Percutaneous coronary intervention followed by intravascular brachytherapy for management of drug-eluting stents in-stent restenosis in patients with complex coronary artery lesions

Abstract

Purpose

Coronary artery disease is the leading cause of death for both men and women in the United States. Percutaneous coronary intervention with drug-eluting stents (DES) has been a major advance in treatment. In-stent restenosis (ISR) occurs in up to 10% of patients, and is often managed with repeat DES placement. However, when DES-ISR occurs, treatment options remain limited. Angioplasty followed by intravascular brachytherapy (IVBT) is one option for such patients.

Material and methods

Outcomes of 78 patients (91 vessels) treated with angioplasty followed by strontium-90 IVBT from 2016-2024 were reviewed. Following vessel preparation with angioplasty, an intravascular catheter was introduced into the index lesion. Radiation was prescribed to an area encompassing the angioplasty injury length with a minimum 10 mm margin. Radiation dose delivered was 23 Gy or 18.4 Gy according to protocol standard. Major adverse cardiac events (MACE), including myocardial infarction and stroke as well as all causes of death were analyzed, as was the need for repeat angioplasty or intervention.

Results

All patients had at least 2 drug-eluting stents previously deployed in the affected vessel, and were not technically suitable for additional stenting. One patient expired while receiving intervention due to cardiac arrest, with no other intraprocedural toxicities reported. Median follow-up was 22.8 months (range, 0.9-60.6 months), and forty-four percent of patients experienced symptomatic relief. Major cardiac adverse events rates at interval follow-up of IVBT included myocardial infarction (18%) and stroke (5%). Death from any cause occurred in 16% of patients at a median time of 9.3 months post-treatment (range, 0.5-29.5 months).

Conclusions

Angioplasty followed by intravascular brachytherapy is a safe and effective therapy for patients with complex coronary artery lesions experiencing stent-in-stent restenosis, who have few other treatment options.

Purpose

Coronary artery disease (CAD) is a condition that occurs when blood flow to the myocardium is reduced usually due to atherosclerotic plaque changes in the lumen of coronary vessels [1]. These plaques can remain stable or progressively narrow the vessel’s lumen, reducing the blood flow to the myocardium and leading to angina-like symptoms. Alternatively, some plaques may rupture and cause thrombosis, resulting in sub-total or total occlusion of distal coronary vessels, which can manifest in a spectrum of acute coronary syndromes (ACS), such as unstable angina, non-ST elevation myocardial infarction (NSTEMI), or ST elevation myocardial infarction (STEMI) [1]. In the United States, approximately 20.1 million adults aged above 20 years have CAD, constituting approximately 7.2% of the general population. Coronary artery disease is the leading cause of mortality, accounting for approximately 20% of all deaths in the United States, and being responsible for 610,000 deaths annually [2-4]. The management of symptomatic ACS is largely accomplished via pharmacotherapy and percutaneous coronary intervention (PCI), using coronary stents to restore the vascular flow. Stenting has been a major advancement in treatment, with over 600,000 stents deployed annually [5]. Among various coronary stents, bare metal stents (BMS) and drug-eluting stents (DES) are the two most popular options. Active antiproliferative pharmacological agents, such as paclitaxel and sirolimus as the active agents for DES, exhibit anti-inflammatory and antiproliferative properties, thereby suppressing neointimal hyperplasia [6]. This results in decreased ISR rate by 50-70% in comparison with BMS, showing improved clinical outcomes in patients undergoing PCI [6, 9-11]. Coronary stents reduce the risk of restenosis by offering a mechanical scaffolding, which physically reduces coronary vascular contraction but, both BMS and DES, induce greater neointimal growth causing ISR [7-13].

In-stent restenosis and stent-in-stent restenosis

In-stent restenosis is defined as a new proliferative re-narrowing of the previously stented lesion that encompass either the stent segment or a 5 mm segment on both sides of the stent, with these lesions affecting at least 50% of the lumen diameter per coronary angiography [14-16]. Once ISR occurs, cardiologists have several management options to perform, including balloon angioplasty, drug-coated balloon (DCB) angioplasty, cutting balloon angioplasty, and the potential use of atherectomy devices. Most of the time, IRS is managed with repeat DES placement [17-20].

With the rapid adoption of DES in routine practice and increasing number of patients requiring PCIs and stenting, the incidence of ISR has also been on the rise, developing a new challenge, i.e., the occurrence of DES-IRS or stent-in-stent restenosis (SISR). These are described as having ≥ 2 previous episodes of ISR, and their management is extremely challenging due to narrowing of the vessel’s lumen from multiple stent layers [21, 22]. Compared with BMS, DES-ISR rates are reported to be < 10%, but are higher in medically complex patients [14]. In low-risk individuals, the restenosis rate is approximately 12-14% [15-17]. A discernable escalation is noted in ≥ 3 stent layers, resulting in an increase in the rate of repeat failure to 41% within one year [23-25]. One option for the management includes implantation of a DCB, primarily utilized in Europe. Recommendations in the United States are less clear, and guidelines do not address treatment options for multi-layered stent restenosis [26-28].

Intravascular brachytherapy (IVBT) was originally approved for the treatment of BMS-related ISR more than 25 years ago, with patency ranging from 60-87% [13, 29-31]. However, due to the efficacy of DES, brachytherapy use decreased significantly [32]. Currently, IVBT provides an alternative to achieve revascularization in patients with multi-layered DES. The utility of IVBT lies in the decreasing rate of major adverse cardiac events [33], and it is especially attractive alternative for patients who have complex lesion(s) with recurrent ISR, and are poor candidates to receive another DES or bypass surgery [34, 35]. This study reported the outcomes and complications of a large registry of patients, who have received IVBT for DES-ISR at a single-institution.

Material and methods

Study population

An analysis of 78 patients involving 91 vessels treated from 2017-2024 was performed. Patients with DES-ISR received IVBT therapy using the Novoste Beta-Cath^® system (Atlanta, Ga, USA) post-PCI with balloon angioplasty. Inclusion criteria encompassed patients with ISR, specifically those with recurrent episodes (> 2 stent layers), defined as SISR or DES-ISR. The presence of two layers of stents contributed to the classification of lesions as complex. The decision to utilize IVBT was at discretion of the treating interventional cardiologist and radiation oncologist. Patients were selected for IVBT under the following criteria: 1. At least two layers of stents were required to have been previously deployed, with no further stenting possible; 2. Patients who failed at least one angioplasty with resultant re-occlusion prior to IVBT; 3. Patients with limited options for revascularization as per the attending interventionalist, referring interventionalist, and radiation oncologist.

Brachytherapy was delivered with the Beta-Cath^® system using a strontium-90 (⁹⁰Sr) isotope, following balloon angioplasty. Radiation dose delivered was 23 Gy to vessels of ≥ 3.5 mm in diameter, while 18.4 Gy was delivered to vessels of < 3.5 mm in diameter, according to the manufacturer. Radiation was prescribed to an area encompassing the angioplasty injury length, with a 10 mm longitudinal margin on each side. Source length was 60 mm, and dwell times were variable depending upon the source activity and vessel lumen size (range, 455-603 seconds).

Post-PCI, a delivery catheter with a radiopaque maker was advanced and localized under fluoroscopy using the B-rail^® (Novoste; Best Vascular, Norcross, Ga, USA) delivery catheter. After obtaining appropriate positioning, the delivery Beta-Cath^® device was attached, and the source was sent via hydraulic pressure in a self-contained system. Two manual timers were initiated when the source reached the target location. After the planned dwell time was reached, the source was hydraulically retracted, and the catheter was removed once the source was identified as contained in the delivery device. A patient and general room survey was performed post-procedure, ensuring the isotope was returned completely to the delivery system. Major adverse cardiac events (MACE) were defined as myocardial infarction (MI), stroke, and all-cause death. Data collection was carried out independently by two investigators, and reviewed by two additional investigators.

Results

The median patient age was 67 years, and baseline demographics and relevant medical histories were recorded for all patients (Table 1). All patients had at least 2 drug-eluting stents previously placed in the affected vessel. Sixty-one treatments were delivered to the left anterior descending artery (LAD) or the right coronary artery (RCA), with the remaining 30 delivered to either the circumflex vessel or marginal artery (Table 2). Sixty-three percent received 23 Gy, while 37% received 18.4 Gy. One patient experienced cardiac arrest from suspected intracoronary thrombosis during receiving the intervention and died despite aggressive resuscitation, including extra-corporeal oxygenation. No other procedure-related toxicities were reported. All patients were symptomatic before IVBT, and 44% experienced symptomatic reduction during follow-up. The most common persistent symptom was angina in 71% of cases. The major adverse cardiovascular events after IVBT included MI in 18%, stroke in 5%, and all-cause death occurring in 16% at a median time of 9.3 months after treatment (range, 0.9-29.6 months) (Table 3). At a median follow-up of 22.8 months (range, 0.9-60.6 months), 77% of patients retained luminal patency of the irradiated lesion, while 23% experienced restenosis.

Table 1.

Baseline characteristics and other comorbidities

Characteristics	Median	IQR
Age (years)	67	59-75.5
Vessel diameter (mm)	3.5	3-3.5
Segment number	1
Injury length (mm)	35	21.5-50
Dose (Gy)	23	18.4-23

IQR – interquartile range

Table 2.

Vessels treated

Vessel treated	Number of lesions (%)
LAD	32 (35)
RCA	29 (32)
LCX	23 (25)
OM	7 (8)

LAD – left anterior descending, RCA – right coronary artery, LCX – left circumflex artery, OM – obtuse marginal

Table 3.

Major adverse events

MACE events	Number of events (%)	Median latency (days)
Myocardial infarction	16 (18)	337 (222-732)
Stroke/TIA	5 (5)	463 (439-802)
All-cause mortality	15 (16)	279 (222-563)

MACE – major adverse cardiac events, TIA – transient ischemic attack

Discussion

In this study, we investigated the safety and efficacy of IVBT in patients with complex lesions experiencing reoccurring DES-ISR. This approach resulted in an acceptable 1-year MACE rate while retaining symptomatic patency of the irradiated lesion in 77% of patients, who would otherwise have minimal therapeutic options. We also found that this approach provided symptomatic improvement in many patients, potentially enhancing quality of life of those with reoccurring DES-ISR.

In-stent restenosis pathogenesis in BMS and DES

Bare metal stents are comprised of stainless-steel, cobalt chromium, or platinum chromium, with a higher incidence of ISR than DES and peak incidence of restenosis occurring at approximately 6 months post-implantation [32, 36, 37]. In BMS, ISR is mainly secondary to smooth muscle hypertrophy and aggressive neointimal hyperplasia [38]. In contrast, DES is composed of stainless steel or cobalt-chromium metal, and contains an active pharmacologic drug, making it more effective in preventing restenosis and reducing stent thrombosis[39]. For DES, neointimal hyperplasia and neoatherosclerosis are the key mechanisms behind DES-ISR [40-42]. ISR post-DES placement can be attributed to various factors, including drug resistance due to the coated polymer (e.g., sirolimus or paclitaxel) on the scaffolding of DES, hypersensitivity reactions to the framework material (e.g., stainless steel and other alloys), under-expanded DES, stent fracture post-DES deployment, stent gaps, uncovered atherosclerotic plaque, and barotrauma outside the stented segment [14]. Additionally, intravascular ultrasound studies have shown that BMS-ISR follow diffuse pattern of stenosis, whereas DES involves stent edges [43].

Importantly, we noted generalized stent under deployment in almost all patients. Once DES-ISR occurs, cardiologists have limited strategies available, with repeated DES placement being the most selected approach in the United States (US) [17-20].

Management of DES-ISR

Intravascular brachytherapy interrupts the cell cycle by inhibiting neointimal proliferation in adventitial fibro-myoblasts inducing apoptosis [44]. IVBT involves the administration of radioactive beta radiation, leading to the disturbance of both single- and double-stranded DNA in rapidly dividing cells [45]. In our study, we utilized ⁹⁰Sr, a pure beta particle emitter with energies up to 0.546 MeV and radioactive half-life of 28.79 years.

IVBT in the management of DES-ISR: Pre-DES and post-DES time

Eight years after the implantation of the first coronary stent in 1986, large cohort studies have demonstrated the superiority of BMS over standard balloon angioplasty in both angiographic and clinical events among patients with CAD [7, 46, 47]. However, BMS posed a challenge due to neointimal growth with ISR. Among various therapies, including rotational atherectomy and laser angioplasty, IVBT emerged as more effective option for treating BMS-ISR [37]. Several trials in pre-DES era have consistently shown IVBT to be superior in the treatment of BMS-ISR [48-50]. However, a well-described complication of IVBT is the late catch-up phenomenon, which can lead to the late lumen loss and stent thrombosis [34, 49-52]. The advent of DES aimed at preventing ISR from occurring in the first place, and it was proven to be superior to BMS [53].

After the introduction of DES, it quickly gained popularity and largely dominated the management of ISR, a trend supported by several studies [54, 55]. Furthermore, the outcomes of two landmark trials, SIRS and TAXUS V, which compared DES and IVBT in the treatment of BMS-ISR, solidified the position of DES as the primary choice for BMS-ISR treatment [51, 52].

Utility of IVBT in complex population

While DES is considered superior to IVBT in de novo lesions, recent data suggest the utility of IVBT in DES-ISR [56]. The management of layered DES and overlapping areas of stents is associated with inferior long-term clinical outcomes compared with a single-layered DES [57]. The use of brachytherapy in the treatment of DES-ISR has gathered attention for its drug-free and additional stent layer-free approach, providing an antiproliferative neointimal growth effect through ionizing radiation [21]. A retrospective study by Negi et al. highlighted the safety and efficacy of IVBT in DES-ISR in complex patients, with more than 95% of participants having > 2 prior episodes of target lesion revascularization (TLR) [34].

In a cohort of 186 patients, predominantly with multiple prior TLR episodes and severe lesions, IVBT using ⁹⁰Sr demonstrated higher procedural success rate and low short-term complication rates. Notably, TLR rates were minimal at 1 months (0.5%), but increased to 3.3% at 6 months, peaked at 19.1% at 2 years, and 20.7% at 3 years. Another study conducted by Mangione et al. reported TLR rate of 24% at 1 year in the treatment of DES-ISR with IVBT, indicating its superiority [58], and our results compare with these favorably.

The applicability of IVBT extends beyond DES-ISR, as evidenced by an observational research conducted by Maluenda et al. [59]. This study involved 563 patients with angina and angiographic evidence of ISR, following DES implantation. Treatment groups included repeat DES (n = 327), IVBT (n = 132), or balloon angioplasty (n = 104). Despite greater lesion complexity and a notably shorter time to previous DES failure in the IVBT group compared with the rest of the cohort, the study showed similarity in the primary endpoint. At the 1-year follow-up, the rates of clinically driven TLR were approximately 10.3%, 14.1%, and 14.6% in the re-DES, IVBT, and balloon angioplasty groups, respectively (p = 0.41). Once again, our study results compare favorably with these outcomes.

Both Negi et al. [34] and Maluenda et al. [59] studies suggest that IVBT is a safe strategy for treating DES-ISR, offering potential advantages, especially in more complex patients with recurrent lesions. Furthermore, several follow-up studies have consistently supported the utility of IVBT in complex patient populations [21, 33, 58, 60-62]. The MACE incidence of our cohorts confirms that of these two studies.

Other approaches in the management of DES-ISR

Addressing SISR remains a significant challenge in interventional cardiology, particularly in the context of DES-ISR, where the optimal therapeutic approach is still uncertain. The exact mechanism of action for DES-ISR remains a subject of controversy, likely stemming from the interplay of various factors, including biological, mechanical, and technical components responsible for ISR. While clear guidelines for treating the initial occurrence of DES-ISR exist in the United States, consensus regarding the treatment of multi-layered SISR has not been established.

DCB: A replacement for IVBT in SISR?

A prospective study conducted in Japan by Habara et al. concluded that DCBs are associated with reduced angiographic late lumen loss (0.18 ±0.45 mm vs. 0.72 ±0.55 mm; p = 0.001), resulting in a notable decline in TLR (8.7% vs. 62.5%; p = 0.0001) [63]. These findings are also supported by the PEPCAD-DES trial involving 110 patients, demonstrating the superiority of DCB angioplasty over plain balloon angioplasty in patients with any type of DES-ISR. The trial indicated late lumen loss (0.43 ±0.61 mm vs. 1.03 ±0.77 mm; p < 0.001) and reduced TLR rates (15.3% vs. 36.8%; p = 0.005) without catch-up at the 3-year follow-up [64, 65]. The ISAR-DESIRE 3 trial enrolled 402 patients and compared paclitaxel-coated balloons (n = 137), paclitaxel-eluting stents (n = 131), and plain balloon angioplasty (n = 134) in patients with DES-ISR. The study concluded that the drug-DCB was non-inferior to DES (p < 0.05) regarding percentage diameter stenosis. Both DCB and DES were superior to the plain balloon angioplasty (plain balloon: 54.1% ±25.0% vs. DCB: 37.4% ±21.8% vs. DES: 38.0% ±21.5%; p < 0.0001 for DCB, DES vs. plain balloon) [66]. A 3-year comparative follow-up of the same study showed no significant differences in TLR, and that paclitaxel-eluting balloons remained superior to plain balloon angioplasty [67]. A recent 10-year follow-up analysis of the ISAR-DESIRE 3 trial by Giacoppo et al., showed the occurrence of the composite endpoint, including all-cause mortality, MI, target lesion thrombosis, or TLR lower in both the DCB and DES compared with the plain balloon group (DCB: 55.9% vs. DES: 62.4% vs. plain balloon; p < 0.001). TLR was significantly lower in both the DCB and DES cohorts when compared with the plain balloon group, revealing no significant difference between the DCB and DES groups [68].

The management of SISR differs significantly between Europe, where DCBs are the standard of care for such patients, and the United States, where the FDA has not yet approved DCBs for DES-ISR. There have been randomized control trials (ISAR-DESIRE 3, PEPCAD, RIBS IV, RESTORE, and BIOLUX), which compared the outcomes of DCB vs. DES in patients with DES-ISR, several of which were powered for clinical endpoints [66, 69-72]. Two other meta-analysis by Giacoppo et al. and Zhu et al. demonstrated that DES implantation was superior to DCB angioplasty in terms of TLR in patients with DES-ISR [68, 73]. Additionally, findings from these studies sparked controversy, given substantial variability observed in several dimensions of these trials, including generation of DES used in the repeat stenting group, participant characteristics, and type of restenosis stent [73]. The controversy surrounding this matter proves challenging to resolve definitively and will require further investigations, especially with an extended follow-up duration, to conclusively assess the efficacy and safety of DES in comparison with DCB for DES-ISR. In this uncertainty, IVBT remains an attractive efficacious primary modality.

Limitations of IVBT

Despite its promising treatment response in patients with SISR, one of the main limitations is the late thrombosis, which is defined as thrombosis post-30 days of IVBT delivery [13, 74]. This can be addressed with dual antiplatelet therapy (DAPT), even though DAPT increases bleeding in high-risk individuals [75]. Other barriers include the additional professional personnel required for IVBT (radiation physicist and radiation oncologist), extensive training, costs of delivery device, catheters, and a secured radiation storage facility. Because of these factors, limited specialty facilities offer IVBT. Additionally, in our study there was no control group, as the patients identified had few options, and we considered that withholding active treatment by placebo or a silent control would be unethical.

Conclusions

Intravascular brachytherapy is a safe and effective treatment option for high-risk complex patients, with minimal procedural and post-procedural complications. It offers a treatment alternative for these patients unsuitable for conventional treatment options while providing the added benefit of symptomatic relief, enhancing their quality of life without administering additional pharmacological agents.

Funding

This research received no external funding.

Disclosures

The study was approved by the Institutional Review Board of Allegheny Health Network.