Patent Publication Number: US-8986241-B2

Title: Apparatus and methods for clot dissolution

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
     The present application is a divisional of U.S. application Ser. No. 12/816,347, filed on Jun. 15, 2010, now U.S. Pat. No.8,241,241, which is a continuation of U.S. application Ser. No. 10/142,005, filed on May 8, 2002, now U.S. Pat. No. 7,763,010, which is a continuation-in-part of U.S. application Ser. No. 09/491,401, filed on Jan. 25, 2000, now U.S. Pat. No. 6,663,613, and of PCT/US01/02406, filed on Jan. 24, 2001, the full disclosures of which are incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates generally to medical devices and methods. More particularly, the present invention relates to devices and methods for dissolving and disrupting occlusive materials from blood vessels. 
     Thrombosis and atherosclerosis are common ailments which result from deposition of thrombus or atheromas, respectively, in the luminal walls of blood vessels. When hardened, such deposits typically result in vascular obstruction and reduced blood flow through the lumens of affected blood vessels. Thrombosis and atherosclerosis are most common in the peripheral blood vessels that feed the limbs of the human body and the coronary arteries which feed the heart. Stasis, incompetent valves, and trauma in the venous circulation cause thrombosis, particularly occurring as a deep vein thrombosis in the peripheral vasculature. When such deposits accumulate in localized regions of the blood vessel, they can restrict blood flow and cause a serious health risk. 
     In addition to forming in the natural vasculature, thrombosis is a serious problem in “artificial” blood vessels or autologous blood vessel grafts, particularly in peripheral femoral-popliteal and coronary bypass grafts and dialysis access grafts and fistulas. The creation of such artificial blood vessels requires anastomotic attachment at at least one, and usually at at least two, locations in the vasculature. Such sites of an anastomotic attachment are particularly susceptible to thrombus formation due to narrowing caused by intimal hyperplasia, and thrombus formation at these sites is a frequent cause of failure of the implanted graft or fistula. The arterio-venous grafts and fistulas which are used for dialysis access are significantly compromised by thrombosis at the sites of anastomotic attachment and elsewhere. Thrombosis often occurs to such an extent that the graft needs to be replaced within a few years or, in the worst cases, a few months. 
     A variety of methods have been developed for treating thrombosis and atherosclerosis in the coronary and peripheral vasculature as well as in implanted grafts and fistulas. Such techniques include surgical procedures, such as coronary artery bypass grafting, and minimally invasive procedures, such as angioplasty, atherectomy, thrombectomy, thrombolysis, transmyocardial revasculaturization, and the like. 
     Of particular interest to the present invention, a variety of techniques have been developed for dissolving clot using thrombolytic agents, such as tissue plasminogen activator (tPA), streptokinase, urokinase, and the like. While such thrombolytic agents can be delivered systemically, the present invention is most particularly concerned with the local delivery of such agents and even more particularly concerned with the local delivery of such agents in combination with mechanical clot disruption. 
     Thrombolytic agents can be very effective at attacking and dissolving relatively soft clot, such as that formed in deep veins. Such agents, however, require time to act, and local delivery catheters often employ isolation balloons to provide high local concentrations of the active thrombolytic agents. Even with such enhanced concentrations, the agents can take extended periods to act, rendering the treatments lengthy and inefficient. In some instances, extensive regions of clot simply cannot be effectively treated using thrombolytic agents alone. In such cases, it has been further proposed to provide a mechanical element to disrupt the clot while the thrombolytic agents are being delivered. See, for example, U.S. Pat. No. 5,947,985 to Mir A. Imran. This patent describes a catheter having axially spaced-apart balloons for isolating a treatment region within a blood vessel. The catheter includes a port for delivering thrombolytic agent between the spaced-apart balloons and a helical wire for removing clot material from the wall to assist in aspiration. While a promising technique, this catheter is not optimized to enhance delivery and mixing of the thrombolytic agent directly into the clot being treated. 
     For these reasons, it would be desirable to provide improved apparatus, methods, and kits for disrupting and dissolving vascular thrombosis, particularly soft clot of the type found in deep vein thrombosis. It would be particularly desirable to provide methods and apparatus which can enhance the thrombolytic activity of thrombolytic agents delivered to the region being treated, and even more particularly enhance the direct introduction into and mixing of the thrombolytic agent within the mass of clot within the blood vessel. It would also be desirable to provide methods and apparatus which provide infusion of thrombolytic agents, aspiration of fluid and/or clot, and passing of a guidewire through a common lumen, with a majority of infusion and aspiration occurring through an opening in the lumen adjacent the clot. At least some of these objectives will be met by the inventions described hereinafter. 
     2. Description of the Background Art 
     Clot disruption catheters which combine the delivery of thrombolytic agents with mechanical disruption are described in, for example, U.S. Pat. Nos. 5,972,019 and 5,947,985. Other clot disruption catheters are described in, for example, U.S. Pat. Nos. 5,954,737; 5,795,322; 5,766,191; 5,556,408; 5,330,484, 5,279,546; 5,116,352; 5,014,093; and WO 96/01591. Catheters having axially spaced-apart isolation balloons for treating thrombus are shown in, for example, U.S. Pat. Nos. 5,947,985 and 5,279,546 and WO 97/11738. Catheters having helical and non-linear guidewires are described in U.S. Pat. Nos. 5,584,843; 5,360,432; 5,356,418; and 5,312,427. Other patents and patent publications of interest include U.S. Pat. Nos. 6,346,116 B1, 6,312,444 B1, 5,957,901; 5,951,514; 5,928,203; 5,908,395; 5,897,567; 5,843,103; 5,836,868; 5,713,848; 5,643,228; 5,569,275; 5,549,119; 5,540,707; 5,501,694; 5,498,236; 5,490,859; 5,380,273; 5,284,486; 5,176,693; 5,163,905; 4,923,462; 4,646,736; and 4,445,509; and WO 99/23952 and WO 99/04701. Publications of interest in the medical literature include LeVeen et al. (1992), American Heart Association Poster Presentation; Tachibana (1993)  JVJR S: 299-303; Kandarpa et al. (1998)  Radiology  168: 739-744; Bildsoe et al. (1989)  Radiology  171: 231-233; and Ritchie et al. (1986)  Circulation  73: 1006-1012. 
     BRIEF SUMMARY OF THE INVENTION 
     The present invention provides apparatus, methods, and kits for disrupting and dissolving thrombus, also referred to as clot, present in a patient&#39;s vasculature, including both the arterial and venous vasculature, as well as grafts. The present invention is particularly intended for treating thrombotic disease within the venous vasculature, such as thrombosis in the superficial vein, the central veins, the femoral-popliteal veins, the iliofemoral vein, and the like. The present invention is also particularly intended for treating arterial thrombotic disease, such as thrombosis in the iliofemoral artery, the superficial femoral artery, and the like. 
     The present invention is advantageous in a number of respects. In particular, the methods and apparatus of the present invention will provide improved introduction and mixing of thrombolytic agents into vascular clot, which in turn will improve the efficiency of clot dissolution, including both reducing the time required for dissolution and/or enhancing the degree to which the clot is dissolved, i.e., reducing the particle size of clot achieved at the end of treatment. The reduction of treatment time will reduce both the cost of treatment and the time during which the patient is undergoing the treatment. The improved degree of clot dissolution will reduce the danger of released emboli, which can be a serious risk to the patient. 
     Various embodiments of the present invention provide apparatus and methods for infusing thrombolytic agents, aspirating clot and/or fluid, and passing a guidewire through a common catheter lumen. Other embodiments provide for separate lumens for infusing, aspirating and/or passing a guidewire. Generally, the embodiments described provide advantageous alternatives for accomplishing desired infusion, aspiration and/or positioning tasks during a clot disruption procedure. Embodiments with only one or two lumens may provide the additional advantage of having a relatively smaller diameter than other devices. 
     In a first aspect, apparatus for disrupting clot over a luminal length of a blood vessel according to the present invention comprises a catheter body having a proximal end, a distal end and at least one lumen. The lumen includes a distal-end opening for allowing passage of a guidewire and fluid flow and at least one side opening proximal to the distal-end opening for allowing fluid flow. The distal-end opening and the at least one side opening generally allow preferential fluid flow through the at least one side opening. The catheter body further includes a first radially expandable body between the distal-end opening and the side opening in the lumen, for inhibiting flow of clot beyond the luminal length of the blood vessel. 
     The dimensions and materials of the catheter body will be selected according to the target site within the vasculature to be treated, i.e., the catheter will be sized to be introduced percutaneously or via a cut down to the vasculature at an entry and then be intravascularly advanced, typically over a guidewire, to the target site. Target sites in the peripheral, coronary, and cerebral vasculature will generally be approached through different access sites and will require catheters having different lengths, diameters, and flexibilities. The constructions of such catheters, however, are well-known and well-described in the patent and medical literature. 
     The luminal length of the blood vessel will usually be at least 3 cm, more usually being at least 10 cm, and typically being in the range from 3 cm to 100 cm, usually from 5 cm to 40 cm. The length of thrombotic disease being treated will vary depending on the location of the disease within the vasculature. For example, deep vein thrombosis will often be disseminated over a length in the range from 5 cm to 100 cm. The apparatus and methods of the present invention will be capable of treating disease disseminated over these lengths as described in more detail below. The apparatus of the present invention need not be adapted to treat the entire length of the diseased region at once. It will often be possible and in some cases desirable to treat discrete lengths within the entire diseased region separately. Such discrete lengths can be treated successively, e.g., by axially translating the treatment device within the blood vessel being treated. Alternatively, the segments could be treated using different devices, optionally introduced from different introduction sites in the vasculature. 
     In some embodiments of the invention, infusion of an agent, aspiration of clot and fluid, and/or passage of a guidewire may be performed through a common lumen. In other embodiments, two or more lumens are used for infusion, aspiration, and guidewire passage. For example, in one embodiment infusion and guidewire passage may occur through one lumen and aspiration may occur through another. In other embodiments, aspiration and guidewire passage may occur through the same lumen and infusion may occur through another. Thus, some embodiments of the present invention provide for infusion and aspiration through the distal-end opening and the at least one side opening, while other embodiments divide these tasks among multiple lumens. Furthermore, many embodiments of the invention allow for a guidewire to remain in place within the at least one lumen while either infusion, aspiration, or both are performed through the distal-end opening and the at least one side opening. 
     As described briefly above, the distal-end opening and the at least one side opening are generally configured to allow for preferential fluid flow through the at least one side opening This preferential flow may be accomplished in any of a number of suitable ways. For example, distal-end opening may be configured to have a cross-sectional area that is significantly smaller that the cross-sectional area of the at least one side opening. In one embodiment, the distal-end opening may have a cross-sectional area of between about 0.1% and about 20%, and preferably between about 1% and about 5%, of the cross-sectional area of the at least one side opening. This difference in cross-sectional areas of the openings will allow a preferential fluid flow through the at least one side opening because fluid will preferentially flow through the larger opening, with the least resistance. 
     In various embodiments, the at least one side opening may include one opening in a side wall of the lumen of the catheter body, multiple smaller spaced-apart openings in the lumen, a combination of multiple smaller openings and one larger opening, and the like. Generally, the at least one side opening may have any suitable configuration for infusing an agent and/or aspiration clot and fluid. 
     In other embodiments, the apparatus allows for preferential fluid flow through the at least one side opening by further including a flow resistor between the distal-end opening and the at least one side opening for inhibiting fluid flow through the at least one lumen. Generally, the flow resistor may comprise any mechanism for inhibiting fluid flow through the at least one lumen such that fluid flow in aspiration and/or infusion occurs preferentially through the at least one side opening. For example, in one embodiment, the flow resistor allows fluid flow (either infusion, aspiration or both) through the distal-end opening at a rate of between about 0.1% and about 20% of the total fluid flow, and preferably between about 1% and about 5% of the total flow. Thus, fluid flow through the at least one side opening would account for between about 80% and about 99.9% of the fluid flow, and preferably between about 95% and about 99% of the total flow. 
     Generally, the optional flow resistor disposed between the distal-end opening and the at least one side opening may have any of a number of suitable configurations for inhibiting flow through the at least one lumen to allow preferential flow through the at least one side opening. In one embodiment, the flow resistor comprises a cylindrical material with at least one channel. Such a flow resistor may be made from any suitable material, such as a silicone-based material. Typically, the cylindrical material will have an outer diameter equal to the inner diameter of the at least one lumen. The at least one channel through the cylindrical material may have any of a number of different configurations in various embodiments of the invention. For example, in one embodiment the channel comprises a cylindrical hole having an inner diameter sufficient to allow passage of a guidewire. The same hole may also allow passage of fluid. In another embodiment, the at least one channel comprises one or more flexible slits to allow passage of the guidewire and fluid. In yet another embodiment, the at least one channel comprises a valve for allowing passage of the guidewire and one or more holes for allowing passage of fluid. Generally, any suitable configuration for the cylindrical material and the at least one channel may be used to inhibit flow of fluid through the lumen distal to the flow resistor. 
     In another embodiment, the flow resistor comprises a membrane with at least one aperture. In yet another embodiment, the flow resistor comprises a ball valve for partially blocking flow of fluid through the at least one lumen, the ball valve having at least one channel, a ball, and a widened area within the channel into which the ball may fall to allow passage of a guidewire through the channel. In yet another embodiment, the flow resistor comprises a compliant membrane coupled to the at least one lumen, the compliant membrane communicating with an inflation lumen, the inflation lumen communicating with an inflation port. Inflation via the inflation port and inflation lumen moves the compliant membrane to partially or wholly block fluid flow through the at least one lumen of the catheter body. Such an inflation lumen may be separate from or in communication with an inflation lumen for an expandable body on the catheter body. 
     Whether a particular embodiment of the present invention uses different cross-sectional areas of the distal-end opening and the at least one side opening, an optional flow resistor, a combination thereof, or some other suitable means, invariably a preferential fluid flow is allowed through the at least one side opening. Such a preferential flow generally allows aspiration and/or infusion to be concentrated at a clot site or treatment site adjacent the at least one side opening. At the same time, some aspiration and/or infusion still typically occurs through the distal-end opening, which may be advantageous in various procedures, for example where some infusion of a thrombolytic agent at a location distal to the clot is desired. 
     Some embodiments of the present invention further include a mechanical agitator near the distal end of the catheter body for mechanically agitating clot over the length of the blood vessel. The mechanical agitator may have a wide variety of specific configurations. Usually, the mechanical agitator will comprise a radially expansible agitator which is rotatable and/or axially translatable relative to the catheter body. In one embodiment, the radially expansible agitator will be self-expanding, e.g., it may comprise a resilient element which may be radially constrained to have a low profile (small diameter) and may be freed from radial constraint to have an enlarged profile (large diameter) with a non-linear geometry. Typically, radial constraint can be provided by a sleeve or sheath which may be axially advanced and retracted relative to the catheter body to cover and uncover the radially expansible agitator. In this way, the catheter can be introduced to a target site within the vasculature with the expansible agitator covered (and thus radially constrained). After the desired target site is reached, the sheath or sleeve can be axially retracted to release the radially expansible agitator so that it expands to engage the clot in the blood vessel. The agitator may then be rotated and/or axially translated to engage and disrupt the clot in combination with the release of a thrombolytic agent, as described in more detail below. Such rotation, oscillation, and/or translation will usually be accomplished using a motor drive unit operatively connected to the agitator, but could in some instances be performed manually in whole or in part. 
     In an alternative embodiment, the radially expansible agitator may comprise a resilient element which can be axially shortened to assume an enlarged profile having a nonlinear geometry. For example, a self-expanding resilient element may be straightened (tensioned) by initially positioning a rod or stylet therein in order to lengthen the element and cause it to straighten to a low profile diameter. The agitator may then be expanded by retracting the rod or stylet to release the agitator from tension and permit the agitator to radially expand as a result of the agitator&#39;s inherent spring force. Alternatively, the agitator may be formed to have a generally straight, low profile configuration and be actively caused to radially expand by pulling on a rod or wire to cause axial shortening. 
     In all cases, the agitator may have a variety of specific geometries, such as a helical geometry, a spiral geometry, a serpentine geometry, a zig-zag geometry, an alternating helix geometry (i.e., two or more helical geometries in tandem where successive helixes are wound in opposite directions), and/or a variety of other random geometries. The geometries will be such that the resilient element can engage against and penetrate into the clot within a blood vessel as the resilient element is radially expanded. As the resilient element is thereafter rotated and/or axially translated, the element will then mechanically engage and disrupt the clot. By simultaneously introducing the thrombolytic agent directly to the region which is being mechanically engaged by the agitator, disruption and dissolution of the clot is significantly enhanced. 
     In other embodiments of the invention, an agent such as a thrombolytic agent may be distributed at the luminal length of the blood vessel by an agent distributing means. In some embodiments, such distributing means will comprise a porous sheath or other perforate or foramenous structure which may be disposed over a radially expansible agitator. The porous sheath may be a thin fabric having a generally uniform porosity along its length. Alternatively, the sheath could be an impermeable membrane having a plurality of holes or ports formed along its length to permit the release of a thrombolytic agent. A wide variety of other perforate or porous structures will also be available. For example, the sheath could comprise a coil having a plurality of successive turns, where bending of the coil causes the turns to separate, creating spaces or apertures for the release of the thrombolytic agent. It would also be possible to form the sheath from an elastic material having pores which are generally closed but which open when the elastic material is tensioned, either by stretching (e.g., due to internal pressurization with the thrombolytic agent) or by deforming the elastic sheath material as the sheath is deformed into its non-linear geometry. 
     In embodiments of the invention which include a mechanical agitator, the sheath may be able to release the thrombolytic agent along substantially the entire length of the agitator which is in contact with the clot to be disrupted. In this way, the thrombolytic agent will be released at the point of mechanical agitation, resulting in both improved distribution of the thrombolytic agent into the clot as well as improved disruption and dissolution of the clot. Usually, the porous sheath will be formed as a relatively closely fitting sleeve over the resilient element, e.g., so that the sheath assumes the same non-linear geometry as the resilient element. Alternatively, however, the sheath may be formed to have larger diameter, e.g., a diameter approaching the luminal diameter of the blood vessel being treated. In the latter case, the thrombolytic agent may be distributed over the entire region of the clot while the agitator presses the sheath into the clot to enhance introduction of the thrombolytic agent and dissolution of the clot. In both cases, the sheath may be elastic, i.e., expansible in response to pressure of thrombolytic agent, or inelastic. Alternatively, the sheath could be a composite of an elastic fabric or membrane reinforced with a grid or network of elastic or inelastic ribs or other reinforcement members. 
     In an alternative embodiment, the agitator may be configured to directly deliver the thrombolytic agent into the clot as the agitator is being driven. For example, when the agitator is in the form of a non-linear element, the element may be formed as a tube having a thrombolytic agent delivery lumen therein. The tube may then be provided with agent delivery ports and/or porous regions to permit the generally uniform release of the thrombolytic agent over the length of the element which is contact with the clot. In this way, the thrombolytic agent may be delivered directly into the clot and dissolution enhanced without the need to provide for a separate thrombolytic agent delivery sheath. 
     Optionally, the clot disruption and dissolution apparatus of the present invention may further comprise means for isolating at least a distal end of the catheter body to reduce blood flow through the region being treated by the catheter. For example, at least a single balloon may be provided on the catheter body distally or proximally of the agitator and thrombolytic agent distribution means on the catheter. When only a single balloon is used for isolation, it will preferably be on the side of the thrombolytic agent distribution means which is downstream from the region being treated. In this way, the isolation balloon will inhibit the loss of the thrombolytic agent as well as the release of emboli downstream. Preferably, isolation means will be provided both on the distal end proximal sides of the agitator and thrombolytic agent distributing means. Typically, the isolation means will comprise a pair of axially spaced-apart balloons disposed on the catheter body. Further optionally, one of the balloons may be disposed on a separate, telescoping portion of the catheter body in order to permit length adjustment of the region to be isolated. Alternatively, a variety of other isolation means, such as deployable flanges, malecot structures, expansible braids, and the like, could also be employed. 
     In the apparatus of the present invention which employ both an agitator and a sheath, the agitator may optionally be replaceable within the sheath and/or axially translatable within the sheath. Still further optionally, the sheath itself may be introduceable over a guidewire, either with or without the agitator being in place within the sheath. Thus, the apparatus may provide for the free interchangeability of two or more agitators and at least one guidewire for initially placing the sheath. It will be appreciated that such replaceability provides great adaptability of the systems of the present invention. For example, the sheath could be introduced to a treatment site within the vasculature over a conventional guidewire or a guidewire with a balloon and/or filter on it. After withdrawing the guidewire, a first agitator could be introduced to within the sheath and the target site treated by both agitation and release of the thrombolytic agent. It would then be possible to reposition the agitator within the sheath to treat a different region of the vasculature. Alternatively or additionally, it would be possible to remove the first agitator and replace it with a second agitator selected to better treat the region and/or to provide for a subsequent treatment step of that region. 
     The catheters of the present invention may optionally be provided with lumen(s) for introduction over a guidewire or a guidewire with a balloon and/or filter on it. For example, the catheter (or a sheath component thereof) may be introduced over a guidewire using a central lumen which also receives the agitator. Alternatively, separate guidewire lumen(s) could be provided on the sheath or elsewhere, e.g., a short guidewire lumen could be provided near the distal tip of the sheath beyond the non-linear region defined by the agitator. Such a short lumen would avoid interference with the agitator. Inflation of a guidewire balloon distal of the catheter may help isolate the region of the vessel from blood flow. A variety of specific designs will be available. 
     The apparatus of the present invention will still further be available of systems comprising at least one sheath together with two or more agitators which are removably replaceable within the sheath. Such systems allow for treatment of different diseases and different regions of the vasculature. The treating physician can either choose the initial combination which is best for a particular disease, or may begin treatment with one combination of sheath and agitator and continue treatment thereafter with another combination of sheath and agitator. 
     In another apparatus aspect, the invention provides an apparatus for disrupting clot over a target region of a blood vessel. The apparatus comprises a catheter body having a proximal end and a distal end. An agitator is disposed near the distal end for mechanically agitating clot over the target region. A port near the distal end is in fluid communication with an agent supply source for distributing an agent along the target region. 
     In many embodiments, the agent will comprise a thrombolytic agent, which may provide an enzymatic action to break down fibrin clot matrix. A variety of other agents may also be used, including group IIb/IIIa Inhibitors (typically to inhibit fibrinogen binding site of platelet membrane, other anti-platelet agents, anti-thrombin agents and agents directed toward prevention of restenosis (which may inhibit coagulation and/or inhibit restenosis by decreasing smooth muscle proliferation and migration), gene therapeutic agents (currently under development, often for preventing restenosis and promoting angiogenesis), chemotherapeutic agents (generally designed to treat malignancies) imaging media, and/or other potential agents. 
     The present invention still further provides a method for disrupting clot over a luminal length of a blood vessel. The method includes first positioning a catheter body with at least one lumen at a location within the luminal length of the blood vessel. The at least one lumen of the catheter body has a distal-end opening and at least one side opening. The method then includes infusing an agent through the distal-end opening and the at least one side opening, where the infusion predominantly occurs through the at least one side opening. 
     Optionally, methods of the present invention also include mechanically agitating the clot over the luminal length of the blood vessel. In some embodiments, the methods comprise infusing the thrombolytic agent in a distributed pattern over the treated length. By “distributed pattern,” it is meant that the thrombolytic agent is not simply released into the treatment region but rather that it is introduced directly into the clot at the interface region where the clot is being mechanically agitated. For example, in the case where mechanical agitation is achieved using a non-linear element, the thrombolytic agent will be delivered at points which are distributed over the non-linear element so that they enter the clot at the “point of attack” described above in connection with the apparatus. The thrombolytic agent can be delivered using a porous sheath which is disposed over the non-linear agent in a sleeve-like manner. Alternatively, the thrombolytic agent can be delivered through a lumen within the non-linear agent and released through a plurality of ports or porous regions in the non-linear element. In both cases, the ability to deliver the thrombolytic agent directly into the clot as it is being mechanically penetrated by the element will enhance distribution of the thrombolytic agent within the clot and improve the efficiency of clot dissolution as well as decrease the particle size reduction achieved in a given period of time. 
     In specific aspects, the methods of the present invention are used to treat predetermined luminal lengths, typically having a length of at least 5 cm, usually at least 100 cm, and most usually in the range from 10 cm to 50 cm. When the blood vessel is a vein, the targeted regions may be selected from the group consisting of vena cava, iliac vein, femoral vein, popliteal vein, common iliac vein, external iliac vein, brachial vein, and subclavian vein. When the target blood vessel is an artery, the preferred arteries are the internal iliac artery, external iliac artery, popliteal artery, coronary arteries, superficial femoral artery, and the brachial artery. 
     Preferably, mechanical agitation comprises rotating and/or axially translating a radially expansible agitator within the blood vessel and against the clot. The exemplary agitators have been described above. Optionally, the mechanical and agitation and thrombolytic agent delivery may be performed within isolated regions of the vasculature, typically provided by inflating one or more balloons within the vasculature at either side of the treatment region. Most preferably, a pair of axially spaced-apart balloons will be disposed on either side of the treatment region to provide isolation, both to maintain higher thrombolytic agent concentrations within the region and to inhibit the release of thrombotic clot prior to sufficient dissolution of the clot. 
     The methods of the present invention allow for a wide variety of particular treatment protocols. For example, the agitator may be driven at different and/or variable speeds. Typically, the agitators will be rotated and/or oscillated at speeds in the range from 0 rpm to 50,000 rpm, preferably from 50 rpm to 5,000 rpm. The speeds may be set and/or adjusted at a wide variety of particular rotational speeds within these ranges. In some cases, the direction of the rotation can be reversed during the course of the procedure. It will further be possible to axially advance or retract the agitator, optionally within a sheath, during the course of treatment to enhance the disruption of the clot and introduction of the thrombolytic into the clot. Still further additionally, it will be possible to vary the width or diameter of the agitator during the course of treatment to enhance disruption. 
     In general, infusing the agent predominantly through the at least one side opening is accomplished via a larger cross-sectional area of the side opening compared to the distal-end opening, via a flow resistor, or by any other suitable means, as described in greater detail above in relation to apparatus of the invention. In some embodiments, one or more agents may be infused through the lumen of the catheter body and clot and/or fluid may be aspirated through the same lumen. In other methods, infusion and aspiration may be performed through separate lumens. In still other embodiments, infusion is performed through a sheath surrounding the catheter body and aspiration is performed through the lumen of the catheter body. In other methods, infusion is through the lumen and aspiration is through the sheath. In some of the embodiments, a guidewire may be left in position in one lumen during infusion, aspiration or both. 
     As just suggested, the treatment methods of the present invention may optionally comprise aspiration of the disrupted clot from the treatment site. Aspiration may be accomplished using a lumen or lumens within the sheath and/or agitator to withdraw the disrupted clot. Optionally, mechanical means, such as an Archimedes screw or other pump, may be incorporated into the catheter to enhance the aspiration and removal of the disrupted clot. In other embodiments, such a pump may be mounted to a separate structure, such as to a sheath removably disposed over the catheter, an inner structure removably disposed within a lumen of the catheter, or the like. Still further embodiments may rely on an aspiration means which remains outside the patient, such as a syringe, vacuum container, or the like. 
     Still further optionally, the disrupted clot and other fluid or fluidized materials within the treatment region may be recirculated to enhance breakup of the clot and activity of thrombolytic agent. For example, pairs of spaced-apart ports or apertures on the sheath may be used to draw in the material within the treatment region and expel that material at a different point within the treatment region. Such recirculation may significantly enhance the thrombolytic activity and decrease the treatment time. 
     As a still further option, it is possible to periodically or continuously introduce blood into the treatment region. tPA acts on plasminogen within the vasculature to breakup thrombus. If the treatment region of the present invention is isolated, it may be beneficial to introduce fresh blood containing plasma in order to enhance the activity of the thrombolytic agent, particularly tPA. Most simply, fresh blood could be introduced by periodically opening an isolation balloon which isolates the treatment region. 
     The methods of the present invention can rely on two or more of the treatment catheters to be used simultaneously. For example, in the treatment of arterio-venous grafts, it is possible to introduce two treatment catheters according to the present invention, each of which has a balloon or other occlusion device at its distal end, to an A-V graft at a point near its middle. By introducing the two treatment catheters in opposite directions, the graft can be isolated very close to the points at which it is anastomosed to the natural vasculature. After such isolation is achieved, the interior of the A-V graft can then be cleaned out according to the methods of the present invention, and preferably the released clot and thrombus may be withdrawn through an access sheath to the A-V graft. 
     The present invention still further comprises kits, including a catheter having an agitator in a thrombolytic agent delivery means. The kits will further include instructions for use according to any of the methods set forth above. In addition to the catheter and the instructions for use, the kits will usually further comprise packaging, such a box, pouch, tray, tube, bag, or the like, which holds the catheter and the instructions for use. Usually the catheter will be maintained sterilely within the package, and the instructions for use will be printed on a separate package insert or piece of paper. Alternatively, the instructions for use may be printed in whole or in part on a portion of the packaging. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a perspective view of clot disruption apparatus constructed in accordance with the principles of the present invention. 
         FIG. 2  is a detailed view of the distal end of the clot disruption apparatus of  FIG. 1 , showing the sheath and agitator components thereof. 
         FIG. 2A  illustrates an aspiration pump which may be integrated into the apparatus of  FIG. 1  for aspiration of disrupted clot material. 
         FIG. 3  illustrates use of the clot disruption apparatus of  FIG. 1  in treating a thrombosed region within a blood vessel according to the methods of the present invention. 
         FIG. 4  illustrates an alternative construction of an agitator useful in the apparatus of the present invention. 
         FIG. 5  illustrates a second alternative construction of an agitator useful in the apparatus of the present invention. 
         FIG. 6  illustrates a third alternative construction of an agitator useful in the apparatus of the present invention. 
         FIG. 7  illustrates a fourth configuration of an agitator useful in the apparatus of the present invention. 
         FIG. 8  illustrates a method and apparatus according to the present invention for treating an isolated region of the vasculature. 
         FIGS. 9 ,  9 A and  9 B illustrate alternative methods and apparatus according to the present invention for treating an isolated region of the vasculature. 
         FIGS. 10A and 10B  illustrate yet another alternative embodiment of the methods and apparatus of the present invention for treating an isolated region of the vasculature. 
         FIG. 11  illustrates a still further embodiment of the apparatus and methods of the present invention for treating an isolated region of the vasculature. 
         FIG. 12  illustrates a first method for treating an arterio-venous graft according to the methods of the present invention. 
         FIG. 13  illustrates a second method employing a pair of clot disruption catheters for treating an arterio-venous graft according to the methods of the present invention. 
         FIG. 14  illustrates a kit for performing the methods of the present invention, wherein the kit is constructed in accordance with the principles of the present invention. 
         FIG. 15  illustrates a clot disruption apparatus having a sheath and a catheter body, the catheter body having a lumen with a distal-end opening and a side opening according to one embodiment of the present invention. 
         FIG. 16   a  illustrates a cross section of the distal end of a clot disruption apparatus having a cylindrical flow resistor and a common lumen for infusion and aspiration, according to one embodiment of the present invention. 
         FIGS. 16   b - d  illustrate frontal views of various configurations of a flow resistor for a clot disruption apparatus as in  FIG. 16   a.    
         FIG. 17  illustrates a cross section of the distal end of a clot disruption apparatus having a cylindrical flow resistor and two separate lumens, one for infusion and one for aspiration, according to one embodiment of the present invention. 
         FIGS. 18   a - b  illustrate a cross section of the distal end of a clot disruption apparatus having a compliant membrane flow resistor and a common lumen for infusion and aspiration, according to one embodiment of the present invention. 
         FIG. 19  illustrates a cross section of a ball valve flow resistor which may be used in the distal end of a catheter body lumen according to one embodiment of the present invention. 
         FIGS. 20   a - g  illustrate a method for disrupting a clot according to one embodiment of the present invention. 
         FIGS. 21   a - g  illustrate a method for disrupting a clot according to another embodiment of the present invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In  FIG. 1 , a clot disruption apparatus  10  is shown to comprise a catheter body  12 , a motor drive unit  14 , and a thrombolytic agent delivery device  16 . The motor drive unit  14  is attached to a hub  18  at a proximal end  20  of the catheter body  12 . The thrombolytic agent delivery device is shown as a syringe which is attached to a side port  22  on hub  18  through a conventional tube  24 . It will be appreciated that other thrombolytic agent delivery devices could also be used, such as pumps, gravity bags, and the like. The thrombolytic agent delivered by device  16  can be any conventional bioactive agent which is capable of disrupting and dissolving clot and thrombus, such as tissue plasminogen activator (tPA), streptokinase, urokinase, heparin, low molecular weight heparin, and the like. The thrombolytic agents may be delivered through the delivery device  16  as a bolus, continuously over time, or as combinations thereof. 
     Use of the present invention will generally be described with reference to thrombolytic agents, often those having enzymatic action which breaks down fibrin clot matrix. In addition to tPA, suitable thrombolytic agents may include Alteplase or Activase™, Tenecteplase, TNK, and TNKase™, all of which are from Genentech, Inc; Anistreplase, a-SK, Eminase™, from Roberts Pharmaceuticals; Reteplase, r-PA, Retavase™, from Centocor, Inc.; Streptokinase, SK, Streptase™, from AstraZeneca, Inc.; and Abbokinase™, Abbott, Inc. A variety of other agents may also be used, including Group IIb/IIIa Inhibitors which may inhibit fibrinogen binding site of platelet membrane, such as Abciximab and ReoPro™, from Centecor, Inc.; Tirofiban and Aggrastat™ from Merck, Inc.; Eptifibatide and Integrelin™ from Cor Therapeutics, Inc.; and other IIb/IIIa inhibitors such as Bitistatin and Kistrin, or other anit-platelet agents (such as aspirin). 
     The invention may also be used with anti-thrombin agents and agents directed toward prevention of restenosis to inhibit coagulation and/or inhibit restenosis by decreasing smooth muscle proliferation and migration, such as Heparin (LMW containing most anticoagulant activity, and also inhibits smooth muscle proliferation and migration), enoxaparine or Lovenox™ dalteparin or Fragmin™, and ardeparin or Normoflo™, Hirudin, Argatroban, PPACK to inhibit thrombin induced platelet activation and platelet secretion of PDGF which may be responsible for smooth muscle proliferation and migration, radioactive agents (such as for vascular brachytherapy, inhibits smooth muscle proliferation), locally delivered nitrate (nitric oxide, prevents reflex vasoconstriction at site of injury and inhibits activation of circulating platelets in order to decrease late luminal narrowing), HA 1077 (which inhibits action of cellular protein kinases and sequestration of cellular calcium, acts as vasodilator, and may inhibit smooth muscle proliferation), and other anti-restenosis agents (such as calcium antagonists, angiotensin converting enzyme inhibitor, anti-inflammatory agents, steroidal agents, anti-mitotic agents, HMG CoA reductase inhibitors, colchicine, angiopeptin, cytoclasin B (inhibits actin polymerization and muscle cell motility. 
     In still further alternatives, the invention may be used, with gene therapeutic agents, new agents and/or agents which under development for preventing restenosis and promoting angiogenesis. Such agents may be delivered via plasmid vectors or by viral vectors. Examples include genes relating to: VEGF, C-myb, FGF, transforming growth factor b, endothelial growth factor, protooncogenes such as C-myc, C-myg, CDC-2, and PCNA. 
     Still further alternative agents may be used with the devices and methods of the present invention, including chemotherapeutic agents (agents used to treat malignancies, such as adriamycin or Doxorubicin™), imaging media (including contrast media and radioactively labeled agents), plasminogen additive (as an adjunct to thrombolytic therapy), immunosuppressive agents, and other potential agents. 
     A motor drive unit  14  includes a sliding switch  26  which controls the rotational speed of the motor and a sliding collar  28  which controls the axial position of an agitator  30  within a sheath  32  of the catheter body  12  ( FIG. 2 ). A non-linear region  34  of the catheter body  12  is defined by the agitator  30  within the sheath  32 . By axially translating the agitator  30  using the collar  28 , the non-linear region of the catheter body can be moved in a proximal or distal direction along the catheter body. The motor drive unit will be capable of rotating the agitator  30  within the sheath  32  at the rotational rates set forth hereinabove. Additionally, the motor drive unit  14  may be adapted in other circumstances to oscillate the agitator, axially reciprocate the agitator, or provide for other mechanical movements of the agitator which can cause or contribute to clot disruption according to the methods of the present invention. 
     Referring now in particular to  FIG. 2 , the sheath  32  comprises a tubular body formed from a polymeric material, a fabric, or other material, and includes a plurality of fluid distribution ports  40  along its length. As illustrated, the fluid distribution ports  40  are only formed over a portion of the length of the sheath. It will also be possible to form the ports over the length which is greater than the non-linear region defined by the agitator  30 . The agitator  30  is shown to be a short helical section having one complete turn. Other geometries will include two-dimensional geometries, such as single humps, S-shapes, zig-zag patterns, and the like. Suitable three-dimensional geometries include helical geometries, alternating helixes, spirals, and the like. In all cases, as the non-linear region of the agitator is rotated within the sheath, the sheath will be caused to trace a three-dimensional envelope within the blood vessel being treated. Usually, the agitator  30  will force the sheath into engagement with clot or thrombus within the blood vessel, and the thrombolytic agent will be released through the ports  40  as the sheath is being engaged by the agitator. In this way, the thrombolytic agent is introduced directly into the clot or thrombus as the clot is being mechanically disrupted. This combination of mechanical and chemical dissolution of the clot is every effective and can reduce the clot disruption time significantly when compared to other thrombolytic techniques. 
     As will be described in more detail below, the apparatus of  FIGS. 1 and 2  may be used with a variety of additional structures to help remove the disrupted clot material. Optionally, a simple external vacuum source  15  may be coupled to the motor drive unit  14  to draw material proximally through an aspiration lumen of the catheter body. A wide variety of aspiration sources may be used, including a simple locking syringe. 
     In some embodiments, a pump element  29  shown in  FIG. 2A  may be disposed within the aspiration lumen to help pump the clot material proximally through the catheter body. As described in detail in co-pending application Ser. No. 09/454,517, filed on Dec. 6, 1999, the full disclosure of which is incorporated herein by reference, pump element  29  may comprise a tubular body  31  having a lumen  33  therein and a helical element  35  disposed thereover. When pump element  29  rotates within an aspiration lumen in catheter body  12  (or alternatively, in a sheath surrounding the catheter body or a separate aspiration catheter extending along catheter body  12 ), material can be urged axially (either proximally or distally, depending on the direction of rotation). Such pumps are sometimes referred to as an “Archimede&#39;s screw.” Pump element  29  may be formed from at least a portion of a shaft drivingly coupling agitator  30  to the motor drive unit, or may comprise a separately driven structure. 
     In some embodiments, such as when the region of the blood vessel to be treated will be isolated both proximally and distally, it may be advantageous to maintain a substantially constant fluid volume within the region of the blood vessel. As described in detail in application Ser. No. 09/751,216, filed on Dec. 29, 2000, the full disclosure of which is incorporated herein by reference, an at least roughly equal quantity of fluid (including the therapeutic agent) may be introduced into the vessel as the total volume aspirated from the vessel by filtering the aspirated fluid from the solid clot material and by reintroducing the filtered fluid back into the vessel. 
     Use of the clot disruption apparatus  10  of  FIGS. 1 and 2  is illustrated in  FIG. 3 . The non-linear region  34  of the catheter body  12  is positioned within a treatment region TR of the blood vessel BV being treated. Once in place, the agitator  30  is rotated, as indicated by arrow  42  and the non-linear region sweeps an ovoid volume within the treatment region TR, disrupting and dissolving clot as the thrombolytic agent is released from the ports  40 . Alternatively or additionally, the non-linear region  34  could be rotated in the direction opposite to arrow  42 , could be rotationally oscillated, axially oscillated, or combinations thereof. 
     As described in the Summary above, the agitator may operate together with a thrombolytic agent delivery sheath (as illustrated in  FIGS. 1-3 ) or may alternatively be configured to deliver the thrombolytic agent directly, e.g., through a lumen in the agitator as illustrated in  FIG. 4 . Agitator  50  of  FIG. 4  includes a non-linear region  52  which consists of a simple, two-dimensional curve which forms a hump in the agitator. The non-linear region has a plurality of thrombolytic agent delivery ports  54  formed over its length so that the nonlinear region  52  can release the thrombolytic agent directly into the thrombus being treated as the agitator is rotated. In a first instance, the agitator  50  may be formed from a resilient material with the non-linear curve being formed so that it assumes the curve when released from constraint. The agitator  50  could then be delivered to a target site within a blood vessel within a separate delivery sheath. When the agitator  50  is advanced from the sheath, it will assume the non-linear geometry illustrated in  FIG. 4 . Alternatively, as shown in  FIG. 5 , the sheath  50  can be delivered with an internal stiffener  56  which tensions the agitator so that the non-linear region  52  (shown in broken line) is straightened (shown in full line) when the stiffener  56  is axially advanced within the lumen  60  thereof. It will also be possible to configure the agitator  50  so that it assumes a straight configuration when free from axial tension and compression. When under compression, however, the agitator will be formed so that it will collapse and assume the non-linear configuration  52  shown in  FIG. 4 . The agitator  50  could also be formed from heat memory alloys which are straight at room temperature but which assume their non-linear configuration when introduced to the body temperature. By introducing such catheters in a cooled environment, e.g., while bathed in cooled saline, they can reach their target site in a straightened configuration and thereafter assume the non-linear configuration as they return to body temperature. 
     In addition to perforate structures for release of the thrombolytic agent, as shown in  FIGS. 4 and 5 , an agitator  62  having a sheath  63  formed as a coiled structure  64 , as shown in  FIG. 6 , may also be used. The coil can be configured to have a non-linear region  64 , such as a simple curve, or any of the other geometries discussed and illustrated above. When in a linear configuration, adjacent turns of the coil will lie close together and form a generally fluid-tight seal. When in the non-linear configuration illustrated in  FIG. 6 , however, adjacent turns of the coil will move apart to form a plurality of spaces or gaps  66  at regions where the coil structure turns. These gaps  66  connect to release the thrombolytic agent as the agitator is rotated. Sheath  63  may be induced into its linear configuration using a stiffening member  68 , as illustrated. 
     An agitator  70  having an alternating helical geometry is illustrated in  FIG. 7 . Non-linear region  72  of the agitator  70  comprises a first helical section  74  and a second helical section  76 . The helical section  74  and  76  are wound in opposite directions so that when the agitator  70  is rotated in the direction of arrow  78 , materials within the blood vessel lumen will be urged to move in the direction of arrows  80  toward a central region of the agitator  70 . In this way, the agitator  70  creates its own isolation region within the blood vessel. The materials being disrupted and dissolved are constantly urged toward the center, to inhibit release from the treatment region. Over time, the materials will become completely broken down, or at least sufficiently broken down so that their release will not present significant risk to the patient. 
     Agitator  70  can comprise a sheath and separate agitator (similar to the design of  FIGS. 1-3 ) or may comprise a monolithic structure where the thrombolytic agent is released directly through perforations or other discontinuities in the agitator wall. In some embodiments of the method, a simple bend in a guidewire may be used to mechanically agitate clot material and a therapeutic agent within an isolated region of the vessel, even using manual rotation of the guidewire. 
     Referring now to  FIG. 8 , the clock disruption catheters of the present invention may be advantageously combined with balloon or other isolation means. Clot disruption catheter  90  comprises a catheter body  92  having a distal isolation balloon  94  and proximal isolation balloon  96  formed thereon. A non-linear region  98  of the catheter body  92  is formed between the isolation balloons  94  and  96 . Conveniently, the isolation balloons  94  and  96  may be formed directly over a sheath  100  which remains stationary while an agitator  102  is rotated, oscillated, and/or axially translated therein. The balloons  94  and  96  may be inflated through a common or separate inflation lumens formed within the sheath  92 . The inflation lumens (not shown) will be isolated from the thrombolytic agent delivery lumen. Thrombolytic agent is delivered through ports  104  formed in the sheath between the isolation balloons  94  and  96 . Radiopaque markers  106  are positioned at either end of the treatment region, typically within the isolation balloons  94  and  96 . The structure of catheter  90  is advantageous in that it will completely contain the thrombolytic agent and all disrupted clot between the isolation balloons  94  and  96 . Optionally, aspiration means can be provided, e.g., through a fourth lumen within the sheath  100 , in order to withdraw materials from the treatment region. 
     Referring now to  FIG. 9 , a catheter  120  having means for recirculating the thrombolytic agent and other materials through a treatment region is illustrated. Catheter  120  comprises spaced-apart isolation balloons  122  and  124 . The catheter is generally similar to that described above with reference to  FIG. 8 . Catheter  120 , however, further includes a pump, typically in the form of an Archimedes screw  126  disposed between a first port  128  and a second port  130  on the body of catheter  120 . Rotation of the Archimedes screw will draw material into the port  130  and expel the material from port  128 . Such recirculation enhances the agitation and thrombolytic activity of the thrombolytic agent which is released through the ports as generally described above with respect to all earlier embodiments. 
     The catheters of the present invention can also be provided with blood bypass and perfusion lumens for a variety of purposes. For example, as illustrated in  FIG. 9A , a catheter  131  having spaced-apart balloons  132  and  133  can have an inlet port upstream of proximal balloon  132  and an outlet port  135  between the balloons  132  and  133 . In this way, fresh blood can be introduced into the otherwise isolated region between the balloons to enhance the thrombolytic activity of the tPA or other thrombolytic agent being released by the catheter. 
     As illustrated in  FIG. 9B , catheter  131  could also be provided with an inlet port  136  upstream of proximal balloon  132  and an outlet port  137  downstream of distal balloon  133  in order to provide perfusion downstream of the region being treated. In both  FIGS. 9A and 9B , the inlet and outlet ports will be connected by internal lumen(s) which are preferably isolated from the lumen(s) which are supplying the thrombolytic agent. 
       FIGS. 10A and 10B  illustrate a catheter  140  comprising catheter body  142  and an inner catheter shaft  144 . A proximal isolation balloon  146  is formed at the distal end of the catheter body  142 . The distal isolation balloon  148  is formed at the distal end of the inner catheter body  144 . Thrombolytic agent distribution ports  150  are formed over a non-linear region  152  of the inner catheter body  144 . In this way, the length of the non-linear region and thrombolytic agent release region  152  can be adjusted by axially extending or retracting the inner catheter member  144  relative to the catheter body  142 . In particular, balloon  146  on catheter body  142  may be anchored at a proximal end of a desired treatment region. The distal isolation balloon  148  may then be extended by a desired distance from the distal tip of the catheter body  142  to create an isolated treatment region therebetween (with both balloons being inflated). The non-linear region  152  may then be rotated with thrombolytic agent released in order to treat the clot and thrombus between the balloons. Optionally, the released emboli can be aspirated through the distal end of the catheter body  142  and withdrawn from the treatment region. After a first portion of the treatment region is remediated, the distal isolation balloon  148  can be deflated, and the distal end of the inner catheter member  144  extended further distally. This creates a new treatment region, which region can be treated in the manner just described, Two, three, or more such iterations can be performed successively in order to treat disseminated disease within a blood vessel lumen. 
     Referring now to  FIG. 11 , a clot disruption catheter  160  comprising expansible filter elements  162  and  164  is illustrated. The filter elements  162  and  164  provide partial isolation of a treatment region therebetween. The filter elements will capture emboli, but generally permit blood flow through the region. Catheter  160  further includes a non-linear region  168  and thrombolytic agent delivery ports  170 , generally as described for previous embodiments. The non-linear region  168  may be rotated in order to effect clot disruption and dissolution, again generally as described above. Filter elements  162  and  164  will serve to capture at least most of the clot which is released. 
     Referring now to  FIG. 12 , a clot disruption catheter, such as catheter  10  may be used to treat an arterio-venous graft AVG. The catheter  10  is introduced through a delivery sheath  180  so that non-linear region  34  lies within a highly thrombosed region of the graft AVG. The catheter is rotated and optionally axially translated, generally as described above. Thrombolytic agent can be released through the delivery device  16 . The delivery sheath  180  can be adapted to provide for aspiration through a syringe  182  in order to retrieve at least a portion of the clot which is released from the graft. 
     Two or more of the clot disruption catheters of the present invention may be used at the same time to treat a diseased region (or more than one diseased regions) within the patient. Referring to  FIG. 13 , an arterio-venous graft AVG can be treated with a pair of identical catheters  200 , each of which includes a distal isolation balloon  202  but which does not include any proximal or other isolation balloons. Each catheter  200  further includes a non-linear region  204  defined by an agitator  206  within an exterior sheath  208 . The AVG can be treated by positioning each distal isolation balloon  202  at a position close to the anastomotic junction with the associated artery and vein. The catheters  200  are introduced through a common delivery sheath  220 , and the agitators  206  may be axially translated (repositioned) within the sheath in order to treat substantially the entire length between the distal isolation balloon  202  and the delivery sheath  220 . Thrombolytic agent will be delivered generally as described above in other embodiments. Similarly, the non-linear regions  204  will be rotated in order to effect clot disruption and enhance thrombolytic agent activity. After treatment is completed, both catheters may be withdrawn through the sheath  220  and the AVG graft closed in the conventional manner. 
     The present invention still further comprises kits including at least some of the system components of the apparatus of the present invention described herein together with packaging, instructions for use, and/or other conventional kit components. For example, as illustrated in  FIG. 14 , a kit  240  may comprise at least a catheter  242 , instructions for use  244 , and packaging  246 . The catheter  242  can be any of the catheters described hereinabove, and the instructions for use  244  may set forth any of the methods of the present invention described hereinabove. The catheter  242  will be packaged within the packaging  246 , typically in a sterile fashion. Conventional medical device packaging may be used, such as a pouch, tube, tray, box, or the like. The instructions for use may be printed on a separate package insert, or may be printed in whole or in part on the packaging. Other kit components, such as a motor drive unit  248 , an additional agitator  250  (optionally including two or more additional agitators having different geometries), may also be added. 
     Referring now to  FIG. 15 , another embodiment of a clot disruption apparatus  260  suitably includes a catheter body  262  having a proximal end, a distal end, and at least one lumen (not visible in  FIG. 15 ). The lumen has at least one side opening  266  and a distal-end opening  268 , both at or near the distal end of catheter body  262 . Catheter body  262  typically further includes a first radially expandable body  270 . Optionally, in various embodiments, catheter body  262  may further include a flow resistor (not shown), a second radially expandable body  274  and/or a plurality of spaced-apart smaller openings  272  into the lumen. Apparatus  260  may optionally further include a sheath  276  with a luminal opening  278  for infusing and/or aspirating fluids, an aspiration mechanism  282  and/or an infusion mechanism  280 . Although not shown in  FIG. 15 , apparatus  260  is typically positioned within a luminal length of a blood vessel  264  by passing apparatus  260  over a guidewire. In some embodiments, a guidewire is included as part of apparatus  260  or as part of a kit including apparatus  260 . Apparatus  260  may optionally further include one or more of the elements described with reference to various embodiments set forth above, such as a mechanical agitator, an aspiration device, and/or the like. 
     Generally, as described in detail above, clot disruption apparatus  260  will be positioned in a luminal length of blood vessel  264  such that one or more agents may be infused at an area of clot. Optionally, agitating means may be used to agitate the clot and aspiration means may be used to aspirate clot and/or fluid containing clot particles, blood, infusate and the like. In one embodiment, infusion is performed through sheath  276  and aspiration is performed through side opening  266  and distal-end opening  268  of the lumen of catheter body  262 . Such functionality is designated by the hollow arrows (infusion) and the dark arrows (aspiration) in  FIG. 15 . Conversely, infusion may alternatively be performed through side opening  266  and distal end opening  268  and aspiration may be performed through sheath  276 . In another embodiment, aspiration and/or infusion may additionally occur through spaced-apart openings  272 . In one embodiment, infusion and aspiration are performed simultaneously, while in others infusion occurs before aspiration. Again in various embodiments, infusion and/or aspiration may be performed with first radially expandable body  270  expanded, with second radially expandable body  274  expanded, with neither expanded, or in some cases with both expanded. 
     In other embodiments of the present invention, described in further detail below, apparatus  260  does not include a similar sheath  276 . In some of these embodiments, infusion, aspiration and passage of a guidewire are all performed through a common lument in catheter body  262 . In other embodiments, separate lumens in catheter body  262  are used for separate functions, for example one lumen may be for infusion and another lumen may be for aspiration and passage of a guidewire. Alternatively, one lumen may be used for infusion and guidewire passage and another may be used for aspiration. In various of these embodiments, infusion, aspiration or both may be performed with a guidewire in place within apparatus  260 , for example with a guidewire tip protruding through distal-end opening  268 . 
     Generally, apparatus  260  enables fluid flow, as in aspiration and/or infusion, to occur preferentially through the at least one side opening  266  while still allowing minimal aspiration and/or infusion through distal-end opening  268 . Such preferential fluid flow is accomplished through any of a number of suitable means. In many embodiments, for example, the cross-sectional area of distal-end opening  268  is significantly smaller than the cross-sectional area of at least one side opening  266 . For instance, in one embodiment the cross-sectional area of distal-end opening  268  is between about 0.1% and about 20%, and more preferably between about 1% and about 5%, of the cross-sectional area of at least one side opening  266 . In various embodiments, this difference in cross-sectional area will be sufficient to provide preferential fluid flow through at least one side opening  266 . 
     In other embodiments, apparatus  260  further includes a flow resistor (not shown in  FIG. 15 ) between at least one side opening  266  and distal end opening  268  for resisting fluid flow through at least one lumen in catheter body  262 . Flow resistor typically acts in conjunction with a difference in cross-sectional areas between distal-end opening  268  and at least one side opening  266  to provide preferential, or predominant, fluid flow through at least one side opening  266 . 
     Referring now to  FIG. 16   a , one embodiment of a clot disruption apparatus distal end  300  suitably includes a catheter body  302  having a lumen  304 , a flow resistor  310  and a first expandable body  314 . Lumen  304  further includes a side opening  306  and a distal-end opening  308 , and flow resistor  310  is configured generally as a cylindrical member having a cylindrical channel  312 . In other embodiments, flow resistor  310  may have any other suitable configuration, as will be described more fully below. In one embodiment, for example, flow resistor  310  may comprise a membrane, disc or the like, having one or more holes, rather than a cylinder having a channel. In other embodiments, as described above, distal end  300  does not include a flow resistor. 
     Generally, distal-end opening  308  will have a significantly smaller cross-sectional area than side opening  306 . For example, in one embodiment the cross-sectional area of distal-end opening  308  is between about 0.1% and about 20%, and more preferably between about 1% and about 5%, of the cross-sectional area of side opening  306 . In embodiments of distal end  300  including flow resistor  310 , channel  312  will typically have a cross-sectional area smaller than distal-end opening. For example, in one embodiment, cross-sectional area of channel  312  is between about 0.1% and about 8%, and more preferably between about 0.5% and about 4%, of the cross-sectional area of side opening  306 . In other embodiments, the cross-section area of channel  312  may be approximately equal to the cross-sectional area of distal-end opening  308 . In embodiments including a membranous or disc-shaped flow resistor, a hole or holes through the membrane or disk will have cross-sectional areas similar to those just described in relation to cylindrical flow resistor  310  and channel  312 . 
     Channel  312  (or channels, or holes, or the like) may have any suitable diameter, configuration or shape for allowing the passage of a guidewire through flow resistor  310 . Channel  312  also typically allows passage of some fluid through flow resistor  310 . In some embodiments, minimal fluid flow may occur with a guidewire in place in channel  312 . Flow resistor  310  does resist flow through lumen  304 , however, thus assisting in the provision of preferential fluid flow through at least one side opening  306  relative to distal-end opening  308 . In one embodiment, the percentage of total fluid flow through flow resistor  310  and distal-end opening  308  is between about 0.1% and about 20% of the total fluid flow through lumen  304 , with the remaining about 80% to about 99.9% flowing through side opening  306 . More preferably, the percentage of total fluid flow through flow resistor  310  and distal-end opening  308  is between about 1% and 5% of the total fluid, with the remaining about 95% to about 99% flowing through at least one side opening  306 . 
     Flow resistor  310  may be made of any suitable material and may have any suitable configuration for allowing passage of a guidewire and for inhibiting fluid flow. In some embodiments, flow resistor  310  is made of a compliant, silicon-based material. Other materials may be used, however, such as but not limited to plastic, metal, polymer, or a combination thereof. Similarly, flow resistor  310  may have any suitable length, shape, diameter or configuration. In most embodiments, the outer diameter of flow resistor  310  will be approximately equal to the inner diameter of lumen  304 , to enhance flow inhibition. Since many diameters of catheter bodies, lumens and the like are contemplated within the scope of the present invention, many possible diameters of flow resistor  310  are also contemplated. 
     Referring now to  FIGS. 16   b - d , flow resistor  310  (shown in front view) may suitably include multiple channels, openings, slits, pores, holes apertures, and/or the like, for allowing passage of a guidewire and/or inhibiting fluid flow. In the embodiment shown in  FIG. 16   b , for example, flow resistor  310  includes a guidewire channel  326  and a fluid channel  328 . Such a configuration may be advantageous, for example, when infusion or aspiration is desired with a guidewire in place to support or position catheter body  302 .  FIG. 16   c  shows another embodiment, in which flow resistor  310  includes a guidewire channel  324  and multiple fluid channels  322 . Of course, in either of the embodiments in  FIGS. 16   b  and  16   c , if a guidewire is not in place within the guidewire channel, fluid may flow through the guidewire channel. In some embodiments, as mentioned above, some fluid flow may occur through a channel even when a guidewire is in place in the channel. 
     Referring now to  FIG. 16   d , yet another embodiment of flow resistor  310  includes multiple slits  320  for allowing passage of a guidewire. Slits  320  typically have some amount of flexibility, to allow passage of the guidewire. In some embodiments, slits  320  do not allow passage of fluid, while in other embodiments fluid may pass through slits  320 . In other embodiments, slits  320  may be combined with one or more channels to allow fluid flow. In still other embodiments, slits may be configured to permit fluid flow in one direction but not another—i.e., they may operate as a one-way valve. 
     Referring now to  FIG. 17 , another embodiment of a clot disruption apparatus distal end  400  suitably includes a catheter body  302  having an infusion lumen  404  and an aspiration lumen  410 , a first expandable body  314  and a flow resistor  310  with a channel  312 . In this embodiment, aspiration lumen  410  includes an aspiration opening  412  and infusion lumen  404  includes a side opening  406  and a distal-end opening  408 . 
     In an embodiment as in  FIG. 17 , infusion is performed via infusion lumen  404  side opening  406  and distal-end opening  408  and aspiration is performed via aspiration lumen  410  and aspiration opening  412 . Guidewire passage occurs through infusion lumen  404 . Due to its positioning within infusion lumen  404 , flow resistor  310  inhibits flow only during infusion. In an alternative embodiment, the functionality of the lumens and openings shown in  FIG. 17  may be switched, such that aspiration occurs via infusion lumen  404  and infusion side opening  406  and distal-end opening  408 , and infusion occurs via aspiration lumen  410  and aspiration opening  412 . In that embodiment, flow resistor  310  inhibits flow during infusion and not during aspiration. Other embodiments are contemplated, for example in which flow resistor  310  inhibits flow in more than one lumen, in which no flow resistor is used, and the like. Generally, any suitable configuration of a clot disruption apparatus distal end for providing preferential or predominant fluid flow from at least one side opening relative to a distal-end opening is contemplated within the scope of the invention. 
     Referring now to  FIGS. 18   a  and  18   b , another embodiment of a clot disruption apparatus distal end  500  suitably includes a catheter body  302  having an infusion/aspiration lumen  304 , a flow resistor  512 , and a first expandable body  314 . In this embodiment, catheter body  302  further includes a flow resistor infusion lumen  510  and a flow resistor infusion opening  506  and the clot disruption apparatus includes a flow resistor infusion port  508  at a proximal location. Infusion/aspiration lumen  304  further includes a side opening  306  and a distal-end opening  308 . Flow resistor  310  comprises a compliant membrane  502  and an attachment mechanism  504 . 
     Generally, in an embodiment as in  FIGS. 18   a  and  18   b , when it is desired to inhibit flow through distal-end opening  308  using flow resistor  310 , an infusate may be infused into flow resistor infusion port  508 , through flow resistor infusion lumen  510  and flow resistor infusion opening  506 , to pressurize and thus move compliant membrane  502 . Compliant membrane  502  is typically attached to an inner surface of infusion/aspiration lumen  304  by any suitable attachment mechanism  504  or adhesive device. When flow inhibition is no longer desired, infusate in flow resistor  512  maybe discharged or otherwise released, to allow compliant membrane to assume its original shape. In various embodiments and configurations, compliant membrane  502  and flow resistor  512  in general may be configured to allow no passage of fluid, some passage of fluid, and/or passage of a guidewire. 
     Referring now to  FIG. 19 , yet another embodiment of a flow resistor  600  may comprise a ball valve. Such a valve suitably includes a ball  604 , a channel  602 , a valve entrance  610 , a valve exit  608 , and a side housing  606 . In one embodiment, when a guidewire (not shown) is inserted through channel  602 , the guidewire moves ball  604  to a position within side housing  606 . When the guidewire is not within channel  602 , ball  604  is free to move anywhere within the valve. During infusion of fluid from proximal (P) to distal (D), ball  604  will naturally be moved by the fluid to a position adjacent valve exit  608 , as shown by the darkened arrow, and will partially or wholly block fluid flow through valve exit  608 . During aspiration of fluid from D to P, ball  604  will naturally be moved by the fluid to a position adjacent valve entrance  610 , as shown by the hollow arrow, and will partially or wholly block fluid flow through valve entrance  610 . 
     Referring now to  FIGS. 20   a - g , one embodiment of a method for disrupting clot according to the present invention is shown. Many various methods according to the present invention may be used for disrupting clot. For example, various steps may be added to or deleted from the process shown in  FIGS. 20   a - g , various additional apparatus may be used, different apparatus may be substituted, the order of steps may be changed and/or the like, without departing from the scope of the present invention. Therefore, the exemplary methods described in  FIGS. 20   a - g  and  FIGS. 21   a - g  are provided for exemplary purposes only and should not limit the scope of the invention. 
     That being said, with reference to  FIG. 20   a , a first step in a method for clot disruption includes positioning a catheter body  702  within a blood vessel  706  at the site of a clot  706 . Catheter body  702  includes a distal balloon  708 , a proximal balloon  710 , a side opening  712 , and a distal-end opening  714 . Typically, catheter body  702  will be positioned within blood vessel  704  by passing body  702  along a guidewire  716 . 
     In a next step, as in  FIG. 20   b , distal balloon  708  is inflated and guidewire  716  removed. From catheter body  702 , as designated by the proximal-pointing arrow. In other embodiments, methods include leaving a guidewire in place during infusion, clot disruption, and/or aspiration. As described above, various embodiments provide minimal fluid flow through distal-end opening  714  with a guidewire in place, while other embodiments provide for no flow through distal-end opening  714  with the guidewire in place. 
     Next, as in  FIG. 20   c , proximal balloon  710  is inflated and an agent to enhance clot disruption, such as a thrombolytic agent, is infused through side opening  712  and distal-end opening  714  (designated by arrows). In some embodiments, infusion may begin before inflating proximal balloon  710 . In other embodiments, infusion, clot disruption and aspiration may all be performed without inflating proximal balloon  710 . Alternatively, infusion may commence concurrently with proximal balloon  710  inflation. Generally, as described in detail above, infusion is performed preferentially through side opening  712 , relative to distal-end opening. This may be accomplished by providing a distal-end opening  714  with a smaller cross-sectional area than side opening  712 , by providing a flow resistor within catheter body  702 , or by a combination of the two. 
     In  FIG. 20   d , with the assistance of the infused agent, clot  706  begins to disrupt or dissolve. Additionally, because some infusion occurs through distal-end opening  714 , secondary clot  718  distal to distal balloon  708  is also disrupted/dissolved. Generally, the majority of the infused agent, which was distributed through side opening  712 , is held within the blood vessel  704  in an area between proximal balloon  710  and distal balloon  708 . Containment of the infused substance largely within this area serves to enhance the clot disruption process and to prevent side effects which may occur from systemic distribution of the agent. 
     Next, in  FIG. 20   e , proximal balloon  710  is deflated and aspiration of blood, disrupted clot  706 , infused agent, and disrupted secondary clot  718  commences. Again due to the relative cross-sectional areas of side opening  712  and distal-end opening, due to the presence of a flow resistor, or both, aspiration occurs preferentially or predominantly through side opening  712 . In other embodiments, aspiration may occur through a separate lumen with one or more separate openings. Also alternatively, aspiration may begin before proximal balloon  710  is deflated or while proximal balloon  710  is deflating. 
     In  FIG. 20   f , disrupted and dissolved clot has been aspirated from blood vessel  704  and guidewire  716  has been repositioned in catheter body  702 , through distal-end opening  714 . Finally, in  FIG. 20   g , catheter body  702  is beginning to be removed from blood vessel  704 , by passing catheter body  702  proximally over guidewire  716  (designated by proximally directed arrows). Guidewire  716  is then removed from blood vessel  704  (not shown). 
     Referring now to  FIGS. 21   a - g , another embodiment of a method for disrupting clot is shown. The method first includes positioning a catheter body  802  in a blood vessel  804  at a location for disrupting clot  806  by passing catheter body  802  over a guidewire  816 . The catheter body  802  suitably includes a distal balloon  808 , a side opening  812  and a distal-end opening  814  communicating with a first lumen (not visible), and second side opening  820  communicating with a second lumen (not visible). 
     Next, in  FIG. 20   b , distal balloon  808  is inflated when catheter body  802  has been positioned in a desired location within blood vessel  804 . Guidewire  816  is left in place within catheter body  802 , the distal end of guidewire  816  protruding from distal-end opening  814 . As in  FIG. 21   c , an agent is then infused preferentially from side opening  812 , with a small amount of fluid flowing or dripping from distal-end opening  814  (designated by arrows). This small amount of agent/fluid may help dissolve smaller, secondary clot  818  distal to distal balloon  808  into harmless particles or dissolved material. 
     In  FIG. 21   d , clot  806  and secondary clot  818  have been disrupted by the agent. In  FIG. 21   e , clot  806 , blood and/or agent is aspirated by second opening  820  and second lumen. When a desired amount of disrupted clot  806  is aspirated, as in  FIG. 2  If, distal balloon  808  is deflated. Finally, as in  FIG. 21   g , catheter body  802  is withdrawn from blood vessel  804  over guidewire  816 . Guidewire  816  may then be removed from blood vessel  804  (not shown). As previously mentioned,  FIGS. 21   a - g  describe only one embodiment of a method of the present invention, and many additional embodiments are contemplated. For example, aspiration and infusion may occur through the opposite lumens from those shown in  FIGS. 21   a - g . Alternatively, guidewire  816  may be removed during a portion of the procedure. These and/or other changes may be made without departing from the scope of the present invention. 
     While the above is a complete description of the preferred embodiments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.