The introduction of the drug-eluting stent (DES) was an important milestone in the treatment of patients with obstructive coronary artery disease. The high effi cacy of these devices in prevention of restenosis compared with bare-metal stents has allowed percutaneous coronary intervention to be used in increasingly complex subsets of patients and lesions. However, because likelihood of treatment failure increases with disease complexity, the number of patients presenting with restenosis after implantation of DES is still fairly high. Although several treatment options are available for these patients—eg, repeat stenting with DES, drug eluting balloons, or balloon angioplasty alone—management remains challenging, with no established best treatment strategy.
4–6 A previous randomised trial showed that repeat stenting with a paclitaxel-eluting stent (PES) is effi cacious and safe in patients with limusstent restenosis, but there is concern about the long-term implication of several stent layers in the coronary vessel wall8 Moreover, although paclitaxel-eluting balloons (PEB) are eff ective in treatment of restenosis associated with bare-metal stents, their role in the management of restenosis after DES implantation has not been comprehensively assessed. In the Intracoronary Stenting and Angiographic Results: Drug Eluting Stent In-Stent Restenosis: 3 Treatment Approaches (ISAR-DESIRE 3) trial, we investigated the efficacy of PEB, PES, and balloon angioplasty in patients with DES restenosis. The objectives of the study were to assess the non-inferiority of PEB compared with PES and the superiority of both PEB and PES compared with balloon angioplasty alone.
PEB in patients presenting with restenosis after implantation of limus-eluting DES is non-inferior to repeat stenting with PES and that PEB or PES is superior to balloon angioplasty alone. Randomised trials14,17–19 in which patients with restenosis after implantation of bare-metal stent were enrolled have shown that DES implantation is the best treatment option. Acute gain is maximised and late loss is minimised, providing superior outcomes in comparison with balloon angioplasty alone and vascular brachy therapy. However, concerns exist about the long-term eff ect of many stent layers in the coronary vasculature; therefore, treatment with drug-eluting balloons is a potentially attractive approach for patients with in-stent restenosis. Two small randomised trials13,20 provided encouraging results with drug-eluting balloons in patients with restenosis after bare-metal stenting when compared with angioplasty alone and repeat stenting with DES. The widespread adoption of DES treatment in the past decade means that, despite high effi cacy, restenosis in clinical practice is most often restenosis after DES.
Moreover, an emerging body of data suggests that important diff erences exist in the processes of restenosis after implantation of bare-metal stents and DES. So far, one randomised trial has focused on the role of repeat DES in patients with restenosis and established that such an approach is effi cacious and safe. This study showed that a PES in patients with restenosis after treatment with a limus-eluting DES was associated with similar outcomes to a sirolimus-eluting stent. Additionally, although second-generation limus-eluting stents have had better results than have PES in de-novo coronary disease,22 their role in the treatment of restenosis after implantation of DES has not been investigated. For these reasons—as well as the mechanistic advantages of a comparison of stents and balloons eluting the same
Patients were assigned to receive PEB or balloon angioplasty. PEB catheters were coated with 3 μg of paclitaxel per mm² of balloon surface with iopromide as hydrophilic spacer (length 10–30 mm; diameter 2·5–4·0 mm). Time zero was defined as the time of randomisation and patients were judged to be enrolled in the study at this timepoint. After treatment allo cations, patients immediately underwent their assigned procedure. We gave all patients an oral loading dose of platelet ADP-receptor antagonist before the intervention. During the procedure, patients were given intravenous aspirin and heparin with or without glycoprotein inhibitors or bivalirudin. The same randomly assigned treatment approach had to be used for all restenotic lesions in patients requiring intervention for several restenotic lesions. The use of more than one balloon or stent per lesion was allowed. Stenting was strongly discouraged in the groups assigned to PEB or balloon angioplasty. Stenting could be done in these groups when large dissections particularly with fl ow limitation were present, or when residual stenosis of more than 50% was present after several balloon dilations. After the intervention, all patients—irrespective of treatment allocation—were prescribed 200 mg aspirin every day for an indefinite period and oral platelet ADPreceptor antagonist for at least 6 months. Other cardiac drugs (eg, β blockers, angiotensin-converting enzyme inhibitors, and statins) were prescribed according to the judgment of the patient’s physician. After their procedure (ie, enrolment), patients remained in hospital for at least 48 h. Blood samples were taken every 8 h for the fi rst 24 h after enrolment and daily afterwards to identify cardiac markers (creatine kinase, creatine kinase-MB, and troponin T). We did daily electro cardiograms (ECGs) until discharge. All patients were assessed at 1 and 12 months by phone or offi ce visit. Repeat coronary angiography was scheduled for all patients at 6–8 months.
Angiographic follow-up data from patients who returned before 6–8 months and underwent angiography and target lesion revascular isation were included in analyses of the primary endpoint. Patients who returned for angiography before 4 months and did not undergo target lesion revascularisation were rescheduled for angiography at the time defi ned in the protocol.Patients were assigned to receive PEB or balloon angioplasty. PEB catheters were coated with 3 μg of paclitaxel per mm² of balloon surface with iopromide as hydrophilic spacer (length 10–30 mm; diameter 2·5–4·0 mm). Time zero was defined as the time of randomisation and patients were judged to be enrolled in the study at this timepoint. After treatment allo cations, patients immediately underwent their assigned procedure. We gave all patients an oral loading dose of platelet ADP-receptor antagonist before the intervention. During the procedure, patients were given intravenous aspirin and heparin with or without glycoprotein inhibitors or bivalirudin. The same randomly assigned treatment approach had to be used for all restenotic lesions in patients requiring intervention for several restenotic lesions. The use of more than one balloon or stent per lesion was allowed. Stenting was strongly discouraged in the groups assigned to PEB or balloon angioplasty. Stenting could be done in these groups when large dissections particularly with fl ow limitation were present, or when residual stenosis of more than 50% was present after several balloon dilations. After the intervention, all patients—irrespective of treatment allocation—were prescribed 200 mg aspirin every day for an indefinite period and oral platelet ADPreceptor antagonist for at least 6 months.
Other cardiac drugs (eg, β blockers, angiotensin-converting enzyme inhibitors, and statins) were prescribed according to the judgment of the patient’s physician. After their procedure (ie, enrolment), patients remained in hospital for at least 48 h. Blood samples were taken every 8 h for the fi rst 24 h after enrolment and daily afterwards to identify cardiac markers (creatine kinase, creatine kinase-MB, and troponin T). We did daily electro cardiograms (ECGs) until discharge. All patients were assessed at 1 and 12 months by phone or offi ce visit. Repeat coronary angiography was scheduled for all patients at 6–8 months. Angiographic follow-up data from patients who returned before 6–8 months and underwent angiography and target lesion revascular isation were included in analyses of the primary endpoint. Patients who returned for angiography before 4 months and did not undergo target lesion revascularisation were rescheduled for angiography at the time defi ned in the protocol.
The first layer can include a first therapeutic agent. The second layer can include a second therapeutic agent. In some embodiments, the first layer can further include a third therapeutic agent. The first layer can be a therapeutic agent reservoir for the second layer. 0013 The first compressibility can be at least 10% (e.g., at least 20%, at least 30%, at least 30%, at least 40%, or at least 50%). The second compressibility can be greater than the first compressibility. The second compressibility can be less than the first compressibility. In some embodiments, when the compressible coating is compressed, the second layer releases an amount of a second therapeutic agent from the medical device. In some embodiments, when the compressible coating is compressed, the first layer releases an amount of the first therapeutic agent into the second layer. When the compressible coating is re compressed, the second layer can release an amount of a first therapeutic agent from the medical device. 0015. In some embodiments, when the compressible coating is repeatedly compressed up to four times (e.g., up to three time, up to two times), the medical device releases between five micrograms and 25 micrograms (e.g., between five micrograms and 20 micrograms, between five micrograms and 15 micrograms, between five and ten micrograms) of the therapeutic agents after each of the compressions. The drug reservoir can increase the amount of bio logically active agent that can be carried by the medical device. The multiple deliveries can result in a more uniform distribution and an increased amount of a biologically active agent to the blood vessel wall. The medical device can deliver one or more biologically active agents, which can follow a specific delivery sequence. For example, the medical device can have two or more populations of frangible microcapsules which can contain different biologically active agents. At one critical pressure, one population of microcapsules can release a biologically active agent. At a different critical pressure, a different population of microcapsules can release a different biologically active agent. In some embodiments, the struc tural elements can provide protection to Surrounding sponge layers from possible abrasive sheer forces that can occur during introduction of a balloon into a body, during transport of the balloon, and/or during angular movements that can occur when the balloon is deployed.
Patients in the IA-DEB and PTA arms presented predominantly with Rutherford Category 5 (84.1% and 77.3%, respectively) when compared with Rutherford Category 4 (14.2% and 17.6%, respectively) and 6 (1.7% and 4.2%, respectively). The salient demographic features of the 2 cohorts are detailed in Table 1 and reflect the challenging nature of CLI patients: 75.7% and 68.9% were diabetics, 8.6% and 12.5% had renal insufficiency (glomerular filtration rate<30 ml/min), and 6.7% and 3.4% were confined to bed in the IA-DEB and PTA arms, respectively. None of the previously mentioned characteristics differ significantly between the 2 arms. Prior TLR was significantly higher in the IA-DEB (32.2%) versus the PTA (21.8%) arm (p ¼ 0.047).
Impaired inflow was significantly higher in the IA-DEB arm (40.7%) versus the PTA (28.8%) arm (p ¼ 0.035). Target lesions were significantly longer (12.9 9.5 cm vs. 10.2 9.1 cm) in the PTA arm versus the IA-DEB arm (p ¼ 0.002). Total occlusions were 38.6% in the IA-DEB arm and 45.9% in the PTA arm (p ¼ 0.114). An incomplete pedal loop occurred frequently, with at least 1 portion of the posterior-plantar, the plantar arch, or the anterior dorsalis path being either occluded or stenotic in 78.2% of IA-DEB arm patients and 70.6% of PTA arm patients (p ¼ 0.118).
Conversely, a complete pedal loop was rarely present in IA-DEB (5.4%) and PTA patients (7.6%; p ¼ 0.485), while complete pedal loop occlusion was present in 7.1% of IA-DEB patients and 11.8% of PTA patients (p ¼ 0.163). Mean lesion lengths in the 167-patient angiography cohort were 5.91 4.17 cm and 7.97 7.46 cm (p ¼ 0.060) with total occlusion present in 31.6% and 32.7% (p ¼ 1.000) of the IA-DEB versus PTA treatment arms, respectively. The percentages of patients evaluable for angiographic core laboratory analysis were 52.6% and 52.7% in the IA-DEB and PTA arms, respectively.
Multiple approaches are proposed for local drug delivery to the vessel wall—injection of nanoparticles loaded with drug, dissolution of the drug in suitable media (contrast media), and drug transfer through drug delivery balloons or DEB. Targeted drug delivery using nanoparticles was validated in preclinical and clinical studies.
Injection catheters allow high concentrations of the drug to be delivered locally. Contrast media adheres to the vessel wall for a few seconds, which could serve as a matrix for local drug delivery. However, these methods deliver only a small amount of the drug to the target area, whereas larger amounts are washed away. Porous balloons13 and double balloons are also used for local drug delivery. The former has multiple holes for drug delivery; the latter uses balloons inflated at proximal and distal ends of the lesion while the occluded area is filled with the drug. Most of these systems were developed before the introduction of DES, with little knowledge about sirolimus and its analogues, and paclitaxel, the only drug proven to reduce restenosis with DES.
What we know about DEB is seen in the recent work done with paclitaxel, which includes a series of preclinical and clinical studies. Methodologies to load the drug to the balloon include spraying, dipping, nanoparticles, and imprinting the drug on the rough surface of the balloon. Controlling the release of the drug into the vessel wall during inflation without losing it during the delivery of the balloon to the target lesion is important. Furthermore, the release kinetics of the drug to the vessel wall is critical to the efficacy and safety of the procedure. With a strong lipophilic nature for retention to the vessel wall, paclitaxel is the drug of choice for DEB.
A process for removing an obstruction from a vessel with an atherectomy system, comprises the following steps: Conventionally inserting into a vessel, into an ob struction, a flexible guide-wire. In case of a tight ob struction, an auger shaped flexible guide-wire can be 65 8 rotated backwards so that the auger section will screw and pull itself through the obstruction. Advancing over the flexible guide-wire a rotary cor ing means located at a distal end of an atherectomy catheter. Advancing the rotary coring means to the obstruc tion and coring the obstruction. During the operation the flexible guide-wire and the flexible sleeve (if pres ent) are prevented from being rotationally dragged by the rotary coring means.
Fluid can be delivered to the obstruction site through the flexible sleeve, around the atherectomy catheter. Such fluid can lubricate and cool the coring process and provide a medium for flushing particles of obstruction material into the atherectomy catheter, especially in conjunction with suction applied to the proximal end of the atherectomy catheter. The fluid may be radio-opaque to assist x-raying the process. Prior to coring, fluid can also be delivered through the atherectomy catheter. A mechanical action of the ro tary coring means and the flexible guide-wire on the cored obstruction material due to the relative motion between them enables the cored material into a continu ous passage defined in the atherectomy catheter and around the flexible guide-wire. Removing the catheter containing the obstruction material out of the vessel.
The sequence of insertion of the components into the artery may vary depending on the nature and the loca tion of the obstruction and the preferences of the medi cal staff. Additional steps may be added to assist the process. A standard guiding catheter, which is either straight or pre-formed, may function as a sleeve and be inserted into the vessel to assist in placing the flexible guide-wire and the atherectomy catheter in the obstruc tion site. When an arterial obstruction is further blocked by a fresh blood clot, as is often the case in a heart attack, the flexible guide-wire can usually be inserted through the clot and the atherectomy system can be used to first clear the clot, preferably while employing suction, and then to continue and core the underlying atherosclo rotic obstruction.
Therefore, the atherectomy system can be an effective tool in treating a heart attack, where the treatment will relieve the immediate threat to the patient's life and continue to provide a long term cor rection to the condition that induced the attack. Differing strategies can be employed when dealing with the process of opening an arterial obstruction. A rotary coring means having an opening approximately equal in area to the artery's internal area can be chosen, however this raises the probability of injuring the artery or of leaving a thin layer of obstruction material hang ing on the arterial wall. Such a thin layer which has no structural integrity of its own may separate from the arterial wall and act as a flap of a one way valve which may block the artery. An alternative strategy is to choose a rotary coring means with an area of less than three quarters of the area of the arterial lumen.
Coring the obstruction with such a rotary coring means usually relieves the patient's symptoms and it leaves sufficient material for the obstruction to remain structurally sta ble, reducing the likelihood of creating a flap, and, by using an undersized rotary coring means the probability of injuring the arterial wall is also reduced, even when dealing with an eccentric obstruction. After the ob struction is cored it is also possible to further increase the lumen by angioplasty, however, this will introduce some of the undesirable side effects that are associated 4,883,458 9 with angioplasty, and the choice of strategy will depend on the patient's specific disease characteristics and the judgement of the medical staff.
Coronary artery disease (CAD) remains the leading cause of death in the US. Over the past three decades since the first percutaneous transluminal coronary angioplasty (PTCA) was performed, advances in percutaneous revascularization have revolutionized the management of patients with CAD. Initial experience with PTCA was plagued with serious complications such as abrupt closure due to dissections, elastic recoil of the artery, and restenosis. Indications for PTCA were limited to focal noncalcified lesions in proximal coronary arteries. The development of coronary artery stents addressed the problems of dissection and elastic recoil, but the risk of in-stent restenosis (ISR) remained high in patients with long lesions, small vessel diameters, bifurcation lesions, diabetics, chronic renal failure, chronic total occlusions (CTO), and saphenous vein grafts (SVG). Multiple strategies such as systemic pharmacologic treatments and modified stent designs have failed to show significant improvements in the rates of ISR. Animal and intravascular ultrasound (IVUS) studies in humans have shown that the primary pathological process in ISR is neointimal proliferation [3–5].
In addition to deep artery trauma and exposure to a ‘‘foreign object’’ from the placement of stents, the residual plaque burden left outside the stent is directly proportional to the amount of neointimal proliferation. In theory, the mechanical debulking of atherosclerotic plaques with the use of rotational or direct coronary atherectomy devices prior to stent placement would be beneficial in three ways: (1) the risk of ISR would be lowered by decreasing the underlying plaque burden, (2) the risk of ISR would also be lowered because of an increase in the acute procedural minimal luminal diameter (MLD), and (3) there would be a decrease in the risk of abrupt closure because of the preservation of the original arterial size and decreased barotrauma to the vessel.
Endovascular therapy for superficial femoral artery (SFA) disease has been recognized as a safe and efficient therapy. The patency rate of treated SFA has been improved through use of the self-expanding nitinol stents. As the population with SFA stenting continues to increase, occurrence of in-stent restenosis (ISR) has become a thoughtful problem. Treatment of SFA-ISR is associated with increased risks of recurrent ISR, recurrent occlusion, and surgical revascularization when compared with focal or diffuse restenosis. No standard treatment exists for the treatment of SFA-ISR. The use of drug-eluting balloons (DEB) reduces restenosis rate after femoro-popliteal percutaneous transluminal angioplasty (PTA). Drug-eluting balloon use has showed promising results in reducing restenosis recurrence in coronary stents.
The drug reservoir can increase the amount of bio logically active agent that can be carried by the medical device. The multiple deliveries can result in a more uniform distribution and an increased amount of a biologically active agent to the blood vessel wall. The medical device can deliver one or more biologically active agents, which can follow a specific delivery sequence. For example, the medical device can have two or more populations of frangible microcapsules which can contain different biologically active agents.
At one critical pressure, one population of microcapsules can release a biologically active agent. At a different critical pressure, a different population of microcapsules can release a different biologically active agent. In some embodiments, the structural elements can provide protection to Surrounding sponge layers from possible abrasive sheer forces that can occur during introduction of a balloon into a body, during transport of the balloon, and/or during angular movements that can occur when the balloon is deployed.
The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description, drawings, and claims.
All procedures were performed percutaneously, with the patient under local anesthesia. Vascular access was achieved via contralateral common femoral artery. A 6-F long sheath was placed in cross-over technique to achieve adequate support. Once diagnostic angiography was completed, the wire was advanced in the distal popliteal artery. All patients underwent balloon angioplasty (plain old balloon angioplasty) for at least 60 s, sizing was 0.8:1 to the reference vessel diameter.
During use, the folded balloon can be delivered to a target location in the vessel, e.g., a portion occluded by plaque, by threading the balloon catheter over a guide wire emplaced in the vessel. The balloon is then inflated, e.g., by introducing a fluid (such as a gas or a liquid) into the interior of the balloon. Inflating the balloon can radially expand the vessel so that the vessel can permit an increased rate of blood flow. After use, the balloon is typically deflated and with drawn from the body. Laser mediated lesion debulking was used, to substitute balloon predilation, at operator discretion. A final post-dilation, at least 180 s, was performed with DEB sizing was 1:1 to the reference vessel diameter.
The balloon has a surface-specific matrix coating consisting of Paclitaxel combined with a hydrophilic spacer. Paclitaxel is an anti-proliferative drug, and the maximum amount on a DEB is 8 mg. The hydrophilic spacer, necessary to separate paclitaxel molecules and facilitate drug elution into the arterial wall, is urea. During inflation of the balloon the drug is almost completely released.
The DEB-treated segment should begin 10 mm proximal and extend toward 10 mm distal to the target SFA lesion. A 5-mm balloon overlap was allowed to obtain a uniform drug elution in the treated vessel. Nitinol stent implantation was allowed, for bail-out stenting (residual stenosis 30% or flow-limiting dissections). Post-procedural patient management. Femoral sheaths were removed when activated clotting time was 150 s. Access site hemostasis was achieved by manual compression in all patients. A complete blood count was obtained before the procedure and before hospital discharge.