose irradiation from a b-particle-emittingstent. Circulation. 1996;93:529 –536.20. Marco J, Fajadet J, Doucet S, Bar O, Jordan C, Carvalo H, Robert G,Cassagneau B. Palmaz-Schatz coronary stenting: predictors of sub-acute thrombosis and restenosis in a single center series. IntervCardiol Monitor.1994;1:5–13.Figure 2. Patient 3. A, Postprocedure coronary dissection, demonstrated both on angiography and IVUS, did not compromise flow intreated area (arrowhead). B, This dissection persisted unhealed at 6-month control (arrowhead). C, At 15 months, irradiated segmentappeared occluded.792 Circulation August 24, 1999

Late coronary occlusion after intracoronary brachytherapy

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Late coronary occlusion after intracoronary brachytherapy

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