Academic Editors: Christian Hengstenberg and George Dangas
Background: Vascular brachytherapy (VBT) used to be an effective treatment modality for management of in-stent stenosis but was superceded by drug eluting stents (DES) which had shown a greater efficacy. However, there is no clear evidence to support superior management for in-stent restenosis (ISR) which continues to be a challenge. Methods: We conducted a systematic review of the literature and appraised PubMed, Medline, Web of science, ProQuest and Cochrane databases from 2000 to 2020. We assessed comparative outcomes including efficacy (as assessed by measuring major adverse cardiac events, target vessel revascularisation, target lesion revascularisation, all-cause mortality, target lesion myocardial infarction and stent thrombosis) and safety of VBT. Results: Of 1083 records obtained, a total of 8 retrospective studies met the inclusion criteria. In the included studies, major adverse cardiac events (MACE) rates ranged from 10% to 17.5% in the VBT group compared to 14.1% to 28.2% in the re-DES group at one year follow up. There were lower rates of target vessel revascularisation (VBT 10–22.8%; control 18–22.9%) and target lesion revascularisation (VBT 10–14.1%, Control 8–22.1%) between the VBT and re-DES groups. There were significantly low rates of all-cause mortality (1–5.4%), target lesion myocardial infarction (0–7%) and stent thrombosis (0–2.1%) in the VBT group at one year. Conclusions: VBT is considered to be an effective and safe treatment strategy in complex patients with multiple risk factors for DES-ISR in initial reports. There are no long-term comparison studies available beyond 1 year. There is a need for randomised controlled trials to objectively assess the role of VBT compared to DES and drug coated balloons.
Cardiovascular diseases are the leading cause of death globally with 17.9 million deaths each year, an estimated 31% of all deaths worldwide [1, 2]. Of these deaths, 85% are due to coronary artery disease (CAD) and cerebrovascular disease [3]. Globally, coronary artery disease affects around 126 million individuals which is approximately 1.72% of the world’s population [4]. The pathogenesis of CAD involves the development of atherosclerotic lesions in the coronary arteries [2].
The initial management of CAD included plain old balloon angioplasty (POBA) however there were significant drawbacks to this technique including re-narrowing of the coronary arteries due to acute vessel closure secondary to dissection, elastic recoil, late vascular remodelling and neointimal proliferation [2]. The rate of restenosis ranged from 30–60% [5]. Elastic recoil occurred in 5–10% of patients immediately (minutes to hours) after the procedure leading to a rebound occlusion of the artery [2]. This often led to severe complications including acute myocardial infarction and the need for emergency coronary artery bypass grafting (CABG) [2]. To overcome these issues, coronary stents (bare metal stents) were invented which prevented late recoil by scaffolding the balloon-dilated artery and sealing the dissection flaps [2]. However, the medium and long term follow up of bare metal stents (BMS) revealed 30–40% incidence of in-stent restenosis (ISR) secondary to proliferation and migration of smooth muscle cells within the stents [2, 6]. To further overcome ISR, drug eluting stents (DES) were introduced. There has been a recent review published by Megaly et al. [7] which examined the outcomes with VBT in recurrent ISR. Megaly et al. [7] included 5 observational studies totalling 917 patients with recurrent ISR (at least 2 episodes). They assessed outcomes such as target vessel revascularisation (TVR) (treated by Percutaneous coronary intervention/PCI or CABG), MI and all-cause mortality. Megaly et al. [7] demonstrated that recurrent ISR is difficult to treat with no consensus on optimal treatment strategy.
Given the absence of an optimum treatment strategy for this condition, we conducted an in-depth review of the different trials and demonstrated the variabilities in the comparisons of morbidities, methodologies and outcomes concluding the performance of VBT as a safe and effective treatment modality compared to other treatment modalities (including re-DES) among published studies.
The timeline of the various major interventions used for CAD and in-stent restenosis (ISR) is illustrated in Fig. 1 [2, 5, 8, 9, 10, 11, 12].
Timeline of major interventions for coronary artery disease and in-stent restenosis in humans. AMI, acute myocardial infraction; BMS, bare metal stent; BVS, bioresorbable vascular scaffold; CABG, coronary artery bypass grafting; CAD, coronary artery disease; DCB, drug coated balloon; DES, drug eluting stent; ISR, in-stent restenosis; VBT, vascular brachytherapy.
DES has emerged to be superior to BMS for coronary artery stenosis and hence have replaced them to a great extent [13, 14, 15, 16]. Despite the effectiveness of DES, there are reports of DES in-stent restenosis (DES-ISR) ranging from 3% to 20% within 5 years of stent implantation, depending on patient and lesion characteristics and DES type especially in patients with more complex lesions [13, 17, 18, 19, 20, 21]. ISR usually occurs between 3 and 20 months after stent placement and when DES-ISR occurs, it is usually not benign and very difficult to treat [17, 22, 23, 24]. The patients usually present with unstable angina (16–66%) or myocardial infarction (1–20%) [25]. Management of DES-ISR continues to be a challenge [20, 23, 26, 27]. Re-stenting of DES-ISR is associated with higher rates of recurrences and less favourable outcomes for the patients likely due to high-risk features that predisposes them to subsequent ISR [17, 23, 24, 26]. This is especially the case when DES is used for smaller arteries, long lesions, complex coronary lesions including diffuse lesions, in patients with diabetes or a history of CABG [15, 20, 23, 28, 29, 30, 31, 32]. Other indications include recalcitrant ISR and coronary bifurcation lesions [33, 34, 35].
Current research suggests that DES-ISR is mostly focal in nature and therefore easier to treat with likely better clinical outcomes compared to diffuse lesions [13, 20, 23, 28, 29, 34]. Cosgrave et al. [29] demonstrated the rate of angiographic restenosis to be 17.8% in the focal DES-ISR lesion group compared to 51.1% in the non-focal group (Odds ratio [OR] 5.0, 95% Confidence interval [CI] 1.1 to 23.0; p = 0.03). The incidence of target lesion revascularisation (TLR) in this study was 9.8% in the focal group and 23% in the non-focal group (p = 0.007) [29]. The late lumen loss was lower in the focal group (0.46 [Interquartile range (IQR) 0.11 to 0.83] compared with 1.08 [IQR 0.14 to 1.8]; p = 0.007) [29]. Thus, the pattern of DES-ISR is a predictor for subsequent reintervention [29, 36].
Current recommendations for DES-ISR.
Multiple alternatives are available for the treatment of DES-ISR including balloon angioplasty, drug coated balloons (DCB), de novo or repeat BMS implantation, repeated DES implantation using the same or a different DES, Vascular brachytherapy (VBT), CABG and more recently bioresorbable scaffolds [16, 18, 20, 26, 37].
BMS are unfortunately associated with a high restenosis rate compared to DES [26]. They have a limited role in the management of DES-ISR in situations where there is a high risk of bleeding secondary to dual antiplatelet therapy [26].
There is Level 1 evidence for the use of DES for treatment of restenosis or re-occlusion if no contraindications exist to extended dual antiplatelet therapy (DAPT) [16, 38, 39]. For this reason, repeat DES implantation for DES-ISR is a common clinical practice [13, 19]. It has been shown to be safe in randomized clinical trials [13, 40]. However, with the current recommendation of using re-DES for DES-ISR, there is debate whether to select same or different type of DES [26, 41, 42]. The reasoning behind switching to a different DES is to overcome drug resistance and specific polymer related problems [26]. However, switching of DES to a different type of DES has not been shown to be beneficial in clinical trials [20, 26]. There seems to be high restenosis recurrence rates post DES implantation for DES-ISR regardless of the use of same or different DES [13, 18, 19, 26].
Implantation of multiple stent layers in the coronary vessels comes with higher
local concentrations of anti-restenotic drugs, greater impairment of normal
vasomotion and increased inflammatory stimuli [13]. Overlying multiple stents
have been found to be suboptimal with high residual stenosis rates despite high
inflation pressures in some patients [19]. This can be attributed to the
under-expansion of the stents which further predisposes to ISR and prove to be a
challenge for further intervention [19, 20, 25]. For this reason, interest has
shifted to DCB that can deliver effective neointimal suppression without
implanting another stent layer [13, 14]. There is evidence to suggest that DCBs
require a shorter course of DAPT (~1 month) compared to DES
[43, 44, 45]. A meta-analysis by Siontis et al. [14] demonstrated everolimus
eluting stent (DES) to deliver best angiographic and clinical outcomes followed
by drug coated balloons. Some randomised trials have shown DCB to deliver
comparable results to DES [13, 39]. However, a recent RIBS-IV trial investigating
intra- stent restenosis of drug eluting stents: paclitaxel-eluting balloon vs
everolimus eluting stent (EES) trial compared second generation everolimus
eluting DES to DCB for DES-ISR [20]. It showed better angiographic and clinical
outcomes with DES over DCB (minimal lumen diameter: 2.03 mm vs 1.80 mm,
p
There is a concern that patients with DES-ISR should be maintained on DAPT until
a complication occurs due to the high likelihood of recurrence of ISR in these
patients [23]. In addition, there has been a suggestion to consider patients who
either have contraindications or show noncompliance to long term DAPT for
coronary artery bypass grafting (CABG) [23]. CABG provides almost complete
revascularisation and hence has better survival and quality of life [46, 47]. It
has a role in patients with recurrent episodes of diffuse ISR in large vessels,
left anterior descending/left main coronary artery lesions and in patients with
multivessel disease [39, 47]. Certain other characteristics such as being
diabetic, having left ventricular dysfunction (Ejection fraction
Ariyaratne et al. [48] assessed the cost effectiveness of percutaneous coronary intervention compared to surgery for multivessel coronary artery disease. They preferred CABG over re-DES to be the cost-effective treatment modality in the long run (over 10 years or lifetime) [48]. Re-DES has higher index procedure costs compared to CABG due to cost of stents and other consumable devices [49]. At short term (~1 year), re-DES is economically superior to CABG across various studies [48]. CABG likely offers survival advantage in the long run however requires longer recovery period and need for intensive rehabilitation post-surgery [48]. Due to this, the costs associated with post procedure hospital stay and physician costs are significantly higher in the CABG group [49]. For left main coronary artery lesions, re-DES is superior to CABG [48]. Results from the freedom trial demonstrated higher life expectancy and quality adjusted life expectancy in the CABG group compared to the re-DES group at 5 year follow up [49]. Re-DES is still preferred strategy for patients with less complex disease due to clinical and economic reasons [50]. Similarly, DCB is a cost-effective treatment strategy in the long run despite the high initial costs [51].
Due to the above issues, there has been recent interest in the use of bioresorbable scaffolds for the treatment of ISR as they dissolve over a period of time (~3–4 years) not leaving a trigger for restenosis [24, 52]. However, this is still in early stages of development with some initial trials not showing any advantages of bioresorbable scaffolds over DES with associated small but significant rates of stent thrombosis [24, 53]. A recent meta-analysis by Chen et al. [54] further demonstrated that bioresorbable scaffolds have higher risk of target lesion failure, stent thrombosis and cardiac death than DES.
Historically VBT was used with some degree of success reducing re-stenosis however; this was limited by the availability of equipment and the expertise of the user [20, 23, 33, 37, 55, 56]. Fig. 2 summarizes some of the advantages (in red) and disadvantages (in blue) of each of VBT, DCB, CABG and re-DES for complex DES-ISR.
Venn diagram demonstrating the advantages (blue) and disadvantages (red) of each of VBT, DCB, CABG and re-DES for DES-ISR. CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy; DCB, drug coated balloon; DES, drug eluting stent; ISR, in-stent restenosis; LAD, left anterior descending; LMCA, left main coronary artery; QOL, quality of life; VBT, vascular brachytherapy.
VBT was the first effective antiproliferative treatment for ISR [57]. It delivers radiation to the areas of in-stent stenosis thereby inhibiting neointimal formation within the stent and exerting anti-inflammatory effects [17, 35, 58]. Both beta radiation and gamma radiation have been used effectively to treat coronary ISR [59, 60, 61]. At one stage, it’s use was widespread, and it was available across hundreds of centres across US [57] however, currently its use is very limited [20, 23]. Contributing factors include the improved clinical outcomes with re-DES, necessity for specialized equipment, subspecialty expertise, complexity of the VBT procedure, issues with radioprotection/radiation dosing and the lack of uptake outside of expert centres [13, 20, 23, 28, 55, 62, 63]. There are limited centres available to deliver VBT with a further limitation of availability of staff with licences to deliver the treatment [62].
Patients with ISR present with acute coronary syndromes (ACS) that require urgent revascularization [64]. To deliver brachytherapy in such scenarios, a team comprising of an interventional cardiologist, radiation oncologist and radiation physicist is required at a short notice which can prove logistically challenging [64].
Some of the practical considerations that hinder widespread availability and use of VBT are dosimetry, shielding, handling and disposal of the radioactive source, operator certifications and regulatory approval [63]. A number of radioisotopes have been used effectively in the past at a range of doses for treating coronary artery disease and ISR as highlighted in the studies included in this review. Certain radioisotopes require medical personnel to leave the room during treatment however certain particles including beta particles has minimal radiation concerns regarding whole body exposure and only requires precautions during handling of these sources especially to the fingers and hands [63]. Once the procedure is completed, it is essential to check the patient, the equipment and the laboratory for any potential contamination. It is further essential to secure the radioactive source in a special shielded container [63]. Delivery of radiation therapy for ISR requires a multidisciplinary approach with only the radiation oncologist being able to prescribe radiation therapy. Hence, the ability to deliver radiation therapy requires specific training and certification for the cardiology team.
Furthermore, there is a role for repeat VBT and stenting post VBT if required. Repeat VBT to the site of stent stenosis has been found to be effective and safe if spaced 12 months from the initial therapy [17, 33]. Zahn et al. [65]have demonstrated that coronary stenting with sirolimus- eluting stents in patients with restenosis after VBT is safe and effective [66].
Due to limited use of VBT for DES-ISR currently, there is lack of available data comparing cost effectiveness of VBT compared to re-DES for DES-ISR. A study by Reynolds et al. [67] comparing Sirolimus eluting stent (SES) to brachytherapy for ISR demonstrated that SES to be economically superior to VBT over a period of 1 year due to reduced rate of repeat TVR, any repeat revascularisation, reduced need for CABG and a trend towards a lower cardiac rehospitalisation rate. The DES (SES) group was associated with higher initial device costs however this was offset by higher physician fees associated in the brachytherapy group such that the total cost for the index procedure and hospitalisation were similar in the two groups [67]. This was mainly due to the need for presence of a radiation oncologist during the procedure [67].
Edge effect in Vascular Brachytherapy.
There have been concerns about the edge effect and late recurrences of stenosis with radiation therapy for ISR [33, 35, 58, 68]. Krotz et al. [58] have described edge effect as a phenomenon of excessive neointimal proliferation at the edges of an irradiated segment which is likely due to axial dose fall off and/or barotrauma by the angioplasty procedure. Thus, edge effect can be significantly reduced by using appropriate radiation source length to avoid geographic miss, the disparity of the effective axial radiation length and the length of the vessel segment having been injured by the angioplasty procedure [58].
Late stent thrombosis.
The issue of late stent thrombosis exists for both DES and VBT [15, 23, 25, 69, 70, 71]. The pathophysiology of late thrombosis in DES has been attributed to delayed arterial healing characterized by persistent fibrin deposition and incomplete endothelialisation around stent struts as long as 4 years after the intervention [30]. DES thrombosis has been associated with renal insufficiency, diabetes, long total stent length, bifurcation stenting, incomplete stent expansion, poor stent apposition, stent strut penetration into a necrotic plaque core, left ventricular dysfunction, stent implantation during ACS and treatment of diffuse ISR [30]. Late recurrence of stenosis usually happens 6 months to 1-year post VBT [15]. There have been some reports to suggest that extending the use of DAPT to 6 to 12 months after irradiation can significantly reduce the rate of late thrombosis [35, 58, 72].
PubMed, Medline, Web of science, Proquest and Cochrane database were systematically searched for studies that assess the efficacy of VBT for DES-ISR. The following medical subject heading terms were included: (coronary brachytherapy or vascular brachytherapy) and (DES restenosis or drug eluting stent restenosis). The reference lists of all included studies were manually searched. The search was conducted for studies published since the year 2000. Fig. 3 summarizes the search selection process.
Flowchart describing search and study selection process. This search strategy identified 1083 records which were screened (removing duplicates, triplicates, irrelevant articles, articles with last layer bare metal stent, articles with no access to full text) and 8 studies were identified for inclusion.
Case reports [73, 74] and initial clinical experience [75] were not included in this review. The study by Kim et al. [76] was excluded as there were no results available for the brachytherapy group for DES restenosis. The authors reported results for conventional treatment for DES restenosis which included both lesions treated with cutting balloon and lesions treated with brachytherapy [76]. The study by Moussa et al. [77] and Mishkel et al. [78] were excluded due to lack of data as there was only one patient who received VBT for DES restenosis in both studies. The study by Ohri et al. [79] assessed the safety of VBT in patients with DES restenosis only. The study by Buchanan et al. [24] was excluded as it requires further analysis of data which was not available to determine the effectiveness of VBT for DES restenosis. The study by Chen et al. [21] was excluded as it did not specify whether the last stent layer was BMS or DES. Megaly et al. published two studies in 2020 [80, 81]. Their study which further characterized the data to determine effects of atherectomy combined with VBT was excluded [81]. There were no studies identified that directly compare VBT to DCB.
All eligible studies are retrospective in nature. The patients in this study
either had VBT for DES-ISR initially or presented with symptoms including angina
requiring VBT (Table 1, Ref. [18, 22, 35, 80, 82, 83, 84, 85]). The patients presenting
with ST segment elevation myocardial infarction (STEMI), cardiogenic shock or
angiographic stent thrombosis were excluded from some of the studies (Table 1).
The baseline clinical characteristics of the patients in the individual studies
are summarized in Table 2 (Ref. [18, 22, 35, 80, 82, 83, 84, 85] Majority of the patients
had cardiac risk factors including age
Clinical Study (year) | Inclusion criteria | Exclusion criteria | First or second-generation DES |
Megaly et al. (2020) [80] | Patients undergoing VBT for DES-ISR between January 2014 and September 2018 at Minneapolis Heart Institute at Abbott Northwestern Hospital. | Patient with DES-ISR lesion treated with brachytherapy in the past. | Mostly second-generation DES. |
Meraj et al. (2019) [83] | Patients undergoing VBT for DES-ISR who presented with ACS or chronic stable angina and were found to have ISR on quantitative coronary stenosis assessment (QSA) between January 2011 and Oct 2016 at Northwell. | Not specified. | |
Varghese et al. (2018) [35] | Patients with angina symptoms or ischemia on non-invasive tests undergoing PCI for recurrent DES restenosis with at least 2 layers of stents with last layer being DES between 2011–2015 at Mount Sinai Hospital, New York. | Patients presenting with cardiogenic shock or stent thrombosis. | First generation DES in 14%, second generation DES in 86%. |
Mangione et al. (2017) [82] | Patients undergoing VBT for resistant DES-ISR between September 2009 to March 2015 at the Brigham and Women’s Hospital. | First generation DES in 5% and second generation DES in 19%. Both in 16%; unknown in 60%. | |
Negi et al. (2016) [84] | Patients with angina and angiographic evidence of DES-ISR undergoing VBT between 2004 and 2012 selected from an ongoing clinical PCI registry at Medstar Washington hospital centre. | Patients presenting with STEMI, cardiogenic shock, angiographic evidence of stent thrombosis or with fewer than 3 years of follow up. | First generation DES in 64% and second generation DES in 36% of patients. |
Maluenda et al. (2012) [22] | Patients presenting with recurrent symptoms of ischemia and angiographic ISR after DES implantation between May 2003 and September 2008 at Washington hospital centre. | Patients presenting with STEMI, cardiogenic shock or angiographic evidence of stent thrombosis. | First generation DES (PES/SES). |
Bonello et al. (2008) [18] | Patients presenting with ischemia/stable or unstable angina (related to the restenotic lesion) and undergoing VBT for DES-ISR with completion of at least 12 months follow up between April 2003 and June 2006 at Washington Hospital centre. | Patients presenting with STEMI, cardiogenic shock or angiographic evidence of stent thrombosis. | First generation DES (PES/SES). |
Torguson et al. (2006) [85] | Patients presenting with stable/unstable angina with documentation of ischemia and angiographic evidence of restenotic lesion within 1 or more DES since 2002 to 8 independent centres. | Patients presenting with STEMI, cardiogenic shock or angiographic evidence of stent thrombosis or patients who were unable to take long term antiplatelet therapy. | First generation DES. |
The control group included patients who met the above inclusion/exclusion criteria and underwent PCI with DES implantation at Washington Hospital centre. | |||
ACS, Acute coronary syndrome; BA, Balloon Angioplasty; DES, Drug eluting stent; ISR, in-stent restenosis; IVUS, Intravascular ultrasound; PES, Paclitaxel eluting stent; PCI, Percutaneous coronary intervention; SES, Sirolimus eluting stent; STEMI, ST segment elevation myocardial infarction; VBT, Vascular brachytherapy. |
Clinical Study | Megaly et al. [80] | Meraj et al. [83] | Varghese et al. [35] | Mangione et al. [82] | Negi et al. [84] | Maluenda et al. [22] | Bonello et al. [18] | Torguson et al. [85] |
Age (years) | 65.7 |
66.6 |
65 |
66 |
65 |
63.7 |
63 |
61.6 |
BMI (Kg/m |
- | 29.6 |
29.2 |
- | 30.1 |
29.9 |
29.9 |
- |
Male (%) | 99 (69%) | 192 (66%) | 248 (75%) | 68 (67%) | 115 (62%) | 350 (62%) | 59 (59%) | 71 (64%) |
Smokers (%) | - | 18 (6.2%) | 46 (14%) | 53 (53%) | 115 (62%) | 104 (18.5%) | 12 (13.3%) | 64 (58%) |
Hypertension | - | 282 (97.2%) | 325 (99%) | 98 (98%) | 177 (95%) | 526 (93.4%) | 90 (90.9%) | 85 (77%) |
Dyslipidaemia | 142 (99.3%) | 273 (94.1%) | 324 (98.7%) | 101 (100%) | 175 (94%) | 533 (95%) | 92 (92.9%) | 92 (83%) |
Diabetes | 72 (50.3%) | 167 (57.6%) | 192 (58.5%) | 53 (53%) | 87 (46.5%) | 244 (43.7%) | 44 (44.4%) | 48 (43.2%) |
Prior CABG | 77 (54%) | 138 (47.6%) | 133 (40.5%) | 48 (48%) | 102 (55%) | 219 (39.2%) | 55 (56.7%) | 39 (35%) |
BMI, Body Mass Index; VBT, Vascular brachytherapy; CABG, Coronary artery bypass grafting. |
The lesion characteristics and radiation therapy used in each of the studies are summarized in Table 3. Most of the patients had focal lesion on angiography in the study by Negi et al, and Torguson et al. [84, 85]. The strontium/Yttrium 90 beta source was used across all studies with some utilization of the phosphorus-32 beta source and iridium-192 beta source (Table 3, Ref. [18, 22, 35, 80, 82, 83, 84, 85]).
Clinical Study | Megaly et al. [80] | Meraj et al. [83] | Varghese et al. [35] | Mangione et al. [82] | Negi et al. [84] | Maluenda et al. [22] | Bonello et al. [18] | Torguson et al. [85] |
Total no of lesions | 143 lesions | - | - | - | 283 lesions | 582 lesions | 122 lesions | |
Re-stenotic pattern | Diffuse in 49.7% | - | - | Diffuse in 53% | Diffuse in 23% | Diffuse in 20.1% | Diffuse in 25% | Diffuse in 26% |
Focal in 35.7% | Focal in 35% | Focal in 73% | Focal in 50.2% | Focal in 44% | Focal in 63% | |||
Proliferative in 3.5% | Proliferative in 12% | Proliferative in 4% | Proliferative in 4.1% | Proliferative in 30% | Proliferative in 11% | |||
Chronic total occlusion in 8.4% of the lesions | Intermediate in 25.3% | |||||||
Type of radiation | Strontium-90/Yttrium beta source | Strontium/Yttrium-90 beta source | Strontium 90/Yttrium 90 isotope | Strontium 90/Yttrium beta isotope | Strontium 90/Yttrium beta isotope | Strontium 90/Yttrium beta isotope | Strontium 90/Yttrium beta isotope | |
Phosphorous-32 beta source | Phosphorous-32 beta source | Phosphorous-32 beta source | ||||||
Iridium-192beta source | Iridium-192 beta source | Iridium-192 beta source | ||||||
Radiation dose | 18.4–36.6 Gy | 19.5 |
18.4–23 Gy | 18–23 Gy | 23–25 Gy | 18–23 Gy | 23–25 Gy | 18–23 Gy |
20 Gy | 20 Gy | 20 Gy | ||||||
15 Gy | 18–21 Gy | 15 Gy | ||||||
Treatment length | 36.6 |
40–60 mm | 30–60 mm | - | 26.30 |
- | - | 46.65 |
Lesion location | ||||||||
LM | - | 12 (4.1%) | 8 (2.4%) | 8 (8%) | - | 19 (3.3%) | 6 (4.9%) | 4 (3.4%) |
LAD | 77 (26.5%) | 125 (38.1%) | 17 (18%) | (21%) | 179 (30.8%) | 26 (21.3%) | 41 (36.6%) | |
LCx | 95 (32.7%) | 126 (38.4%) | 19 (19%) | (23%) | 107 (18.4%) | 25 (20.5%) | 18 (16%) | |
RCA | 79 (27.2%) | 114 (34.8%) | 40 (40%) | (35%) | 203 (34.9%) | 42 (34.34%) | 35 (31.3%) | |
Lesion length (mm) | - | 22.6 |
- | 10–25 mm | - | - | 16 |
- |
Lesion diameter (mm) | 3.5 |
3.1 |
- | - | - | - | - | - |
LAD, Left anterior descending; LCx, Left circumflex; LM, Left main artery; RCA, Right coronary artery; VBT, Vascular brachytherapy. |
Multiple studies have demonstrated lower rates of MACE with VBT compared to re-DES for DES-ISR (Table 4, Ref. [18, 22, 35, 80, 82, 83, 84, 85, 86], Supplementary Table 1), however, due to the paucity of data one study showed lower rates of MACE with VBT while another study showed lower rates of MACE with re-DES. MACE rates ranged from 10% to 17.5% in the VBT group when compared to re-DES group where it ranged from 14.1% to 28.2% at one year follow up. In studies with no comparison group, the MACE rates ranged from 16.8% to 26% at 1 year (Table 4). Further follow up at 3 years revealed MACE rates of 31.9 (TLR MACE in the study by Negi et al. [84]) to 34.3% in the study by Megaly et al. [80].
Clinical study | Megaly et al. (2020) [80] | Meraj et al. (2019) [83] | Varghese et al. (2018) [35] | Mangione et al. (2017) [82] | Negi et al. (2016) [84] | Maluenda et al. (2012) [22] | Bonello et al. (2008) [18] | Torguson et al. (2006) [85] | |
Comparison group | Nil | Nil | Non-VBT |
Nil | Nil | Re-DES | Nil | Re-DES | |
Balloon Angioplasty | |||||||||
Total number of patients | 116 | 290 | 328 | 101 | 186 | 563 | 99 | 111 | |
VBT | 116 | 290 | 197 | 101 | 186 | 132 | 99 | 61 | |
Control arm | NA | NA | 131 | NA | NA | 327 (re-DES) | 0 | 50 | |
104 (balloon angioplasty) | |||||||||
Follow up time | Median follow up of 24.7 months | 24 months | 1 year | 3 years | 3 years | 1 year | 1 year | 8 months | |
Maximum follow up 63 months | |||||||||
Length of DAPT | Indefinite | Indefinite | 1 year in DES arm and 3 years in VBT arm | Indefinite | Minimum of 12 months | Minimum of 12 months | Indefinite aspirin and at least 12 months of clopidogrel | Indefinite aspirin with at least 6 months of clopidogrel in the re-DES group and at least 12 months in the VBT group | |
Immediate success of VBT | 100% | - | 100% | 98% | 100% | 99.8% | 100% | Not specified | |
MACE |
|||||||||
VBT (1 year) | 20.1% | - | 13.2% | - | 16.8% | 17.5% | 26% | 10% | |
Control (1 year) | - | - | 28.2% | - | - | 14.1% (re-DES) | - | 24% | |
18% (balloon angioplasty) | |||||||||
TVR | |||||||||
VBT (1 year) | - | - | 15.2% | 24% | 19.1% | 22.8% | 22% | 10% | |
Control (1 year) | - | - | 22.9% | - | - | 19.5% (re-DES) | - | 18% | |
19.6% (balloon angioplasty) | |||||||||
TLR | |||||||||
VBT (1 year) | 18.9% | 12.4% | 10.7% | - | 12.1% | 14.1% | 10% | 10% | |
Control (1 year) | - | - | 22.1% | - | - | 10.3% (Re-DES) | - | 8% | |
14.6% (balloon angioplasty) | |||||||||
All- cause mortality | |||||||||
VBT (1 year) | - | 1.7% | 1% | - | 5.4% | 4.3% | 4% | 2% | |
Control (1 year) | - | - | 4.6% | - | - | 3.8% (Re-DES) | - | 4% | |
3.5% (balloon angioplasty) | |||||||||
Target lesion MI |
|||||||||
VBT (1 year) | 5.6% | 3.4% | 3% | 0% | 1.5% | 2.7% | 7% | 2% | |
Control (1 year) | - | - | 6.9% | - | - | 2.5% (Re-DES) | - | 2% | |
2.3% (balloon angioplasty) | |||||||||
Stent thrombosis | |||||||||
VBT (1 year) | 2.1% | - | 1% | 1% | 0.5% | 0% | 2% | 0% | |
Control (1 year) | - | - | 1.5% | - | - | 1.2% (Re-DES) | - | 0% | |
0% (balloon angioplasty) | |||||||||
ACS, Acute coronary syndrome; BA, Balloon angioplasty; BMS, Bare metal stent;
DAPT, Dual antiplatelet therapy; ISR, In-stent restenosis; MACE, Major adverse
cardiac events; MI, Myocardial Infarction; Re-DES, Repeat DES; TLR, Target lesion
revascularisation; TVR, Target vessel revascularisation; VBT, Vascular
brachytherapy. Megaly et al. [80]- TLF/MACE composite of TLR (with PCI or CABG), target lesion MI and target lesion related cardiac death; Varghese et al. [35]- MACE composite of TLR, MI and all cause death; Negi et al. [84]- MACE composite of TLR/TVR (the reported value is TLR MACE), MI and death; Maluenda et al. [22]- MACE composite of TLR, Q wave MI and death/all-cause mortality; Bonello et al. [18]- MACE composite of TVR, MI and death; Torguson et al. [85]- MACE defined as TVR, Q wave MI and death. Megaly, Negi and Varghese et al. [35, 80, 84] used the universal definition of myocardial infarction [86]; Meraj et al. [83] defined MI as creatinine kinase or MB fraction greater than 10 times the upper limit of normal, or the development of a new pathological Q wave on ECG; Maluenda et al. [22] defined Q wave MI as an elevation in creatine kinase-MB |
Varghese et al. [35] demonstrated VBT to be superior to the non-VBT group for multilayered DES-ISR. They found significantly lower MACE in the VBT group (13.2%) compared to the non-VBT group (28.2%) at one year follow up (p = 0.01) [35]. Thus, VBT has been shown to be a feasible option for patients with multilayered DES-ISR.
Maluenda et al. [22] also compared VBT with balloon angioplasty for DES-ISR and the results were comparable between the two groups at one year with MACE of 17.5% in the VBT group, 14.1% in the re-DES group and 18% in the balloon angioplasty group (p = 0.57).
There were comparable rates of TVR between the VBT and re-DES groups in the study by Maluenda et al. [22] (22.8% in the VBT group, 19.5% in the re-DES group, 19.6% in the balloon angioplasty group; p = 0.79) at one year. The TVR rates ranged from 10% to 24% in the VBT group at one year (Table 4). There was an increased proportion of TVR in the non-VBT/DES group (ranging from 18–22.9%) compared to the VBT group (10–22.8%) as highlighted in Table 4. Mangione et al. [82] demonstrated an increase in TVR in the VBT group from 24% at one year to 42% at 3 years however there is no comparison group available for this study.
In the studies by Maluenda et al. and Torguson et al., there were comparable TLR rates of 14.1% and 10% at one year compared to 10.3% (p = 0.41) and 8% (p = 1.0) in the re-DES group [22, 85]. Varghese et al. [35] demonstrated TLR of 10.7% in the VBT group compared to 22.1% in the non-VBT group at one year (p = 0.07). There was increase in TLR in the VBT group from 18.9% at one year to 30.8% at 3 years in the study by Megaly et al. [80] and increase from 12.1% at one year to 19.4% at 3 years in the study by Negi et al. [84] however there are no comparison groups in these studies.
In the studies that compared VBT to re-DES/other modalities, all-cause mortality ranged from 1% to 4.3% in the VBT group at one year compared to 3.5% to 4.6% in the re-DES/non-VBT group (Table 4). Overall all-cause mortality ranged from 1% to 5.4% in the VBT group at one year (Table 4).
There was an increase in the all-cause mortality in the VBT group from 1.7% at one year to 2.1% at 2 years in the study by Meraj et al. [83]. Similarly, there was an increase in all-cause mortality from 5.4% in the VBT group at one year to 13.2% at 3 years in the study by Negi et al. [84].
Target lesion MI rates ranged from 0 to 7% in the VBT group compared to 2 to 6.9% in the re-DES group (Table 4). In the study by Varghese et al. [35], there was higher rates of target lesion MI in the non-VBT group compared to the VBT group at one year (6.9% in the re-DES group, 3% in the VBT group; p = 0.13). There was an increase in the rate of target lesion MI over a period of one year to three years across all studies that followed patients for that duration and ranged from 6% to 10.5% in the VBT group [80, 82, 83, 84].
There are significantly lower rates of stent thrombosis between the VBT and control groups (Table 4). The stent thrombosis rates ranged 0–2.1% in the VBT group compared to 0–1.5% in the non-VBT/re-DES group (Table 4). There was no significant increase in the stent thrombosis rates at 3 years in any of the studies. The patients included in these studies were on dual antiplatelet therapy for at least 12 months (Table 4).
Brachytherapy has been established to be a safe treatment modality for DES-ISR particularly in complex patients [18, 56, 79, 84, 87].
The studies included in this review demonstrated VBT to be a safe procedure with
high rate of immediate procedural success, no procedural adverse events in
This review compiles studies that specifically address the question of role of VBT for DES-ISR. Our review demonstrated VBT to be a safe and effective treatment modality for complex patients having multiple risk factors for DES-ISR. VBT may have improved clinical outcomes that include MACE, TVR, TLR and lower target lesion MI at 1 year compared to re-DES for DES-ISR and also multilayered ISR although there is paucity of data available. Our review demonstrated low rates of stent thrombosis in both VBT (0–2.1%) and re-DES/non-IVBT groups (0–1.5%) secondary to the use of DAPT for at least one year in both groups, hence preventing late stent thrombosis.
There are some inconsistencies between the definitions of MACE outcomes and MI in the eligible studies. These inconsistencies along with different inclusion and exclusion criteria render the lack of generalizability of the results (Tables 1,4) and it makes it challenging to compare the findings between studies. The criteria for MACE and MI need to be standardised across various studies to enable direct comparison of outcomes. Certain studies included patients who presented for VBT for DES-ISR with no exclusion criteria [82, 83] whereas some studies excluded patients with features such as cardiogenic shock, stent thrombosis, STEMI or inability to take long term DAPT [18, 22, 35, 84, 85] which could impact the findings.
The 2018 European Guidelines on Myocardial revascularization recommends re-DES and DCB for the management of DES-ISR with no role for vascular brachytherapy [39]. There is still a belief that DCB angioplasty could be less effective than repeat DES for DES-ISR [89]. A recent meta-analysis by Giacoppo et al. [89] compared DCB to repeat DES stenting for DES-ISR. They pooled individual patient data from the 10 randomized clinical trials comparing DCB with DES till date [89]. Their analysis demonstrated DCB angioplasty to be less effective than repeat DES implantation in the treatment of DES-ISR at 3 years [89]. The risk of primary safety endpoint which was a composite of all-cause death, MI, or target lesion thrombosis at 3 years was higher with the DCB angioplasty than with repeat DES implantation (20.3% vs 13.4%; hazard ratio [HR] 1.58, 95% CI 1.16 to 2.13) [89]. Similarly, in the RIBS IV study, which compared 3-year safety and efficacy of drug eluting balloons (DEB) and EES in patients with DES-ISR, demonstrated reduced combined clinical outcome measure of cardiac death, MI and TLR in the EES arm compared to the DEB arm (19 [12.3%] vs 31 [20.1%]; p = 0.04; HR 0.57 [95% CI 0.34 to 0.96]), driven by a lower need for TLR (11 [7.1%] vs 24 [15.6%]; p = 0.015; HR 0.43 [95% CI 0.21 to 0.87]) [90]. However, the recently published results from the DEB-DRAGON-Registry which compared the 3-year outcomes following thin-strut DES versus DEB for treatment of ISR demonstrated no significant differences in TLR (11.2% vs 11.2%; HR 0.91 [95% CI 0.55 to 1.51], p = 0.707), TVR (13.4% vs 14.2%; HR 0.86 [95% CI 0.55 to 1.36], p = 0.523), and device oriented composite end point, defined as a composite of cardiac death, TLR and target vessel MI (14.2% vs 14.2%; HR 0.91 [95% CI 0.58 to 1.42], p = 0.667) between the thin-DES and DEB group at 3 years [91].
Vascular brachytherapy was once one of the primary strategies for management of
ISR in both native coronary arteries and saphenous venous grafts (level I
evidence) [37]. Its role diminished once drug eluting stents came into
existence and proved to have better clinical outcomes compared to VBT. In this
review, the rates of TVR ranged from 10 to 24% in patients with DES-ISR at one
year (Table 4). The patients in the VBT group are generally sicker with more
complex disease and hence it is not a fair comparison. The retrospective studies
included in this review had very complex patients with multiple cardiac risk
factors including hypertension (
DES-ISR involves neointimal hyperplasia secondary to tissue injury caused by PCI and stent implantation within an arterial segment [64]. This cellular proliferation expands into the media and then further into the arterial lumen. VBT delivered locally targets this neoproliferative process [64]. To cover the detailed pathophysiology is beyond the scope of this review however we believe that VBT still has a role in this complex subset of patients. Currently, there are a few centres across the world that continue to utilise VBT for this complex subset of patients with DES-ISR [92, 93]. Unfortunately, there is lack of long-term studies with no randomised studies comparing VBT to re-DES or DCB for DES-ISR. This is likely due to the practicality issues as outlined earlier in this review.
It is noted that patients with ISR require an urgent revascularisation procedure which can be challenging. There are alternative approaches to using VBT for these patients including either deferring the coronary intervention until the brachytherapy procedure or if the patient needs an urgent intervention, to perform balloon angioplasty alone (without a stent) and refer for staged brachytherapy within 7 to 10 days [94, 95]. There have been publications of case reports recently whereby VBT has been used in patients with multiple prior DES-ISR, POBA, balloon angioplasty failure with good clinical response [96]. A recent study by Rawal et al. [97] has further demonstrated VBT to improve quality of life and patient reported outcomes in short and median term. There are generally significantly worse outcomes when VBT is combined with DES or BMS and hence this should be avoided [21].
VBT can potentially prove to be a cost-effective treatment modality considering radiation therapy centres are expanding across the world with the radiation oncologist and the rest of the radiation delivery team (including radiation therapists, radiation oncology medical physicists, and nurses) present on site. Furthermore, the source required for vascular brachytherapy is available onsite as well. Hence, there is minimal additional cost involved to deliver vascular brachytherapy for DES-ISR. The most commonly used source for vascular brachytherapy in the included studies was the beta catheter system which does not require additional lab or staff shielding [21]. The beta radiation can only penetrate a very short distance in human tissues with no radioactivity detectable on the patient’s body surface on routine surveillance scans during VBT [21].
It is recommended that future randomised controlled trials use intravascular
imaging, either intravascular ultrasound (IVUS) or optical coherence tomography
(OCT). Intravascular imaging has an important role in guiding management by
providing important insights into the mechanism of DES-ISR [7]. As an adjunct to
angiography, intravascular imaging provides tomographic assessment of lumen area,
plaque size, distribution and composition [98]. IVUS detects the presence of
neointimal hyperplasia within the stent, stent underexpansion, edge problems and
stent fracture [25, 26, 28, 99]. It can highlight whether the ISR is focal or
diffuse which is a predictor for future reintervention [29, 99]. OCT further
provides a better axial resolution (15
It is recommended that future trials include patients who can take DAPT for at least 12 months to prevent late stent thrombosis [80]. Furthermore, future trials will need to ensure longer length of irradiation to cover areas proximal and distal to the lesions to prevent geographic mismatch/higher incidence of edge restenosis [80].
No long-term comparison of outcomes are available beyond 1 year between VBT and re-DES in the studies available. All of the studies are retrospective in nature and most of the studies are single centre studies. There is a lack of consistent measurement even when defining MACE across various studies which makes comparison of the studies challenging. In addition, there was limited use of intravascular ultrasound (IVUS) or intravascular optical coherence tomography (OCT) in studies reviewed despite its importance in determining the intravascular pathology at a tissue level.
We note the costs involved in setting up a centre for VBT however if a radiation therapy setup is already available at a centre, the additional cost involved for delivering VBT should be minimal.
Our review recognised VBT to be a safe and effective treatment modality for complex patients with multiple risk factors for DES-ISR. It may have a potential role in the future management of DES-ISR. VBT has been shown to be an effective and safe treatment strategy in complex patients with multiple risk factors for DES-ISR in initial reports.
There is limited evidence available from retrospective studies, long term (
AM, SSD, DB and JD contributed to the design of the review. AM acquired the data and wrote the first detailed version of the draft. AM, SSD, JD and DB contributed to the detailed review of the literature. AM, SSD, JD and DB critically revised the intellectual content of this work.
Not applicable.
We would like to thank all the peer reviewers for their opinions and suggestions.
This research received no external funding.
The authors declare no conflict of interest.