Drug-Eluting Intra-Coronary Stents: Have We Got the Magic Bullet?
V Bhatia, R Bhatia, S Dhindsa
Department of Internal Medicine, SUNY, Buffalo, NY, USA
Department of Internal Medicine, Mercy Hospital of Buffalo, 565, Abbott Road, Buffalo, NY, 14220
|How to cite this article:|
Bhatia V, Bhatia R, Dhindsa S. Drug-Eluting Intra-Coronary Stents: Have We Got the Magic Bullet?
.J Postgrad Med 2003;49:291-296
|How to cite this URL:|
Bhatia V, Bhatia R, Dhindsa S. Drug-Eluting Intra-Coronary Stents: Have We Got the Magic Bullet?
. J Postgrad Med [serial online] 2003 [cited 2021 Oct 22 ];49:291-296
Available from: https://www.jpgmonline.com/text.asp?2003/49/3/291/1158
Much research has been done on many mechanical devices and drugs to prevent restenosis, providing the rationale for an enormous number of clinical trials, but none have been proven to be effective.,,, Despite the use of multiple percutaneous revascularization techniques, including balloon angioplasty, repeated stenting, laser therapy, platelet inhibitors, heparin-coated stents and atheroablation, approximately half of the 30 % of patients in whom restenosis occurs after coronary stenting, have recurrent restenosis.,,,,,,,,,, In the present paper, we briefly describe the mechanisms of in-stent restenosis and have reviewed the literature to discuss the novel strategy of coating stents with anti-proliferative drugs to prevent this complication. We have also addressed the benefits and shortcomings of using these drug-eluted stents.
Pathology of stent restenosis
The initial events immediately after stent placement result in de-endothelialization and the deposition of a layer of platelets and fibrin at the injured site in the coronary artery. Activated platelets express adhesion molecules such as P-selectin and glycoprotein (GP) Ib [alpha], which attach to circulating leukocytes via platelet receptors such as P-selectin glycoprotein ligand and begin a process of rolling along the injured surface. Under the influence of cytokines, leukocytes bind tightly to the leukocyte integrin (i.e., Mac-1) class of adhesion molecules via direct attachment to platelet receptors such as GP Ib[alpha] and through cross-linking with fibrinogen to the GP IIb/IIIa receptor. The migration of leukocytes across the platelet-fibrin layer and into the tissue is driven by chemical gradients of cytokines released from smooth muscle cells (SMCs) and resident leukocytes. Growth factors are released from platelets, leukocytes, and SMCs, which influence the proliferation and migration of SMCs from the media into the neointima. The resultant neointima consists of SMCs, extracellular matrix, and macrophages recruited over several weeks. Over even longer periods of time, there is a shift to fewer cellular elements with greater production of extracellular matrix. In addition, there is eventual re-endothelialization of at least part of the injured vessel surface.
Experience with systemically administered drugs, such as antiplatelet agents, anticoagulants, calcium-channel blockers, angiotensin-converting-enzyme inhibitors, cholesterol-lowering agents, and antioxidants, has proven almost universally negative. These agents were previously tested in animal models and found to be beneficial. The lack of efficacy in human studies may be in part due to insufficient concentration of the drug at the injury site or lack of chronic dosing. In general, although animal models provide new insights into the mechanism of restenosis, biological and mechanical differences mean that therapeutic success of anti-restenotic therapies has not been achieved in human beings. The recent introduction of intracoronary radiation has emerged as a promising modality to attenuate the intimal hyperplastic reaction.,, Despite the lack of benefit for preventing restenosis in de-novo lesions, brachytherapy was shown to be effective in reducing recurrent restenosis. However, larger studies and long-term follow-up showed alarming long-term sequelae such as edge restenosis and late thrombosis, raising some concerns about the potential toxicity of a cytotoxic approach.,, Similarly, the results with oral administration of an anti-proliferative agent, sirolimus, have failed to show any benefit and in fact there was a higher incidence of adverse events in the recipients of such a therapy.
The potential usefulness of immunosuppressive agents in the treatment of restenosis arises from parallels between tumour cell growth and the benign tissue proliferation, which characterizes intimal hyperplasia. With drug-coated stents, there is site-specific drug delivery, which reduces systemic toxicity and thus is an attractive therapeutic method to achieve an effective local concentration of a drug for a designed period. The safety and efficacy of such an approach critically depends on the delicate combination of drug, polymer, and the kinetics of release. Drug-eluting stent is a device that releases single or multiple bioactive agents into the bloodstream that can deposit in or around tissues adjacent to the stent. The drug can be simply linked to the stent surface, embedded and released from within polymer materials, or surrounded by and released through a carrier. The carrier can coat (strut-adherent) or span (strut-spanning) the stent struts. Sirolimus is a natural macrocyclic lactone with potent immunosuppressive and antimitotic action, which was approved in 1999 as an anti-rejection drug in renal transplant recipients. The cellular action of rapamycin (sirolimus), a natural fermentation product produced by Streptomyces hygroscopicus, is mediated by binding to the FK506 binding protein. By inhibiting a kinase known as the target of rapamycin, it restricts the proliferation of smooth-muscle cells by blocking cell-cycle progression at the G1/S transition. The finding that rapamycin possesses both anti-proliferative and anti-migratory activity suggests that it could contribute to the control of arterial re-narrowing after percutaneous intervention. Marie Claude Morice and colleagues report the first randomised double-blind trial (RAVEL study) comparing the coronary stent coated with sirolimus with a standard uncoated stent. The trial included 238 patients with single coronary lesions at 19 different medical centres. Patients with complex coronary lesions were excluded. Stents were coated with the agent prior to insertion. This was achieved by applying a mixture of synthetic polymers blended with sirolimus with a second coat of drug-free polymers to serve as a diffusion barrier. The polymers act as a drug reservoir and permit the gradual elution of sirolimus. The stent was designed to release 80% of the drug within 30 days after implantation. The angiographic rate of restenosis at 6 months was 26.6% in the standard-stent group and 0% in the drug-stent group. There were no reported cases of subacute thrombosis. The mean late luminal loss was ZERO in the sirolimus-eluting stent group and 0.80 mm in the conventional stent group. During a follow-up period of up to 1 year, the overall rate of major cardiac events (MACE) was 5.8% in the sirolimus-stent group and 28.8% in the standard-stent group. The results of this trial generated a lot of enthusiasm and many had started believing that it was the end of restenosis after percutaneous coronary interventions. Two-year follow-up findings indicated that these results had been sustained at 2-year follow-up with an event-free survival of 90%, compared with 80.5% in the control arm, and a 2.5% target lesion revascularization rate. Additionally, there was no stent thrombosis observed during the study years. In another study done by Maurice MC et al, the beneficial impact of sirolimus-coated stents on neointimal growth inhibition was persistent at 2 years' follow-up. These results have been further tested in a large US multicentre randomised trial, called SIRIUS (Data unpublished, results declared at the 14th annual TCT symposium, September 2002 by Moses JW et al). In this trial 1,058 patients were randomised to 2 treatment arms: 533 patients received a CYPHER™stent (rapamycin-coated) and 525 received a bare metal Bx VELOCITY™coronary stent (standard-stent). Eight-month angiographic follow-up showed minimal in-stent late lumen loss (0.17 mm) in patients treated with the sirolimus-coated stents. The 3.2% rate of angiographic in-stent restenosis represents a 91% reduction vs. the control arm (bare metal stent), and the 8.9% angiographic in-lesion restenosis (including a 5-mm area at each end of the stent) represents a 75% reduction vs. the control arm. At 9-month follow-up, the event-free survival rate was 92.7% in the sirolimus-treated cohort vs. 80.7% in the bare metal stent cohort (p 80% endothelial coverage. Neointimal healing was nearly complete, with only rare fibrin deposits. Results of another trial called the C-Sirius trial were declared recently. It was a Canadian, multicentre, randomised, double-blind trial enrolling 100 patients and it showed the safety and efficacy of sirolimus-eluting stents in maintaining in-stent minimal lumen diameter (MLD) at 8 months in de novo native coronary lesions. No in-stent stenosis was reported in this trial in sirolimus group and in-stent late loss was 91% less in the sirolimus group (0.09 mm vs. 1.01 mm) as compared with the uncoated stent group. The positive results of the RAVEL and SIRIUS trials can now be extended to patients with long lesions in smaller vessels. All the major trials of the sirolimus-eluting stents showed benefits in diabetic patients also. The total lack of restenosis in RAVEL trials in diabetic patients is striking. Data from the SIRIUS trials shows 83% reduction of in-stent restenosis and 65% reduction of in-segment restenosis in diabetic patients, and bypass surgery is often performed in this group instead of primary angioplasty or stenting. Diabetes is a formidable limitation to the success of conventional percutaneous coronary interventions (PCI). If the data from these trials are borne out, it will have a great impact on how diabetics are managed with coronary revascularization. In a preliminary early cost-effectiveness sub-study of the SIRIUS trial, the use of a drug-eluting stent, compared to a standard bare-metal stent, added more than $2,000 to the procedure's initial cost. The drug-eluting stent reduced the need for later medical care, but the resulting cost savings only partly erased its extra initial cost. The final results of the cost-effectiveness of these stents in the SIRIUS trial showed that during initial hospitalisation, costs were higher in the drug-eluting group, which were explained by the cost of the device itself.  During the 12-month follow-up period, there were substantial reductions in the need for repeat revascularization. Despite higher in-hospital costs, the group receiving the sirolimus stent showed cost savings of about $2,500 at 12-months follow-up. Given the initial cost differential of about $2,800 higher associated with the drug-eluting stent, the difference at one year was only about $300 per patient.
Paclitaxel-eluting stents (Taxol-coated stents)
The taxanes (for example, Paclitaxel) are potent anti-proliferative agents used in cancer chemotherapy. Paclitaxel promotes polymerisation of the alpha and beta subunits of tubulin by reversibly and specifically binding the beta subunit of tubulin, and thus stabilizes microtubules. A stent coated with paclitaxel is also safe and effective for decreasing neointimal proliferation within the stented segment and reducing the incidence of clinically significant in-stent or edge restenosis. Three randomised trials (ASPECT, ELUTES and TAXUS I) found that the paclitaxel-coated stent significantly reduced late lumen loss, neointimal volume index, and angiographic restenosis at 6 months (0 to 4 vs. 10 to 27 % for a bare stent). Paclitaxel-coated stents dramatically inhibited neointimal hyperplasia, as evidenced by angiography and IVUS evaluations at 6 months, according to the ASian Paclitaxel-Eluting stent Clinical Trial (ASPECT) study. The binary restenosis rate was reduced significantly from 27% in patients receiving control, bare metal stents to 12% in those receiving low-dose paclitaxel-coated stents and to just 4% in patients receiving higher dose paclitaxel-coated stents, demonstrating an important dose-dependent relationship. Mean diameter stenosis was reduced from 38% in the control arm to 24% in the low-dose group, and to only 12% in patients treated with higher dose paclitaxel-coated stents. The TAXUS program is a series of clinical studies designed to collect data on the TAXUS paclitaxel-eluting stent (Boston Scientific, Natick, Massachusetts) for the reduction of restenosis after angioplasty and stenting. The TAXUS II trial consists of 2 sequential cohorts: (1) a slow-release (SR) formulation, and (2) a moderate-release (MR) formulation. Both delivery systems employ the same total loaded dose (1 microgram/mm 2), with different biphasic release rates. The primary difference between the 2 systems takes place within the first 48 hours following implantation, during which the amount of drug released is substantially greater (8- to 10-fold) with the MR than with the SR formulation. After 48 hours, there is a sustained release during the course of the next 10 days in both groups. The control stent used in this trial was the NIRx Conformer stent (Medinol, Tel Aviv, Israel), which is a 15-mm stent premounted on a 20-mm balloon delivery system in available diameters of 3.0 mm and 3.5 mm. Six-month quantitative coronary angiographic analysis revealed a significantly lower binary restenosis rate in the stented segment for both the SR and MR arms compared with control (2.3% vs. 4.7% vs. 19.0%, respectively, P
Concerns and controversies
It is still premature to comment on the safety profile of stents coated with potent antimitotic agents such as sirolimus and paclitaxel. These agents inhibit smooth muscle cell proliferation, and therefore have a mechanism of action similar to that of radioactive stents. Synthetic polymers are often used as carriers for these agents, and polymer biocompatibility remains a concern, as polymers often induce an exaggerated inflammatory reaction. Chronic, low-grade inflammation, poor wound healing responses with incomplete endothelialisation, and intra-intimal haemorrhage have been noted in porcine coronary arteries treated with paclitaxel-coated stents. Accelerated atherosclerosis immediately proximal and distal to QP2-coated stents has also been reported in humans although preliminary trial data suggest that this may not be a major issue., Delayed stent thrombosis has also been described with QP2-coated stents. Concern regarding this phenomenon has prompted many clinical trials investigating stents eluting antimitotic agents to treat enrolled patients with oral antithrombotic agents for up to 6 months after implantation of these stents. Lack of a long-term effect on restenosis as described with radioactive stents may also become apparent in the future. It has been postulated that the prevention of restenosis in recent clinical trials of drug-eluting stents represents a near-absent or incomplete phase of intimal healing. Up to this point, the negative findings of drug-eluting stents in 90 and 180-day animal studies-at a time when healing is complete-may correspond to a reasonable approximation of 2 to 3 years in humans. However, there is still paucity of long-term trial data (is this safety data or efficacy data?)(>2 years). Continued long-term follow-up of patients with drug-eluting stents for MACE and angiographic restenosis is therefore imperative. At best, drug-eluting stents may have solved the in-stents restenosis problems; at worst, they may lead to adverse long-term late thrombosis and restenosis. The added cost of these stents may, at least initially, limit their use to patients at high risk of in-stent stenosis and this is an issue yet to be addressed. In spite of all these concerns, the CypherTM sirolimus-eluting stent (Cordis/Johnson & Johnson) has been approved by the US FDA for the treatment of restenosis, making it the first drug-eluting stent on the US market. The stents will cost $3195 regardless of their length or diameter. Although many other potential problems with these stents may be foreseen, the small numbers of patients enrolled and the short follow-up periods of the clinical trials evaluating drug-eluting stents remain the most important limitations.
|1||Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. Benestent Study Group. N Engl J Med 1994;331:489-95.|
|2||Serruys PW, Kay IP, Disco C, Deshpande NV, de Feyter PJ. Periprocedural quantitative coronary angiography after Palmaz-Schatz stent implantation predicts the restenosis rate at six months: results of a meta-analysis of the Belgian Netherlands Stent study (BENESTENT) I, BENESTENT II Pilot, BENESTENT II and MUSIC trials. Multicenter Ultrasound Stent In Coronaries. J Am Coll Cardiol 1999;34:1067-74.|
|3||Topol EJ, Mark DB, Lincoff AM, Cohen E, Burton J, Kleiman N, et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1999;354:2019-24.|
|4||Moer R, Myreng Y, Molstad P, Albertsson P, Gunnes P, Lindvall B, et al. Stenting in small coronary arteries (SISCA) trial. A randomized comparison between balloon angioplasty and the heparin-coated beStent. J Am Coll Cardiol 2001;38:1598-603.|
|5||Eltchaninoff H, Koning R, Tron C, Gupta V, Cribier A. Balloon angioplasty for the treatment of coronary in-stent restenosis: immediate results and 6-month angiographic recurrent restenosis rate. J Am Coll Cardiol 1998;32:980-4.|
|6||Bauters C, Banos JL, Van Belle E, Mc Fadden EP, Lablanche JM, Bertrand ME. Six-month angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation 1998;97:318-21.|
|7||Dauerman HL, Baim DS, Cutlip DE, Sparano AM, Gibson CM, Kuntz RE, et al. Mechanical debulking versus balloon angioplasty for the treatment of diffuse in-stent restenosis. Am J Cardiol 1998;82:277-84.|
|8||Radke PW, Klues HG, Haager PK, Hoffmann R, Kastrau F, Reffelmann T, et al. Mechanisms of acute lumen gain and recurrent restenosis after rotational atherectomy of diffuse in-stent restenosis: a quantitative angiographic and intravascular ultrasound study. J Am Coll Cardiol 1999;34:33-9.|
|9||Jolly N, Ellis SG, Franco I, Raymond RE, Jolly M, Hammel J, et al. Coronary artery stent restenosis responds favorably to repeat interventions. Am J Cardiol 1999;83:1565-8, A7.|
|10||vom Dahl J, Radke PW, Haager PK, Koch KC, Kastrau F, Reffelmann T, et al. Clinical and angiographic predictors of recurrent restenosis after percutaneous transluminal rotational atherectomy for treatment of diffuse in-stent restenosis. Am J Cardiol 1999;83:862-7.|
|11||Elezi S, Kastrati A, Hadamitzky M, Dirschinger J, Neumann FJ, Schomig A. Clinical and angiographic follow-up after balloon angioplasty with provisional stenting for coronary in-stent restenosis. Catheter Cardiovasc Interv 1999;48:151-6.|
|12||Kastrati A, Elezi S, Dirschinger J, Hadamitzky M, Neumann FJ, Schomig A. Influence of lesion length on restenosis after coronary stent placement. Am J Cardiol 1999;83:1617-22.|
|13||Elezi S, Kastrati A, Pache J, Wehinger A, Hadamitzky M, Dirschinger J, et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol 1998;32:1866-73.|
|14||Lau KW, Ding ZP, Johan A, Lim YL. Midterm angiographic outcome of single-vessel intracoronary stent placement in diabetic versus nondiabetic patients: a matched comparative study. Am Heart J 1998;136:150-5.|
|15||Kasaoka S, Tobis JM, Akiyama T, Reimers B, Di Mario C, Wong ND et al. Angiographic and intravascular ultrasound predictors of in-stent restenosis. J Am Coll Cardiol 1998;32:1630-5.|
|16||Leon MB, Teirstein PS, Moses JW, Tripuraneni P, Lansky AJ, Jani S, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med 2001;344:250-6.|
|17||Waksman R, Raizner AE, Yeung AC, Lansky AJ, Vandertie L. Use of localised intracoronary beta radiation in treatment of in-stent restenosis: the INHIBIT randomised controlled trial. Lancet 2002; 359:551-7.|
|18||Grise MA, Massullo V, Jani S, Popma JJ, Russo RJ, Schatz RA, et al. Five-year clinical follow-up after intracoronary radiation: results of a randomized clinical trial. Circulation 2002;105:2737-40.|
|19||Lansky AJ, Popma JJ, Columbo A. Follow-up angiographic comparison of the low dose vs high dose phosphorous-32 radioactive isostent: results from expanded IRIS and Milan Dose A studies. J Am Coll Cardiol 1999;33:17A-17A.abstract.|
|20||Costa MA, Sabat M, van der Giessen WJ, Kay IP, Cervinka P, Ligthart JM et al. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999;100:789-92.|
|21||Brara PS, Moussavian M, Grise MA, Reilly JP, Fernandez M, Schatz RA, et al. Pilot trial of oral rapamycin for recalcitrant restenosis. Circulation 2003;107:1722-4.|
|22||Schwartz RS, Edelman ER, Carter A, Chronos N, Rogers C, Robinson KA, et al. Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group. Circulation 2002;106:1867-73.|
|23||Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346:1773-80.|
|24||Degertekin M, Serruys PW, Foley DP, Tanabe K, Regar E, Vos J, et al. Persistent inhibition of neointimal hyperplasia after sirolimus-eluting stent implantation: long-term (up to 2 years) clinical, angiographic, and intravascular ultrasound follow-up. Circulation 2002;106:1610-3.|
|25||Sousa JE, Costa MA, Sousa AG, Abizaid AC, Seixas AC, Abizaid AS, et al. Two-year angiographic and intravascular ultrasound follow-up after implantation of sirolimus-eluting stents in human coronary arteries. Circulation 2003;107:381-3.|
|26||Sousa JE, Costa MA, Abizaid A, Sousa AG, Feres F, Mattos LA, et al. Sirolimus-eluting stent for the treatment of in-stent restenosis: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2003;107:24-7.|
|27||Guagliumi G, Farb A, Musumeci G, Valsecchi O, Tespili M, Motta T, et al. Sirolimus-eluting stent implanted in human coronary artery for 16 months: pathological findings. Images in cardiovascular medicine. Circulation 2003;107:1340-1.|
|28||Schampaert E EAC, Reeves F, Laurence M. C-SIRIUS: The Canadian Multicenter, Randomized, Double-Blind Study of the Sirolimus-Eluting Stent in the Treatment of Patients With De Novo Coronary Artery Lesions. Data presented in 52nd annual scientific session of ACC. 2003.|
|29||DJ C. Are Drug-eluting Stents Worth Their Extra Cost? American College of Cardiology 52nd Annual Scientific Session. 2003.|
|30||Park SJ SW, Ho DS, et al. The clinical effectiveness of paclitaxel-coated coronary stents for the reduction of restenosis in the ASPECT trial. Circulation 2001;104:II-464.|
|31||Gershlick AH DSI, Chevalier B, et al. Local drug delivery to inhibit coronary artery restenosis: data from the ELUTES (Evaluation of Paclitaxel Eluting Stent) clinical trial. Abstract. Circulation 2001;104:II-416.|
|32||Grube E, Silber S, Hauptmann KE, Mueller R, Buellesfeld L, Gerckens U, et al. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38-42.|
|33||Tanabe K, Serruys PW, Grube E, Smits PC, Selbach G, van der Giessen WJ, et al. TAXUS III Trial: in-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation. Circulation 2003;107:559-64.|
|34||Liistro F, Stankovic G, Di Mario C, Takagi T, Chieffo A, Moshiri S, et al. First clinical experience with a paclitaxel derivate-eluting polymer stent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome. Circulation 2002;105:1883-6.|
|35||Virmani R, Liistro F, Stankovic G, Di Mario C, Montorfano M, Farb A, et al. Mechanism of late in-stent restenosis after implantation of a paclitaxel derivate-eluting polymer stent system in humans. Circulation 2002;106:2649-51.|
|36||Grube E HK, Colombo A, et al. SCORE trial interim safety results: despite efficacy, late stent thrombosis with the QuaDDS-QP2 stent.Abstract. J Am Coll Cardiol 2002;39:38A.|
|37||Farb A, Heller PF, Shroff S, Cheng L, Kolodgie FD, Carter AJ, et al. Pathological analysis of local delivery of paclitaxel via a polymer-coated stent. Circulation 2001;104:473-9.|
|38||Honda Y, Grube E, de La Fuente LM, Yock PG, Stertzer SH, Fitzgerald PJ. Novel drug-delivery stent: intravascular ultrasound observations from the first human experience with the QP2-eluting polymer stent system. Circulation 2001;104:380-3.|
|39||Serruys PW, Degertekin M, Tanabe K, Abizaid A, Sousa JE, Colombo A, 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. Circulation 2002;106:798-803.|
|40||Liistro F, Colombo A. Late acute thrombosis after paclitaxel eluting stent implantation. Heart 2001;86:262-4.|
|41||Kay IP, Wardeh AJ, Kozuma K, Foley DP, Knook AH, Thury A, et al. Radioactive stents delay but do not prevent in-stent neointimal hyperplasia. Circulation 2001;103:14-7.|
|42||Virmani R, Kolodgie FD, Farb A, Lafont A. Drug eluting stents: are human and animal studies comparable? Heart 2003;89:133-8.|