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Vascular Radiation in a Drug-Eluting Stent World

2003; Lippincott Williams & Wilkins; Volume: 108; Issue: 4 Linguagem: Inglês

10.1161/01.cir.0000080229.68147.4f

1524-4539

Paul S. Teirstein, Spencer B. King,

Acute Myocardial Infarction Research

HomeCirculationVol. 108, No. 4Vascular Radiation in a Drug-Eluting Stent World Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBVascular Radiation in a Drug-Eluting Stent WorldIt's Not Over Till It's Over Paul S. Teirstein, MD and Spencer King, MD Paul S. TeirsteinPaul S. Teirstein From the Division of Cardiovascular Disease (P.S.T.), Scripps Clinic, La Jolla, Calif, and Fuqua Heart Center and the Atlanta Cardiovascular Research Institute (S.K.), Atlanta, Ga. and Spencer KingSpencer King From the Division of Cardiovascular Disease (P.S.T.), Scripps Clinic, La Jolla, Calif, and Fuqua Heart Center and the Atlanta Cardiovascular Research Institute (S.K.), Atlanta, Ga. Originally published29 Jul 2003https://doi.org/10.1161/01.CIR.0000080229.68147.4FCirculation. 2003;108:384–385Have you ever wondered how those who developed the iron lung for victims of polio felt about Jonas Salk? Given the promise of drug-coated stents, one wonders if the extensive work done in perfecting vascular brachytherapy may soon be valued only as an historical anecdote.After innumerable therapeutic failures, vascular brachytherapy was the first effective antiproliferative treatment for restenosis. To date, more than a dozen randomized trials have demonstrated its safety and efficacy.1–11 After redilatation of in-stent restenosis, brachytherapy reduces the risk of subsequent recurrence by ≈50%. Its adoption by the interventional cardiology community was widespread and extraordinarily rapid. Today, less than 3 years after FDA approval, brachytherapy is used in more than 400 US catheterization laboratories, and each year >40 000 patients receive brachytherapy for in-stent restenosis. The current enthusiasm for drug-eluting stents, however, may soon make vascular brachytherapy obsolete. Drug-coated stents may abolish, or nearly abolish, in-stent restenosis. Because coronary brachytherapy has only been proven effective as a treatment for in-stent restenosis, its fate in the drug-eluting stent world is uncertain. When drug-eluting coated stents are widely available, vascular brachytherapy risks being discarded just as quickly as it was embraced only a few years ago.Will drug-coated stents transform vascular brachytherapy into a cure without a disease? Let's examine the evidence. As of October 2002, we have data from numerous large randomized trials. The largest of these, a randomized, double-blind study of the SIRolImUS-eluting stent in de novo native coronary lesions (SIRIUS), was a 1058-patient multicenter, blinded trial comparing sirolimus-eluting stents with placebo in patients with intermediate-length (15 to 30 mm) de novo, native coronary artery lesions. Restenosis of the target lesion was observed in only 8.9% of treated patients compared with 36.6% of placebo patients, for a 75% reduction (Final Results of Large-Scale US Study Confirm Positive Performance of Cordis CYPHER Sirolimus-Eluting Stent, Johnson and Johnson Press Release, September 24, 2002). Similarly, in the 536-patient TAXUS II trial (which treated patients with somewhat shorter de novo lesions), the slow-release paclitaxel stent demonstrated a target lesion restenosis rate of only 5.5% (Boston Scientific Announces Final Results of its TAXUS II Drug-Eluting Stent Clinical Trial, Boston Scientific Press Release, September 26, 2002).At first glance, it does appear that in-stent restenosis will become as rare as the horse-drawn carriage, and vascular radiation as relevant as the buggy whip. But not so fast. Perhaps the rumors of brachytherapy's demise are premature. For example, will all patients and lesion subtypes benefit equally from drug-eluting stents? In the SIRIUS trial, diabetics treated with sirolimus stents had a profound reduction in restenosis, but restenosis was still observed in 17.6% of diabetic patients. Indeed, restenosis in insulin-requiring diabetics was as high as 35% (compared with 50% for corresponding placebo patients). Similarly, in SIRIUS, patients with small-diameter vessels (<2.5 mm) treated with sirolimus stents had very significant reductions in restenosis, but restenosis was still observed in 18.6% of the active study arm. Furthermore, absolutely no data exist regarding the effectiveness of drug-eluting stents for saphenous vein graft stenoses. Likewise, long, diffuse disease has not been studied. Also, there appears to be a lack of drug effect where drug is lacking, particularly at sites of balloon-mediated injury outside of the stent margins. Most current drug coatings are hydrophobic, resulting in little or no diffusion beyond the stent margin. This probably explains why restenosis, when observed in a patient with a drug-coated stent, usually occurs at the stent margins. Can devices be designed to extend drug effect laterally into areas of balloon injury at stent margins? Perhaps most uncertain is the effectiveness of drug-eluting stents for the treatment of in-stent restenosis. Conflicting early results using sirolimus-coated stents have placed a question mark beside this indication. In Sao Paulo, excellent efficacy was observed in a 25-patient registry with relatively short, in-stent restenosis, whereas in Rotterdam, significant failures were found in a 16-patient registry with more complex disease, frequently requiring multiple stents. Finally, the increased cost of drug-eluting stents may reduce utilization. Although Medicare reimbursement for drug-eluting stents has been secured, if several stents are needed for a single procedure, the increased payment to hospitals will not adequately reimburse the hospital's costs. Interestingly, despite approval outside of the United States, acceptance has been slower than expected, largely due to a lack of reimbursement.Meanwhile, vascular radiation trials are proliferating, and new indications may be forthcoming. Already, excellent-quality data exist supporting the effectiveness of γ-radiation for the treatment of saphenous vein graft in-stent restenosis.9 Recent trials have also proven the effectiveness of radiation for superficial femoral artery obstructions.12 Ongoing investigation may also find a role for brachytherapy for the treatment of diseased dialysis grafts.Some believe drug-eluting stents will more than double the current number of patients undergoing stent implantation. If so, even a very small percentage of failures will translate into a substantial absolute number of candidates for brachytherapy. Undoubtedly, when drug-eluting stents are widely available, utilization of vascular radiation therapy will markedly decrease if physicians re-stent in-stent restenosis with the new technology. However, at present, coated stents have no track record for in-stent restenosis. Failures such as those observed in Rotterdam may occur, and brachytherapy may make a comeback, particularly to treat drug-eluting in-stent restenosis.Those of us in the vascular radiation world welcome drug-coated stents because of the tremendous benefits they will provide to our patients. It is some consolation that even if radiation departs as a widespread treatment, it will still leave a legacy. As the first effective antiproliferative therapy, brachytherapy helped pave the way for drug-coated stents. Many of the lessons learned by the study of vascular brachytherapy have been useful as we begin the investigation of drug-eluting stents. For example, the concept of "geographic miss" encountered during the initial brachytherapy studies is directly applicable to drug-coated stenting. The mandate to meticulously avoid injury of vascular segments outside the therapeutic margins is critical to both procedures. Similarly, the potential for late thrombosis as an adverse effect of any antiproliferative therapy was first discovered during brachytherapy investigation and has prompted prolonged dual-antiplatelet therapy during all drug-coated stent trials. As always in medicine, each advance stands on the shoulders of its predecessors.The earlier analogy of in-stent restenosis to polio may be accurate, but such analogies are rare. Medicine has not eradicated, or even nearly eradicated, many common diseases. Many previous "cures" were ultimately imperfect or not applicable to all patients. If drug-eluting stents are found to have imperfections, we may all be surprised to see in-stent restenosis persisting into our future. If so, the half-life of vascular brachytherapy may need to be recalculated. It's not over till its over.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Dr Teirstein serves as a consultant for companies that manufacture vascular brachytherapy and drug-eluting stent technologies. He also holds patents and receives royalties from the sale of radiation delivery catheters. Dr King serves as a consultant for and receives research support from companies that manufacture vascular brachytherapy and drug-eluting stent technologies. He also receives royalties from the sale of radiation delivery catheters.FootnotesCorrespondence to Paul S. Teirstein, MD, Division of Cardiovascular Diseases, Scripps Clinic, 10666 N Torrey Pines Rd, La Jolla, CA 92037. E-mail [email protected]References1 Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med. 1997; 336: 1697–1703.CrossrefMedlineGoogle Scholar2 King SB III, Williams DO, Chougule P, et al. Endovascular β-radiation to reduce restenosis after coronary balloon angioplasty: results of the Beta Energy Restenosis Trial (BERT). Circulation. 1998; 97: 2025–2030.CrossrefMedlineGoogle Scholar3 Waksman R, White LR, Chan RC, et al. Intracoronary γ-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation. 2000; 101: 2165–2171.CrossrefMedlineGoogle Scholar4 Raizner AE, Oesterle SN, Waksman R, et al. Inhibition of restenosis with β-emitting radiotherapy: report of the Proliferation REduction with Vascular Energy Trial (PREVENT). Circulation. 2000; 102: 951–958.CrossrefMedlineGoogle Scholar5 Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary γ-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med. 2001; 334: 250–256.Google Scholar6 Verin V, Popowski Y, de Bruyne B, et al. Endoluminal β-radiation therapy for the prevention of coronary restenosis after balloon angioplasty. N Engl J Med. 2001; 344: 243–249.CrossrefMedlineGoogle Scholar7 Sapirstein W, Zuckerman B, Dillard J. FDA approval of coronary-artery brachytherapy. N Engl J Med. 2001; 344: 297–299.CrossrefMedlineGoogle Scholar8 Waksman R, Raizner AE, Yeung AC, et al. Use of localized intracoronary β radiation in treatment of in-stent restenosis: the INHIBIT randomized controlled trial. Lancet. 2002; 359: 543–544.CrossrefMedlineGoogle Scholar9 Waksman R, Ajani AE, White RL, et al. Intravascular γ radiation for in-stent restenosis in saphenous vein bypass grafts. N Engl J Med. 2002; 346: 1194–1199.CrossrefMedlineGoogle Scholar10 Grise MA, Massullo V, Jani S, et al. Five-year clinical follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation. 2002; 105: 2737–2740.LinkGoogle Scholar11 Popma JJ, Suntharalingam M, Lansky AJ, et al. 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Kereiakes D and Willerson J (2003) Vascular Brachytherapy Boon or Bust?, Circulation, 108:4, (389-390), Online publication date: 29-Jul-2003. Tripuraneni P (2003) The future of CART in the era of drug eluting stents: "It's not over until it's over.", Brachytherapy, 10.1016/S1538-4721(03)00104-1, 2:2, (74-76), Online publication date: 1-Jan-2003. July 29, 2003Vol 108, Issue 4 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000080229.68147.4FPMID: 12885730 Originally publishedJuly 29, 2003 PDF download Advertisement