Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
Table of Contents | Next Article »
Circulation. 2000;102:2674-2676

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Teirstein, P. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Teirstein, P. S.
Related Collections
Right arrow Restenosis
Right arrow Catheter-based coronary and valvular interventions: other
Right arrow Catheter-based coronary interventions: stents

(Circulation. 2000;102:2674.)
© 2000 American Heart Association, Inc.

Editorial

Fulfilling the Promise of Percutaneous Angioplasty

Paul S. Teirstein, MD

From the Division of Cardiovascular Diseases, Scripps Clinic, La Jolla, Calif.

Correspondence to Paul S. Teirstein, MD, Division of Cardiovascular Diseases, SW206, Scripps Clinic, 10666 N Torrey Pines Rd, La Jolla, CA 92037. E-mail radman{at}scrippsclinic.com


Key Words: Editorials • angioplasty • restenosis • radiation • stents • vessels

It is ironic that in 1964, Dotters’ initial application of percutaneous transluminal angioplasty (PTA) targeted femoral-popliteal stenoses.1 Now, nearly 4 decades later, although angioplasty has gained wide acceptance as a first-line treatment for diseased coronary, iliac, and renal arteries, its role in femoral-popliteal vessels remains controversial and poorly defined. The initial PTA procedure is nearly always a success. Improved technology, including slick guidewires, sleek balloons, and sinuous stents can reliably open most femoral-popliteal obstructions. However, one cannot attempt angioplasty in the lower legs without running into its Achilles heel: restenosis. In contradistinction to angioplasty in the coronary, iliac, and renal vasculature, restenosis rates after lower-extremity PTA are unacceptably high. The femoral-popliteal system has unique anatomic and physiological properties. Blood flow rates are low, resistance is high, and lesions are often very long, with poor run-off. These characteristics raise the risk of recurrence to well over 50%, and in some reports, over 80%.2 3 Alternative surgical approaches using saphenous and prosthetic grafts provide better long-term patency but cause significantly more morbidity.4 Often, patients with peripheral vascular disease also have cardiac, cerebrovascular, and/or renal disease that increases the risk of major surgery. Although surgery is often embraced for limb salvage, surgery for the treatment of claudication is generally avoided. It is not surprising, therefore, that so many vascular medicine specialists currently recommend conservative medical therapy and walking programs as a first-line treatment for symptomatic femoral-popliteal disease.

Over the past decade, much has been learned about the mechanism of restenosis. There are 2 major components of restenosis: the first is the mechanical renarrowing of the dilated region; the second is the biological proliferative response to injury.5 6 Percutaneous angioplasty is a purely mechanical intervention. In recent years, our mechanical tools have improved considerably. Careful quantitative angiography has taught us that using these new tools to optimize the initial luminal dimension can reduce restenosis by mitigating the consequences of intimal hyperplasia. Stents, for example, provide a mechanical scaffolding that opens the lumen wide and limits recoil. Thus, stents reduce restenosis predominantly by allowing the lumen to better accommodate the ingrowth of neointimal tissue.7 Stents, however, do not reduce, and in fact actually increase, the proliferative response to injury. Clearly, mechanical solutions alone will never eliminate restenosis. An effective solution requires targeting both the mechanical obstruction and the biological response to injury that results in neointimal tissue growth within the lumen.

In this issue of Circulation, Minar et al8 provide the first scientific evidence, in the form of a double-blind, randomized trial, that endovascular {gamma}-radiation can reduce restenosis after PTA of femoral-popliteal disease. When 113 patients with long-segment femoral-popliteal lesions were randomized to either the {gamma}-emitter 192Ir or placebo, restenosis at 6-month follow-up was 53.7% in placebo compared with 28.3% in treated patients (P<0.05). Cumulative patency at 12 months was 35.3% in the placebo versus 63.6% in the treated group (P<0.005). Similar improvements were noted in the ankle-brachial index and the peak velocity ratio. Radiation was successful despite enrollment of an extremely heterogeneous and, in many cases, high-risk patient population, including very lengthy de novo, recurrent, stenotic, and occluded lesions. Although 2 small registries previously also documented high patency rates after {gamma}-radiation of femoral-popliteal disease,9 10 the power of the present study is its double-blind, randomized design. Despite the small sample size of the study, highly significant differences were observed between the treated and placebo groups. Thus, by use of PTA to treat the mechanical component of restenosis and then adjunctive radiation to target the biological component, for the first time, an acceptable long-term clinical outcome was achieved.

This report adds considerably to the growing body of evidence that radiation therapy is an effective anti-restenosis treatment.11 Recently, {gamma}-radiation has proved efficacious for the treatment of coronary artery restenosis in 3 separate, double-blind, randomized trials.12 13 14 15 On the basis of these data, on June 19, 2000, a US Food and Drug Administration panel voted unanimously to recommend approval of {gamma}-radiation to treat in-stent native coronary artery restenosis. Several recent randomized trials have also proved positive for the ß-emitters 90Y, Sr/90Y, and 32P.16 17

In addition to its positive angiographic, noninvasive, and clinical findings, the present report also highlights several caveats important to the implementation of vascular radiation therapy. First, the protocol entry criteria wisely excluded the use of stents. Recent data from several coronary radiation trials point to a strongly unfavorable interaction between radiation and freshly implanted stents.18 19 It appears that radiation prevents cell growth so powerfully that endothelialization of newly implanted stents is inhibited, leaving stent struts relatively bare for an extended time period. Therefore, in the absence of prolonged anti-platelet therapy, the presence of freshly implanted stents at the time of irradiation increases the risk of late stent thrombosis. In the present study, no stents were implanted during the radiation procedure, and late thrombosis was not observed.

Second, in some coronary radiation studies, the beneficial anti-restenosis effect of radiation within the treated segment was reduced at follow-up by the presence of new narrowings at the lesion margins. This so-called "edge effect" was most pronounced in studies using the 32P radioactive stent.20 21 Edge effect is believed to be due to endovascular injury incurred by the angioplasty procedure that extends outside of the irradiated region. Common recent practice, therefore, is to provide an adequate margin of radiation at either end of the treated (ie, injured) vessel segment. In the present study, the investigators used a very wide, 10-mm radiation margin, and no edge effects were observed.

Third, in Figure 3 of their article, the authors provide angiographic images from a case of radiation failure. Although this patient clearly sustained recurrent restenosis after radiation, the length of the recurrent stenotic segment was significantly shorter than the initial stenosis. This phenomenon of a "partial response" has also been observed in coronary radiation studies and is relevant because of the well-known improved long-term outcome when shorter versus longer lesions are subjected to repeat angioplasty.

Fourth, it should be recognized that although in the present study restenosis rates at 6 months were improved by 47%, there were still many radiation failures. Radiation is not a "cure-all," and some patients who receive this new therapy with high hopes will be profoundly disappointed. Our failures, however, do provide us with the opportunity for improvement. For example, in this study, 12 Gy was prescribed at 3 mm from a noncentered source. Perhaps a higher dose will improve efficacy. Delivery of higher doses, however, must be approached cautiously. Delivery of a higher dose with the noncentered delivery system used in this study might result in excessive radiation exposure to the vessel wall actually making physical contact with the delivery catheter. A more sophisticated delivery system, such as the centering device currently under investigation in the Peripheral Artery Radiation Investigational Study (PARIS) trial, will improve dose homogeneity and may more safely allow prescription of a higher dose.22

Finally, it should be observed that although the 12-month results described in this report are extremely encouraging, longer follow-up of these patients, as well as patients in other vascular radiotherapy trials, is essential to document the durability and long-term safety of this new technology. It will also be important to document that late failures, if and when they occur, do not result in further clinical deterioration due to regression or elimination of critical collateral blood supply.

An effective anti-restenosis therapy will most likely have a major impact on percutaneous revascularization. In particular, when one considers the current challenges associated with femoral-popliteal disease management, the influence of radiation could be profound. Recently, a middle-aged diabetic woman sat in my office and described her complaint of claudication. She said she could "live with it." She told me her doctor suggested she increase her walking because "other treatments aren’t so good." Her husband then said, "But when you come back from your walks, you’re always in tears."

Although femoral-popliteal disease is often not life-threatening, claudication can certainly be life-altering. With no "good" treatment available for so many years, physicians have often relied on conservative therapy. However, if ongoing trials duplicate the results of the present study, internists, vascular surgeons, radiologists, and cardiologists will have to reevaluate their approach to patients with claudication. A simple, minimally invasive therapy that is safe, effective, and durable will prompt an increased need to make the proper diagnosis and a much lower threshold for more invasive treatment.

The promise of percutaneous angioplasty is its simple elegance. The broken promise is recurrence and the need for repeat procedures. Over the past decade, we have created an armamentarium of sophisticated tools to combat the mechanical challenges of angioplasty. Now, using radiotherapy, we can add biological warfare to the fight. In the near future, numerous novel, nonradioactive technologies, such as drug-eluting stents, sonotherapy, and photodynamic therapy, will be vigorously tested and may prove to be more efficacious, safe, or user-friendly than vascular brachytherapy. With this all-fronts attack on the biological as well as the mechanical components of restenosis, the promise of angioplasty may finally be fulfilled for many of our patients.

Acknowledgments

Although the views expressed here are not necessarily shared by my colleagues, I am indebted to Drs Gary Roubin, Sriram Iyer (interventional cardiologists), Moshin Saeed, Harry Knowles (interventional radiologists), Ralph Dilley, and Giacomo DeLaria (vascular surgeons) for their educational efforts on my behalf.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

Dr Teirstein receives research funding from Cordis, Guidant, Boston Scientific, Novoste, and Isostent; he also serves as a consultant to Guidant and Cordis. Dr Teirstein owns patents on radiation delivery devices and may receive royalties on the sale of these devices.

References

  1. Dotter CT, Judkins MP. Transluminal treatment of arteriosclerotic obstruction: description of a new technic and a preliminary report of its application. Circulation. 1964;30:654–670.[Abstract/Free Full Text]
  2. Gray BH, Sullivan TM, Childs MB, et al. High incidence of restenosis/reocclusion of stents in the percutaneous treatment of long-segment superficial femoral artery disease after suboptimal angioplasty. J Vasc Surg. 1997;25:74–83.[Medline] [Order article via Infotrieve]
  3. Capek P, McLean GK, Berkowitz HD. Femoropopliteal angioplasty: factors influencing long-term success. Circulation. 1991;83(suppl I):I-70–I-80.
  4. Taylor LM Jr, Edwards JM, Porter JM. Present status of reversed vein bypass grafting: five-year results of a modern series. J Vasc Surg. 1990;11:193–206.[Medline] [Order article via Infotrieve]
  5. Popma JJ, Califf RM, Topol EJ. Clinical trials of restenosis after coronary angioplasty. Circulation. 1991;84:1426–1436.[Free Full Text]
  6. Kuntz RE, Safian RD, Levin MJ, et al. Novel approach to the analysis of restenosis after the use of three new coronary devices. J Am Coll Cardiol. 1992;19:1493–1499.[Abstract]
  7. Kuntz RE, Gibson CM, Nobuyoshi M, et al. Generalized model of restenosis after conventional balloon angioplasty, stenting and directional atherectomy. J Am Coll Cardiol. 1993;21:15–25.[Abstract]
  8. Minar E, Pokrajac B, Maca T, et al. Endovascular brachytherapy for prophylaxis of restenosis after femoropopliteal angioplasty: results of a prospective, randomized study. Circulation. 2000;102:2694–2699.[Abstract/Free Full Text]
  9. Bottcher HD, Schopohl B, Liermann D, et al. Endovascular irradiation: a new method to avoid recurrent stenosis after stent implantation in peripheral arteries: technique and preliminary results. Int J Radiat Oncol Biol Phys. 1994;29:183–186.[Medline] [Order article via Infotrieve]
  10. Liermann DD, Boettcher HD, Kollatch J, et al. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoro-popliteal arteries. Cardiovasc Intervent Radiol. 1994;17:12–16.[Medline] [Order article via Infotrieve]
  11. Kuntz RE, Baim DS. Prevention of coronary restenosis: the evolving evidence base for radiation therapy. Circulation. 2000;101:2130–2133.[Free Full Text]
  12. 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.[Abstract/Free Full Text]
  13. Teirstein PS, Massullo V, Jani S, et al. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation. 2000;101:360–365.[Abstract/Free Full Text]
  14. Waksman R, White LR, Chan RC, et al, for the Washington Radiation for In-Stent Restenosis Trial (WRIST) Investigators. Intracoronary {gamma}-radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation. 2000;101:2165–2171.[Abstract/Free Full Text]
  15. Leon MB, Teirstein PS, Lansky AJ, et al. Intracoronary gamma radiation to reduce in-stent restenosis: the Multicenter Gamma I Randomized Clinical Trial. J Am Coll Cardiol. 1999;33(suppl A):19A. Abstract.
  16. Erbel R, Verin V, Popowski Y, et al. Intracoronary beta-irradiation to reduce restenosis after balloon angioplasty: results of a multicenter European dose-finding study. Circulation. 1999;100(suppl I):I-154. Abstract.
  17. Raizner AE, Oesterle SN, Waksman R, et al. Inhibition of restenosis with beta-emitting radiation (32P): the final report of the PREVENT trial. Circulation. 1999;100(suppl I):I-75. Abstract.
  18. Costa MA, Sabaté M, van der Giessen WJ, et al. Late coronary occlusion after intracoronary brachytherapy. Circulation. 1999;100:789–792.[Abstract/Free Full Text]
  19. Waksman R. Late thrombosis after radiation: sitting on a time bomb. Circulation. 1999;100:780–782.[Free Full Text]
  20. Albiero R, Nishida T, Adamian M, et al. Edge restenosis after implantation of high-activity 32P radioactive ß-emitting stents. Circulation. 2000;101:2454–2457.[Abstract/Free Full Text]
  21. Serruys PW, Kay IP. I like the candy, I hate the wrapper: the 32P radioactive stent. Circulation. 2000;101:3–7.[Free Full Text]
  22. Löffler EG, van Krieken FM. Nucletron afterloading technology for brachytherapy: the peripheral system. In: Waksman R, ed. Vascular Brachytherapy. Armonk, NY: Futura Publishing Co; 1999:499–504.



This article has been cited by other articles:


Home page
 Am. J. Pathol.Home page
J. Perree, T. G. van Leeuwen, R. Kerindongo, J. A. E. Spaan, and E. VanBavel
Function and Structure of Pressurized and Perfused Porcine Carotid Arteries: Effects of in Vitro Balloon Angioplasty
Am. J. Pathol., November 1, 2003; 163(5): 1743 - 1750.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Teirstein, P. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Teirstein, P. S.
Related Collections
Right arrow Restenosis
Right arrow Catheter-based coronary and valvular interventions: other
Right arrow Catheter-based coronary interventions: stents

Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2000 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.