Method for the prevention of restenosis

Process for local administration of heparin or other agents to inhibit arterial smooth muscle cell proliferation utilizing a catheter.

BACKGROUND OF THE INVENTION 
Recently an alternative approach to coronary bypass surgery has been 
developed. In this non-operative procedure for the improvement of blood 
flow in patients with coronary artery disease, a catheter with an 
inflatable balloon at the distal end is inserted into the femoral artery 
or by brachial cutdown, and is positioned by fluoroscopic control at the 
appropriate coronary ostium. The process is known as percutaneous 
transluminal coronary angioplasty (PTCA). 
The balloon at the distal end of the catheter has a predetermined maximum 
diameter. It is filled with a radio opaque dye to permit visualization. 
Alternatively, the balloon itself may be radio opaque. When the balloon is 
positioned in the stenosis it is inflated at pressures of from 2 to 11 
atmospheres for from 15 to 60 seconds and then deflated. The inflation 
cycle may be repeated several times to achieve satisfactory results. 
Normally the luminal diameter of the stenotic vessel increases at least 
20% as a result of the treatment. 
Angioplasty is not limited to the cardiac vasculature. It has been employed 
for treatment of single, large atherosclerotic lesions of the renal, iliac 
and even vertebral arteries. The effect of the expanded balloon is to 
literally blow open the stenotic zone. Disruption of the wall is marked, 
including fracture of the calcium in the lesion, tearing of the plaque 
itself and extravasation of plaque lipid and gruel into the adjacent 
vessel wall. 
The clinical results of angioplasty include endothelial denudation, 
vascular wall damage, and rupture of the tunica intima vasorum. These 
injuries have been found to result in many cases in unregulated 
proliferation of the arterial smooth muscle cells (SMC) with a resulting 
restenosis. A recent study by Levine et al (The American Journal of 
Cardiology, Volume 55, pages 673 to 676, March 1985) has shown that 
restenosis may be expected to occur in as many as 40% of patients that 
have undergone angioplasty. Often the only practical treatment for 
restenosis is to repeat the treatment. This may cause further damage to 
the cell wall and the need for subsequent repetition of the angioplasty 
procedure. 
Heparin is a mucopolysaccharide composed of amino sugar and uronic acid 
residues which is obtained from beef, porcine, sheep, whale and other 
mammalian tissue by extraction with a solution of potassium acetate, 
alkaline ammonium sulfate and the like. Commercial heparin preparations 
are now widely available from a number of pharmaceutical companies. 
Heparin preparations are clinically utilized principally as 
anticoagulants. 
Recently it has become known that in addition to its anticoagulant 
activities, heparin is a powerful inhibitor of arterial smooth muscle 
proliferation. See, for example, Guyton et al. Circulation Research Volume 
46, Number 5 pages 625 to 633, 1980 and Hoover et al. Circulation Research 
Volume 47, Number 4, pages 578 to 583, 1980. 
My co-pending U.S. patent application Ser. No. 364,408, filed Apr. 2, 1982 
describes and claims catheters which can be used to insert a solubilizing 
agent into an artery to dissolve plaque thereby relieving arterial 
constrictions. The disclosure of this application is incorporated herein 
by reference.

FIGS. 1 and 2 illustrate the solubilizing fluid delivery, balloon carrying 
element of a catheter useful in the practice of this invention. In the 
embodiment illustrated it comprises a main catheter body generally 
designated as 1 with a distal end 2 and a proximate end 3 formed with a 
main catheter body wall 4. The main catheter body 1 is formed with three 
conduits; a ring balloon expansion conduit 5, a central balloon expansion 
conduit 6 and a fluid delivery conduit 7. The catheter body 1 carries two 
ring balloons 8 and 9 at either end, and an optional central balloon 10 
disposed intermediate the spaced balloons. It also carries a third conduit 
7 which exits through the catheter body. Conduits 5, 6 and 7 are fitted 
with appropriate valves 11, 12 and 13. 
THE INVENTION 
It has been found that catheters of the class described are useful for 
delivering heparin or other SMC growth regulators to the site of the 
angioplasty and depositing it in and about the site of the vascular wall 
damage to retard SMC growth. 
The term `heparin` as used herein refers to any of a variety of heparin 
products which inhibit SMC proliferation. Heparin from various sources is 
known to be heterogeneous. There are both anticoagulant and 
non-anticoagulant fractions. Each has varying degress of N- and 
O-sulfation and acetylation. Fractions with anticoagulant activity may 
contain as many as 20 saccharide moieties. It has been found that both 
anticoagulant and non-anticoagulant fractions manifest inhibition of SMC 
proliferation, and that heparin fractions or derivatives containing at 
least six saccharide monomers have this activity. Fractions and 
derivatives with varying degrees of sulfation manifest varying abilities 
to inhibit SMC proliferation. The active materials are described in detail 
in the Circulation Research publications cited above. All such fractions 
and derivatives are useful in the practice of this invention and are 
included within the term heparin. 
The operation of the catheter to form a chamber within the artery is 
schematically illustrated in FIG. 3. 
In FIG. 3, 14 is the arterial wall of an artery constricted due to the 
presence of plaque body 15. The figures shows the main catheter body 1 
held in place by the inflation of spaced balloons 8 and 9. The inflation 
of the balloons forms a chamber 16 in the artery and, as shown, 
surrounding the plaque. The catheter 1 is shown with the central balloon 
10 in the deflated configuration. It also shows the delivery end of the 
third conduit 7. 
In the practice of this invention, the two balloon catheter illustrated in 
the figures is employed following conventional angioplasty which removes 
at least a portion of the plaque. The angioplasty catheter is removed and 
the catheter 1 is inserted. The catheter 1 is guided by standard 
procedures which may include the use of a flexible probe, a guide wire 
and/or a fluoroscope to a position overlaying the original site of the 
plaque body 15 preferably, but not necessarily, in the position shown in 
FIG. 3 with the distal end balloon 8 just beyond the distal end of the 
original site and proximate end balloon 9 just ahead of the proximate end 
of the site. When the balloons 8 and 9 are inflated by forcing fluid such 
as isotonic saline through valve 11 and conduit 5, the catheter is held in 
place by the pressure of the balloons and a chamber 16 is formed 
surrounding the site. The closing of valve 11 will maintain the pressure 
in the conduit 5 and balloons 8 and 9 so that the catheter is held in 
place. The position of the catheter can be checked fluoroscopically or by 
passing a small amount of solubilizing liquid containing a dye into the 
chamber. If the position is not satisfactory the pressure can be released 
sufficiently to slightly deflate the ring balloons 8 and 9, the catheter 
moved in the appropriate direction, and the balloons reinflated. 
Once the catheter is in place, the heparin is forced under pressure through 
the conduit 7 and the chamber 16 on and into the adjacent surfaces. 
Pressures of 200 to 1000 mm Hg are generally sufficient for this purpose 
although variations from this range are acceptable. The preferred range is 
300 to 1000 mm Hg. The pressure at which the fluid is forced into the 
chamber may be generated by a pump upstream of valve 12. After the heparin 
is injected, the catheter is held in place for 5 to 60 seconds to hold the 
heparin in the chamber and provide time for it to stick to and penetrate 
the depths of the adjacent arterial tissue defined by the chamber in high 
concentration and not be prematurely washed away or diluted with the 
flowing blood. Balloons 8 and 9 are deflated, and the catheter removed. 
Because of the large number of functional groups present, heparin is a 
highly charged molecule. When forced through the chamber 16 it enters the 
damaged wall and readily interacts with the surfaces of the various cells 
within the injured wall, as well as with the connective tissue between the 
cells. In effect it "sticks to" the injured site and inhibits, but does 
not completely stop the multiplying of SMC. Because heparin is `sticky` it 
will stay in an effective position until the injury is healed. 
The general process by which the injured artery repairs itself involves the 
bathing of the injured area with platelets and other cell growth promoters 
in the blood. The cells within the injured area of arterial wall continue 
to divide and multiply to generate new cellular tissue and repair the 
wound. When the growth reaches the appropriate level, the body's feedback 
mechanism signals the growth to stop. Restenosis occurs when the feed back 
mechanism is not functioning properly and the SMC continues to multiply in 
an uncontrolled manner in the damaged angioplasty site. The presence of 
the heparin appears in some manneer to control the multiplication of the 
SMC cells so that they continue to multiply, but in a controlled manner 
until the regular control mechanism of the body takes over. The heparin 
affects only the deeper SMC cells and does not affect the surface 
endothelial cells. 
An alternative procedure to the use of the two balloon catheter as 
described above is to use the three balloon catheter. In this method the 
catheter is inserted and placed over the plaque using the procedure 
described. The first step is to inflate the middle balloon, 10 to rupture 
the plaque. The balloon is deflated; after restoration of blood flow for a 
brief period, expansion of balloons 8 and 9 create a chamber around the 
angioplasty site. The heparin is then administered as described above. The 
chamber is held in place for 5 to 60 seconds so that the heparin can stick 
to and enter the adjacent surfaces, the balloons are deflated and then the 
catheter is removed. 
The catheter body can be prepared from any of a number of readily 
available, non-toxic, flexible polymers including, for example, 
polyolefins, such as polyethylene or polypropylene, and polyvinyl halides, 
such as polyvinyl chloride or polyvinylidene chloride. The balloon can be 
fabricated from similar materials manufactured so as to be expansible 
under pressure and with sufficient elasticity to collapse when the 
pressure is released and negative pressure applied. The dimensions of the 
balloons will be such that they will reach the desired diameter at a 
pressure of from about 75 to 150 mm Hg and hold the dimensions even if the 
pressure is increased to as high as 5 or more atmospheres. 
The absolute dimensions selected for the balloons will depend upon the 
diameter of the arteries involved. For example, the ring balloons may be 
from 2 to 5 mm in length and their expanded diameters will be 
approximately the same. The central balloon will be of the same diameter 
range as the end balloons, but the length will be from about 10 to 50 mm.