Drug eluting stent for the treatment of dialysis graft stenoses

[0001] In the late stages of kidney disease it is often necessary for patients to repeatedly undergo dialysis where their blood is removed, cleansed in a dialysis machine and then returned to their bloodstream. Since arteries cannot be punctured numerous times during a dialysis process and remain functional, grafts are used. The grafts are implanted just below the patient's skin, typically on the patient's arm, to give the physician easy access to the artery and vein and the circulating blood. The graft can be easily palpated and punctured easily with needles so that the dialysis technician can access the patient's bloodstream.

[0002] Unfortunately, these grafts do not last long since they develop thrombosis and restenosis, particularly at the distal anastamosis. Wherever a graft is inserted, an injury repair process occurs, typically at the distal anastamosis where there is initially some thrombosis forming a matrix deposit. The cells migrate into that area, and the patient ends up developing a restenosis at the distal anastamosis. This stenosis developing in the distal anastamosis restricts the flow of blood flow through the graft. A blood clot will form proximal to that stenosis. The physician will usually then remove the blood clot from the graft with a balloon and then dilate the stenosis. The graft will stay open for awhile but the restenosis and rethrombosis process will reoccur, with the time interval between successive stenoses being shorter and shorter. After a few stenoses, the graft is considered a failure, requiring that the physician close the graft down and create a new one. Unfortunately, patients only have a limited number of sites where these grafts can be placed.

[0003] Stents have been used to maintain patency in stenosed dialysis access grafts. These stents are typically plain biliary stents. See, e.g., U.S. Pat. No. 5,591,226 (Trerotola et al.) U.S. Pat. No. 5,755,775 (Trerotola et al.), US 2004/0015180 (Yencho et al.) and George X. Zaleski, Brian Funaki, Jordan Rosenblum, Jennifer Theoharis and Jeff Leef, “Metallic Stents Deployed in Synthetic Arteriovenous Hemodialysis Grafts,” American Journal of Roentgenology 2001; 176:1515-1519. (The entire contents of these publications and all other publications mentioned anywhere in this disclosure are hereby incorporated by reference.) Examples of self-expanding stents that have been used in dialysis grafts include the Gianturco Z-stent (Cook) and the Wall Stent (Boston Scientific).

[0004] When the dialysis needles are inserted into the graft through the stent they will frequently impact the stent because the stent cell openings are very small. If the needle impacts the stent, it can dislodge it. It can also dull the needle, making it impossible to enter so that the needle has to be removed and reinserted, causing more trauma to the graft. Injury to stents after needle puncture has been observed. See, e.g., Lane et al., “Puncture-Induced Deforming of a Metallic Stent Within a Dialysis Access Graft Causing Thrombotic Failure: Case Report and Description of Salvage,” Journal of Vascular and Interventional Radiology 1998; 9:837-839. Lane et al. at page 839, recommends that one refrain from placing needle access in any dialysis graft segment containing a stent. This recommendation is based upon their observation that needle access deforms stents. See also, Rhodes and Silas, “Dialysis Needle Puncture of Wallgrafts Placed in Polytetrafluoroethylene Hemodialysis Grafts,” Journal of Vascular and Interventional Radiology 2005 16:1129-1134.

[0005] Accordingly, a new method and system for increasing the lives of dialysis grafts are needed.

[0006] Directed to remedying disadvantages in the prior art, disclosed herein is a drug eluting stent construction including a stent having a first end, an opposite second end, a first stent part along a length thereof proximate to the first end and spaced from the second end, and a second stent part along a length thereof proximate to the second end and spaced from the first end. Stent cells in the second part have a Maximum Circular Uncovered Stent Area (MCUSA) greater than stent cells in the first part. A first drug or drug combination is on the first part but not on the second part, and a second different drug or drug combination is on the second part. The first drug or drug combination can include an anti-restenotic drug, and the second different drug or drug combination can include an overlaying anti-thrombotic drug covering both the first part and the second part.

[0007] According to another definition of the invention, a stent construction is provided which includes a stent having a first cell pattern proximate to one end of the stent and a second cell pattern proximate to an opposite end of the stent. The first cell pattern has smaller cell dimensions than those of the second cell pattern.

[0008] According to a further definition of the present invention, a stent construction is provided which includes a stent having a first end and an opposite second end. The stent has a first zone along a length thereof proximate to the first end and spaced from the second end and a second zone along a length thereof proximate to the second end and spaced from the first end. A first drug or drug combination is on the first zone but not on the second zone, and a second different drug or drug combination is on the second zone. The drugs can be applied to the stent by dip coating, roll coating, electrostatic coating, vapor deposition coating or spray coating.

[0009] Pursuant to another embodiment of the present invention, a method is provided which includes positioning a stent construction having a first stent portion adjacent one end thereof and a second stent portion having a different construction than that of the first stent portion adjacent an opposite end thereof at a stenosis at a distal graft-vein anastamosis with the first stent portion adjacent the stenosis. The stent construction can be positioned with the second stent portion adjacent the vein as an arterial venous anastomosis stent, or with the second stent portion adjacent the graft or the vein as a dialysis graft stent.

[0010] Other objects and advantages of the present invention will become more apparent to those persons having ordinary skill in the art to which the present invention pertains from the foregoing description taken in conjunction with the accompanying drawings.

[0011] FIG. 1 is an enlarged schematic view of a stent of the present invention having a small cell portion and a large cell portion.

[0012] FIG. 2 is a view of a first alternative of the stent of FIG. 1.

[0013] FIG. 3 is a view of a second alternative of the stent of FIG. 1.

[0014] FIG. 4 is an enlarged view taken on circle 4 of FIG. 1 showing the coating on the struts in the small cell portion.

[0015] FIG. 5 is an enlarged view taken on circle 5 of FIG. 1 showing the coating on the struts in the large cell portion.

[0016] FIG. 6 is an enlarged view taken on circle 6 of FIG. 1 showing a small open-cell layout with a dialysis needle illustrated.

[0017] FIG. 7 is an enlarged view taken on circle 7 of FIG. 1 showing a large open-cell layout with a dialysis needle illustrated.

[0018] FIG. 8 is an enlarged view taken on circle 8 of FIG. 2 showing a small closed-cell layout with a dialysis needle illustrated.

[0019] FIG. 9 is an enlarged view taken on circle 9 of FIG. 2 showing a large closed-cell layout with a dialysis needle illustrated.

[0020] FIG. 10 is an enlarged view taken at the intersection of the small cell portion and the large cell portion of the stent of FIG. 1 showing the maximum circular unsupported surface areas (MCUSA) for both portions.

[0021] FIG. 11 is a schematic view of a stenosis at a distal graft-vein anastomosis.

[0022] FIG. 12 shows a stent of the present invention in an operative position in the view of FIG. 11.

[0023] FIG. 13 shows a stent of the present invention in an alternative operative position in the view of FIG. 11.

[0024] A stent of the present invention is illustrated schematically in FIG. 1, generally at 100, and can be balloon-expandable or self-expandable. As discussed in detail later and with reference to FIGS. 12 and 13, it can be a dialysis graft stent or an arterial venous anastomosis stent. Stent 100, which is preferably formed as a single unitary construction, includes two zones or portions, and can be formed by laser cutting a hypo tube as would be apparent to those skilled in the art from this disclosure. The first portion is shown on the left side of FIG. 1 generally at 110 and a (longer) second portion is shown on the right side generally at 120. The stent 100 can be formed with generally any strut and link configuration as is known. The stent 100, when expanded, can have an internal diameter of between four and eight mm and a length between fifteen and seventy mm, or more particularly, a diameter of approximately six mm and a length of approximately thirty mm.

[0025] The first portion 110 has a tighter cell dimension than that of the second portion 120, where the cell dimension is defined by the Maximum Circular Unsupported Surface Area (“MCUSA”). For example, cells in the first portion 110 can have an MCUSA of 2.0 to 5.0 mm² or approximately 3.5 mm², while the MCUSA of cells in the second portion 120 can be 6.0 to 80 mm² or approximately 19.0 mm². The cells in the second portion 120 are large enough to easily accommodate dialysis needles therethrough such as “14” and “16” Gauge needles, having respective diameters of 1.63 mm and 1.29 mm, and respective cross-sectional areas of 2.09 mm² and 1.31 mm². Dialysis needles are shown in FIG(S). 12 (and 13) at 130 and 136.

[0026] Today's coronary artery drug eluting stents have maximal circular uncovered surface areas (MCUSA) for individual cells ranging from one to five mm², which indicates that these cell sizes are acceptable in the drug eluting stent area of the subject stent 100. Areas greater than 2.1 mm² permit a 14 Gauge needle to penetrate with only a low probability of touching the stent. The probability of introducing a 14 Gauge needle without touching the stent increases as the areas of the individual cells increase, with areas of at least five mm² being acceptable.

[0027] The first portion 110 has cells 140 having a smaller MCUSA than that of the cells 142 of the second portion 120 so that the first portion can hold and effectively transmit drugs from a coating 148 to the anastomotic stenosis, as shown in FIG. 12 for example. These drugs are lipophilic so the cell size needs to be small to provide drug to the entire area to prevent hyperplasia from occurring, which creates restenosis. The second portion 120 can have a different drug coating 150 for transmitting drugs into the bloodstream. Blood clot formation in grafts is a problem and can be exacerbated by the presence of the stent, a foreign body. Accordingly, an anti-thrombotic drug can be provided throughout the entire length of the stent 100 or at least in the non-drug eluting stent area 120. A purpose of the anti-thrombotic coating is thus to reduce the likelihood of thrombosis being initiated by the stent 100. This is especially true for metallic stents made of materials such as stainless steel, cobalt chrome, and nitinol. Furthermore, thrombosis is exacerbated by stents damaged by needle penetration, suggesting that an anti-thrombotic coating can retard that thrombosis.

[0028] The drug of the first portion 110 is shown coated on struts 160 of the first portion in FIG. 4. FIG. 5 shows struts 170 in the cell pattern of the second portion 120 coated with a different second drug 150. While the struts 160, 170 are illustrated as having rectangular cross-sections, other shapes as would be apparent to those skilled in the art can be used. Further, the struts within the same stent can have different widths.

[0029] The first stent portion 110 can have an anti-restenotic drug coating 148. The drug of this coating can be eluted from a nonabsorbable or absorbable polymer placed on a metallic stent or eluted from a stent composed of a mixture of a bioabsorbable polymer and drug or drugs. Biocompatible, nonabsorbable polymers include alkylene vinyl alcohol copolymers such as ethylene vinyl acetate (EVA), alkylene vinyl alcohol copolymers such as ethylene vinyl alcohol (EVAL), poly (n-butyl methacrylate (PMBA), SOLEF polymers such as poly (vinylidene fluoride-co-hexafluoropropene (PVDF-co-HFP and poly (vinylidene fluoride) (PVDF) and combinations thereof. Biocompatible, bioabsorbable polymers include blends of polyesters, poly (D,L-lactide), poly (L-lactide), polyglycolide, and poly (D,L-lactide-co-glycolide). See U.S. Pat. No. 6,673,385 (Ding et al.) and US 2004/0086542 (Hossainy et al.).

[0030] The anti-restenotic drug can be a single drug or a combination of drugs that are eluted at similar or different rates. The drugs include but are not limited to: (1) antiproliferative drugs such as everolimus, sirolimus, ABT-578, and paclitaxel; (2) anti-inflammatory drugs such as corticosteroids (e.g., clobetasol, dexamethasone, and momentasone), inhibitors of the NFkB and p38 pathways; (3) immunosuppressants such as tacrolimus and pimecrolimus; and (4) pro-healing drugs such as 17-beta estradiol, nitric oxide donors, and nitric oxide generators (e.g., chelated copper catalysts).

[0031] The struts 170 of the second stent portion 120 can have an anti-thrombotic coating 150 as mentioned above especially on the luminal surfaces thereof. This coating 150 can include: (1) anti-thrombotics including heparan or heparin; and (2) antiplatelet drugs including nitric oxide donors or nitric oxide generators (chelated copper catalysts).

[0032] More particularly, the first drug or drug combination can include an anti-restenotic drug and the second different drug or drug combination can include an overlaying anti-thrombotic drug covering both the first zone or portion 110 and the second zone or portion 120. See U.S. 2005/0192662 (Ward). The drugs can be applied by techniques known in the art including spray coating, dip coating and roll coating. Another coating application technique uses “depot” technology (see, e.g., US 2005/0234544 (Shanley)), or applies the coating in channels or grooves on the stent surfaces.

[0033] To assist in the placement of the strut in the body, radiopaque markers 180, 184 are provided at opposite ends of the first portion. These (metal) radiopaque markers can have a construction as is known in the prior art, for biodegradable stents. The markers can also be provided at the opposite end of the stent 110, that is, at the right end of FIG(S). 1 (and 2 and 3).

[0034] It may be to reduce the effect of bending stresses at the juncture of the first and second portions 110, 120, that a transitional portion 200 can be provided therebetween as shown in FIG. 2 for the first alternative stent 210. The transitional portion 200 can have a cell pattern with cells having an MCUSA greater than those of the first portion 110 but smaller than those of the second portion 120. Alternatively, the second portion 120 can have a gradually increasing MCUSA for cells at the end adjacent the first portion 110 to the opposite end 220, as illustrated in FIG. 3 by the second alternative stent 230.

[0035] The patterns of the cells 140 of the first stent portion 110 and/or the cells 142 of the second stent portion 120 can have an “open” cell construction such as illustrated in FIG. 6 as well as in FIG. 7. Examples of open cell designs are those of the RX Herculink Plus stent and the Multi-Link Zeta stent. While FIG. 6 shows at 240 a small open cell construction with a small MCUSA, FIG. 7 shows at 250 a large open cell construction with a large MCUSA. The relative sizes can be understood from the cross-section of the dialysis needle 260 drawn in these figures. Alternatively, the first portion 110 and/or the second portion 120 can have a closed cell construction, such as illustrated in FIGS. 8 and 9. FIG. 8 shows at 270 a small closed cell layout, and FIG. 9 shows a large closed cell layout at 280 with a larger MCUSA than that of the layout 270. Examples of closed cell designs are the Palmax Genesis stent and the Cypher Sirolimus-Eluting Coronary stent.

[0036] The stent cell size can be increased by increasing the distance between the struts, as can be seen from comparing FIG. 6 with FIG. 7, and FIG. 8 with FIG. 9. Alternatively, it can be increased by switching from a closed cell design to an open cell design by eliminating a link, as can be understood from comparing FIGS. 8 and 9 with FIGS. 6 and 7. See, e.g., Garasic, J Metal., Circulation 101: 812-818, 2000. To increase the MCUSA of the open and/or closed cell configurations, the length of the strut links 300 can be increased. If the links 300 have undulations 310, one way of increasing the lengths of the links is to increase the lengths of the undulations 310. Another way is to increase the number of undulations 310 per link 300. A third way is to increase the lengths of the straight portions 320, 330 on one or both sides of the undulations 310 as can be seen by comparing FIGS. 6 and 7 and by comparing FIGS. 8 and 9.

[0037] The stent 100, for example, can have a strut and link configuration as disclosed in U.S. Pat. No. 6,616,689 (Ainsworth et al). The links 300 of the second portion 120 can each be approximately two to six mm long, and the links 300 of the first portion 110 can each be approximately one to three mm long. Alternatively, the links 300 of the second portion 120 can be approximately one to five mm longer than the links of the first portion 110. Another definition of the invention is for the links 100 in the first cell portion 110 to have lengths which provide MCUSA's of two to five mm² of the cells 140 in the first portion 100, when expanded. Links 300 in the second cell portion 120 can have lengths which provide MCUSA's of six to eighty mm² of cells 142 in the second portion of the stent 100 when expanded. Alternatively, the links 300 can have lengths which provide MCUSA's of approximately 3.5 mm² in the first portion 110 of the stent 100 when expanded and the links in the second portion 120 can have lengths which provide MCUSA's of approximately 19 mm² in the second portion of the stent when the stent is expanded. In other words, the short links (as on the left portion of FIG. 1, for example) would be in the area of the stent that would contain the drug and would be placed at the graft vein anastamoses, as depicted in FIGS. 12 and 13.

[0038] The underlying stent 100 itself can be made of a biodegradable metal or polymer. Examples of biocompatible, bioabsorbable polymers include blends of polyesters, poly (D,L-lactide), poly (L-lactide), polyglycolide, poly (D,L-lactide-co-glycolide), poly(hydroxyvalerate), poly(lactide-co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate), polyester amide, poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters) (e.g., PEO/PLA), polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, and poly(iminocarbonate) polydioxanone. Examples of usable biodegradable metals for the stent 100 include magnesium alloys such as an alloy of, magnesium, yttrium and rare earth, and usable bioerodible metals include magnesium, zinc, and iron. The underlying stents can be metal stents or polymer stents; they can be bioabsorbable, bioerodable, and/or biodegradable polymeric stents with or without metallic components. Metals including cobalt chromium alloy (Elgiloy), stainless steel (316L), Nitinol, tantalum, and nickel-titanium alloy can be used as the stent material.

[0039] The first portion 110 of the stent 100 can be shorter than the second portion 120. It can be approximately one-third of the length of the total stent 100, while the second portion can be two-thirds of the length. Alternatively, the first portion 110 can have a stent length approximately between twenty and fifty percent of the length of the stent 100, and the second portion 120 can have a length approximately between fifty and eighty percent of the length of the stent. As an example, the stent 100, when expanded, can have an internal diameter of between four and eight mm and a length between fifteen and seventy mm, or more specifically a diameter of approximately six mm and a length of approximately thirty mm.

[0040] FIG. 11 shows a stenosis at a distal graft-vein anastomosis. Referring to the reference numerals in that figure, disclosed therein are proximal artery 410, blood flow 420, distal artery 430, stenosis 440, distal anastomosis 450, central vein 460, distal vein 470, and (PTFE) graft 480.

[0041] The stent 100 can be used as a dialysis graft stent as shown in FIG. 12. The catheter for inserting the stent 100 in position as shown in FIG. 12 is illustrated in phantom lines at 510 on the right side of the drawing. A first dialysis needle 130 can be inserted through the graft 480 and a first stent cell in the second stent portion 120 and into the blood channel 530 in the graft; and a second dialysis needle 136 can be inserted through the graft 520 and a second stent cell in the second stent portion 120, or through the graft 520 directly into the blood channel 530 in the graft. Blood from the blood channel 530 at a proximal area is withdrawn through the inserted first dialysis needle 136, processed in a dialysis machine 540, and returned through the inserted second dialysis needle into the blood channel at a distal area thereof.

[0042] Alternatively, the stent 100 can be used as an arterial venous anastomosis stent as shown in FIG. 13. The catheter for inserting the stent in the position of FIG. 13 is illustrated in the upper left portion of that figure in phantom lines at 560. Both of the dialysis needles 136, 130 pass directly in the graft 480, and not through the stent 110, and into the blood channel 530. The open cell design is useful in this alternative placement of the stent even though the dialysis needles 130, 136 will not be inserted through the cells in this embodiment for two reasons. First, venous flow can go through more easily because it is less restricted. Second, because of the anti-thrombotic coating, there is reduced likelihood of thrombosis in the venous segment.

[0043] In summary, the present invention can include a self-expanding or balloon-expandable stent comprised of nitinol or biodegradable polymer and having two cell patterns. An open cell pattern in the area proximal to the anastamosis is provided in order to facilitate needle punctures of the (PTFE) graft. The performance of this area can be further enhanced by rounding the edges of the stent struts to better deflect needles that strike the strut. The stent has a less open pattern in the area that would be opposed to the anastamotic area. This tighter cell design enhances drug delivery by providing additional surface onto or into which drugs can be placed. In addition, it decreases diffusion distances and thereby decreases the likelihood that there would be areas unaffected by the drug.

[0044] Another definition of the invention is a drug coated stent in which the area in contact with the PTFE graft is coated with a polymer that is nonfouling or anti-thrombotic or has affixed to it or elutes a drug that prevents/inhibits thrombosis. An example is a hydrogel to which is tethered a heparin or nitric oxide donor/generator. The closed cell area of the stent that is in contact with the stenotic vein-graft anastamosis elutes a drug that inhibits restenosis. The drug can be a single drug such as everolimus of paclitaxel, or a drug combination such as everolimus with a anticoagulant/antithrombotic; everolimus with a nitric oxide donor/generator; everolimus with an anti-inflammatory; or everolimus with an immunosuppressant. This area may also be coated with an antifouling coating that prevents clot formation.

[0045] The stent is designed to be deployed via a catheter inserted directly through the dialysis graft material or via an artery or vein that leads to or from the graft. The small cell region of the stent can be positioned at the site of the anastamotic stenosis. The large cell region of the stent can be positioned in the graft area. The biodegradable polymer can be one that has a property to self-expand to bring the drug eluting portion of the device in contact with the anastamotic stenosis and then degrade faster than the graft is expected to fail. This advantageously permits another such stent to be inserted before the graft occludes.

[0046] From the foregoing detailed description, it will be evident that there are a number of changes, adaptations and modifications of the present invention which come within the province of those skilled in the art. The scope of the invention includes any combination of the elements from the different species or embodiments disclosed herein, as well as subassemblies, assemblies, and methods thereof. However, it is intended that all such variations not departing from the spirit of the invention be considered as within the scope thereof.