The birth, decline, and contemporary re-emergence of endovascular brachytherapy for prevention of in-stent restenosis

Brachytherapy

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The birth, decline, and contemporary re-emergence of endovascular brachytherapy for prevention of in-stent restenosis Mohamed H. Khattab1,*, Alexander D. Sherry2, Colin M. Barker3 1

Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 2 Vanderbilt University School of Medicine, Nashville, TN 3 Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN

ABSTRACT

Despite the advent of drug-eluting stents and dual antiplatelet therapy in the interventional management of cardiovascular disease, restenosis rates remain high with significant sequelae. Endovascular brachytherapydpopular in the 1990s and early 2000sdhas recently resurfaced as a cost-effective treatment option. In this work, we outline the history of endovascular brachytherapy starting with its earliest promise in the 1990s. We discuss the development of drug-eluting stents and dual antiplatelet strategies and their impact on the perceived benefit of endovascular brachytherapy. For the contemporary era, we propose novel roles for endovascular brachytherapy in complex coronary artery disease and in high-risk patients managed with drug-eluting stents. We discuss the impetus for reducing the requirement and duration of dual antiplatelet therapy using endovascular brachytherapy. We also review innovative opportunities for endovascular brachytherapy after bare-metal stent placement in both coronary and noncoronary territories and offer economic arguments in favor of endovascular brachytherapy. Trials of endovascular brachytherapy in these regimes are merited. Ó 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Keywords::

Endovascular brachytherapy; Restenosis; Intravascular brachytherapy

The early history of angioplasty, stenting, and endovascular brachytherapy Charles Dotter, considered the father of interventional radiology, performed the first percutaneous transluminal angioplasty (PTA) in 1964 (1). This procedure was made possible by his demonstration of flow-directed balloon and dual lumen catheterization, as well as his development of an automated fluoroscopy system. He first reported this technique in an 82-year-old woman who refused amputation of a gangrenous limb; after successful dilatation of

Received 30 March 2020; received in revised form 13 September 2020; accepted 18 September 2020. Sources of Funding: none. Khattab et al. Endovascular Brachytherapy for In-Stent Restenosis. Disclosures: MHK receives research funding support from Varian Medical Systems and BrainLAB, Inc. ADS has no conflicts of interest or disclosures to report. CMB is on the advisory board for Boston Scientific and Medtronic. * Corresponding author. Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 2220 Pierce Avenue, Preston Research Building, Rm B-1003, Nashville, TN 37232-5671. Tel.: (615) 322-2555, fax: (615) 343-3075. E-mail address: [email protected] (M.H. Khattab).

her superficial femoral artery, she died years later of unrelated causes (1). Inspired by this achievement, the German radiologist and cardiologist Andreas Gruentzig hoped to imitate this approach in the coronary arteries. Facing significant resistance to this procedure from his colleagues in Germany, he moved to Switzerland. In 1997, using a balloon catheter, he engineered on his own kitchen table; Gruentzig successfully performed the first percutaneous coronary angioplasty (PTCA), successfully treating a high-grade stenosis of a left anterior descending artery to global acclaim. Although Gruentzig’s first patient demonstrated patency 23 years after PTCA, this would not represent most patients treated with angioplasty alone (2). Indeed, a large proportion of subsequent patients who underwent PTCA were found to have acute vessel or plaque recoil as well as constrictive remodeling. To address this limitation, Ulrich Sigwart and Jaques Puel would, in 1986, be the first to develop bare-metal stents (BMSs) to increase luminal caliber of the target artery and partially counter the effects of vessel recoil and remodeling (3,4). Their innovation beckoned a new field of interventional endovascular therapy, and, in the United States alone, over 1.8 million stents are placed annually, with a global stent market estimated at $7.98 billion in 2016 (5,6).

1538-4721/$ - see front matter Ó 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.brachy.2020.09.012

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Although the use of stents marked a major milestone in the treatment of coronary artery disease, acute and late thrombosis of stents, as well as in-stent restenosis, introduced new challenges. Early studies showed that, after angioplasty and stenting, complete reocclusion occurred in about 25% of cases within 2 weeks of stent implantation despite anticoagulation (3,7). Moreover, 30e35% of patients were observed to have in-stent restenosis beyond the acute time period (8e10). Mechanistically, restenosis is thought to be due to neointimal hyperplasia. Mechanical microtrauma of the luminal wall, secondary to stent placement, incites a fibroproliferative reaction involving smooth muscle cells and proteoglycan-rich extracellular matrix deposition, resulting in extensive vascular remodeling (11,12). This proliferative thickening is driven by an inflammatory and reparative paradigm and is influenced by a variety of factors, including platelet/fibrin deposition (13). Neointimal growth itself may occlude the vessel, or recurrent atherosclerotic changes may occur in the nascent neointima, that is neoatherosclerosis, that leads to fibroatheroma formation with or without plaque rupture at an accelerated rate compared with atherosclerosis of native vessels (14). In short, stent reocclusion can occur as a result of acute thrombosis, late thrombosis, late vascular remodeling, and/or restenosis. The use of endovascular brachytherapy (EVBT) for the prevention of restenosis followed shortly after Gruentzig’s achievements in PTCA and advances in coronary stenting by Sigwart and Puel. Given the fibroproliferative reaction driving stent reocclusion, it was hypothesized that EVBT may reduce the incidence of both in-stent thrombosis and restenosis, extrapolated from the successes of radiation in the management of other benign proliferative connective tissue disorders. The use of brachytherapy for benign hyperproliferative disease dates back to the early 1900s, when brachytherapy was used to treat hypertrophic scars seen in keloid formation (15). A major obstacle to the application of brachytherapy to the vasculature was the need for smaller brachytherapy sources and safe endovascular approaches. In 1992, Wiedermann et al. overcame these challenges and successfully performed intracoronary irradiation in animal models (16). In 1994, B€ ottcher et al. published the first human study of EVBT in 13 patients alongside PTA, BMS implantation, and heparinization in the superficial femoral artery (15). In this seminal work, stent patency remained 100% in short-term followup, a stark contrast to historical controls at that time. These promising results prompted a bevy of independent investigations of EVBT in porcine and rabbit models between 1994 and 1996 at Columbia, Baylor, and Emory, which demonstrated effective inhibition of arterial neointimal proliferation (Table 1) (17e27). During this period, Condado et al. reported the first experience of human coronary artery EVBT in 21 patients after PTCA (28). Encouraged by these mounting data coevolving in both the peripheral and coronary circulation literature, Teirstein

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et al. published the landmark randomized control trial SCRIPPS in the New England Journal of Medicine in 1997, offering the first high-level clinical evidence that EVBT reduces coronary neointimal hyperplasia (29). In this study of 55 patients with coronary restenosis undergoing PTCA and BMS placement, 26 patients were randomized to EVBT with iridium-192 up to 30 Gy. Compared with 29 patients randomized to PTCA and BMS alone, the EBVT arm showed 40% reduction in restenosis at 6month followup ( p 5 0.01), and at 3 years, restenosis rates were nearly halved in the EVBT plus PTCA plus BMS arm compared with the PTCA plus BMS arm (30). These results in the coronary arteries were corroborated in larger studies in 2000 and 2001 such as the Gamma-One Trial, SCRIPPS III, and WRIST-Plus study, culminating in the U.S. Food and Drug Administration approval of coronary EVBT in 2001 (31e34). In the peripheral artery literature, eight randomized trials published between 2000 and 2005 examined the utility of EVBT in the femoropopliteal artery system with encouraging results (Table 1) (35e43). For example, the Vienna 2 study reported a 12-month patency rate of 63.6% with PTA and EVBT compared with 35.3% with PTA alone ( p ! 0.005) (40). A Cochrane review and meta-analysis of these trials found EBVT improved overall patency at 2 years (odds ratio (OR) 2.36, 95% confidence interval (CI) 1.36e4.10, p 5 0.002), as well as reduced restenosis at 6 months (OR 0.27, 95% CI 0.11e0.66, p 5 0.004), 12 months (OR 0.44, 95% CI 0.28e0.68, p 5 0.0002), and 24 months (OR 0.41, 95% CI 0.21e0.78, p 5 0.007) (44). From these trials, it appeared that EVBT would become a mainstay in the interventional treatment of cardiovascular disease.

Does endovascular brachytherapy have relevance in the drug-eluting stent era? Beginning in 2001, the introduction of drug-eluting stents (DESs), delivering localized highly concentrated antihyperplastic drug, revolutionized the cardiovascular literature (45e47). The incidence of coronary restenosis was dramatically reduced to less than 10% with DESs, a magnitude of benefit greater than that seen with the addition of EBVT to BMS implantation (48,49). Thus, it was assumed that there may not be a continued role for EVBT in the DES era (50). It is quite notable that while all of the aforementioned trials evidencing the successes of EVBT were conducted with BMSs, that the aforementioned DES monotherapy restenosis rates were reported at very shortterm followup (1 year) and increased thereafter, and that restenosis even at those rates translated into a significant need for invasive revascularization to prevent mortality. No randomized trial has ever compared restenosis rates after DESs with or without EVBT although there could be plausible further improvement reducing rates of restenosis and reintervention.

Table 1 Notable studies in the endovascular brachytherapy literature Study

Trial

Design

Site

Size Experimental arm

Teirstein et al. (29) SCRIPPS Randomized

Coronary

55 EVBT þ PTCA þ BMS

Leon et al. (31)

Coronary

252 EVBT þ PTCA þ BMS

Coronary

130 EVBT þ PTCA þ BMS

Gamma-1 Randomized

Randomized

Varghese et al. (105)

Retrospective cohort Coronary

328 EVBT þ PTCA

Primary endpoint

PTCA þ BMS Late luminal loss and late loss-index at 6 months PTCA þ BMS Composite of death, myocardial infarction, repeat revascularization PTCA þ BMS Composite of death, myocardial infarction, repeat revascularization at 6 months PTCA þ DES Major adverse cardiac events

Vienna 2 Randomized

Femoropopliteal 117 EVBT þ PTA

PTA

Patency at 6 months

Pokrajac et al. (40) Vienna 3 Randomized

Femoropopliteal 134 EVBT þ PTA

PTA

Restenosis at 12 months

Wolfram et al. (112) Vienna 5 Randomized

Femoropopliteal 94 EVBT þ PTA þ BMS

PTA þ BMS

Gallino et al. (36)

Restenosis O50% at 6 months Restenosis 6 months after PTA

Minar et al. (40)

Randomized Randomized

Femoropopliteal 77 EVBT þ PTA Femoropopliteal 100 EVBT þ PTA

PTA PTA

Silverman et al. (66)

Case series

Renal

21 EVBT þ PTA

N/A

Chan et al. (62)

Case report

Carotid

1 EVBT þ PTA þ BMS

N/A

Seemann et al. (63)

Case report

Carotid

1 EVBT þ PTA þ BMS

N/A

0.38 mm vs. 1.03 mm, p 5 0.03 32.4% vs. 55.3% 28.2% vs. 43.8% ( p 5 0.01) at 6 months ( p 5 0.02) 19% vs. 58% at 6 months 29.2% vs. 67.6% ( p ! 0.001)

15.2% vs. 22.9% at 1 year 13.2% MACE with EVBT vs. 28.2% with PTA alone ( p 5 0.01) 28.3% vs. 53.7% ( p ! 0.05) 23.4% vs. 53.3% ( p ! 0.05) at 12 months 33% vs. 35% ( p 5 0.89) 17% vs. 35% ( p ! 0.001)

0% vs. 33% at 12 months, 2.0%  34.2 vs. Absolute change in p 5 0.042 40.6%  32.6 angiographically defined degree of stenosis at 12 ( p 5 0.002) at and 24 months 12 months, and 7.4%  43.2 vs. 37.7%  34.5 ( p 5 0.043) at 24 months Restenosis at 12 months 35% vs. 44% ( p 5 0.51) Greater than 50% restenosis 23% vs. 42% ( p ! 0.028) at 1 year N/A 5% (1 of 21) restenosis at last followup (median 42 months, range 14e 84 months) N/A Free of restenosis at 6 months N/A Free of restenosis at 2 years

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Tongeren et al. (43) VARA Zehnder et al. (38) Swiss

17% vs. 54% ( p 5 0.01)

(2020)

Randomized

Randomized

Primary endpoint result (if not restenosis)

-

Krueger et al. (35)

Femoropopliteal 335 EVBT þ protbucol þ PTA; PTA EVBT þ PTA; probucol þ PTA Femoropopliteal 30 EVBT þ PTA PTA

PAB

Restenosis

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Waksman et al. (34) WRIST

Control

EVBT 5 endovascular brachytherapy; PTA 5 percutaneous transluminal angioplasty; PTCA 5 percutaneous coronary angioplasty; BMS 5 bare-metal stent.

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Table 2 Modern estimated rates of restenosis and thrombosis Site

Restenosis

Timeframe

Sequelae of restenosis

Thrombosis risk

Coronary Three-vessel and left main disease Cervical carotid Severe Moderate Renal Intracranial/flow diverters Femoropopliteal

16% 26%

5 years 5 years

Myocardial infarction

1.3% at 4 years

Stroke

0.33%e33%

12% 40% 15e44% 38% 15e40%

10 years 10 years Short-term Short-term Short-term

Renal failure/insufficiency, hypertensive crisis Stroke Gangrene, amputation

13.4% at 5 years

There are a number of reasons why EVBT should continue to have an important role in the modern era, particularly in high-risk patients. First, there is persistent acute and late restenosis even with modern DESs and dual antiplatelet therapy (DAPT), and the risk of thrombosis is increased with DESs compared with BMSs (Table 2). Second, a DES is now used in increasingly more advanced approaches for more complex disease at greater risk for restenosis. Third, demographic and epidemiological trends suggest that the rate of restenosis will increase over time. Fourth, prolonged DAPT is associated with hemorrhagic risks that may be avoidable with EVBT. Fifth, BMSs may be more appropriate in select patients with coronary artery disease than DESs, and in this subset, historical trials suggest that EVBT is beneficial. Restenosis rates in the modern era after stent therapy in the coronary arteries The coronary arteries are the most common site for endovascular interventions, yet as many as 200,000 repeat coronary revascularizations are performed each year in the United States alone (51,52). The rate of clinically significant restenosisdrestenosis that requires revascularizationdis 7e10% at 1 year and up to 16% at 5 years with DES implantation (53e55). For patients with left main coronary artery or three-vessel disease, the SYNTAX trial found 5-year revascularization rates of 26.7% (56). DESs are also associated with increased late thrombotic risk compared with BMSs, which may be theoretically mitigated with the addition of EVBT to DES implantation (57). Restenosis rates in the modern era after stent therapy in the carotid, renal, and femoropopliteal arteries DESs are not standard of care in the treatment of none coronary artery stenosis, and BMSs are used in the carotid, renal, and femoropopliteal arteries. Modern restenosis rates in the cervical carotid arteries, despite DAPT, are high, progressively increase, and require invasive revascularization. Of 2191 patients in the CREST trial, 58 patients in the stent arm (6.0%) had severe restenosis (defined as $70% lumen occlusion) at 2 years and required repeat revascularization (58). At 10 years, the incidence of severe restenosis or occlusion grew to 12.2% (59). The International Carotid

Stenting Study (ICSS) found a cumulative 5-year risk of 40.7% of moderate restenosis, defined as $50% lumen occlusion (60). Although patients with moderate restenosis do not necessarily have an indication for repeat revascularization, the ICSS did find that moderate restenosis was associated with significant morbidity and an increased risk of ipsilateral stroke (HR 3.18, 95% CI 1.52e6.67, p 5 0.002) (60). Furthermore, the risk of carotid stent thrombosis is highly variable and has been reported in up to 33% of patients (61). EVBT has been used for cervical carotid disease in case reports and should be more thoroughly studied as a means to meaningfully reduce restenosis (62,63). In the less well-studied renal artery system, restenosis rates after BMS placement have been reported between 15 and 44%, and EVBT has been shown to be technically feasible in this territory, although the benefit of EVBT has never been explored in randomized trials (64e66). Finally, in the femoropopliteal artery system, restenosis at 1 year has been reported in 15e40% of patients and often requires repeated intervention(s) (67). Stent thrombosis typically occurs in 13% of patients at 5 years (68). EVBT should be revisited as a strategy to mitigate these high rates of restenosis.

Stenosis rates after flow diverter placement for intracranial aneurysms There are far fewer data for novel stent devices such as flow-diverting stents, which are now standard of care for intracranial aneurysms. Flow diverters effectively occlude the aneurysm sac by diverting blood flow away from the sac, leading to stasis and subsequent thrombotic occlusion. However, the patency of the parent artery is still at high risk for stenosis, which increases the risk for ischemic cerebral disease and stroke. In fact, more recent studies have found that these stents are associated with stenosis in up to 38% of patients in short-term followup, despite a DAPT duration between 6 and 18 months (69). As data on flow-diverting stents mature, the risk of long-term stenosis may even exceed the short-term rate of 38%. Revascularization of high-risk stenosed intracranial vessels is a formidable clinical challenge, especially as these vessels are often in the deep anterior and posterior cerebral circulation and usually

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require craniotomy for surgical revascularization. Randomized studies should explore whether EVBT offers meaningful reduction in parent artery stenosis after flow diverter placement for intracranial aneurysms. Contemporary stent complexity In the modern era, stents are being used to treat complex disease associated with a greater risk of restenosis. Lesions that were formerly treated with surgical bypass are now being treated percutaneously, including lesions at bifurcations and even triple-vessel disease in patients who are not operative candidates (56,70). In the BASKET-PROVE trial, the risk of restenosis increased with the number of stented segments ( p 5 0.001) and the total number of stents ( p ! 0.001) (71,72). Every additional 1 mm increase in stent length was correlated with a 2% increase in the risk of restenosis (71,72). In the SIRTAX trial, patients with multiple overlapping DESs were more likely to require revascularization and experience major adverse cardiac events (73). Furthermore, drug may not be eluted optimally at stent margins, and this may promote focal areas of restenosis (74). Finally, there is an appreciable trade-off with second-generation and third-generation DESs. Secondand third-generation DESs aim to reduce the risk of restenosis, but adversely increase the probability of late thrombosis because of an inflammatory reaction to the polymer coating, even in light of the anti-inflammatory action of DAPT (75). EVBT appears ideally suited to address complex high-risk scenarios, such as multilayer coronary restenosis, as an additional measure to DESs. Trials are needed to investigate efficacy of EVBT with DESs as well as criteria for selecting patients who benefit from DESs plus EVBT. Patient population As United States and global demographics shift to older patient populations with more comorbidities, such as diabetes mellitus and chronic kidney disease, the incidence of restenosis may continue to rise along with these known risk factors (76e78). In the ICSS study evaluating carotid stenting, female sex (HR 1.54, 95% CI 1.25e1.91, p ! 0.0001), current smoking (HR 2.22, 95% CI 1.65e2.98, p ! 0.0001), former smoking (HR 1.68, 95% CI 1.30e 2.16, p ! 0.001), noneinsulin-dependent diabetes (HR 1.35, 95% CI 1.05e1.74, p 5 0.018), and age (HR 1.01, 95% CI 1.00e1.03, p 5 0.027) were associated with an increased risk of moderate restenosis (60). Risk factors for renal artery restenosis include body mass index and smoking status (79e83). Risks of prolonged dual antiplatelet therapy Although DESs have been invaluable in reducing restenosis, earlier generation DESs implanted in the coronary arteries led to some concerns regarding an increased risk of

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cardiac death (57,84e86). Several studies suggest that restenosis remained a risk up to 5 years after implantation because of continued inflammation, polymers within DESs, and/or the drugs themselves (87,88). This concern for late stent occlusion after DES implantation is founded on a multifactorial process implicating a reactive, inflammatory late healing of the neointima. Thus, DAPT is used for at least 6e12 months and up to 30 months after stent implantation, although prolonged DAPT also confers a new set of significant risks (89). In a meta-analysis of patients receiving DAPT after DES placement, prolonged DAPT at a median of 17 months increased the risk of major bleeding (OR 2.64, 95% CI 1.31e5.30, p 5 0.006) compared with short-term DAPT at a median of 6 months; moreover, prolonged DAPT lacked a concordant survival benefit or reduction in myocardial infarction, restenosis, or cerebrovascular accident (90). In the Dual Antiplatelet Therapy Study comparing 30 months of DAPT versus 12 months, patients randomized to 30 months had a small reduction of in-stent thrombosis (1.1% vs. 0.4%, p ! 0.001) but an increased risk of major bleeding (2.6% vs. 1.7%, p 5 0.007) (91). Prolonged DAPT may also complicate the delivery of other unrelated interventions or surgeries (92,93). As the risks and costs of prolonged DAPT are increasingly appreciated, EVBT may offer a novel avenue for reducing the requirement and/or duration of DAPT, particularly for patients at lower risk for restenosis and higher risk for bleeding (94,95). Hemorrhagic complications from DAPT are even more relevant in the treatment of intracranial disease, where hemorrhages are often immediately catastrophic and DAPT is recommended for at least 3 months (96). In a metaanalysis of flow diverters for intracranial aneurysms, intraparenchymal hemorrhage was found in 3% of patients (95% CI 2%e4%), and postoperative and subarachnoid hemorrhage occurred in 3% of patients (95% CI 2%e4%) (97). In patients with ruptured aneurysms treated with flow diverters, thromboembolic or hemorrhagic complications occur in 25% of patients, and even in unruptured aneurysms, these complications are present in 4.7% of patients (98). Implementation of EVBT in this setting to decrease reliance on DAPT may reduce the incidence of DAPTassociated complications. Cost effectiveness of DESs and modern role for BMSs There is a significant cost of DESs that may be particularly relevant for underinsured patients and patients in lowto middle-income countries (99,100). In the United States, and only among Medicare beneficiaries aged 66e85 years old, over 1.57 billion dollars in annual Medicare expenditures are directed toward DESs, mostly placed in patients without acute coronary syndrome (101). Taking into account only hospital charges inclusive of Medicare and non-Medicare beneficiaries, over 8.9 billion dollars in hospital charges alone are attributed to revascularization with

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Table 3 Opportunities for innovation in endovascular brachytherapy Site

Setting

All sites

High-risk patients including diabetes, smoking, obesity, stent factors (length, complexity), contraindications/risks of DAPT, short artery diameter After DES placement (standard) Multiply recurrent stenosis After BMS placement in select patient subset Bifurcations and trifurcations After BMS placement (standard) After DES placement (emerging) After BMS placement (standard) After DES placement (emerging) After BMS placement (standard) After DES placement (exploratory) After flow diverter placement After balloon aortic valvuloplasty

Coronary

Femoropopliteal Renal Carotid Intracranial Aortic valvular stenosis

DAPT 5 dual antiplatelet therapy; BMS 5 bare-metal stent; DES 5 drug-eluting stent.

placement of DESs (102). This does not include the added costs of prolonged DAPT associated with DESs. According to the Berkeley Center for Health Technology, the procedural cost in U.S. hospitals for PTCA with DES placement ranges from $7,419 to $35,427 per procedure, with an average of $13,162 (103). Thus, if there are roughly 200,000 reinterventions for existing coronary stents annually, 2.63 billion dollars can be attributed to reocclusion either through preventable restenosis or thrombosis in the United States alone. EVBT may lower these costs associated with repeated intervention for restenosis by reducing the incidence of restenosis. For treatment of na€ıve disease, costs may be reduced in cases where DESs may not confer a clear clinical benefit by substituting BMSs and EVBT (104). Investigators at the Massachusetts General Hospital have estimated an annual cost savings of $200 million if selected patients with coronary artery disease had BMS implantation instead of DESs without any clinical compromise (104). EVBT, if added to BMSs in this subset of patients, could offer a unique clinical benefit in a costeffective manner, and studies should prospectively evaluate what factors define this subset.

The future of endovascular brachytherapy, a timetested treatment, in modern high-risk disease All the aforementioned challenges in modern endovascular stenting call for novel mitigation strategies. Although many advancements are being explored, EVBT is an evidenced, definitive, and facile technology. EVBT must be resurfaced from a forgotten era and reevaluated as a means for reducing neointimal hyperplasia associated with DESs, restenosis, disease recurrence, repeated intervention, DAPT, cost, and mortality (Table 3). In 2018, a cohort study from Mt. Sinai supported the role of coronary EVBT in the modern DES and DAPT era (105). In this retrospective study by Varghese et al., 197 patients with multilayer restenosis treated with EVBT plus standard of care (PTCA with or without atherectomy) were compared with 131 patients treated with PTCA with or without atherectomy with or without DESs. The addition of EVBT to percutaneous coronary management resulted in a significant reduction in major cardiac events at 1 year (28.2% vs. 13.2%, p 5 0.01) with adjustment for confounding factors (HR 0.37, 95% CI 0.18e0.73, p ! 0.01), suggesting the continued

Table 4 Comparison of beta and gamma endovascular brachytherapy sources Gamma irradiation (iridium 192)

Beta irradiation (strontium/yttrium 90)

Benefits

More suitable for larger vessels

Drawbacks

Requires shielding

Steeper dose drop-off No radioprotective equipment required, can be performed in catheterization Short procedural time Long half-life of strontium/yttrium-90 (28 years) More challenging to use for larger vessels due to dose asymmetry

Shorter source half-life (iridium-192) of 74 days requiring more source exchange Transport after intervention to the brachytherapy suite depending on radiation safety protocol

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importance of coronary EVBT as an adjunct to current standard of care with the most modern DES and DAPT. Prospective studies asking the questions of Varghese et al. are sorely needed. There are three approved radiation sources for EVBT. Of these, 90Sr/90Y and 32P are beta emitters, which have significant advantages over gamma sources (Table 4) (106). 90 Sr/90Y, for example, has a dose drop-off rate of 50% per millimeter (107). This source originally demonstrated clinical efficacy in the START trial and again in the START 40/20 trial (108,109). As an electron source with strict dose drop-off, 90Sr/90Y eliminates the need for additional radiation shielding protection because personnel in the catheterization laboratory receive insignificant exposure during the rather expedient (!5 min) treatment time, increasing the accessibility of this procedure (110,111). In summary, EVBT should not be summarily dismissed as a therapeutic even in the DES era. EVBT has a promising body of historical evidence supporting its investigation in the reduction of modern restenosis after DES implantation in coronary arteries and after BMS implantation in carotid, renal, and femoropopliteal arteries. Trials are needed to study whether EVBT reduces disease recurrence, repeat interventions, cost, DAPT, and complications associated with modern endovascular interventions.

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