Although the widespread adoption of drug eluting stents (DES) has seen a dramatic reduction in rates of in-stent restenosis (ISR), it remains a significant barrier in the long-term management of coronary artery disease. ISR is defined angiographically as a greater than 50% stenosis at the site of previous drug eluting (DES) or bare metal stent (BMS) placement [1]. Clinical restenosis is the presence of an angiographic restenosis with symptoms of coronary ischaemic or a positive functional ischaemia study. Angiographic stenoses above 70% are also typically classified as clinically significant even in the absence of ischaemic symptoms [1].

ISR typically occurs as the result of two distinct but often co-existent pathophysiological processes, these being neointimal hyperplasia and neoartherosclerosis. Neointimal hyperplasia is characterised by a progressive inflammatory reaction to vessel wall injury and the persistent foreign body insult posed by the stent scaffold. This process results in vascular smooth muscle cell proliferation and migration leading to neointimal proliferation and eventual restenosis of the vessel lumen [2-4]. Intravascular imaging studies have found that BMS are more prone to progressive neointimal hyperplasia without development neoartherosclerotic lesions which are more common with DES.

Neoartherosclerosis is a pathophysiological process of progressive atherosclerosis within the regenerating neointima after stent placement. While the same pathological processes as in native vessel atherosclerosis underpin neoatherosclerosis, it is an accelerated process occurring within months to years of stent placement [2].

A potential mechanism of this accelerated plaque formation is incomplete endothelisation of the neointima which allows increased accumulation of circulating lipids and foamy macrophages with the subsequent development of fibroatheromatous plaque [2-5].

While overall a profound improvement over plain old balloon angioplasty (POBA) the use of BMS was associated with reported ISR rates ranging from 20% to over 40% [6]. With introduction and development of newer generation DES, along with improvements in stent scaffolds, the rates of ISR have continued to fall, with a recent comparison trial of everolimus- and zatarolimus-eluting stents reporting an overall ISR rate of 5.61% [7].

Risk factors for ISR can be classified as patient-, lesion-, or procedure-related (Table 1).

Traditional patient-related risk factors for coronary artery disease (age, diabetes, hypertension, smoking) increase the risk of ISR [1,8-11]. Long, complex (B2/C), and small vessel lesions seem to be at particular risk for ISR [1,11-13]. Bifurcation stents are also at increased risk of ISR, likely secondary to the increased wall shear stress placed on these stents [14]. Of procedure-related risks for ISR, stent under expansion and stent malapposition appear to be the most significant [1].

Stent type plays a significant role in the underlying risk of developing ISR. First-generation DES versus BMS significantly reduced rates of ISR (RR = 0.35 [0.31–0.39]) and second-generation DES confer additional protection against ISR when compared to first-generation DES (RR = 0.67 [0.58–0.77]) [14]. Sirolimus-eluting stents (SES) have been found to be more effective in preventing the occurrence of ISR compared to paclitaxel-eluting stents (PES) [15].

Table 1: Risk factors for ISR.

Both sirolimus and paclitaxel inhibit neointimal proliferation, however, they do so through differing mechanisms. Sirolimus, a macrolide antibiotic, is an immunosuppressive agent with some anti-inflammatory properties [16]. Sirolimus, along with other limus agents, stop cell-cycle progression at the G1/S phase transition and are as such classed as cytostatic agents [16]. Pacitaxel, instead, is a cytotoxic agent which disrupts the assembly of microtubules during the G2/M phase of the cell-cycle [16]. This cytotoxic action may theoretically induce necrosis of neointimal cells leading to vessel [16]. The drug-delivery system, both stent and polymer-coating, is likely another factor behind the varying rates of ISR between DES. Comparison studies have the polymer-coating of SES have improved elution of the drug compared with PES, with more drug being sequestered in PES [17]. The long-term effects of this sequestered paclitaxel on endothelisation and vessel wall healing are not known. In terms of the stent scaffold itself, thinner stent struts have been associated with lower rates of ISR, due to a theoretical reduction in vessel wall injury during implantation when compared to thicker struts [15]. The most widely accepted angiographic classification of ISR was first proposed by Mehran et al (Table 2) [14]. The risk of recurrent ISR increases with angiographic class from I to IV [18,19].

Coronary angiography is typically the initial diagnostic tool utilised in assessing ISR lesions. Angiography allows the assessment of stenosis severity and location with respect to the implanted stent. Multiple angiographic classifications of ISR lesions have been created, the most widely adopted being the Mehran classification (Table 2). The Mehran classification stratifies lesions into four classes of increasing severity, with higher classes being associated with high rates of ISR recurrence [18,19]. While angiography is useful in the diagnosis of ISR it is less helpful in identifying the underlying cause or evaluating the structure of ISR lesions. Recently, more advanced imaging techniques have been utilised in the management of ISR.

Table 2: Angiographic classification of ISR lesions [14].

The use of intracoronary imaging is well established in the management of de novo coronary lesions. It is now emerging as an invaluable tool in the assessment and management of restenotic lesions and is especially helpful in determining the underlying cause of ISR.

Intravascular ultrasound (IVUS) or optical coherence tomography (OCT) allows detailed assessment of the extent of ISR lesions and the detection of mechanical causes such as stent under-expansion, stent recoil or stent fracture. Further, these intracoronary imaging modalities allow the detailed assessment of the neointima, helping guide the optimal management approach.

In de novo coronary artery disease fractional flow reserve (FFR) has established itself as an important tool in the assessing the clinical significance of moderate severity lesions and is a useful in helping guide the need for intervention [20]. Several small scales, observational trials have found that FFR guided intervention (cut-off > 0.75) is safe and effective in the management of ISR lesions with low rates of adverse outcomes in patients where intervention is deferred based on FFR measurement [21-23]. Revascularization rates in FFR guided intervention (cut-off value of < 0.75) vary markedly, ranging between 10% to 44%, and likely reflect the small scale of individual trials [21-23]. Studies have yielded mixed results regarding the correlation between percent diameter stenosis (DS %) on angiography and FFR values, with individual trials finding that DS% either over- or underestimates FFR values when compared with severity matched de novo lesions [21-23]. This uncertainty reinforces the dangers of overreliance on angiography alone and the importance of functional assessment of moderate severity ISR lesions.

Although instantaneous wave-free ratio (iFR) has been shown to correlate well with FFR in native vessel lesions, its use in the evaluation of ISR is not well established [24].

Management of ISR

The prevention of ISR is key to ensuring satisfactory long-term outcomes following percutaneous coronary intervention (PCI). Hypertension, dyslipidaemia, and diabetes have been shown to increase the risk of ISR, and as such, aggressive medical management of these cardiovascular risk factors is an important part of the prevention of ISR outside of the cardiac cath lab [1-2]. Adequate lesion preparation and correct stent selection during de novo PCI are important steps in minimising the risk of ISR.

Management of ISR lesions begins with a thorough assessment of both the patient and lesion for both the need and suitability for intervention. Intracoronary imaging is useful in evaluating ISR lesions and determining the underlying cause, such as stent under-expansion. Imaging can also help guide the use of more advanced imaging techniques, such as rotational atherectomy. Clinical and functional assessment (such as with FFR) of ISR is vital in the cases of moderate severity lesions as avoiding unnecessary intervention is key given the recurrent nature of ISR with compounding treatments increasing the risk of subsequent ISR and further limiting future treatment options.

Trials have examined a wide variety of PCI approaches and techniques; however, most take an ‘all-comers’ approach grouping all ISR lesions together to assess an individual intervention. This makes practical application of trial evidence more challenging, given the lesion specific approach needed when dealing with ISR.

Overall, the management of any ISR lesion should be tailored to the underlying pathophysiological mechanism. The interventionalist must also consider the lesion location, time course, and any previous interventions. Patient factors such as age, comorbidities, or suitability for coronary artery bypass grafting (CABG) all need to be considered. The presentation of ISR, whether with ACS or ‘silent’ restenosis, is an important factor in delineating the management approach.

Below we review commonly utilised interventions and their most frequent use cases in the management of ISR. Following we present a proposed algorithm for the approach to ISR lesions. Given the individualised nature of ISR, no one algorithm can cover the optimal management of all the various lesion types. Instead the presented algorithm is designed as a general approach to managing these complicated lesions.

Adequate lesion preparation is key in ensuring good long-term outcomes when managing ISR. Rotational atherectomy (RA) is useful in selected ISR cases, particularly those with heavily calcified neoatherosclerosis or cases of stent underexpansion resistant to high-pressure balloon angioplasty. While studies have demonstrated the safety and efficacy of rotational atherectomy in ISR, long-term outcomes remain poor with high rates of restenosis and target lesion revascularisation (TLR), likely reflecting the severity of the underlying lesions [27-30]. Care must be taken to avoid shaving metal particles or entrapping the burr on an underexpanded stent. The negative results of earlier trials such as the Angioplasty versus Rotational Arthectomy for Treatment of Diffuse In-Stent Restenosis Trial (ARTIST) may be due to the use of RA for debulking previously placed hardware in addition to neointimal tissue, as well as the use of older, larger sized burrs [31].There is limited evidence for the use of orbital atherectomy in the management of ISR, with small trials showing a similar efficacy and safety profile to RA [32,33].Excimer laser coronary atherectomy (ELCA) uses light energy to produce heat and shockwaves dcbulking the neointima. ELCA overcome some of the limitations of RA in the ISR setting by avoiding the risk of metal particle embolisation and burr entrapment. Small scale studies have shown trends toward improved angiographic results and reduced TLR rates with the use of ELCA and DCB or DES when compared to DCB/DES with or without scoring-balloon preparation [34-38]. However, these trials did not achieve statistical significance, likely due to their limited sample sizes. While the exact underlying mechanism of reduced TLR with ELCA is unknown, it is thought likely due to induction of endothelial cell apoptosis leading to reduced neointimal proliferation [36]. Another potential mechanism is due to ECLA softening of neointimal plaque leading to reduced balloon pressures and therefore less vessel wall injury [38].Intravascular lithotripsy is a relatively new technique used as an alternative or in addition to RA in heavily calcified lesions. The use of intravascular lithotripsy in ISR is not well established, however, case reports do exist demonstrating good results and is a potential direction for future research [39-41]. The chief benefit of lithotripsy over RA is negating the risks of burr entrapment on the in situ stent scaffold. Cutting and scoring balloons use blades or wires respectively to incise neointimal tissue during inflation. Randomised trials failed to show angiographic improvement with their use when compared to POBA alone [42]. They are now more commonly used in preparing ISR lesions prior to DES placement or drug-coated balloon (DCB) although there is limited evidence for this practice. The Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug-Eluting Stent In-Stent Restenosis (ISAR-DESIRE IV) trial showed a non-statistically significant improvement in angigrpahic outcomes at 6-months when a scoring balloon was used prior to PES placement [43]. It is theorised that the incising of the neointima improves anchoring of either DES or DCB and improves drug elution into the neointimal tissue [3].

Traditionally, all ISR was managed with repeat balloon angioplasty (POBA). This has now been superseded by the use of drug-coated balloons (DCB) or second DES implantation. High-pressure balloon angioplasty still plays a significant role in the management of ISR due to stent underexpansion [44]. Supplementary modalities such as rotational atherectomy, laser atherectomy, and intracoronary lithotripsy have also been utilised in addition to POBA in cases of stent underexpansion, especially when underexpansion is due to underlying vessel calcification. Overall, except in cases of stent underexpansion, POBA has largely been superseded by more advance PCI techniques.

Angioplasty with DCB has been shown to improve restenosis rates when compared with POBA in the management of ISR [4-5]. DCB are coated in an antiproliferative drug which becomes adherent to the neointima after balloon expansion. First generation DCBs utilised paclitaxel as an antiproliferative agent while newer generation DCB with sirolimus coatings have shown similar efficacy with no evidence to suggest superiority of one particular antiproliferative agent [45]. Recent evidence suggests that DCB angioplasty for management of drug-eluting stent ISR (DES-ISR) may have worse outcomes when compared with repeat DES placement. The DAEDALUS study confirmed the efficacy of DCB in managing BMS-ISR [46]. Subgroup analysis demonstrated higher rates of restenosis and TLR when DCB was utilised for management of DES-ISR [46]. However, there was no difference in all-cause mortality, myocardial infarction, or target lesion thrombosis between DCB and additional DES in the management of DES-ISR [46]. It has been theorised the higher restenosis rates seen with DCB in DES-ISR is due a degree of antiproliferative drug resistance, whereas the neointima of BMS-ISR lesions are still sensitive to antiproliferative agents. Without the structural support of a stent these partially resistant lesions remain more prone to restenosis. More recently, the randomised Drug Eluting Balloon for In Stent Restenosis (DARE) trial demonstrated non-inferiority of DCBs when compared to everolimus-eluting stent for management of ISR. The study included 287 patients with either BMS- and DES-ISR [47]. DCBs were found to be non-inferior to EES on the primary outcome of minimum lumen diameter at 6-months. TLR rates were also similar between the two groups at 12-months [47]. Unfortunately this trial did not include a sub-group analysis of DES-ISR patients and so it is unclear whether the benefit of DCBs was restricted to BMS-ISR patients [47].The success of DCB depends on the adherence and tissue retention of the antiproliferative drug. Animal models have shown the microinjury may aid in neointimal uptake of antiproliferative drug, enhancing the effect of DCB [48]. Scoring balloons utilise nitinol wires over a standard balloon scaffold to cause microinjury to the neointima and their use prior to DCB has been shown to reduce restenosis rates, theoretically due to better penetration of anti-proliferative agents into the injured neointima [49].

Treatment of ISR with additional DES has shown to reduce restenosis and TLR rates when compared to POBA. When compared to DCB, DES is equally effective in the management of BMS-ISR and has reduced restenosis rates in DES-ISR, with the DAEDALUS study showing a 37% decrease in 3-year TLR rates with DES versus DCB for DES-ISR [50]. Overall studies have shown higher restenosis rates in DES-ISR when compared to matched BMS-ISR lesions, implying the potential for the development of drug resistance as cause of recurrent DES-ISR [50]. It has been suggested that the use of a different type of DES would avoid issues with drug resistance; however evidence for the efficacy of this strategy is mixed. The RIBS III trial initially reported reduced restenosis rates and improved minimal lumen diameter on follow up angiography in the different DES group [51]. However, later trials found no significant difference in outcomes with the use of same- or different-type DES [52]. There is limited evidence to suggest the superiority of one type of DES over another. Head-to-head studies have found similar outcomes for PES, SES, and EES in the management of ISR [52-54]. Newer generation ZES and EES have been found to have lower rates of TLR and restenosis in de novo vessel lesions, whether this carries over to ISR lesions is unclear [55].Safety concerns over the use of multiple layers of DES exist. The New Tokyo registry has shown higher mortality when more than two layers of overlapping of DES are deployed [56]. There is no increase mortality risk in patient with 1-2 layers of DES [56]. Due to these concerns of increased mortality typically a third layer of DES is typically avoided and other modalities are utilised to treat such refractory ISR.There is some evidence supporting the use of DCB prior to DES deployment. In a small series, Basavarajaiah et al. demonstrated good angiographic and low TLR/TVR rates with the use of a PCB prior to limus-based DES deployment in patients at high risk of recurrent ISR [57].The theoretical advantage of this approach being the potential synergistic effects on neointimal formation of the dual antiproliferative agents [57].

Intravascular brachytherapy involves the localised delivery of B-radiation from radioactive Strontium-90 using a specialised intravascular catheter, dampening the proliferative response of the neointima. Although only available at a handful of institutions, brachytherapy has shown reasonable results in observational trials and is a useful option in cases of refractory ISR with multi-layered stents [58-59]. Treatment can be repeated usually at 12-month intervals. Due to the significantly delayed endothelisation following brachytherapy patients are usually maintained on lifelong dual-antiplatelet therapy.

Trials examining the use of systemic antiproliferative medications to the treatment of ISR have yielded mixed results. The OSIRIS trial found that a 10-day, high-dose course of oral sirolimus at time of PCI lead to a reduction in restenosis rates and improved minimum lumen diameter at follow up angiography at 200 days [60]. However, the authors did not find a sustained benefit to systemic sirolimus therapy with no significant differences in 4-year target vessel revascularisation (TVR) or MACE rates with long-term oral sirolimus [61]. Long-term sirolimus was, however, well tolerated with no increase in diagnosed malignancies in the sirolimus group [61]. A 2013 systematic review including 488 patients following de novo BMS implantation did find that oral sirolimus was effective in preventing ISR, with reduced rates of TLR [62]. Overall, the use of systemic anti-proliferative therapy for management of ISR is not well-establish and not supported by the current literature.

Stent Under expansion

The overarching principle to managing ISR secondary to stent underexpansion is to attempt to re-expand the insitu stent. High-pressure balloon angioplasty remains the most common initial step in this process. It is a technically simple procedure and often results in a good angiographic outcome.Stent edge-related injury and its associated complications remain a risk during POBA and may lead to poor outcomes. Another potential complication of POBA is balloon slippage which may result in vessel wall injury or edge dissection. Gradual up-sizing of balloons and the use of shorter, low-profile balloons may reduce the risk of edge-related complications. Cutting or scoring balloons may mitigate the risk of balloon slippage by allowing better seating during balloon inflation.If following high-pressure balloon angioplasty the stent remains underexpanded cutting balloons may be used to incise the neointimal, potentially allowing better tissue extrusion and stent expansion. RA may also be utilized and may be especially helpful in lesions with significant calcification preventing stent expansion.

The management of neointimal hyperplasia is likely the most contentious aspect of ISR management. The interventional approach depends on two key characteristics, the type of in situ stent (DES vs BMS) and the number of existing stent layers. In patients with a single stent layer management is with DCB or DES placement. DCB should likely be considered first-line in BMS-ISR patients given their proven non-inferiority to DES placement and the advantage of reducing the amount of in situ hardware, simplifying any future treatment. In the case of DES-ISR the optimal approach is less clear and repeat DES placement may be the preferred option. In either case, lesion preparation is key to achieving optimal outcomes and the use of scoring/cutting balloons should be considered prior to DCB deployment. In patients with two existing stent layers repeat DES placement should be avoided if possible due to increased mortality rates when there are >2 stent layers present. The use of DCB should be considered in these patients as this may provide an adequate result and may obviate the need for more aggressive options. Ultimately, if DCB does not achieve an acceptable result or is deemed unsuitable these patients should be considered for CABG or intravascular brachytherapy.

Stent fracture is almost universally managed with repeat DES placement. Significant lesion preparation may be required to facilitate this but care must be taken avoid metal embolization if RA is used. If DES placement would result in more than two layers of stents or a specific lesion is not amenable to DES placement the patient should be referred for CABG.

ISR remains one of the main limitations in coronary intervention. DES and DCB do provide the best angiographic and clinical results in the treatment of ISR. Ongoing research is needed to assess the efficacy of newer stent technologies, with updated anti-proliferative drugs and polymers, in the management of ISR.

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