Prevention Of In-stent Restenosis Research Articles

Preoperative sizing and prevention of in-stent restenosis in patients with peripheral arterial occlusive disease

Preoperative sizing and prevention of in-stent restenosis in patients with peripheral arterial occlusive disease

In-Stent Restenosis and Stent Thrombosis: An Elusive Target

In-Stent Restenosis and Stent Thrombosis: An Elusive Target

Outcomes of Percutaneous Coronary Intervention for In-Stent Restenosis Versus De Novo Lesions: A Meta-Analysis.

Background In-stent restenosis (ISR) is commonly encountered even in the era of contemporary percutaneous coronary intervention (PCI). There is a paucity of data on the comparative outcomes of PCI for ISR lesions versus de novo lesions. Methods and Results An electronic search was conducted for MEDLINE, Cochrane, and Embase through August 2022 for studies comparing the clinical outcomes after PCI for ISR versus de novo lesions. The primary outcome was major adverse cardiac events. Data were pooled using a random-effects model. The final analysis included 12 studies, with a total of 708 391 patients, of whom 71 353 (10.3%) underwent PCI for ISR. The weighted follow-up duration was 29.1 months. Compared with de novo lesions, PCI for ISR was associated with a higher incidence of major adverse cardiac events (odds ratio [OR], 1.31 [95% CI, 1.18-1.46]). There was no difference on a subgroup analysis of chronic total occlusion lesions versus none (Pinteraction=0.69). PCI for ISR was associated with a higher incidence of all-cause mortality (OR, 1.03 [95% CI, 1.02-1.04]), myocardial infarction (OR, 1.20 [95% CI, 1.11-1.29]), target vessel revascularization (OR, 1.42 [95% CI, 1.29-1.55]), and stent thrombosis (OR, 1.44 [95% CI, 1.11-1.87]), but no difference in cardiovascular mortality (OR, 1.04 [95% CI, 0.90-1.20]). Conclusions PCI for ISR is associated with higher incidence of adverse cardiac events compared with PCI for de novo lesions. Future efforts should be directed toward prevention of ISR and exploring novel treatment strategies for ISR lesions.

Paclitaxel exerts antiplatelet and antithrombotic activities: Additional benefit from use of paclitaxel-coated balloons and -eluting stents in coronary revascularization and prevention of in-stent restenosis

IntroductionPaclitaxel is a microtubule-stabilizing drug used to treat several types of cancer, including ovarian and breast cancer. Because of its antiproliferative effect on vascular smooth muscle cells, balloons and stents are coated with paclitaxel for use in coronary revascularization and prevention of in-stent restenosis (ISR). However, mechanisms underlying ISR are complicated. Platelet activation is one of the major causes of ISR after percutaneous coronary intervention. Although the antiplatelet activity of paclitaxel was noted in rabbit platelets, the effect of paclitaxel on platelets remains unclear. This study investigated whether paclitaxel exhibits antiplatelet activity in human platelets. Methods and resultsPaclitaxel inhibited platelet aggregation induced by collagen but not that induced by thrombin, arachidonic acid, or U46619, suggesting that paclitaxel is more sensitive to the inhibition of collagen-induced platelet activation. Moreover, paclitaxel blocked collagen receptor glycoprotein (GP) VI downstream signaling molecules, including Lyn, Fyn, PLCγ2, PKC, Akt, and MAPKs. However, paclitaxel did not directly bind to GPVI and cause GPVI shedding, as detected by surface plasmon resonance and flow cytometry, respectively, indicating that paclitaxel may interfere with GPVI downstream signaling molecules, such as Lyn and Fyn. Paclitaxel also prevented granule release and GPIIbIIIa activation induced by collagen and low convulxin doses. Moreover, paclitaxel attenuated pulmonary thrombosis and delayed platelet thrombus formation in mesenteric microvessels without significantly affecting hemostasis. ConclusionPaclitaxel exerts antiplatelet and antithrombotic effects. Thus, paclitaxel may provide additional benefits beyond its antiproliferative effect when used in drug-coated balloons and drug-eluting stents for coronary revascularization and prevention of ISR.

Prevention of in-stent restenosis with drug-eluting balloons in patients with postirradiated carotid stenosis accepting percutaneous angioplasty and stenting

ObjectiveTo investigate the technical safety and outcome of in-stent restenosis (ISR) prevention with drug-eluting balloon (DEB) in patients with postirradiated carotid stenosis (PIRCS) undergoing percutaneous angioplasty and stenting (PTAS).MethodsBetween 2017...

Recent advances in cardiovascular stent for treatment of in-stent restenosis: Mechanisms and strategies

Treatments of atherogenesis, one of the most common cardiovascular diseases (CVD), are continuously being made thanks to innovation and an increasingly in-depth knowledge of percutaneous transluminal coronary angioplasty (PTCA), the most revolutionary medical procedure used for vascular restoration. Combined with an expanding balloon, vascular stents used at stricture sites enable the long-time restoration of vascular permeability. However, complication after stenting, in-stent restenosis (ISR), hinders the advancement of vascular stents and are associated with high medical costs for patients for decades years. Thus, the development of a high biocompatibility stent with improved safety and efficiency is urgently needed. This review provides an overview of current advances and potential technologies for the modification of stents for better treatment and prevention of ISR. In particular, the mechanisms of in-stent restenosis are investigated and summarized with the aim to comprehensively understanding the pathogenesis of stent complications. Then, according to different therapeutic functions, the current stent modification strategies are reviewed, including polymeric drug eluting stents, biological friendly stents, pro-healing stents, and gene stents. Finally, the review provides an outlook of the challenges in the design of stents with optimal properties. Therefore, this review is a valuable and practical guideline for the development of cardiovascular stents.

Drug-eluting stents: new presumed effects over in-stent restenosis prevention

Drug-eluting stents: new presumed effects over in-stent restenosis prevention

Drug-eluting stents: new presumed effects over in-stent restenosis prevention.

Drug-eluting stents: new presumed effects over in-stent restenosis prevention.

Effects of a Matrix Metalloproteinase Inhibitor-Eluting Stent on In-Stent Restenosis.

BackgroundThe aim of this study was to compare changes in the extracellular matrix after implantation of a stent that elutes a matrix metalloproteinase (MMP) inhibitor (GM6001); and to determine the effects of the GM6001-eluting stent upon prevention of in-stent restenosis (ISR).Material/MethodsWe included 48 Guangxi Bama mini-pigs in this study. A GM6001-eluting stent was placed in one iliac artery and a stent that did not elute GM6001 was placed in the contralateral iliac artery. The iliac arteries were removed at 6 hours as well as 1, 7, 14, 56, 84, and 336 days after stent placement. Arteries were analyzed for morphometry, gelatinase content, different phenotypes of vascular smooth muscle cells (VSMCs), collagen content, apoptotic rate, and cell density.ResultsThe vascular lumen areas of the GM6001 group were significantly increased and the neointimal areas were significantly reduced compared with the control group from the 7 days to the 336 days. In the 2 groups, expression of MMP-2 and MMP-9 peaked simultaneously, but GM6001-eluting stents inhibited expression of MMP-2 and MMP-9 in the vascular media and neointima (especially around the struts) significantly. In the GM6001 group, expression of tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2, myosin heavy chain 10 (MYH-10, marker of the proliferative phenotype of VSMCs), collagen content, percentage of apoptotic cells, and cell density were also decreased significantly compared with those in the control group.ConclusionUse of GM6001-eluting stents resulted in persistent and potent inhibition of intimal hyperplasia, an increase in luminal area, and no obvious thrombosis in the arteries of the mini-pigs.

The Comparative Effects of Ticagrelor and Clopidogrel on Arterial Injury and In-Stent Restenosis and Thrombosis of Carotid Artery in Atherosclerotic Rabbits

Introduction - Carotid artery angioplasty and stenting (CAS) is expanding as a method to treat carotid artery disease worldwide. Until now a combination of aspirin and clopidogrel has been used pre and post CAS. Ticagrelor, a P2Y (12) inhibitor, has an important role in coronary artery angioplasty. There is lack of evidence about the impact of ticagrelor on carotid artery disease and CAS. Our aim was the comparative evaluation of ticagrelor and clopidogrel on carotid balloon-injury and in-stent restenosis (ISR) and thrombosis in rabbits. Methods - After a pharmacokinetic study to standardise the appropriate dose of ticagrelor, we enrolled 48 New Zealand White rabbits. They were fed a high-cholesterol diet for 8 weeks prior to and up to 4 weeks following interventions in the right carotid artery (RCA). Aspirin was administered orally (10mg/kg/day) to all rabbits, beginning 7 days before the procedures and continued until euthanasia (4 weeks later). At 8th week of age, all rabbits were randomly assigned into the following equivalent (N=12) groups: A1) Balloon injury and clopidogrel (30 mg/kg/day), A2) Balloon injury and ticagrelor (21mg/kg bd), B3) Balloon injury and CAS and clopidogrel (30 mg/kg/day), B4) Balloon injury and CAS and ticagrelor (21mg/kg bd). During CAS a balloon expandable 2,25x8 mm bare metal stent was implanted in the RCA. Before euthanasia optical coherence tomography (OCT) and angiography were carried out to evaluate the patency of both carotid arteries. Blood samples to measure platelet aggregation and lipid profile were obtainedas well. Rabbits were then immediately euthanized and both carotid arteries (right-RCA and left-LCA) were excised for histological analysis. Results - Among groups, no significant differences were seen regarding balloon injury, stent implantation success rates and platelet aggregation measurements (p>0.05). All groups had similar lipid levels (total cholesterol, triglycerides) and weight by the end of the study. Notably, 3 rabbits in the B3 group appeared with thrombotic total occlusion of the carotid stents and were excluded from morphometric analysis. None such episode was observed after CAS in ticagrelor-treated rabbits. In balloon injury rabbits, the OCT-calculated neointimal areas in RCAs were: A1: 4.20±0.96mm2, A2: 3.78±1.31mm2, p=0.781, while the mid-stent neointimal areas were: B1: 1.74±0.51mm2 and B2: 1.45±0.62mm2, p=0.654. The histological findings in balloon-injured rabbits were in agreement with those from OCT analysis, since the percentage of intima/(media + intima)(%) in RCA did not differ between groups: A1 (68.48±12.31%) vs A2 (64.22±13.22%) (p=0.812). Importantly the atherosclerotic lesions in non-injured LCAs did not differ between all groups (p>0.1). Conclusion - In atherosclerotic rabbits undergoing carotid artery balloon injury with or without stent implantation, clopidogrel and ticagrelor seemed to be equally effective in terms of neointimal formation and ISR prevention. . Importantly, ticagrelor treatment prevented thrombotic stent occlusions compared to clopidogrel treatment. Further studies are needed to clarify the impact of P2Y(12) inhibitors on carotid in-stent restenosis and thrombosis in humans.

Prevention of in-stent restenosis with endothelial progenitor cell (EPC) capture stent placement combined with regional EPC transplantation: An atherosclerotic rabbit model.

Even with drug-eluting stents, the risk of in-stent restenosis (ISR) remains high. The goal of this study was to investigate the use of an endothelial progenitor cell (EPC) capture stent plus regional EPC transplantation to reduce the ISR rate. Endothelial progenitor cell capture stents were fabricated using fibrin gel and anti-CD34 plus anti-VEGFR-2 dual antibodies. Twenty male New Zealand white rabbits established as an atherosclerotic model were randomly divided into two groups: group 1 (n = 10), in which EPC capture stents were deployed into the right iliac artery; and group 2 (n = 10), in which sirolimus-eluting stents were placed. In both groups, EPCs were transplanted into target vessels beyond the stents, with outflow blocked. Radiologic-pathologic correlation outcomes were reviewed after 2 months. The technical success rate of EPC capture stent placement plus EPC transplantation was 100%. The ISR rate in group 1 was lower than in group 2 (1/10 vs. 4/10; p > 0.05). Minimal luminal diameters were larger in group 1 than in group 2 (computed tomographic angiography, 1.85 ± 0.15 mm vs. 1.50 ± 0.20 mm; duplex ultrasound, 1.90 ± 0.10 mm vs. 1.70 ± 0.30 mm; p > 0.05). Transplanted EPCs were tracked positively only in group 1. Pathologic analysis demonstrated neointimal hyperplasia thickness of 0.21 ± 0.09 mm in group 1 vs. 0.11 ± 0.07 mm in group 2 (p < 0.05). Endothelial progenitor cell capture stent placement plus local EPC transplant decreases the ISR rate through thrombosis reduction rather than through neointimal hyperplasia inhibition.

Potential for Robotizing Ultrasound Technologies for Endovascular Surgery

Current endovascular surgical technology requires the development and introduction of new methods allowing the drawbacks of existing technologies to be overcome. These methods include combined approaches to recanalization of arteries and prevention of instent restenosis, which can be achieved by combining minimally invasive techniques. It is proposed that the reliability and efficacy of these methods, increasing comfort and radiation safety of the surgeon, can be ensured by introducing new robotic systems into endovascular surgery.

Favorable manipulation of macrophage/endothelial cell functionality and their cross-talk on silicon-doped titania nanotube arrays.

Inflammatory reactions and the functionality of endothelial cells (ECs) on the surfaces of coronary stents are critical in the prevention of in-stent restenosis and subsequent neoatherosclerosis. However, the interactions between immune cells and ECs on modified coronary stent surfaces have long been underestimated. In the present study, silicon (Si)-doped titania nanotube arrays (TNA-Sis) were obtained via the facile anodization of magnetron-sputtered Ti-Si coatings. The synergetic effects of titania nanotube arrays (TNAs) and chemical cues (Si) on the functionality of macrophages (MΦs)/ECs and their cross-talk were investigated. The results indicated that TNA-Sis specimens, in comparison with TNAs alone, not only promoted the initial vitality of ECs, enhanced the expression of vascular endothelial growth factor (VEGF) and nitric oxide (NO), and activated multiple cell signaling pathways (vWF, PECAM, eNOS), but also induced a favorable immune response through the polarization of MΦs to a pro-healing M2 phenotype via the activation of cell autophagy, resulting in the downregulation of inflammatory reactions. This beneficial immune response further facilitated cross-talk between ECs and MΦs, resulting in profoundly increased functionality of ECs on TNA-Sis surfaces. This study demonstrated that using TNA-Sis surface coatings for coronary stents may be a promising strategy to prevent in-stent restenosis.

Is rosuvastatin better than atorvastatin and simvastatin in the prevention of in-stent restenosis and atherosclerosis progression in patients after superficial femoral artery stenting due to chronic lower limb ischaemia? The preliminary case-control study

Is rosuvastatin better than atorvastatin and simvastatin in the prevention of in-stent restenosis and atherosclerosis progression in patients after superficial femoral artery stenting due to chronic lower limb ischaemia? The preliminary case-control study

Electrosprayed Montelukast/poly (lactic-co-glycolic acid) particle based coating: A new therapeutic approach towards the prevention of in-stent restenosis

Drug-eluting stents (DESs), have shown promising results in prevention of in-stent restenosis after percutaneous coronary intervention (PCI). The elevated level of leukotrienes (LTs) detected in injured arteries after PCI, together with the potential role of LTs in inflammatory cascades and structural alterations in arterial wall provides the rationale for development of therapeutic strategies for prevention of in-stent restenosis using LTs receptor antagonists. Montelukast (MK) is a selective cysLT1 receptor antagonist, with anti-inflammatory and anti-proliferative properties, which has been used for treatment of various diseases. Here, we report on the fabrication of MK/PLGA particles by electrospraying, aiming towards the development of particle based coating of DESs. The electrosprayed particles incorporated with 3% and 6% w/w MK exhibited fairly spherical shape with smooth surfaces and narrow size distribution. Sustained release of MK for up to 40days was obtained for both formulations, with higher initial burst release and drug release rate for the particles with higher drug loading. The LTD4 induced proliferation and migration of human coronary artery smooth muscle cells (HCASMCs) by 35% and 85%, respectively, which was substantially antagonized using MK incorporated particles. Nevertheless, MK antagonism preserved the normal proliferation and migration of human coronary artery endothelial cells (HCAECs). Moreover, MK antagonism inhibited the LTD4 induced phenotypic transition of HCASMCs from contractile to synthetic type. The electrosprayed MK-PLGA particles can be employed as a coating for DESs to inhibit the formation of neointimal hyperplasia responsible for in-stent restenosis, yet preserve the healing rate of the stented vessel. Statement of significantMontelukast (MK) is a selective cysLT1 receptor antagonist, with anti-inflammatory and anti-proliferative properties. The LTD4 induced proliferation and migration of human coronary artery smooth muscle cells by 35% and 85%, respectively, which was substantially antagonized using MK incorporated particles. MK antagonism preserved the normal proliferation and migration of human coronary artery endothelial cells. The MK antagonism inhibited the phenotypic transition of human coronary artery smooth muscle cells from contractile to synthetic one induced by LTD4. The electrosprayed MK-PLGA particles can be employed as coating for DESs to inhibit formation of neointimal hyperplasia, responsible for in-stent restenosis.

Systems of local drug delivery to arterial wall for prevention of in-stent restenosis

New generation, drug-eluting stents used in the treatment of coronary and peripheral atherosclerotic disease (CPAD) significantly reduced restenosis and revascularization rates as well as frequency of thrombosis as compared to bare metal stents and first-generation drug eluting stents. However, despite fast development of this technology several reports have been published recently that describe cases of late and very late stent thrombosis, restenosis and neoatheroslerosis within arterial segments with previously implanted stents. For this reason many research are being conducted with the aim to design alternative methods for intra-arterial drugs delivery in order to reduce restenosis and revascularization rates, yet eliminating adverse effects mentioned above. One of possibilities is lipophilic and antiproliferative drug coated balloon technology, which offers high drug concentration in arterial tissue and restenotic effect in selected clinical situations despite the short balloon inflation time. A particularly interesting option is intra-arterial delivery of drugs with different mechanisms of action, regardless of their lipophilicity by loading them into biodegradable nanospheres. In this paper, currently used systems for local drug delivery have been described including their limitations and opportunities. In addition, we provided a brief description of the project sponsored by Polpharma Scientific Foundation, which aimed to evaluate potentials of local delivery of biodegradable nanospheres loaded with everolimus, which could be used to reduce restenosis rate after stent implantation.

Effect of Pioglitazone in Preventing In-Stent Restenosis after Percutaneous Coronary Intervention in Patients with Type 2 Diabetes: A Meta-Analysis.

BackgroundThe benefits of pioglitazone in patients with type 2 diabetes mellitus (T2DM) after percutaneous coronary intervention (PCI) is unclear.ObjectivesTo evaluate the effect of pioglitazone on prevention of in-stent restenosis (ISR) in patients with T2DM after PCI.MethodsAll full-text published relevant studies compared the effect of pioglitazone with control group (placebo or no pioglitazone treatment) on ISR in patients with T2DM after PCI were identified by searching the databases including PubMed, EMBASE, Cochrane Library and ISI Web of Science through October 2015. The endpoints were defined as the rate of ISR, late lumen loss, in-stent neointimal volume, target lesion revascularization (TLR) and major adverse cardiac events (MACE).ResultsSix studies (5 RCTs and 1 retrospective study), comprising 503 patients, were included into this meta-analysis. In the pioglitazone group, as compared with the control group, the risk ratio for ISR was 0.48 (I2 = 14.5%, P = 0.322; 95%CI 0.35 to 0.68, P<0.001), the risk ratio for TLR was 0.58 (I2 = 6.0%, P = 0.363; 95%CI 0.38 to 0.87, P = 0.009). The result showed there was no association between the use of pioglitazone and the events of MACE (I2 = 36.7%, P = 0.209; RR 0.56, 95%CI 0.30 to 1.05, P = 0.071). For the considerable heterogeneity, further analysis was not suitable for the endpoints of late lumen loss (I2 = 81.9%, P<0.001) and neointimal volume (I2 = 75.9%, P = 0.016).ConclusionsThe treatment of pioglitazone was associated with a reduction in ISR and TLR in T2DM patients suffering from PCI, except the incidence of MACE.

174. Post-Deployment Modifications of Stent with Endothelial Cells

Accelerated restoration of a functional endothelial layer in the injured arteries following stent angioplasty has been pursued over the past 20 years as an approach for preventing uncontrolled expansion of neointimal tissue and subsequent in-stent restenosis. To achieve enhanced re-growth of endothelium over the denuded arterial segments, strategies based on the pre-procedure seeding of stents with syngeneic/autologous endothelial cells (EC) and protocols involving stent surface modification to expedite capture and proliferation of circulating endothelial progenitor cells (EPC) have been explored. The main hurdle for the clinical translation of these “pro-healing” stents is the impediment in establishing an integral EC/EPC monolayer arrangement immediately after stent deployment, which is paramount for aborting platelet attachment to the exposed sub-endothelium and preventing inflammatory cell recruitment. The current work investigates a novel practical way to attain coverage of stent struts with syngeneic/autologous EC simultaneously with stent implantation. Stainless steel surfaces of tubing and stents were consecutively modified with 1% polyallylamine bisphosphonate, 4 mM sulfo NHS-LC-LC-biotin and 100 µg/ml avidin. Control samples were prepared omitting avidin attachment step. Rat aortic endothelial cells (RAEC) were surface modified in suspension with 1 mM sulfo NHS-LC-LC-biotin for 10 min, followed by pelleting and resuspension in PBS. Stainless steel tubing samples (avidin-coated or control; n=3 for both) were placed in succession inside 2 separate loops of polypropylene tubing that were mounted on a Chandler loop apparatus that models continuous blood flow. RAEC were resuspended in 20 ml of DMEM (2.5×105 EC/ml) and 10 ml of EC suspension was used to fill each loop. After 45 min of biotinylated RAEC recirculation through the avidin-modified and control steel samples (25 dynes/cm2, 37°C), the samples were removed, fixed in 4% PFA, inverted and stained with Hoechst 33258. The density of fluorescent nuclei associated with avidin-modified and control stainless steel surface was determined by fluorescence microscopy, demonstrating a 50-fold higher attachment density of biotinylated EC on avidin-modified surfaces. Firefly luciferase expressing RAEC (via lentiviral transduction) were surface modified with 1 mM sulfo NHS-LC-LC-biotin and intraluminally delivered (2×105 cells) into temporally isolated segments of rat carotid arteries immediately after deployment of PAB/sulfo NHS-LC-LC-biotin/avidin modified (N=4) or PAB only modified control stents (N=4). The animals underwent bioluminescent imaging 2 days post-stent deployment showing a 14.5-fold higher luminescent signal in animals treated with avidin-modified, than with control stents, demonstrating preferential attachment of biotinylated EC to the avidin-modified steel substrate and attesting to the viability of the delivered cells. Post-deployment binding of biotinylated EC to the surface of the avidin-modified stent can present a viable method of stent re-endothelialization and may have a therapeutic value in the prevention of in-stent restenosis and thrombosis.

Magnetic chondroitin targeted nanoparticles for dual targeting of montelukast in prevention of in-stent restenosis

Magnetic nanoparticles and sodium montelukast encapsulated in rosin gum nanoparticles were targeted by chondroitin sulfate coated on their surface. They showed adhesion to endothelial cells and efficiently suppressed the VCAM-1 expression.

Network meta-analyses on in-stent restenosis treatment: dealing with complexity to clarify efficacy and safety.

Major advances have occurred during the last decade in the prevention of in-stent restenosis (ISR). Notably, drug-eluting stents (DES) drastically reduced the incidence of ISR as compared with that seen with bare-metal stents (BMS) (1). However, DES-ISR still occur especially when these devices are used in adverse clinical and anatomic scenarios (1). In addition, BMS are frequently used in selected patient subsets, including those unable to maintain a prolonged dual antiplatelet regimen and those at high bleeding risk (1). Therefore, nowadays treatment of ISR still represents a real challenge in every day clinical practice (2-4). Although the acute results obtained by repeated interventions are largely favorable the long-term outcome of these patients is frequently shadowed by clinical recurrences (2-4). Of concern, the underlying anatomic substrate of DES-ISR appears to be particularly complex and prone to recurrent ISR (2). Furthermore, recent evidence suggest that ISR presentation, formerly considered a benign phenomenon, is frequently associated with unstable symptoms, including a significant number of patients fulfilling current criteria for myocardial infarction (2). Many randomized clinical trials have compared different therapeutic strategies in patients with ISR (2-4). These include plain balloon angioplasty (BA), cutting balloon angioplasty, BMS, ablative devices, brachytherapy, DES and drug-coated balloons (DCB). Recent clinical practice guidelines suggest that both DES and DCB are effective (recommendation/evidence IA) for patients suffering from ISR (5). Nevertheless, the therapy of choice for these patients currently remains unsettled. Indeed, most randomized trials used surrogate late angiographic parameters (including percent diameter stenosis, binary restenosis, minimal lumen diameter and late lumen loss) as a measure of efficacy (2-4). This was a reasonable strategy to ensure an adequate enrollment of the required number of patients presenting with this relatively rare condition within a short time frame. Indeed, these trials provided major evidence on relative efficacy of these interventions. However, most randomized studies eventually enrolled a limited number of patients and, therefore, additional evidence is still warranted in order to establish the relative clinical efficacy and safety of these competing interventions.