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Circulation. 1999;99:192-194

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(Circulation. 1999;99:192-194.)
© 1999 American Heart Association, Inc.

Editorials

Radiation for Restenosis

Watchful Waiting

Spencer B. King, III, MD

From Andreas Gruentzig Cardiovascular Center, Emory University Hospital, Atlanta, Ga.

Correspondence to Spencer B. King III, MD, Andreas Gruentzig Cardiovascular Center, Emory University Hospital, 1364 Clifton Rd NE, Suite F606, Atlanta, GA 30322.


Key Words: Editorials • restenosis • angioplasty • radioisotopes • coronary disease

Na sarandisis" is an ancient Greek admonition, which loosely translated means, "When meeting someone you are attracted to, wait 40 days and 40 nights prior to making the commitment." In the attempt to control restenosis, love at first sight has frequently led to disappointing and expensive outcomes. Endovascular radiation therapy to prevent restenosis has appeared very attractive, and Teirstein et al, in this issue of Circulation,1 have contributed some of the "na sarandisis."

Endovascular radiation therapy has been shown by preclinical evaluation to have an effect not previously seen with other agents. From this experience, we have learned several things regarding the nature of restenosis. Initially we were taught that restenosis was primarily a proliferation of smooth muscle cells creating an endoluminal narrowing. Later it was suggested that a major component of restenosis was "negative remodeling" of the artery. Another paradigm suggested that a space-occupying thrombus was necessary for restenosis to occur and that it was subsequently replaced by in-growth of smooth muscle cells. These concepts all led to different approaches to suppress the restenotic process.

The success of endovascular radiation therapy to control arterial renarrowing in preclinical models2 3 4 5 6 has strongly supported the concept of restenosis as primarily a wound-healing phenomenon. Serial experimental observations with animal models of balloon-overstretch angioplasty and endovascular radiation therapy failed to show bulky thrombotic lesions, although luminal platelet and fibrin deposition was common.4 Endoluminal neointima formation was dramatically inhibited, and the chronic contracture of arteries was suppressed and sometimes reversed, probably owing to an effect on periadventitial fibroblastic scar formation. Whether smooth muscle cells of the media, fibroblasts, or monocytes, as recently suggested by Rubin et al,7 are the principal cell types responsible for initiating this process, radiation delivered just after injury dramatically inhibits this process in experimental animals and patients. The inhibition of late lumen loss with this method is strong evidence that the restenosis process is similar to other scar formation, such as keloid and pteyrigium (previously also suppressed by low-dose radiation therapy) and not due to colonization of bulky thrombus. These observations help explain the lack of reduction in restenotic events when acute thrombotic events have been effectively inhibited with potent IIb/IIIa inhibitors.8 9 10

Clinical observations seem to support the preclinical work.11 12 13 14 Several studies using endovascular radiation have now shown, angiographically and by intravascular ultrasound, a significant inhibition of neointimal proliferation and chronic vascular contracture after balloon angioplasty12 13 14 15 and an important reduction in neointima proliferation after stenting.11

There are many questions remaining regarding the use of endovascular radiation therapy. Will there be any change in the risk of thrombotic events after interventions? As yet, acute thrombotic events have not become a problem in early clinical trials, although an alteration in reendothelialization might increase the risk of thrombosis. Will inhibition of the healing response lead to coronary aneurysm formation? One study13 that used high-dose {gamma}-radiation resulted in some aneurysm formation, and although those patients have remained stable for the past 3 years (J.A. Condado, MD, oral personal communication, October 1998), this concern has led to planning for limits on maximum radiation doses delivered to the vessel wall in ongoing clinical evaluations. Fortunately, in several endovascular radiation studies, aneurysm formation has not been observed.11 12 16 Will atherosclerosis be induced by endovascular radiation, as it has been from external radiation for malignancies? Although a rare event, the occurrence of premature atherosclerosis in patients receiving mantle radiation for Hodgkin's disease and other conditions raises this question.17 18 These changes may take many years to develop, and therefore it will be difficult to rule out this possibility in the time frame of most radiation studies. Certainly, radiation should not be used in arteries free of atherosclerosis, and therefore whether acceleration of atherosclerosis will be induced will be a very difficult determination to make. Randomized trials followed in the long-term will be helpful in this regard.

Two other questions that are of more immediate importance have been addressed in the article by Teirstein et al.1 First, is radiation therapy preventing the restenosis process or simply delaying it? Second, is there any support for the concept that very-low-dose radiation therapy may promote the restenotic response?

Teirstein et al in their landmark study11 showed that endovascular radiation could dramatically reduce the 6-month angiographic occurrence of restenosis in patients who had undergone previous restenosis, most of whom had restenosis within coronary stents. The present study supports the stability of the results at 2 years, judged by clinical outcome. Although there have been 4 deaths in the follow-up period, these were equally divided between the radiation and control groups. Only 1 late angiographic restenosis has been documented in the radiated group, and that occurred at 11 months, not an unusual time frame for patients followed up without radiation. Although the present study did not include routine angiographic follow-up, and therefore no definitive statement can be made about restenosis or other late angiographic effects, the sustained freedom from clinical events is encouraging. One should be cautious in interpreting clinical events, however, because the 6-month angiographic follow-up markedly influences the clinical end point of target-lesion revascularization. Revascularization of the target lesion remains the major driving factor in the significant difference in clinical outcome at 2 years. The major importance of this clinical observation remains the absence of excess adverse clinical events in the late follow-up period in the group receiving radiation. The absence of other clinical complications is especially encouraging because the radiation source used in this trial emitted {gamma}-radiation, which would be expected to threaten vascular integrity in the deeper tissues more than similarly dosed ß-radiation. Many of the current ongoing trials are using ß-radiation sources because of their advantages of ease of use, less whole-body radiation, and less radiation exposure for catheterization laboratory personnel. Therefore, investigators using these sources should take comfort from the experience of Teirstein et al with {gamma}-radiation.

The other question that has recently arisen is whether low-dose radiation may actually induce the restenotic process. Radiation, in addition to inhibiting the cell cycle directly, releases oxidative free radicals that cause tissue damage. Progression of narrowing has been observed in zones in which the artery has been injured but that are outside the target lesion. This has been seen at the margin of radioactive stents, which may be a major limitation to their use, and at the margin of relatively short radioactive catheter systems. Progression in such injured nontarget segments within the same vessel also occurred in the study by Teirstein et al.1 The value of randomization, however, is once again demonstrated, because 3 of these cases were in the placebo group and 4 in the irradiated group. This question deserves further attention and emphasizes the need for complete radiation coverage by the catheter to encompass all injured tissues.

What will be the future of radiation? Various devices have been developed in addition to catheter-based radiation systems using {gamma}- and ß-radiation, ranging from radioactive stents to liquid- or gas-filled balloon-type systems. Others will undoubtedly emerge. The question of practical application of these systems will involve not only preclinical documentation of efficacy but also controlled trials to demonstrate the value of these various interventions and their ultimate safety.

Will radiation be used as an adjunct to stenting or in place of stenting? The system our group has been associated with (Novoste Beta Cath) is currently being evaluated in an 1100-patient trial of optimal balloon angioplasty alone and also suboptimal angioplasty plus stenting. The results of such trials will soon establish the value of these methods. One possibility is that stents with or without radiation may be used for ideal stent lesions, ie, large vessels with short lesions, and that balloon angioplasty without stenting may be used for unfavorable stent lesions, eg, long lesions, small vessels, and restenotic lesions.

Regulatory issues abound. The US Food and Drug Administration must approve all use of endovascular radiation treatment for restenosis, and they are carefully watching all ongoing trials. The Nuclear Regulatory Commission, although not charged with monitoring medical care, does have responsibility for ensuring safety from radiation sources. The training for use of endovascular radiation for nonmalignant applications has traditionally been handled differently from training for cancer radiation therapy. Endovascular radiation therapy for restenosis prevention remains a new and evolving field. The ultimate training required to ensure safety of the patient and personnel involved will depend on numerous variables, including the radiation sources used, the radiation energy emitted, and the systems by which the radiation is delivered. Extremely important in these considerations is the safety of the patient in the performance of the entire procedure. To ensure safety, the input of physicians trained in the performance of these procedures is critical. Until all these elements are understood, watchful waiting would seem to be the most prudent approach for regulatory bodies.

For many of us, the initial infatuation with this attractive technology has been enhanced by further observations such as those by Teirstein et al.1 Watchful waiting ("na sarandisis") continues to be the prudent course, but with the results of the randomized trials forthcoming, the end of the 40 days and 40 nights may be rapidly approaching.

Footnotes

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

References

  1. Teirstein PS, Massullo V, Jani S, Russo RJ, Cloutier DA, Schatz RA, Guarneri EM, Steuterman S, Sirkin K, Norman S, Tripuraneni P. Two-year follow-up after catheter-based radiotherapy to inhibit coronary restenosis. Circulation. 1999;99:243–247.[Abstract/Free Full Text]
  2. Wiedermann JG, Marboe C, Amols H, Schartz A, Weinberger J. Intracoronary irradiation markedly reduces restenosis after balloon angioplasty in a porcine model. J Am Coll Cardiol. 1994;23:1491–1498.[Abstract]
  3. Mazur W, Ali MN, Dabaghi SF, Cristead C, Abukhalil J, Paraside P, DeFelice CA, Schulz D, Berner BM, Fajardo LF, French BA, Raizner AE. High-dose rate intracoronary radiation suppresses neointimal proliferation in the stented and ballooned model of porcine restenosis. Circulation. 1994;90(suppl I):I-652. Abstract.
  4. Waksman R, Robinson KA, Crocker IR, Gravanis MB, Cipolla GD, King SB III. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine: a possible role for radiation therapy in restenosis prevention. Circulation. 1995;91:1533–1539.[Abstract/Free Full Text]
  5. Hehrlein C, Gollan C, Donges K, Metz J, Riessen R, Fehsenfeld P, von Hodenberg E, Kubler W. Low-dose radioactive endovascular stents prevent smooth muscle cell proliferation and neointimal hyperplasia in rabbits. Circulation. 1995;92:1570–1575.[Abstract/Free Full Text]
  6. Laird JR, Carter AJ, Kufs WM, Hoopes TG, Farb A, Nott SH, Fischell RE, Fischell DR, Virmani R, Fischell TA. Inhibition of neointimal proliferation with low-dose irradiation from a B-particle–emitting stent. Circulation. 1996;93:529–536.[Abstract/Free Full Text]
  7. Rubin P, Williams JP, Riggs PN, Bartos S, Sarac T, Pomerantz R, Castano J, Schell M, Green RM. Cellular and molecular mechanisms of radiation inhibition of restenosis, I: role of the macrophage and platelet-derived growth factor. Int J Radiat Oncol Biol Phys. 1998;40:929–941.[Medline] [Order article via Infotrieve]
  8. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994;330:956–961.[Abstract/Free Full Text]
  9. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med. 1997;336:1689–1696.[Abstract/Free Full Text]
  10. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation. 1997;96:1445–1453.[Abstract/Free Full Text]
  11. Teirstein PS, Massullo V, Jani S, Popma JJ, Mintz GS, Russo RJ, Schatz RA, Guarneri EM, Steuterman S, Morris NB, Leon MB, Tripuraneni P. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med. 1997;336:1697–1703.[Abstract/Free Full Text]
  12. King SB III, Williams DO, Chougule P, Klein JL, Waksman R, Hilstead R, Macdonald J, Anderberg K, Crocker IR. Endovascular B-radiation to reduce restenosis after coronary balloon angioplasty: results of the Beta Energy Restenosis Trial (BERT). Circulation. 1998;97:2025–2030.[Abstract/Free Full Text]
  13. Condado JA, Waksman R, Gurdiel O, Espinosa R, Gonzalez J, Burger B, Villoria G, Acquatella H, Crocker IR, Seung KB, Liprie SF. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation. 1997;96:727–732.[Abstract/Free Full Text]
  14. Liermann DD, Boettcher HD, Kollach J, Schopol B, Strassman G, Strecker EP, Breddin KH. 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]
  15. Bonan R, Arsenault A, Tardif JC, Tanguay JFL, Crepeau J, Gallo R, Gosselin G, Joyal M, Lucier G, Crocker IR. Beta Energy Restenosis Trial, Canadian Arm. Circulation. 1997;96(suppl I):I-219. Abstract.
  16. Verin V, Urban P, Popowski Y, Schwager M, Nouet P, Dorsaz P, Chatelain P, Kurtz J, Rutishauser W. Feasibility of intracoronary beta-irradiation to reduce restenosis after balloon angioplasty: a clinical pilot study. Circulation. 1997;95:1138–1144.[Abstract/Free Full Text]
  17. Hancock SL, Tucker M, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA. 1993;270:1949–1955.[Abstract]
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