Passive and Active Polymer Coatings for Intracoronary Stents: Novel Devices to Promote Arterial Healing

Coronary stent implantation is the second great advance in the treatment of obstructive coronary artery disease since the introduction of balloon catheter angioplasty. However, in-stent restenosis (ISR) caused by neointimal hyperplasia has been a major limitation of stents, occurring in up to 30% of cases. Advances in coronary stent technology both in terms of stent design and function and especially drug-eluting stents (DES) have significantly improved the safety and efficacy of percutaneous coronary intervention (PCI) with stenting, including marked reduction in ISR. This has led to use of DES for increasingly challenging clinical and lesional subsets, with potential for increased risk of stent-associated complications, especially late stent thrombosis (LST). Because restenosis and stent thrombosis are caused by multiple and often interrelated factors, ideal agents for stent coatings should inhibit thrombus formation, inflammatory reaction, and cellular proliferation, while supporting reendothelialization. To avoid undesirable effects of currently applied (durable) polymers, biocompatible, and bioabsorbable polymers as well as DES delivery systems that minimize polymer burden have been produced and tested. Bioabsorbable stents, both polymeric and metallic, have been developed to decrease potential late complications after stent implantation. Novel strategies to address some of these challenges are in various stages of research and development. In this article we outline developments in the field of passive and active stent coatings and evaluate the ongoing role of such coatings in the contemporary era of DES.     

Bare-Metal Stents Versus Drug-Eluting Stents for Primary Angioplasty: Long-Term Outcome

Percutaneous transluminal coronary intervention (PCI) is the most used myocardial revascularization technique for patients with coronary artery disease. Primary PCI with stent implantation is widely considered the gold standard for the treatment of ST-elevation myocardial infarction patients. Coronary stents, compared with balloon angioplasty, have reduced focal lesion restenosis. To reduce in-stent restenosis, drug-eluting stents (DES) were designed to locally release drugs inhibiting neointimal growth. Recent concerns have emerged on the potential higher risk of stent thrombosis with DES that might be even more pronounced among myocardial infarction patients. For these reasons, DES for primary PCI remains an “off-label” use. In the last several years, a number of randomized trials and registries have tested the safety and efficacy of DES in primary PCI. Data from these studies were analyzed in several meta-analyses, reasonably consistently demonstrating that the use of DES significantly decreased the need for revascularization without an increase in the incidence of death, recurrent infarction, or stent thrombosis at long-term follow-up.     

Intravascular brachytherapy versus drug-eluting stents for the treatment of patients with drug-eluting stent restenosis

Drug-eluting stents (DESs), although promising technology, still are associated with restenosis; therefore, we evaluated the safety and efficacy of intravascular radiation therapy for the treatment of DES in-stent restenosis (ISR). Treatment of DES ISR has not been established, although intravascular radiation therapy is an effective treatment for patients with ISR of bare metal stents. Other modalities are conventional percutaneous coronary intervention (PCI), including restenting with DES. Radiation for Eluting Stents in Coronary FailUrE (RESCUE) is an international, Internet-based registry of 61 patients who presented with ISR of a DES and were assigned to intravascular radiation therapy with commercially available systems after PCI. Outcomes of these patients were compared with those of a consecutive series of 50 patients who presented with ISR of a DES and were assigned to repeat DES (r-DES) treatment. Baseline clinical and angiographic characteristics were similar between groups, except for more Cypher stents as the initial DES that restenosed in the r-DES group than in the intravascular radiation therapy group (88.5% vs 69%, p = 0.01). At 8 months there were fewer overall major adverse cardiac events in the intravascular radiation therapy group compared with the r-DES group (9.8% vs 24%, p = 0.044). The need for target vessel and target lesion revascularizations was similar in the 2 groups at 8 months. There has been no report of subacute thrombosis in either group. In conclusion, intravascular radiation therapy as adjunct therapy to PCI for patients presenting with ISR of a DES is safe and should be considered an alternative therapeutic option for this difficult subset of patients.     

Evolving standard in the treatment of coronary artery disease. Drug-eluting stents

Coronary stent implantation is the predominant method of percutaneous coronary interventions (PCI). This is to be attributed to the ease of use beside the better short and long term clinical outcome as compared to balloon angioplasty. Nevertheless, improvements in operator skill and stent technology together with better use of adjunctive pharmacological therapy have contributed to the improvement in clinical outcome. However, the main limitation of coronary stenting is still represented by in-stent restenosis (ISR) with an estimated rate of 17-32%. Thus, compared to coronary bypass surgery, the major adverse cardiac events following stent implantation are still higher and mainly represented by the need for re-intervention. The advent of drug eluting stents (DES) has led the experts to predict that with DES there will be little or no difference between PCI and coronary bypass surgery in terms of long-term outcome leading to a further expansion of indications. The clinical trial programs of the 2 available DES for clinical use (sirolimus-eluting stent, SES - Cypher and paclitaxol-eluting stent - Taxus) have been able to demonstrate the safety and clinical efficacy of both. Nevertheless, off-label use in patients on high risk for restenosis confirmed these data. At least for SES as was demonstrated by 2 "real world" registries. Thus, the introduction of DES represents a remarkable evolution for new standards in coronary artery disease treatment and offers hope to those patients considered to be "high risk" such as diabetics, patients with ISR, diffuse disease in whom surgery was previously the only therapeutic option. This paper will discuss the main results of the clinical trial programs of the DES (mentioned above) available for clinical use in the present time and analyze technical and procedural aspects which could affect long term outcome.     

Drug‐eluting stents for the treatment of in‐stent restenosis – ‘real world’ double centre experience in consecutive patients

OBJECTIVES. We evaluated clinical outcome of consecutive patients with in stent restenosis (ISR) treated with drug‐eluting stents (DES) at two intervention centres from April 2002 to April 2004, reflecting ‘real world’ practice. BACKGROUND. ISR is the major limitation to successful long‐term outcome after implantation of bare metal stents during percutaneous coronary intervention (PCI). The optimal strategy for the treatment of ISR has yet to be determined. METHODS. 121 consecutive patients with significant ISR were treated with DES. Sirolimus DES were used in 60 patients and paclitaxel DES in the remainder. All patients were followed up to evaluate the incidence of major adverse cardiac events (MACE), angina class and clinically driven angiography. Data were collected between 7 and 27 months after the procedure (mean follow up of 16.5 months). RESULTS. Overall MACE rate at 16.5 months was 13.2% (16 patients) including 4 deaths (3%). Fifteen (12.3%) patients underwent clinically driven angiography. Eight patients (6.6%) developed ISR within the treated segment, of whom, four underwent further PCI and 4 CABG. Mean Canadian angina class decreased from 2.46±0.7 pre‐procedure to 0.69±0.6 at follow up. All patients achieved an improvement in angina, with 59% being rendered angina free and 87% free of MACE. There were no differences in clinical outcome in those who received a paclitaxel and sirolimus DES. CONCLUSIONS. The use of DES implantation for the treatment of ISR is safe, effective and associated with low recurrence rates in a ‘real world’ large cohort of patients with a complex mix of anatomical and clinical factors.     

Focal in-stent restenosis and in-stent thrombosis within the same bare-metal stent 5 years after deployment in a saphenous vein graft

Complications of percutaneous coronary intervention include in-stent restenosis (ISR) and in-stent thrombosis (IST) which have different underlying pathophysiological processes and different treatment strategies. ISR is primarily due to excessive neointimal growth and occurs in 20-30% of bare-metal stents (BMS). Drug-eluting stents (DES) have decreased the rates of ISR (< 10%), but are potentially associated with increased IST related to delayed arterial healing and stent strut exposure. ISR of BMS typically occurs within 6 months of stent deployment. IST usually occurs within 12 months of DES deployment. We present a case of focal ISR and IST within the same BMS, confirmed with intravascular ultrasound, 5 years after deployment in a saphenous vein graft.     

Drug-Eluting Stents for In-Stent Restenosis and Acute Myocardial Infarction

In-stent restenosis (ISR) remains the "Achilles' heel" of percutaneous stent angioplasty treatment of patients with atherosclerotic disease of the coronary arteries. Recently, drug-eluting stents (DES) have ushered in a revolution in the treatment of these patients, yet, to date, their efficacy and safety have been demonstrated primarily for native de novo coronary lesions. For ISR, intracoronary brachytherapy using beta- or gamma-radiation is considered the standard of care. Nevertheless, DES are used for ISR lesions in clinical practice. This review outlines the few results currently available from small observational studies and larger registries. The designs of two ongoing randomized trials evaluating the sirolimus-eluting and the paclitaxel-eluting stent versus brachytherapy in patients with ISR lesions are also presented. Patients with acute myocardial infarction (AMI) have mostly been investigated in the context of small, uncontrolled studies and registries. The incomplete evidence to date is that implantation of sirolimus-eluting stents in patients with AMI is safe and effective.     

Coexistent in-stent restenosis, late incomplete stent apposition and mural thrombus in a zotarolimus-eluting stent

Drug-eluting stents (DES) have been demonstrated to dramatically reduce the rate of in-stent restenosis (ISR). However, some studies found an increased rate of late incomplete stent apposition (ISA) and late stent thrombosis (ST) in DES compared to traditional bare-metal stents (BMS). Endeavor stent, a new cobalt-alloy DES coated with phosphorylcholine and zotarolimus, has been reported to have a very favorable safety profile with few documented late-acquired ISA and late ST. In the present report, we described an interesting case with coexistent ISR, late ISA and mural thrombus in an Endeavor zotarolimus-eluting stent 8 months after primary percutaneous coronary intervention.     

Drug-eluting stents versus repeat vascular brachytherapy for patients with recurrent in-stent restenosis after failed intracoronary radiation

Recurrent in-stent restenosis (ISR) following intracoronary radiation therapy (IRT) continues to be a therapeutic challenge. The present study aims to evaluate the clinical outcomes of patients who were treated with drug-eluting stent (DES) implantation versus repeat IRT for recurrent ISR after brachytherapy failure. A cohort of 88 patients who were previously treated with brachytherapy for ISR and presented with angina and recurrence of angiographic restenosis were evaluated for treatment with either DES [sirolimus-eluting stents (SES) or paclitaxel-eluting stents (PES); n = 34] or percutaneous coronary intervention (PCI) and repeat radiation (gamma or beta radiation; n = 54). The two groups had similar baseline clinical and angiographic characteristics. The in-hospital outcomes were similar between both groups. At long-term follow-up of 9.7 +/- 4.1 months for the DES group and 10.3 +/- 3.5 months for the repeat IRT group, there were no deaths or myocardial infarctions (MI). There was a trend toward more target vessel revascularization-major adverse cardiac events (TVR-MACE) in the DES group (p = 0.09). In addition, the patients in the DES group had a significantly lower survival rate compared to those in the repeat IRT group (p = 0.018). For patients who had recurrent ISR following IRT, either DES implantation or repeat radiation is safe and is associated with excellent immediate outcomes. Yet, at long-term follow-up, repeat IRT was associated with less recurrences and need for repeat revascularization when compared to DES implantation. Therefore, repeat IRT should be considered as an option for this difficult patient subset.     

Decreased risk of stent fracture‐related restenosis between paclitaxel‐eluting stents and sirolimus eluting stents: Results of long‐term follow‐up

Objective: To compare the outcomes between paclitaxel‐eluting stents (PES) and sirolimus‐eluting stents (SES) for the treatment of drug‐eluting stent (DES) fracture. Background: DES fracture is considered as an important predictor of in‐stent restenosis (ISR). However, little data are available evaluating the optimal treatment for this complication of coronary stenting. Methods: From January 1, 2004 to December 31, 2008, patients with DES ISR treated with a second DES were identified and evaluated for stent fracture. Stent fracture was defined by the presence of strut separation in multiple angiographic projections, assessed by two independent reviewers. Target lesion revascularization (TLR) at 6 and 12 months were the primary end points. Results: Of 131 lesions with DES ISR treated with a second DES, we found 24 patients (24 lesions, 18.2%) with angiographically confirmed stent fracture. Of these, 20 patients (20 lesions) treated with either PES (n = 11/55%) or SES (n = 9/45%) were included in the study. TLR at 6 months occurred in 9% of patients treated with PES and 22% of those treated with SES (P = 0.41). After 12 months, TLR was 9% and 55.5%, respectively (P = 0.024). Conclusions: This study demonstrates a high incidence of stent fracture in patients presenting with DES ISR in need of further treatment with another DES. The suggested association between treatment of stent fracture‐associated DES ISR with PES as compared with SES, and better long‐term outcomes, is in need of confirmation by larger prospective registries and randomized trials. © 2011 Wiley Periodicals, Inc.     

Treatment of in-stent restenosis with sirolimus-eluting-stents -- a six month clinical and angiographic follow-up

Summary Treatment of in-stent restenosis (ISR) remains a therapeutic challenge since many pharmacological and mechanical approaches have shown disappointing results except for brachytherapy. Drug-eluting stents (DES) have been reported to effectively reduce ISR in de novo lesions. We studied 55 consecutive patients with ISR in native coronary arteries and 7 with ISR in saphenous vein grafts (SVG) with elective indication for percutaneous coronary intervention (PCI), who underwent successful implantation with DES. No in-hospital postprocedural major adverse cardiac events were observed. All but one patient (n=61) underwent an angiographic follow-up at 183±30 days. Grade of stenosis was assessed by quantitative coronary angiography (QCA) at index procedure and at control angiography. Restenosis (>50%) occurred in 5 patients (8.2%). Target vessel revascularization was performed in an additional 4 patients. Minimal intimal hyperplasia was observed in all segments covered by DES (late loss 0.08±0.37 mm, loss index 0.11±0.47). One patient suffered from subacute stent thrombosis due to discontinuation of clopidogrel medication. At six month follow-up two patients had died. Death was not related to a restenosis in the treated segment. Conclusion Our experiences with DES treatment of ISR lesions show good angiographic and clinical results at index procedure and at the 6 month follow-up with low sub acute thrombosis rate as compared with existing treatment modalities. Restenosis rate seems to be at least as low as reported for brachytherapy.      

Correlates of clinical restenosis following intracoronary implantation of drug-eluting stents

Despite significant decreases in restenosis and repeated intervention achieved using drug-eluting stents (DESs), the benefit has not been homogenous across all patient and lesion subsets. Identification of correlates of DES restenosis may allow a differing management approach and lead to improved patient outcomes. The study population consisted of 3,535 consecutive patients (5,046 lesions) who underwent successful sirolimus- or paclitaxel-eluting stent implantation for >or=1 native coronary artery or bypass graft lesion from April 2003 to September 2006. From this cohort, 197 patients (237 lesions) were identified to have in-stent restenosis (ISR) requiring revascularization within 12 months of stent implantation. This group was compared with the remainder of the patient population. Logistic regression analysis was performed to identify independent predictors of DES ISR. Independent correlates of DES ISR using multivariate analysis included both clinical and procedural factors. Clinical predictors were age, hypertension, and unstable angina. Procedural predictors were left anterior descending artery intervention, number of stents implanted, stented length/lesion, and lack of intravascular ultrasound guidance. Implantation of >or=3 stents was associated with a significantly higher restenosis risk (9.7% vs 5.1%; p=0.0003). A 10-mm increase in stented length was associated with an adjusted odds ratio of 1.18 (95% confidence interval 1.03 to 1.35). Diabetes, stent diameter, and stent type were found not to be predictive of DES ISR. In conclusion, correlates of DES ISR included both clinical and procedural factors. Limiting the number of stents and stented length, in addition to intravascular ultrasound guidance, may minimize DES ISR.     

Classification and Current Treatment Options of In-Stent Restenosis

Coronary stent implantation is currently performed in > 80% of percutaneous coronary interventions. Its main late complication is the development of in-stent restenosis (ISR), occurring in 10-80% of lesions treated in daily practice. The classification by Mehran et al. is most commonly used. Current therapeutic options to treat ISR include repeat balloon angioplasty, repeat stenting, cutting balloon angioplasty, directional coronary atherectomy, rotational coronary atherectomy, brachytherapy, and drug-eluting stents (DES). DES have been effective in reducing binary restenosis in de novo lesions in randomized controlled trials. The novel use of DES to treat ISR has been shown to be safe and effective in multiple studies involving sirolimus- and paclitaxel-eluting stents. As DES implantation becomes more widespread, ISR in DES is emerging as a new problem. The use of debulking techniques to treat ISR in DES is to be cautioned against. In this new era, the optimal treatment of this new problem is currently unknown. We await further data to see whether repeat DES implantation may help solve this vexing clinical problem.     

The future of drug eluting stents

In-stent restenosis (ISR) is the major drawback of percutaneous coronary interventions, occurring in 10-40% of patients. Drug eluting stents (DES) are successful in a large majority of patients in preventing restenosis for the first year after implantation. Recently, new stents have emerged that are loaded with anti-inflammatory, antimigratory, antiproliferative, or pro-healing drugs. These drugs are supposed to inhibit inflammation and neointimal growth and subsequently ISR. The future of DES lies in the development of better stents with new stent designs, better polymers including biological polymers and biological biodissolvable stent coatings, and new, better drugs.     

Kissing drug-eluting balloons for the treatment of unprotected distal left main bifurcation drug-eluting stent restenosis

The advent of drug-eluting stents (DES) associated with improvements in interventional techniques, encouraged the use of percutaneous coronary intervention (PCI) for unprotected left main (ULM) stenosis because of the lower need of repeat revascularization compared to the bare-metal stents (BMS). Nevertheless, ULM DES in-stent restenosis (ISR) continues to occur. The choice of treatment strategy (medical treatment, repeated PCI, or coronary artery bypass graft) for ULM DES-ISR depends primarily on several clinical and angiographic factors, making optimal patient selection crucial in the appropriate treatment of ULM-ISR lesions and achievement of favorable long-term outcomes. We describe in this report a successful modern approach to manage a distal ULM DES-ISR following a 2-stent strategy, consisting in the kissing inflation of two DEBs in both branches of the bifurcation.     

Drug‐eluting stents versus bare‐metal stents for treatment of bare‐metal in‐stent restenosis

Objectives : We compared the long‐term outcomes of drug‐eluting stents (DES) versus bare‐metal stents (BMS) for treatment of bare‐metal in‐stent restenosis (ISR). Background : There are no randomized trials or observational studies directly comparing the safety and efficacy of DES versus BMS for treatment of bare‐metal ISR. Methods : We examined data on all patients who underwent percutaneous coronary intervention (PCI) for ISR at Cleveland Clinic between 05/1999 and 06/2007. We compared the efficacy and safety of DES to BMS for treating bare‐metal ISR. The primary end point was a composite of death, myocardial infarction (MI), or target lesion revascularization (TLR). The secondary endpoints were individual components of the primary endpoint. Results : Of the 931 patients identified over 8 years, 706 had bare‐metal ISR and met our study criteria. Of the 706 patients with bare‐metal ISR, 362 were treated with DES and 344 with BMS. There were 230 cumulative events for a median follow‐up of 3.2 years. After adjusting for 27 variables, DES were associated with lower primary endpoint compared to BMS for treatment of bare‐metal ISR (21% vs. 45%, adjusted hazard ratio [HR] 0.63; 95% confidence interval [CI], 0.42–0.95; P = 0.03). The individual secondary endpoint of death (8% vs. 24%, P = 0.005) favored DES, but MI (3% vs. 8%, P = 0.31), and TLR (13% vs. 20%, P = 0.23) failed to reach statistical significance. Conclusions : In our multivariate analysis of patients with bare‐metal ISR, DES use was associated with significantly lower death, MI, or TLR when compared to BMS. © 2010 Wiley‐Liss, Inc.     

Balloon pin‐hole rupture during percutaneous coronary intervention for recurrent,calcified in‐stent restenosis: A case report

Percutaneous coronary intervention (PCI) for patients with in‐stent restenosis (ISR) is generally considered safe and effective. However, due to increased tissue hardness, PCI for calcified intra‐stent ISR is technically challenging. Here, we report severe angioplasty‐related complications in a patient presenting with calcified, recurrent ISR following PCI. After receiving drug‐coated balloon (DCB) angioplasty for an initial ISR, the patient developed recurrent ISR during the follow‐up period. Intravascular imaging revealed intra‐stent calcifications and balloon angioplasty was subsequently performed. During the angioplasty, a pin‐hole balloon rupture occurred, consequently causing coronary dissection as visualized by intravascular imaging. To prevent acute coronary occlusion, stent implantation was required. The present case report suggests that, following detection of intra‐stent calcified stenosis, both careful balloon inflation as well as optimal ablation device selection are required to prevent potential complications and obtain successful procedural outcomes.     

Registry data evaluating the effectiveness of drug-eluting stents for the treatment of symptomatic in-stent restenosis

BACKGROUND: In this new-era of drug-eluting stents (DES) the impact of symptomatic in-stent restenosis (ISR) is diminishing. However, world wide bare-metal stents remain widely used and therefore, it is imperative to establish a simple and effective form of treatment. The objective of this registry database was to evaluate the 'real-world' effectiveness of DES for the treatment of symptomatic bare-metal stent ISR. METHODS: All patients presenting with symptomatic ISR were evaluated between February 2003 and February 2005. Patients had 9-month angiographic follow-up with primary endpoint evaluation of binary restenosis (>50%). Secondary endpoints included in-segment late loss, target lesion revascularization (TLR) and the difference in late loss between sirolimus (n=23) and paciltaxel (n=36) eluting stents. RESULTS: Fifty eight patients with fifty nine ISR lesions were evaluated, 36% of patients had diabetes mellitus. All procedures were performed safely with no adverse peri-procedural events documented. At 9-month follow-up the median in-segment late loss was 0.24 mm (IQR 0.1, 0.53), with a binary restenosis rate of 17%. At long-term follow-up greater than 1 year, the incidence of TLR was 10%. No difference in the angiographic parameter of in-segment late loss was seen between the sirolimus and paclitaxel-eluting stents. CONCLUSIONS: In this cohort of patients with long-term angiographic and clinical follow-up, DES is an effective and safe treatment for symptomatic bare-metal stent ISR.     

Angiographic patterns of drug-eluting stent restenosis and one-year outcomes after treatment with repeated percutaneous coronary intervention

Patterns of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation and outcomes after treatment have not been studied systematically in all comers. We compared patterns of ISR and outcomes of repeated percutaneous coronary intervention in consecutive patients with DES-ISR. A total of 137 patients with 182 lesions underwent repeated percutaneous coronary intervention for DES-ISR at Columbia University Medical Center from August 2004 to April 2006. DES-ISR was treated with repeated DES placement in 84% of patients and balloon angioplasty in 16%. There was 1 stent thrombosis at 30 days, and at 1 year, major adverse cardiac events occurred in 10% of patients, driven primarily by an 8% rate of target-lesion revascularization. After exclusion of 12 patients with multiple ISR lesions, data were further analyzed from 125 patients with 152 DES-ISR lesions, of which 118 were originally treated with sirolimus-eluting stents and 34 were treated with paclitaxel-eluting stents (PES-ISR). Baseline features were well matched between the 2 groups, except that patients with PES-ISR were older. A focal pattern of ISR was observed in 69.5% of patients overall. However, patients originally treated with a PES had a significantly higher frequency of diffuse-intrastent ISR in comparison with sirolimus-eluting stent ISR (30.3% vs 13.6%, p = 0.03). In conclusion, the pattern of ISR in most DES-ISR in this unselected patient population was focal, with higher rates of diffuse intrastent restenosis seen with PES-ISR. Treatment with either repeated DES implantation or balloon angioplasty for DES-ISR was safe and associated with low overall rates of target-lesion revascularization and major adverse cardiac events at 1 year.     

Benefits of drug eluting stents versus bare metal stents in ST-elevation myocardial infarction: a contemporary review

The efficacy of drug-eluting stents (DES) in reducing the rates of in-stent restenosis after percutaneous coronary intervention (PCI) compared to bare metal stents (BMS) in stable coronary artery disease has been well demonstrated. Thus, the Food and Drug Administration has approved the utilization of DES for stable coronary disease. However, there is still much debate surrounding the implantation of DES for patients with ST-segment elevation myocardial infarction (STEMI) given safety concerns about the possibility of increased rates of stent thrombosis with DES. The review of the current body of evidence comparing DES with BMS is consistent with results from previous trials in stable coronary disease and reveals lower rates of revascularization with DES in STEMI patients. The ultimate decision regarding the appropriate stent during PCI needs to be individualized as patients' compliance with dual antiplatelet therapy is critical. The data suggest that PCI with DES in STEMI patients who adhere to long-term dual antiplatelet therapy is safe and effective. Randomized trials with longer-term follow-up are necessary to better elucidate the safety and efficacy of DES versus BMS in patients with STEMI.