CME Offering: Vascular Brachytherapy: A New Approach to Renal Artery In-Stent Restenosis

Christopher D. Jahraus, MD and Ali S. Meigooni, PhD
Christopher D. Jahraus, MD and Ali S. Meigooni, PhD
Learning objectives. At the conclusion of this activity, the participant should be able to: 1) describe conventional approaches to the management of renal artery in-stent restenosis and the justification for using vascular brachytherapy in this setting; 2) compare the advantages and disadvantages of various radiation sources in performing renal vascular brachytherapy; 3) review the major trials of renal vascular brachytherapy; and 4) identify the limitations of existing data. Activity instructions. Successful completion of this activity entails reading the article, answering the test questions and obtaining a score of over 70%, and submitting the test and completed evaluation form to the address listed on the form. Tests will be accepted until the expiration date listed below. A certificate of completion will be mailed to you within 60 days. Estimated time to complete this activity: 1 hour Initial release date: April 6, 2004 Expiration date: April 6, 2005 Target audience. This educational activity is designed for cardiologists, nurses and cardiovascular technologists. Accreditation statements. Physicians: HMP Communications is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications designates this continuing medical education activity for a maximum 1 credit hour in category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies. Nurses: HMP Communications is an approved provider of continuing nursing education by the Pennsylvania State Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation. This continuing nursing education activity was approved for 1.2 contact hour(s). Provider approved by the California Board of Registered Nursing (Provider Number 13255) for 1.2 contact hours. ASRT. Radiologic Technologists: Activities approved by the American Medical Association (AMA category 1) are eligible for ARRT Category B credit as long as they are relevant to the radiologic sciences. Radiologic technologists, registered by the ARRT, may claim up to 12 Category B credits per biennium. This activity is approved for 1 AMA category 1 credit. SICP. This activity is approved for 1 contact hour by the Society of Invasive Cardiovascular Professionals. Commercial support disclosure. This educational activity has been supported by an educational grant from Novoste Corporation. Faculty disclosure information. All faculty participating in Continuing Medical Education programs sponsored by HMP Communications are expected to disclose to the activity audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Jahraus and Meigooni have no real or apparent conflicts of interest. This article contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither HMP Communications nor Novoste Corporation recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings.
ABSTRACT: Renovascular hypertension is frequently the result of atherosclerosis and has been successfully treated with percutaneous angioplasty. Stenting of vessels has helped to significantly lower the rate of restenosis after angioplasty; however, neointimal hyperplasia frequently results in growth of tissue through the stent, causing in-stent restenosis. Similar problems are seen in coronary stenting, and vascular brachytherapy has been shown to effectively prevent repeat in-stent restenosis. While coronary and renal restenoses occur by a common physiologic mechanism, their anatomic differences have prevented widespread adaptation of vascular brachytherapy to renal in-stent restenoses. A number of recent reports have demonstrated efficacy of renal vascular brachytherapy, but thus far, no large-scale, randomized data is available. Herein is reviewed the subject of renal vascular brachytherapy and the studies that are presently used in its justification. J INVAS CARDIOL 2004;16:224–228 Key words: angioplasty, vascular brachytherapy, endovascular, radiotherapy, renal artery stenosis, stent Introduction Since the time of its introduction in 1978, percutaneous transluminal renal angioplasty (PTRA) has evolved into a major component of the management of renal artery stenosis.1 Part of this evolution has resulted from the introduction of metallic stents, which have aided in the durable maintenance of vessel patency.2,3 Nonetheless, similar to experiences in coronary stenting, stented renal arteries have been found to have a significant rate of in-stent restenosis (ISR).4 Dependent upon the study examined and, accordingly, the time of follow up, clinical or radiologic evidence of ISR in renal artery patients varies from 16–41%.4–8 Strongest predictors of ISR include a history of smoking, vessel diameter less than or equal to 4.0–4.5 mm and extended time of follow up.4,9 Extrapolating from coronary ISR data, additional predictors would include diabetes and lesion length.10 Conventional Approaches to Renal ISR A variety of approaches to renal ISR have been attempted, but presently, none has proven superior to other available means. Bax and colleagues published a study examining repeat balloon angioplasty for renal ISR in 15 patients.11 Most of the patients in this study had balloon angioplasty alone, but some had second stents placed as well. Surrogate markers were used as indicators for repeat angiography after treatment, and by 11 months, 25% had failed angiographically, and 50% had refractory hypertension. Interestingly, their average follow up was shorter than the average time to development of ISR after first stenting (13 months). Thus, one might suspect that with longer follow up, their 25% angiographic failure rate would increase. A case report employing a variation on this approach using cutting balloon angioplasty was published by Munneke and colleagues. In it, the authors concluded there was a theoretical advantage to this approach over conventional balloon angioplasty.12 One report using endovascular resection of hyperplastic tissue causing renal ISR can be found in the literature. High-speed rotational atherectomy was used in this report by Rao and Chandra to debulk the restenosis.13 In a single patient, they revascularized a restenosed renal stent and followed this by placement of a second stent. Follow up was restricted to 6 months; however, at that time, the patient was well without the use of antihypertensives. Specific approaches to the prevention of de novo renal ISR have been attempted, but none have been particularly successful. Building on an animal study that suggested possible benefit,14 a patient-based German study used gold-coated stents and found no difference in the rate of ISR over conventional stainless steel devices.15 A trial involving restenosis of renal arteries status-post angioplasty but not stenting showed no advantage to using verapamil in an attempt to prevent restenosis.16 One might presume the same to be true of ISR in stented renal arteries. Vascular Brachytherapy History. Radiotherapy has long been used to prevent proliferation of tissue in both malignant and benign conditions. However, it has only recently been applied in the setting of neointimal hyperplasia causing ISR. In November 2000, the United States Food and Drug Administration (FDA) approved two devices to deliver vascular brachytherapy (VBT) for coronary artery ISR.17,18 Part of the foundation for this approval was a study by Teirstein and colleagues, which demonstrated a greater than 75% reduction in the rate of coronary ISR for patients receiving VBT from a gamma-emitting iridium source (192Ir) compared to those being treated with a placebo “source.”19 Subsequent to this, King and colleagues published a study of 23 patients treated with a beta-emitting strontium source (90Sr/90Y).20 They found the 90Sr/90Y system to be as effective at preventing restenosis as the previously described 192Ir system, but they noted numerous shielding and dosimetric advantages of the 90Sr/90Y system. King’s study was also fundamental in FDA clearance of VBT devices and procedures. However, it was not until two years after FDA approval that the first multicenter, randomized, blinded trial of a 90Sr/90Y source was published.21 Unlike the trials by Teirstein and King, the Stents and Radiation Therapy (START) trial was restricted to patients with previously placed stents and ISR. Thus, it examined the ability of VBT to prevent repeat ISR in patients who had already experienced 1 episode and were presumably at higher risk for another. Repeat ISR at 8 months post-procedure was reduced from 45.2% in the placebo group to 28.8% in the active treatment group. VBT source selection. At present, 3 VBT systems are approved for use in the US.22 These are a 90Sr/90Y-based beta-emitting system (Novoste™ Beta-Cath™ System, Novoste Corporation, Norcross, Georgia); a phosphorous (32P)-based beta-emitting system (Galileo® III Intravascular Radiotherapy System, Guidant Corporation, Indianapolis, Indiana); and an 192Ir-based gamma-emitting system (Checkmate™ Intravascular Brachytherapy System, Cordis Corporation, Miami Lakes, Florida). At present, there have been no large-scale published trials of one system versus another, nor of one emitter type versus another. Thus, treatment advantages or disadvantages are largely theoretical in nature. However, beta emitters have distinct logistic advantages over gamma emitters in that they require less shielding and result in significantly lower dose to the operator.20,22 Comparatively, 192Ir source use results in operator exposure similar to fluoroscopy.22 The shielding advantage of beta-emitting isotopes is the result of greater attenuation by tissue, and for the same reason, beta emission may represent somewhat of a disadvantage in larger diameter vessels.23 Despite the decreased tissue attenuation associated with 192Ir, treatment time is significantly longer than 90Sr/90Y-based treatments.22 Another consideration is source centering within the vessel by a centering device. For cardiac VBT, it has been proposed that cardiac motion would cause oscillation of the source such that even for a non-centered source, the net effect is one of “centering.”20 The 32P system utilizes a centering balloon to center the source within the vessel lumen, while the 90Sr/90Y and 192Ir systems commercially available in the US do not. A dosimetric study on source centering demonstrated that the alteration in dose for an off-center source is somewhat greater for 32P than for 90Sr/90Y.24 Renal Artery VBT Given the success of coronary VBT, it follows logically that renal artery VBT would be effective as well. However, renal arteries exhibit unique structural and biophysical challenges to the radiotherapist. Their larger diameter relative to coronary vessels creates dosimetric difficulties not seen in coronaries. FDA approval of VBT systems covers coronary vessels, but use in renal arteries is presently done off label. Nonetheless, to date, 7 publications have described a total of 21 patients treated with renal artery VBT, all for ISR in existing stents.25–31 Details of each study are shown in Table 1. No randomized data is presently available; however, the 2 multi-patient studies are described below. The largest of the trials, a Swiss study by Stoeteknuel-Friedli and colleagues, utilized 192Ir to treat 11 patients.29 Two additional patients were attempted but could not be accessed with the large brachytherapy sheaths their system required. Patients in this trial were treated to a dose of 12 Gy, utilizing a prescription point 5 mm from the source axis. By the authors’ calculations, this would result in a dose of 25 Gy at the inner surface of the vessel wall and 12 Gy at the adventitia. Prior to delivery of VBT, previously stented arteries exhibiting ISR were dilated with balloons measuring 5 or 6 mm. No centering device was used during VBT delivery. During follow up, 1 of the 11 patients died of a cause unrelated to VBT or renal artery stenosis/ISR. Of the 10 evaluable, 20% had evidence of recurrent ISR at 1 year post-treatment; however, 18 months from VBT, 1 additional patient experienced complete occlusion of the treated artery resulting in renal necrosis. The only other multi-patient report was published by Jahraus and colleagues at the University of Kentucky.25 This report included 5 patients treated with a non-centered 90Sr/90Y source. Four of the patients had cases of conventional ISR, and 1 experienced ISR in a vessel supplying a renal allograft. Mean dose delivered was 2029 cGy prescribed to the vessel wall after angioplastic dilatation to 5 or 6 mm. In the Kentucky study, surrogate markers of target vessel failure were used rather than angiography or duplex ultrasonography as was done in the Swiss study. Target vessel failure was defined by any 1 of 3 criteria: (1) loss of blood pressure control as evidenced by a sustained elevation in systolic blood pressure, (2) intensification of antihypertensive regimen or (3) elevation of serum creatinine greater than 0.5 mg/dL. Of the 4 conventional ISR patients, none met criteria for target vessel failure during a follow up of 1 to 7 months. However, the transplant patient failed, and 5 months post-treatment, repeat angiography revealed 80% restenosis. A number of important points can be gleaned from these trials. First, neither study involved a centered source. At first glance, this would seem unimportant in the Swiss trial, as position would not be expected to affect a gamma-emitting source as readily. However, the authors’ own calculations suggest that a maximum potential dose at the lumenal surface could reach 44 Gy if the source lodged itself in the least optimal way, a dose dramatically higher than the 25 Gy prescribed. Likewise, the beta-emitting source used by Jahraus and colleagues could over-dose or under-dose areas if so lodged. These same issues have been raised for coronary VBT and have been countered by the notion that a broad range of dose may be acceptable.22 In the Kentucky experience, the authors postulated that oscillations of the source train caused by blood flow within the vessel would likely be self correcting. At present, the only VBT system available in the US that uses a centering balloon is the 32P system. The authors found no report of renal VBT performed with this system. Thus, although a theoretical advantage exists, it has yet to be tested. While no evaluation of proper dose range in renal VBT has been addressed specifically, authors have typically extrapolated from coronary data. Between the 2 largest studies, dose administered to the vessel wall ranged from 1690 to 2500 cGy. The greatest difference between the Swiss experience and the Kentucky experience is the choice of radiation source. Some of the dosimetric advantages of a gamma-emitting source were discussed in conjunction with the issue of source centering. Additionally, other authors have expressed concern that the beta-emitting source may not be as desirable in larger caliber vessels (such as renal arteries) due to a steep dose fall-off.10 This did not seem to present a problem to the Kentucky authors; however, future studies should be mindful of this possibility. Nonetheless, for physicians practicing in the US, it may be a moot point, as Cordis, manufacturer of the only gamma-emitting system available in the US, indicates that the system is no longer available, effective January 2004. Based upon dosimetric data23 and the Kentucky experience, it is the opinion of the authors that given appropriate dosimetric calculations, beta emitters will likely suffice in this application, although this remains to be seen. An update and expansion of the Kentucky experience is currently in progress. Pre-publication analyses suggest continued evidence of their method’s efficacy. A significant concern of radiotherapists is the future applicability of VBT as a whole. Within the past year, multiple studies have been published employing drug-coated stents in the management of ISR and as a means of preventing ISR de novo. Paclitaxel- and sirolimus-coated stents have shown the greatest promise32,33 and have dramatically decreased the need for coronary VBT. However, they may not be useful in renal VBT, as the largest diameter available is 3.5 mm. This will likely not be sufficient for a 5 or 6 mm diameter renal vessel, and thus, development of renal VBT remains an important issue. Conclusion Renal VBT is an emerging modality in the management of renal artery ISR. While no large-scale, randomized data is presently available, 2 multi-patient studies and several case reports suggest a probable benefit. Formation of a multicenter, randomized trial will be necessary to adequately evaluate this promising approach.
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