Drug-Eluting Balloon
2009; Lippincott Williams & Wilkins; Volume: 2; Issue: 4 Linguagem: Inglês
10.1161/circinterventions.109.873703
ISSN1941-7632
Autores Tópico(s)Peripheral Artery Disease Management
ResumoHomeCirculation: Cardiovascular InterventionsVol. 2, No. 4Drug-Eluting Balloon Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBDrug-Eluting BalloonThe Comeback Kid? Ron Waksman and Rajbabu Pakala Ron WaksmanRon Waksman From the Division of Cardiology, Department of Internal Medicine, Washington Hospital Center, Washington, DC. and Rajbabu PakalaRajbabu Pakala From the Division of Cardiology, Department of Internal Medicine, Washington Hospital Center, Washington, DC. Originally published1 Aug 2009https://doi.org/10.1161/CIRCINTERVENTIONS.109.873703Circulation: Cardiovascular Interventions. 2009;2:352–358Balloon angioplasty revolutionized coronary revascularization; however, elastic recoil and restenosis caused by cellular proliferation are major drawbacks of angioplasty. Intracoronary stenting, which could tackle dissections and eliminate elastic recoil, became the next mode of intervention but was limited by stent thrombosis and increased neointimal hyperplasia, leading to in-stent restenosis. Drug-eluting stents significantly attenuate the cellularity and reduce the need for repeat revascularization; however, late stent thrombosis, dependency on prolonged dual antiplatelet therapy, and continued restenosis led to a quest for new treatment modalities. In recent years, drug-eluting balloons (DEB) have emerged as a potential alternative to combat restenosis. Paclitaxel was identified as the primary drug for DEB because of its rapid uptake and prolonged retention. DEB technology demonstrated safety and efficacy in preclinical and in randomized clinical trials for patients with in-stent restenosis. Further studies for de novo lesions in small vessels, for lesions in the superficial femoral artery, and those for below the knee signal its safety and efficacy for broader indications. This review will discuss the rationale, concept, and available DEB technologies, along with preclinical and clinical data, to support the DEB as a new technology for endovascular intervention. It will also assess the potential of the balloon to become the "comeback kid" of percutaneous coronary intervention in the form of DEB.The use of percutaneous balloon angioplasty to recanalize narrowed coronary arteries and endovascular vessels revolutionized revascularization.1 Balloon angioplasty, however, was associated with subintimal dissection, abrupt vessel closure, and restenosis. Stents tackle dissection, eliminate the elastic recoil and late negative vessel remodeling,2 but increase inflammation, thereby leading to more intimal hyperplasia resulting in in-stent restenosis (ISR).3 The major limitation of stents is stent thrombosis, which is controlled with antiplatelet therapy. Drug-eluting stents (DES) are another breakthrough in stent technology because of their ability to minimize cellular proliferation and to reduce restenosis rates to single-digit levels.4,5 DES carry with them the new phenomena of late and very late stent thrombosis, with a hazard ratio of up to 0.6 per year as a result of delayed healing, local inflammation, and impaired endothelial function, which lead to prolonged dual antiplatelet therapy.6 Restenosis is also reported with DES, especially in complex subsets of patients and lesions.7 These DES limitations prompted innovation for improved solutions, such as the local delivery of drugs via nonstent-based platforms, including drug-eluting balloons (DEB). This review will discuss the rationale, concept, and available DEB technologies, along with the preclinical and clinical data available to support the DEB as a new technology for endovascular intervention.RationaleRationale for the development of DEB derives mainly from the limitations of DES. Nonstent-based local drug delivery using DEB maintains the antiproliferative properties of DES, but without the limitations of DES. Moreover, DEB may be used in subsets of lesions where DES cannot be delivered or where DES do not perform well, such as in torturous vessels, small vessels, or long diffuse calcified lesions, which can result in stent fracture; or perhaps when scaffolding obstructs major side branches or in bifurcated lesions. The discovery that sustained drug release is not a requisite for the long-lasting antiproliferative effect of paclitaxel and the fact that the uptake of paclitaxel by vascular smooth muscle cells is rapid and can be retained up to 1 week, resulting in prolonged antiproliferation, have given rise to the concept of local paclitaxel delivery through coated balloons.8 The most appealing indication for paclitaxel-eluting balloons would be for the treatment of ISR.Additional potential advantages of DEB include (a) homogenous drug transfer to the entire vessel wall; (b) rapid release of high concentrations of the drug sustained in the vessel wall no longer than a week, with little impact on long-term healing; (c) absence of polymer could decrease chronic inflammation and the trigger for late thrombosis; (d) absence of a stent allows the artery's original anatomy to remain intact, notably in cases of bifurcation or small vessels, thereby diminishing abnormal flow patterns; and (e) with local drug delivery, overdependence on antiplatelet therapy could be curtailed (Table 1). Table 1. DES Versus DEBDESDEBDAPT indicates dual antiplatelet therapy.Platform of drug deliveryStent scaffoldingBalloonRetentionPolymer basedEmbedded imprintedDrug doseLow: 1 year shelf life. B. Braun Melsungen AG (Berlin, Germany) has licensed the technology for use in its SeQuent Please DEB catheter, but with an improved coating procedure and better balloon technology. Coroflex DEBlue is comprised of a paclitaxel-eluting balloon in combination with a thin strut CoCr BMS. Table 2. Drug-Eluting or Delivery Balloon SystemsNameManufacturerPrinciplePaccocathBayer (Bavaria Medizin Technologie, Oberpfaffenhofen, Germany)Paccocath technology (paclitaxel embedded in hydrophilic iopromide coating)SeQuent PleaseB. Braun Melsungen AG (Melsungen, Germany)Improved Paccocath technologyCoroflex DEBlueB. Braun Melsungen AGDrug-eluting balloon with a thin strut CoCr stentDIOREurocor (Bonn, Germany)Paclitaxel coated onto microporous balloon surface and foldedMAGICALEurocorFolded balloon in combination with stentElutexAachen Resonance (Aachen, Germany)Folded balloonGENIEAcrostak Corporation (Winterthur, Switzerland)Liquid drug delivery catheterIN.PACT AmphirionINVAtec (Italy)FreePac, a proprietary coating that balances hydrophilic and lipophilic propertiesIN.PACT FalconINVAtecFreePacAdvance PTXCook Medical (Bloomington, Ind)DEBN/ALutonix Inc (Maplegrove, Minn)DEBIN.PACT Amphirion is a drug-eluting percutaneous transluminal angioplasty balloon catheter designed to treat atherosclerosis in arteries located below the knee. It features the Amphirion percutaneous transluminal angioplasty balloon with FreePac, a proprietary, natural coating. FreePac reduces the total drug elution time to 30 to 60 seconds; balloon inflation beyond 60 seconds can be maintained without additional drug release. IN.PACT Falcon is a drug-eluting percutaneous transluminal coronary angioplasty balloon catheter designed specifically to treat atherosclerosis in the coronary arteries. It features the Falcon percutaneous transluminal coronary angioplasty balloon platform with FreePac. In clinical evaluation is the Advance PTX, a drug-eluting percutaneous transluminal angioplasty balloon designed to increase long-term patency. Lutonix, Inc is also developing DEB for coronary and small vessel use.DIOR uses folded balloon technology that prevents early wash-off during insertion and tracking. DIOR can be inflated up to 60 seconds for full drug release or less for partial release. The first inflation for 20 seconds will release 35% of the drug and subsequent inflation of 20 seconds will release another 35%. Another DEB using the same coating method as Dior is Elutex, which releases 20% of the drug per inflation. MAGICAL is a system in which a BMS can be delivered using DIOR. GENIE is a liquid drug delivery catheter available in various diameters and shaft lengths. After determining the vessel diameter and lesion length, the balloons are inflated with diluted paclitaxel. The GENIE therapy can include the whole vessel, stent edges, and adjacent vessel segments.Nonpaclitaxel DEB Preclinical StudiesSheiban et al28 tested the efficacy of a genistein-coated balloon (anti-inflammatory falconoid, 0.7 μg/mm2) in a porcine coronary artery stent model. They reported that at 4 weeks, peri-stent inflammatory cell count (mononucleocytes) was significantly less in vessels treated with genistein-coated balloons compared with those treated with noncoated balloons (39�32 versus 96�29 mm2, P=0.019). However, at 6 to 8 weeks, the reduced inflammatory cell count did not translate into reduced neointimal hyperplasia (0.13�0.11 versus 0.14�0.09, P=0.835).Tharp et al29 tested Ca2+-activated K+ channel (KCa3.1) inhibitor TRAM-34-coated balloon (20 mg/mL in acetone) in a porcine coronary artery angioplasty model. In vessels treated with control balloons, KCa3.1, c-jun, and c-fos mRNA levels were increased 2 hours postangioplasty, whereas repressor element 1-silencing transcription factor expression decreased. Smooth muscle myosin heavy chain expression was unchanged at 2 hours but decreased 2 days postangioplasty. Use of TRAM-34-coated balloons prevented KCa3.1 upregulation and repressor element 1-silencing transcription factor downregulation at 2 hours, smooth muscle myosin heavy chain and myocardin downregulation at 2 days, and attenuated subsequent restenosis 14 and 28 days postangioplasty.Paclitaxel DEB: Preclinical TrialsMori et al30 demonstrated that when cells are exposed to paclitaxel, the drug is retained up to 6 days. Herdeg et al14 demonstrated that a short, single-dose application of paclitaxel on human smooth muscle cells had a sustained antiproliferative effect up to 14 days.In a porcine model, Scheller et al15 have shown that after a 60-second dilatation most of the drug is released from the balloon (≈90%), and 40 to 60 minutes later, they could still detect 10% to 15% of the drug in the vessel wall, thus suggesting that paclitaxel is rapidly transferred from the balloon and retained by the tissue for a long time. They also demonstrated that treatment with a paclitaxel-coated balloon led to a dose-dependent reduction in stent neointimal area (up to 63%), without any effect on re-endothelialization of stent struts. A dose-dependent inhibitory effect was demonstrated only when paclitaxel was dissolved in acetone with iopromide, but no effect was demonstrated when dissolved in ethyl acetate, suggesting that the use of proper dissolution agents is important. In another porcine coronary artery study, Speck et al16 have shown that treatment with a paclitaxel-coated balloon reduced in-stent neointimal area by 54%, whereas sirolimus-eluting stents reduced it by only 26%. In a balloon overstretch and stented porcine peripheral artery model, Albrecht et al17 have shown that the use of a 480-μg paclitaxel-coated balloon allowed a 68% decrease in diameter stenosis and a 56% decrease in late lumen loss.Recently, Cremers et al,20 using balloons coated with paclitaxel (5 μg/mm2) dissolved in acetone with iopromide, have shown that 10-second and 60-second inflations yielded similar results. They also demonstrated that multiple 60-second inflations using a single balloon or multiple balloons yielded results similar to that of single 10-second inflation, suggesting that a short inflation time of a single balloon seems equally effective as multiple or prolonged inflations, which may be used occasionally in conditions at higher risk of recurrence of ISR. In a head-to-head comparison of Paccocath and DIOR DEB, Cremers et al21 have shown that matrix-coated Paccocath led to a highly significant (P<0.01) reduction of all parameters, including neointimal proliferation, compared with both the uncoated control and the roughened DIOR balloon.Paclitaxel DEB: Clinical StudiesDEB for ISRIn a small study of 5 patients (11 segments with lesion length 16.5�7.0 mm and 67�15% stenosis) with at least second episode of ISR within the same stent using a Remedy delivery catheter, Buszman et al31 administered 100 μg of paclitaxel diluted in 2 mL of 0.9% NaCl over 60 seconds, repeating the dose for each 10 mm of the lesion. In all patients, a lower rate of target vessel revascularization was achieved compared with a control. No adverse events were observed in the peri-procedural period or during the 6-month follow-up. Follow-up angiography at 6 months revealed ISR in 3 segments (27.2%) and in-stent late lumen loss of 0.2�0.93 mm.In the randomized, double-blind, multicenter Paclitaxel-Coated Balloon Catheter for In-Stent Restenosis (PACCOCATH ISR I) trial, Scheller et al22 enrolled 52 patients with a clinical evidence of stable or unstable angina and a single restenotic lesion in stented coronary artery. The primary end point was angiographic late lumen loss in-segment. Secondary end points included binary restenosis and major adverse cardiovascular events (MACE). Patients were randomly assigned to either paclitaxel-coated balloon (3 μg/mm2) or uncoated catheter (Bavaria Medizin Technologie, Oberpfaffenhofen, Germany). At 6 months, the in-segment late lumen loss was significantly less in the coated balloon group (P=0.002). The coated balloon group had 5% binary restenosis and 4% MACE compared with 43% and 31%, respectively, in the uncoated balloon group (P=0.002 and 0.02; Table 3). Table 3. Angiographic and Clinical Results From Paccocath ISR and PEPCAD II TrialsTrialGroup, No. Patients6-mo Late Loss In-Stent, mm6-mo Late Loss In-Segment, mm6-mo Restenosis In-Segment, n (%)6-mo TLR, n (%)TLR (% at mo)MACE (% at mo)MACE includes TLR, myocardial infarction, acute and subacute stent thrombosis, stroke, and death.Paccocath ISR IRx (n=26)0.09�0.490.03�0.481 (5)00 (0% at 24)1 (4% at 24)Control (n=26)0.76�0.860.74�0.8610 (43)6 (23)6 (23% at 24)9 (35% at 24)Paccocath ISR IIRx (n=28)0.19�0.430.18�0.412 (8)2 (8)3 (11% at 24)5 (18% at 24)Control (n=28)0.74�0.860.86�0.7315 (58)14 (50)14 (50% at 24)16 (57% at 24)PEPCAD IIRx (n=66)0.19�0.380.17�0.424/57 (4)2/64 (3.1)4 (6% at 12)6 (9% at 12)Taxus (n=65)0.47�0.710.38�0.6112/59 (20)10/60 (16.7)10 (15% at 12)15 (22% at 12)PACOCATH ISR I and II pooled data after complete 2-year follow-up confirmed these results.26 A total of 108 patients were enrolled in both studies. Quantitative coronary angiography revealed no differences in baseline parameters. After 6 months, in-segment late lumen loss was less in the drug-coated balloon group compared with the uncoated balloon group (P<0.001), resulting in a binary restenosis rate of 25/49 versus 3/47 (P<0.001). Until 12 months postprocedure, 20 patients in the uncoated balloon group compared with 2 patients in the coated balloon group required target lesion revascularization (TLR; P=0.001). From 12 to 24 months, only 2 MACE, 2 stroke in the uncoated group, and 1 TLR in the coated balloon group were recorded (Table 3).PEPCAD II was a prospective, randomized, multicenter, 2-arm phase II pilot study.32 The objectives were to examine the safety and efficacy of the SeQuent Please DEB in the treatment of ISR in native coronary arteries for procedural success and preservation of vessel patency compared with the Taxus DES. The primary end point was angiographic late loss at 6 months, and the secondary end points were procedural success (≤30%), 6-month binary restenosis rate, MACE, and MACE at 1 and 3 years. The SeQuent Please was safe and had a high procedural success rate. At 6-month follow-up, in-segment late lumen loss was 0.38�0.61 mm in the DES group versus 0.17�0.42 mm (P=0.03) in the DEB group, resulting in a binary restenosis rate of 12/59 (20%) versus 4/57 (7%; P=0.06). At 12 months, MACE rates were 22% and 9% (P=0.08). This difference was primarily due to the need for TLR in 4 patients in the DEB group compared with 10 patients in the DES group (P=0.15; Table 3). The difference between SeQuent Please and Taxus is not surprising. The use of SeQuent Please in the treatment of ISR confirms the results of Paccocath ISR I and II, in that the restenosis rate with Taxus is similar to that in other trials using this DES for the treatment of BMS restenosis.DEB for de Novo LesionsDEB for de novo lesions is less studied. The only registry available is PEPCAD I, which targeted small vessels.33 This was a prospective, nonrandomized, multicenter, 1-arm phase II pilot study. The primary end point was late loss at 6 months, with secondary end points of binary restenosis and MACE at 6 months, and MACE at 1 and 3 years. Of the 114 patients treated with DEB, 32 required stenting postprocedure. The results were quite different between the balloon-alone group and the DEB with BMS group. Although the late loss in the DEB-alone group was only 0.18�0.38 mm and the binary restenosis 5.5%, the DEB with BMS had higher late loss and restenosis of 0.73�0.74 mm and 44.8%, respectively. In addition, the rate of stent thrombosis in the DEB and BMS group was 6.3%. The authors attributed the poor results of the DEB with BMS to geographic miss and concluded that the paclitaxel-eluting balloon catheter, SeQuent Please, was safe, was associated with a high procedural success rate in small de novo lesions, and exhibited low late lumen loss after 6 months in small vessel disease. The question of DEB in conjunction with BMS remains a concern because of high restenosis rates.DEB for Bifurcation LesionsIn a short-term study of only 3 patients, Herdeg et al34 used the GENIE catheter for treatment of ISR of coronary artery bifurcation lesions. They delivered liquid paclitaxel into whole bifurcation lesions without repeating stent implantation, using the kissing balloon technique. At 6 months, they reported no MACE and angiographically patent vessels.In the Drug Eluting Balloon in Bifurcation Utrect (DEBIUT) Fanggiday et al23 tested the safety and efficacy of the Dior balloon in 20 patients with bifurcation lesions. They sequentially treated main and side branches with the Dior balloon, followed by provisional stenting of only the main branch with a BMS. At 4-month follow-up, no major coronary events or vessel closure was reported. There were no angiographic data in the report.DEB for Peripheral Artery DiseaseIn the Local Taxan with Short Exposure for Reduction of Restenosis in Distal Arteries (THUNDER) multicenter trial, Tepe et al24 randomly assigned 154 patients with stenosis or occlusion of a femoropopliteal artery to treatment with paclitaxel-coated catheters, uncoated catheters with paclitaxel dissolved in the contrast medium, or uncoated catheters (control). The primary end point was late lumen loss at 6 months. They reported no adverse events. At 6 months, the mean late lumen loss was significantly less with paclitaxel-coated catheters compared with control or contrast medium groups (P<0.001). The rate of revascularization of target lesions at 6 months was 20/54 in the control group, 2/48 in the paclitaxel group (P 70% of coronary interventions in the United States. DES technology has high success and low restenosis rates but has very late stent thrombosis and long-term dependency on dual antiplatelet therapy. DEB technology is proven to be effective with paclitaxel in preclinical trials and clinically for the treatment of ISR. The DEB has also shown low restenosis and TLR rates when used as the sole modality, without a stent for the treatment of de novo lesions in small vessels. Additionally, 2 randomized studies proved safety and efficacy of DEB in superficial femoral and popliteal arteries. However, many unanswered issues remain. Will it work with drugs other than paclitaxel? How consistent and homogenous is the drug elution? Will it work as adjunct therapy to BMS in the case of suboptimal angioplasty? Current results suggest higher restenosis and TLR rates when stents are implanted post-DEB angioplasty. Nearly 30% of patients undergoing balloon angioplasty will have to crossover to stenting if the results are not favorable when these technologies are coupled, which will rule out the option of using DEB for de novo lesions. Perhaps, stents should be placed before the DEB but, if so, what is the advantage over DES? Finally, the amount of drug on the balloon is excessive, given that 80% of it is washed into the blood stream primarily for long peripheral lesions when longer balloons are used, which could result in potential systemic toxicity.
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