- Email: [email protected]
Mechanical Approaches to Restenosis
Saturday, March 2, 1996 reduce the likelihood of shrinkage remodeling. This will require further elucidation of the mechanisms governing these remodeling processes. Strategies devised against cell proliferation may also have favorable consequences in promoting enlargement remodeling. Certain antiproliferative strategies that have concomitant effects on cell phenotype, matrix production, and the regulation of apoptosis may promote enlargement remodeling, as well as inhibit intimal hyperplasia. A treatment strategy targeted against both intimal hyperplasia and shrinkage remodeling has the greatest potential for longterm efficacy. The development of such a treatment strategy is the next great challenge in interventional cardiovascular medicine.
Morishita R, Gibbons GH, Ellison KE, et al. Single intraluminal delivery of antisense cdc2 kinase and PCNA oligonucleotides results in chronic inhibition of neointimal hyperplasia. Proc Nat! Acad Sci USA 1993; 90:8474-8478. Schwartz SM, Bennett MR. Death by any other name. Am) Pathol 1995; 147:229-234. Von der Leyen H, Gibbons GH, Morishita R, et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Nat! Acad Sci USA 1995; 92:11371141.
Diagnosis
Selected Bibliography Finkel T, Epstein SE. Gene therapy for vascular disease. FASEB) 1995; 9:843-851. Gibbons GH, Dzau V). Emerging concept of vascular remodeling. New Eng!) Medicine 1994; 330:1431-1438. Glagov S, Zarins C, Giddens DP, Ku DN. Hemodynamics and atherosclerosis: insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med 1988: 112:1018-1031. Henderson), Chambers], )eddy TA, Chamberlain), Whittingham TA. Serial investigation of balloon angioplasty induced change in the superficial femoral artery using colour duplex ultrasound. Br) Radiol 1994; 67:546-551. Isner ]M, Kearney M, Bortman S, Passeri). Apoptosis in human atherosclerosis and restenosis. Circulation 1995; 91:2703-2711. Langille BL. Remodeling of developing and mature arteries: endothelium, smooth muscle and matrix. ) Cardiovasc Pharmacol 1993; 21(suppl I):Sl1-S17. Mann M), Gibbons GH, Kernoff RS, et al. Genetic engineering of vein grafts resistant to atherosclerosis. Proc Nat! Acad Sci USA 1995; 92:4502-4506. Morishita R, Gibbons GH, Ellison KE, et al. Intimal hyperplasia after vascular injury is inhibited by antisense cdk 2 kinase oligonucleotides.) Clin Invest 1994; 93: 1458-1464. Morishita R, Gibbons GH, Ellison KE, et al. Novel molecular strategy using cis element "decoy" of E2F binding site inhibits smooth muscle proliferation in vivo. Proc Nat! Acad Sci USA 1995; 92:5855-5859.
62
4:00 pm Intravascular US Characterizations of Angioplasty Mechanisms and Restenosis Rodney A. White, MD (See earlier article on "Intravascular US Evaluation of Atherosclerosis")
Treatment 4:10 pm Mechanical Approaches to Restenosis Barry T. Katzen, MD Learning objective: To describe mechanical devices used to improve both initial and longterm results of percutaneous intervention, including "debulking" to remove plaque, stents, and derivatives of stent technology.
Restenosis remains the principal cause of failure of percutaneous transluminal angioplasty (PTA) despite the specific anatomic site being addressed. Results of angioplasty vary from site to site, but, overall, long-term results are better in larger vessels (aorta, iliac arteries) and worse in small to medium-sized vessels (renal, coronary, and superficial femoral arteries). In an attempt to increase patency rates, a variety of new devices have been developed to both extend percutaneous revascularization to more patients and to prolong time to restenosis, making intervention more cost-effective. Atherectomy Atherectomy was first described by Simpson when a new device was developed to remove plaque to produce lumenal widening. The method can be used for both coronary and pe-
Saturday, March 2, 1996 ripheral applications. It has been cal1ed directional atherectomy to distinguish it from other methods of plaque removal with rotational techniques. While the device requires a larger sheath size compared with simple PTA of the same size, it has the advantage of producing a smooth lumen, without intimal dissection, and with reduced rates of abrupt closure in the peripheral circulation. This technique is also distinguished by the removal of plaque suitable for macroscopic and microscopic examination. Histologic studies have shown that media can occasional1y be sampled during atherectomy and that this may be associated with an increased rate of restenosis, possibly caused by increased injury to the arterial wall. Recently, because of increased use of intravascular ultrasound (NUS), angiography has been a suboptimal endpoint of atherectomy due to the inherent limitations of 2D longitudinal imaging. In clinical applications, some patients maintain long-term patency fol1owing atherectomy, but no definite evidence shows that any benefit is gained from atherectomy compared with PTA. In the Coronary Angioplasty versus Excisional Atherectomy Trial, no therapeutic gain was documented. A new trial is under way comparing "optimal" directional coronary atherectomy versus percutaneous transluminal coronary angioplasty (PTCA), using ultrasound for optimization. In clinical practice, because of increasing pressure for cost-effective therapy, peripheral atherectomy is reserved for specific applications (infra-inguinal focal stenoses, eccentric, for patients with blue-toe syndrome, short segment total occlusions [infra-inguina!], and in short-segment disease where techniques of rapid thrombolysis are used). In these patients, a high risk of a lamellar thrombus exists, and atherectomy may result in the reduced risk of distal embolization. Its application in the iliac aItery is limited, but by using newer atherectomy devices, a 6.0-mm lumen can be achieved with an 8-F device. Rotational atherectomy is distinguished by treating the stenotic vessel 3600 by using devices that apply rotational forces or methods. Examples include the Kensey-Nash device and the more widely used and approved Rotoblator, which uses diamond burrs rotating at high speeds to ablate plaque. This technique has proved effective in achieving excel1ent initial outcomes, particularly in the coronary arteries, especially when calcium is present. Application
in peripheral circulation has been limited by the mechanics of introducing larger burrs percutaneously, but infrapopliteallesions can be effectively opened. In the coronary circulation, no definite benefit concerning restenosis has been documented, although a multicenter study of optimal use of this device (STRATIS) is under way.
II
The transluminal extraction catheter device combines rotational cuning with simultaneous suction to avoid passage of particulate material downstream and to reduce embolic burden. This device has not gained wide acceptance and has not proved to reduce restenosis. It may have value in the treatment of occluded coronary artery bypass grafts. Intravascular Stents
Since their initial clinical trials and subsequent introduction into clinical practice, intravascular stents have been used primarily for improving the initial outcome of intervention. As a permanent implant, they may be effective in overcoming elastic recoil, constraining flow limiting intimal dissections occurring after PTA, and improving results of intervention, in particular, unfavorable lesions such as osteal lesions or those with calcification. Recent results of the Benestent and Benestent II trial have shown benefit when using balloonexpandable stents in coronary angioplasty, with significant benefit in patency and restenosis reduction compared to PTCA alone. While complications associated with aggressive anticoagulation muted the apparent benefit, recent improvements in technique, including use of lVUS and high-pressure bal100n inflation, reduced the need for aggressive anticoagulation and established an increased benefit for coronary stenting. Traditional indications for stent implantation have been principally associated with improving initial outcome. Based on highly favorable clinical experience with deploying stents during acute revascularization, some investigators have begun to evaluate the long-term benefits of stents, particularly in the iliac arteries. Experience from a randomized prospective trial comparing PTA to primary stenting presented by Richter suggests that "primary" stenting may produce long-term results superior to angioplasty alone in the iliac arteries. Long-term patency beyond 12 months may be prolonged by at least 10% at longer intervals after interven-
63
Saturday, March 2, 1996 tion. These findings correlate well with clinical observations in our own institution and a gradual change in indications has been occurring.
Kim D, Gianturco LE, Porter DH, et al. Peripheral directional atherectomy: 4-year experience. Radiology 1992; 183:773-778.
Stents are also being evaluated for vehicles to deliver pharmacologic agents and even l3-irradiation for more active treatment of restenosis. The Benestent II trial includes the use of heparin-coated stents in a randomized trial with PTCA. Fischell recently presented initial animal results with P32 deployed with the use of Palmaz-Schatz stents. These techniques, and others, offer great promise in maximizing the benefits of permanent implants for restenosis.
Kuntz RE, Safian RD, Levine MJ, Reis GJ, Diver DJ, Bairn DS. Novel approach to the analysis of restenosis following three new coronary intervention. Circulation 1992; 19: 1493-1499.
Another example of using an interventional device for delivery of pharmacologic benefit is "endoluminal paving" with hydrogel polymers, which has recently been shown to reduce both early thrombus formation and long-term intimal hyperplasia occurring after vascular trauma in animals. While only investigational at this time, this approach, and the use of other biodegradable stents, offer promise in achieving the mechanical benefits of stents without permanent implantation. Combining stents with graft coverings, such as polytetrafluoroethylene and polyester, also may offer promise in reducing restenosis. Preliminary results of clinical trials in Europe with a self-expanding Nitinol stent covered with polyester have not shown definite benefit.
Selected Bibliography Dolmatch BL, Gray RJ, Horton KM, Rundback ]H, Kline ME. Treatment of anastomotic bypass graft stenosis with directional atherectomy: short-term and intermediateterm results. J Vasc Interv Radiol 1995; 6: 105-113. Fischell E. Inhibition of neonintimal proliferation with a Beta particle emitting stent. Presented during the IV International Interdisciplinary Stent Symposium in Frankfurt, Germany, September 1-3, 1995. Fischman DL, Leon MB, Baim DS, et al. Randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994; 331:496-501. Hill-West JL, Chowdhury SM, Slepian MJ, Hubbell JA. Inhibition of thrombosis and intimal thickening by in situ photopolymerization of thin hydrogel barriers. Proc Natl Acad Sci 1994; 91:59675971.
64
McLean GK. Percutaneous peripheral atherectomy. J Vasc Interv Radiol 1993; 4: 465-480. Rees CR, Palma JC, Becker GJ, et al. Preliminary report of a multi-center study of the Palmaz stent in atherosclerotic stenoses involving the ostia of the renal arteries. Radiology 1991; 181:507-514. Richter GM. Stents in peripheral arteries: randomized study. Presented during the IV International Interdisciplinary Stent Symposium in Frankfurt, Germany, September 1-3, 1995. Serruys PW, de Jaegere P, Kiemeneij F, et al. Comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Eng!] Med 1994; 331:489-495. Topol EJ, Leya F, Pinkerton CA, et al. Comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N Engl J Med 1993; 329:221-227. Vroegindeweij D, Kemper FJ, Tielbeek AV, Buth J, Landman G. Recurrence of stenoses following balloon angioplasty and Simpson atherectomy of the femoropopliteal segment: randomized comparative I-year follow-up study using colour flow duplex. Eur J Vasc Surg 1992; 6:164-171. 4:30 pm Pharmacological Approaches to Restenosis P. Macke Consigny, PhD
Learning objectives: (1) To understand the physiologic processes that contribute to restenosis. (2) To understand the pharmacologic approaches developed to inhibit restenosis. (3) To understand why the responses of animal arteries to injury may not exactly mimic the responses of human arteries. (4) To understand the principles of local drug delivery to inhibit restenosis.
Morishita R, Gibbons GH, Ellison KE, et al. Single intraluminal delivery of antisense cdc2 kinase and PCNA oligonucleotides results in chronic inhibition of neointimal hyperplasia. Proc Nat! Acad Sci USA 1993; 90:8474-8478. Schwartz SM, Bennett MR. Death by any other name. Am) Pathol 1995; 147:229-234. Von der Leyen H, Gibbons GH, Morishita R, et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Nat! Acad Sci USA 1995; 92:11371141.
Diagnosis
Selected Bibliography Finkel T, Epstein SE. Gene therapy for vascular disease. FASEB) 1995; 9:843-851. Gibbons GH, Dzau V). Emerging concept of vascular remodeling. New Eng!) Medicine 1994; 330:1431-1438. Glagov S, Zarins C, Giddens DP, Ku DN. Hemodynamics and atherosclerosis: insights and perspectives gained from studies of human arteries. Arch Pathol Lab Med 1988: 112:1018-1031. Henderson), Chambers], )eddy TA, Chamberlain), Whittingham TA. Serial investigation of balloon angioplasty induced change in the superficial femoral artery using colour duplex ultrasound. Br) Radiol 1994; 67:546-551. Isner ]M, Kearney M, Bortman S, Passeri). Apoptosis in human atherosclerosis and restenosis. Circulation 1995; 91:2703-2711. Langille BL. Remodeling of developing and mature arteries: endothelium, smooth muscle and matrix. ) Cardiovasc Pharmacol 1993; 21(suppl I):Sl1-S17. Mann M), Gibbons GH, Kernoff RS, et al. Genetic engineering of vein grafts resistant to atherosclerosis. Proc Nat! Acad Sci USA 1995; 92:4502-4506. Morishita R, Gibbons GH, Ellison KE, et al. Intimal hyperplasia after vascular injury is inhibited by antisense cdk 2 kinase oligonucleotides.) Clin Invest 1994; 93: 1458-1464. Morishita R, Gibbons GH, Ellison KE, et al. Novel molecular strategy using cis element "decoy" of E2F binding site inhibits smooth muscle proliferation in vivo. Proc Nat! Acad Sci USA 1995; 92:5855-5859.
62
4:00 pm Intravascular US Characterizations of Angioplasty Mechanisms and Restenosis Rodney A. White, MD (See earlier article on "Intravascular US Evaluation of Atherosclerosis")
Treatment 4:10 pm Mechanical Approaches to Restenosis Barry T. Katzen, MD Learning objective: To describe mechanical devices used to improve both initial and longterm results of percutaneous intervention, including "debulking" to remove plaque, stents, and derivatives of stent technology.
Restenosis remains the principal cause of failure of percutaneous transluminal angioplasty (PTA) despite the specific anatomic site being addressed. Results of angioplasty vary from site to site, but, overall, long-term results are better in larger vessels (aorta, iliac arteries) and worse in small to medium-sized vessels (renal, coronary, and superficial femoral arteries). In an attempt to increase patency rates, a variety of new devices have been developed to both extend percutaneous revascularization to more patients and to prolong time to restenosis, making intervention more cost-effective. Atherectomy Atherectomy was first described by Simpson when a new device was developed to remove plaque to produce lumenal widening. The method can be used for both coronary and pe-
Saturday, March 2, 1996 ripheral applications. It has been cal1ed directional atherectomy to distinguish it from other methods of plaque removal with rotational techniques. While the device requires a larger sheath size compared with simple PTA of the same size, it has the advantage of producing a smooth lumen, without intimal dissection, and with reduced rates of abrupt closure in the peripheral circulation. This technique is also distinguished by the removal of plaque suitable for macroscopic and microscopic examination. Histologic studies have shown that media can occasional1y be sampled during atherectomy and that this may be associated with an increased rate of restenosis, possibly caused by increased injury to the arterial wall. Recently, because of increased use of intravascular ultrasound (NUS), angiography has been a suboptimal endpoint of atherectomy due to the inherent limitations of 2D longitudinal imaging. In clinical applications, some patients maintain long-term patency fol1owing atherectomy, but no definite evidence shows that any benefit is gained from atherectomy compared with PTA. In the Coronary Angioplasty versus Excisional Atherectomy Trial, no therapeutic gain was documented. A new trial is under way comparing "optimal" directional coronary atherectomy versus percutaneous transluminal coronary angioplasty (PTCA), using ultrasound for optimization. In clinical practice, because of increasing pressure for cost-effective therapy, peripheral atherectomy is reserved for specific applications (infra-inguinal focal stenoses, eccentric, for patients with blue-toe syndrome, short segment total occlusions [infra-inguina!], and in short-segment disease where techniques of rapid thrombolysis are used). In these patients, a high risk of a lamellar thrombus exists, and atherectomy may result in the reduced risk of distal embolization. Its application in the iliac aItery is limited, but by using newer atherectomy devices, a 6.0-mm lumen can be achieved with an 8-F device. Rotational atherectomy is distinguished by treating the stenotic vessel 3600 by using devices that apply rotational forces or methods. Examples include the Kensey-Nash device and the more widely used and approved Rotoblator, which uses diamond burrs rotating at high speeds to ablate plaque. This technique has proved effective in achieving excel1ent initial outcomes, particularly in the coronary arteries, especially when calcium is present. Application
in peripheral circulation has been limited by the mechanics of introducing larger burrs percutaneously, but infrapopliteallesions can be effectively opened. In the coronary circulation, no definite benefit concerning restenosis has been documented, although a multicenter study of optimal use of this device (STRATIS) is under way.
II
The transluminal extraction catheter device combines rotational cuning with simultaneous suction to avoid passage of particulate material downstream and to reduce embolic burden. This device has not gained wide acceptance and has not proved to reduce restenosis. It may have value in the treatment of occluded coronary artery bypass grafts. Intravascular Stents
Since their initial clinical trials and subsequent introduction into clinical practice, intravascular stents have been used primarily for improving the initial outcome of intervention. As a permanent implant, they may be effective in overcoming elastic recoil, constraining flow limiting intimal dissections occurring after PTA, and improving results of intervention, in particular, unfavorable lesions such as osteal lesions or those with calcification. Recent results of the Benestent and Benestent II trial have shown benefit when using balloonexpandable stents in coronary angioplasty, with significant benefit in patency and restenosis reduction compared to PTCA alone. While complications associated with aggressive anticoagulation muted the apparent benefit, recent improvements in technique, including use of lVUS and high-pressure bal100n inflation, reduced the need for aggressive anticoagulation and established an increased benefit for coronary stenting. Traditional indications for stent implantation have been principally associated with improving initial outcome. Based on highly favorable clinical experience with deploying stents during acute revascularization, some investigators have begun to evaluate the long-term benefits of stents, particularly in the iliac arteries. Experience from a randomized prospective trial comparing PTA to primary stenting presented by Richter suggests that "primary" stenting may produce long-term results superior to angioplasty alone in the iliac arteries. Long-term patency beyond 12 months may be prolonged by at least 10% at longer intervals after interven-
63
Saturday, March 2, 1996 tion. These findings correlate well with clinical observations in our own institution and a gradual change in indications has been occurring.
Kim D, Gianturco LE, Porter DH, et al. Peripheral directional atherectomy: 4-year experience. Radiology 1992; 183:773-778.
Stents are also being evaluated for vehicles to deliver pharmacologic agents and even l3-irradiation for more active treatment of restenosis. The Benestent II trial includes the use of heparin-coated stents in a randomized trial with PTCA. Fischell recently presented initial animal results with P32 deployed with the use of Palmaz-Schatz stents. These techniques, and others, offer great promise in maximizing the benefits of permanent implants for restenosis.
Kuntz RE, Safian RD, Levine MJ, Reis GJ, Diver DJ, Bairn DS. Novel approach to the analysis of restenosis following three new coronary intervention. Circulation 1992; 19: 1493-1499.
Another example of using an interventional device for delivery of pharmacologic benefit is "endoluminal paving" with hydrogel polymers, which has recently been shown to reduce both early thrombus formation and long-term intimal hyperplasia occurring after vascular trauma in animals. While only investigational at this time, this approach, and the use of other biodegradable stents, offer promise in achieving the mechanical benefits of stents without permanent implantation. Combining stents with graft coverings, such as polytetrafluoroethylene and polyester, also may offer promise in reducing restenosis. Preliminary results of clinical trials in Europe with a self-expanding Nitinol stent covered with polyester have not shown definite benefit.
Selected Bibliography Dolmatch BL, Gray RJ, Horton KM, Rundback ]H, Kline ME. Treatment of anastomotic bypass graft stenosis with directional atherectomy: short-term and intermediateterm results. J Vasc Interv Radiol 1995; 6: 105-113. Fischell E. Inhibition of neonintimal proliferation with a Beta particle emitting stent. Presented during the IV International Interdisciplinary Stent Symposium in Frankfurt, Germany, September 1-3, 1995. Fischman DL, Leon MB, Baim DS, et al. Randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994; 331:496-501. Hill-West JL, Chowdhury SM, Slepian MJ, Hubbell JA. Inhibition of thrombosis and intimal thickening by in situ photopolymerization of thin hydrogel barriers. Proc Natl Acad Sci 1994; 91:59675971.
64
McLean GK. Percutaneous peripheral atherectomy. J Vasc Interv Radiol 1993; 4: 465-480. Rees CR, Palma JC, Becker GJ, et al. Preliminary report of a multi-center study of the Palmaz stent in atherosclerotic stenoses involving the ostia of the renal arteries. Radiology 1991; 181:507-514. Richter GM. Stents in peripheral arteries: randomized study. Presented during the IV International Interdisciplinary Stent Symposium in Frankfurt, Germany, September 1-3, 1995. Serruys PW, de Jaegere P, Kiemeneij F, et al. Comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Eng!] Med 1994; 331:489-495. Topol EJ, Leya F, Pinkerton CA, et al. Comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N Engl J Med 1993; 329:221-227. Vroegindeweij D, Kemper FJ, Tielbeek AV, Buth J, Landman G. Recurrence of stenoses following balloon angioplasty and Simpson atherectomy of the femoropopliteal segment: randomized comparative I-year follow-up study using colour flow duplex. Eur J Vasc Surg 1992; 6:164-171. 4:30 pm Pharmacological Approaches to Restenosis P. Macke Consigny, PhD
Learning objectives: (1) To understand the physiologic processes that contribute to restenosis. (2) To understand the pharmacologic approaches developed to inhibit restenosis. (3) To understand why the responses of animal arteries to injury may not exactly mimic the responses of human arteries. (4) To understand the principles of local drug delivery to inhibit restenosis.