Drug-Eluting Stents Target Restenosis
An innovative technology continues to evolve.
The advent of percutaneous transluminal angioplasty (PTCA) has revolutionized the way we treat many patients with vascular disease. The technique is limited, however, by its inability to treat complex lesions and by acute closure in the coronary circulation. Researchers have developed intravascular stents to eliminate these drawbacks and allow endoluminal treatment of a wide variety of lesions. The use of stents has vastly improved initial results in certain vascular beds, including the coronary and renal arteries, where plaque burden is high and primary patency is crucial.
Now that most vascular lesions have been treated with endovascular therapy, the long-term results of these interventions are appropriately being compared with those of standard surgical therapy (which typically has better long-term results, albeit with increased periprocedural morbidity). Restenosis secondary to intimal hyperplasia remains a limiting factor in the long-term success of intervention for coronary artery lesions, ostial renal artery stenoses, angioplasty of AV graft stenoses, and for infrainguinal (femoral-popliteal) lesions.
THE ROOT OF RESTENOSIS
A number of investigators have examined the role that vessel wall injury plays in the development of intimal hyperplasia and restenosis. Deep vessel injury incurred during angioplasty has been associated with a higher degree of restenosis secondary to intimal hyperplasia in a porcine coronary model.1 Intravascular stents may further injure the arterial wall based on the profile of the stent strut. Using a porcine iliac model, we compared standard Palmaz stents (Cordis Corporation, a Johnson & Johnson company, Miami, FL) with those possessing a more aggressive strut profile (ie, the Clemson stent, manufactured for this experiment). We found that the novel stents were more likely to rupture the internal elastic lamina (IEL) and induced increased restenosis secondary to intimal hyperplasia.2 Arteries with ruptured IEL developed 10 times the intimal hyperplasia compared with arteries with an intact IEL. This difference may be even more pronounced in arteries with a high plaque burden. The “ideal” stent would possess several important characteristics to eliminate this exaggerated healing response and prevent restenosis. Drug-eluting (drug-coated) stents are a step in the right direction.
SUPPORT AND DELIVER
Certain pharmacologic agents have been shown to reduce intimal hyperplasia in animal models and have subsequently been tested in humans, principally in the coronary arteries, where in-stent restenosis (defined as >50% reduction in angiographic luminal diameter) can reach 30% to 60% in patients with diabetes, in diffuse lesions, and in vessels <3.0 mm in diameter.3
The use of drug-eluting stents constitutes a two-pronged attack on atherosclerotic vessels: (1) the stent acts as a mechanical scaffold within the artery to prevent elastic recoil and maintain acute vessel patency, and (2) the drug acts within the local microenvironment to prevent intimal hyperplasia.
Although a myriad of pharmacologic agents have been studied, three have shown promise in animals and in humans, including actinomycin D, paclitaxel, and sirolimus. These drugs act on different portions of the cell cycle to inhibit smooth muscle cell growth and prevent intimal hyperplasia. Unfortunately, peer-reviewed journals provide very little clinical data on drug-eluting stents; much of the following information is gleaned from preliminary data presented in abstract form.
Actinomycin D is an antineoplastic agent derived from the bacteria Streptomyces parvulus that has been shown to reduce intimal hyperplasia in animal models. It acts by inhibiting cell kinases, thereby decreasing synthesis of specific proteins necessary for cell replication and division. In addition, actinomycin D forms a stable complex with double-stranded DNA, preventing RNA synthesis. Preliminary data from trials in coronary arteries suggest a significant rate of TLR and MACE, and little benefit compared with standard stenting for de novo lesions in coronary arteries.
Another antineoplastic agent, paclitaxel, has shown significant promise in the prevention of restenosis in animals and humans. Paclitaxel was originally derived from the needles of the Pacific yew tree, taxus brevis, and has subsequently been purified and synthesized. This drug is FDA approved for treating ovarian cancer. Paclitaxel acts by enhancing microtubule assembly and stabilizing polymerized microtubules, thereby inhibiting processes dependent on microtubule turnover, including mitosis, cell proliferation, and cell turnover. The first clinical trial (a feasibility study) using a drug-eluting stent in humans revealed no major adverse clinical events at 30 days, and no instances of in-stent thrombosis. At 6 months, researchers observed minimal restenosis by angiography and intravascular ultrasound. In April 2001, researchers halted the pivotal study, a randomized, multicenter trial comparing drug-coated and bare stent, due to issues surrounding subacute stent thrombosis and periprocedural MI.4,5
A third drug, sirolimus, is a macrolide antibiotic first found in soil samples taken from Easter Island. This immunosuppressive agent exerts antiproliferative and anti-inflammatory effects. Sirolimus acts by binding to cellular receptors, preventing downregulation of cyclin-dependent kinases within the cell. This ultimately causes G1 cell cycle arrest and cytostatic inhibition of the cell cycle. The results of the feasibility study of a sirolimus-covered stent were recently published.6 This study, performed in Brazil and the Netherlands, followed 45 patients treated with the study stent. At 6 months, no patients had developed angiographic restenosis (defined as >50% diameter stenosis), which was confirmed by intravascular ultrasound at 4 and 12 months.
Another study, the pivotal RAVEL trial, examined 238 patients randomized to bare stents versus sirolimus-covered stents in de novo coronary lesions.7 There was nearly complete abolition of intimal hyperplasia in the sirolimus group compared with controls (P<.001) at 6 months. Importantly, no “edge effects” were seen—that is, the two groups showed no difference in plaque volume at the proximal and distal edges of the stent. Sirolimus, therefore, seems to offer substantial promise in preventing restenosis following angioplasty and stenting; upcoming clinical trials will investigate its role in the renal and infrainguinal beds.
The results of a number of industry-sponsored clinical trials involving drug-eluting stents are shown in Table 1. Again, much of the data were gathered from oral presentations and not from peer-reviewed literature and is, therefore, preliminary in nature.
Investigators remain cautiously optimistic about the early results of drug-eluting stents for the prevention of restenosis. Certainly, these engines for drug delivery represent a major advance in our ability to prevent recurrent lesions, especially in the vascular territories previously outlined. There is no doubt these tools will have a major impact on the practice of interventional cardiology and peripheral vascular intervention in the future.
Timothy M. Sullivan, MD, is Director of Endovascular Surgery Practice in the Division of Vascular Surgery at the Mayo Clinic, in Rochester, Minnesota. Dr. Sullivan may be reached at (507) 285-0416; firstname.lastname@example.org.
1. Sangiorgi G, Taylor AJ, Farb A, et al. Histopathology of postpercutaneous transluminal coronary angioplasty remodeling in human coronary arteries. Am Heart J. 1999;138:681-687.
2. Sullivan TM, Ainsworth SD, Langan EM, et al. Effect of endovascular stent strut geometry on vascular injury, myointimal hyperplasia, and restenosis. J Vasc Surg. 2002;36(1):143-149.
3. Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis: Classification and implications for long-term outcome. Circulation. 1999;100:1872-1878.
4. Grube E, Gerkens U, Rowold S, et al. Inhibition of in-stent restenosis by the qanam drug eluting polymer stent: Two year follow-up. J Am Coll Cardiol. 2001;37(suppl A):19.
5. Hiatt BL, Ikeno F, Yeung AC, Carter AJ. Drug-eluting stents for the prevention of restenosis: In quest for the Holy Grail. Cather Cardiovasc Interv. 2002;55:409-417.
6. Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: A quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation. 2001;103:192-195.
7. Serruys PW, Degertekin M, Tanabe K, et al. Intravascular ultrasound findings in the multicenter, randomized, double-blind RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) trial. RAVEL Study Group. Circulation. 2002;106(7):798-803.