- Email: [email protected]
IIIa inhibitors: Combination therapy for the future
Drug-eluting stents and glycoprotein IIb/IIIa inhibitors: Combination therapy for the future Martin B. Leon, MD,a and Ameet Bakhai, MD, MRCPb New York, NY, and London, United Kingdom
Background Although coronary stenting has improved the results of coronary interventions compared to coronary angioplasty alone, in-stent restenosis remains a significant limitation of this procedure. Drug-eluting stents with or without glycoprotein IIb/IIIa inhibitor therapy represent an additional advance in the evolution of this strategy. Methods
We review the currently available trials comparing studies of non-drug– eluting and drug-eluting stents using sirolimus and paclitaxel agents and their derivatives.
Results Ten studies are available that compare drug-eluting to traditional non-drug– eluting stents. A variety of antiplatelet regimes have been used. The majority of these studies are in the process of being published. No head-to-head studies comparing different drug-eluting stents are available. Conclusions
Drug-eluting stents using sirolimus and paclitaxel in combination with enhanced antiplatelet strategies represent an important advantage over non-drug– eluting stents for the reduction of in-stent restenosis. The rate at which drug-eluting stents are adapted into widespread practice depends heavily on whether they are safe, efficacious, and costeffective in various clinical settings. (Am Heart J 2003;146:S13–7.)
Since Andreas Gru ¨ ntzig implemented the first catheter-based technique for treating symptomatic coronary stenoses 25 years ago,1 the goal of interventionists has been to make this procedure safe, durable, and complication free, with consistent results applicable to treatment of a wide range of patients and, ultimately, to eliminate restenosis, the Achilles heel of coronary angioplasty. The introduction of intracoronary stents as an adjunct to coronary angioplasty has considerably improved results. Stenting reduces restenosis in large vessels with a diameter ⬎3 mm and yields better longterm results than conventional percutaneous transluminal coronary angioplasty (PTCA) alone. In-stent restenosis remains the main limitation of stenting technology predominantly due to neointimal proliferation. As a result, additional approaches—such as brachytherapy and molecular genetics techniques— have been investigated to eliminate this complication; however, to date, no therapies have been shown to eliminate restenosis.
From the aCardiovascular Research Foundation, Lennox Hill Hospital, New York, NY, and bSt Mary’s NHS Trust, London, United Kingdom. Reprint requests: Martin B Leon, MD, Director and CEO, Cardiovascular Research Foundation, Lennox Hill Hospital, 130 77th Street, New York, NY 10012. E-mail: [email protected] © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/j.ahj.2003.09.004
Problems associated with percutaneous intervention Stents are deployed in ⬃80% of interventions today, either after balloon angioplasty2,3 or simultaneously with balloon angioplasty (direct stenting). Direct stenting trials have, on the whole, shown similar clinical results to the traditional predilation and subsequent stenting approach. However, direct stenting trials have the additional benefit of reducing radiation exposure and resource use in carefully selected lesion types. A drawback of currently available stents is that they are metallic and therefore have thrombogenic properties that need to be overcome using anticoagulation therapy.4 Such therapy exposes the patient to an increased risk of major bleeding complications and may prolong hospital stay.5 Stent thrombogenecity is an important precursor to neointimal hyperplasia, which leads to in-stent restenosis. In-stent restenosis occurs in approximately 15% to 20% of patients within 6 to 9 months. Initially, routine stent usage was shown to reduce the rate of repeat revascularizations in patients with intermediate and large vessels with focal lesions compared with balloon angioplasty alone. However, improvements in stent technology have led to more complex anatomy being tackled, including small vessels, chronic total occlusions,6 bifurcations,7 diffuse disease,8 and challenging patients (eg, patients with diabetes mellitus or those presenting with acute myocardial infarction). The use of stents in more complex
American Heart Journal October 2003
S14 Leon and Bakhai
Table I. Factors leading to higher rates of stent thrombosis Physiologic
Clinical
Procedural
Small vessels
Patients with acute myocardial infarction Raised platelet count Hypercoagulability disorders
Flow-limiting coronary dissections postprocedure Need for multiple stents at target site Inadequate stent deployment/vessel apposition Use of brachytherapy resulting in damaged vessel left uncovered by stenting
Long target lesions Multiple vessel procedures Pre-existing thrombus at target site
Diabetes mellitus
interventions has led to an increase in stent thrombosis. The variables that may increase the chance of stent thrombosis are shown in Table I.9
In-stent restenosis Compared with coronary balloon angioplasty, stents reduce the need for repeat intervention by preventing vessel elastic recoil and negative remodeling by acting as scaffolds for the vessel. However, stent expansion with or without predilation can cause stretch injury to the vessel endothelium, internal elastic lamina, and media resulting in activation of stress-induced protein kinases, leading to thrombus formation and platelet activation. Important inflammatory changes stimulate the production of growth factors and cytokines, which activate receptors on the smooth muscle cell surface. A variety of signal transduction mechanisms also activate and accelerate the cell cycle. There is a proliferation of smooth muscle cells, production of matrix, and migration of these cells predominantly from the medial layer to the inner vessel layer (intima), although they may migrate through the struts of the stent to form a layer within the lumen of the stent. The resulting abnormal neointimal cells express proinflammatory molecules (including cytokines, chemokines, and adhesion molecules) that further trigger a cascade of events that lead to proliferative neointimal disease and eventually stent stenosis. Using a variety of approaches, studies have clearly demonstrated that blockade of smooth muscle cell proliferation results in preservation of normal vessel phenotype and function, thus reducing the occurrence of neointimal hyperplasia and stent failure.
Drug-eluting stents Drug-eluting stents (DES) are the latest in a long line of interventions devised to overcome the problem of in-stent restenosis. Many different drug classes may be
considered for use in DES, for example, agents that are anti-inflammatory or immunomodulators, antiproliferative agents, drugs which affect migration and extracellular matrix production, and drugs that promote healing and re-endothelialization. A DES is coated with a substance (carrier vehicle or polymer) that is designed to control the release of a drug into the surrounding vessel wall. The intention of this time-release process is to decelerate the growth of unwanted cells (restenosis) and allow the vessel to heal or endothelialize. Some new DES designs use pores or wells, with or without polymers, to act as the carrier vehicle. Although many drugs have been considered for DES,10,11 currently, the main drugs used are paclitaxel, sirolimus, and their derivative agents. Dexamethasone, because of its anti-inflammatory properties, has also been used in recent studies.
Paclitaxel and its derivatives Paclitaxel (Taxol) was the first stent-based antiproliferative agent under clinical investigation to provide profound inhibition of neointimal thickening, depending on delivery duration and dosage. Paclitaxel and related drugs are used as cancer chemotherapeutic agents; their principal mechanism of action is inhibition of microtubule disassembly. Investigators have found that paclitaxel inhibits smooth muscle cell proliferation and migration in vitro and in vivo in balloon injured rat arteries.12 Paclitaxel has also been shown to prevent neointimal hyperplasia in stented pig coronary and rabbit iliac arteries.13,14
Sirolimus and its derivatives Sirolimus (formerly known as rapamycin) is a macrolide antibiotic with immunosuppressant properties. It is also an inhibitor of smooth muscle cell proliferation and migration. It inhibits smooth muscle cell proliferation by binding to its receptor, the FK506 binding protein (FKBP12), and thereby blocking cell cycle progression by preventing the downregulation of the cell division kinase (CDK) inhibitor p27kip1. Deletion of p27kip1 confers resistance to sirolimus, while overexpression of p27kip1 using gene transfer techniques inhibits neointimal hyperplasia. It is of note that the related immunosuppressant drug tacrolimus15 also binds to FKBP12 but does not inhibit smooth muscle cell proliferation and migration. Other sirolimus analogs such as ABT-578 and everolimus have similar FKBP binding properties and are also potent antiproliferative and immunosuppressive agents.
Glycoprotein IIb/IIIa inhibitors As platelet activation and aggregation after trauma to the endothelium serve as a catalyst for thrombin gener-
American Heart Journal Volume 146, Number 4
ation, the platelet is an attractive target for therapies directed at reducing thrombotic complications during percutaneous coronary intervention (PCI). The platelet glycoprotein (GP) IIb/IIIa inhibitors block the final common pathway of platelet activation and aggregation. The effect of GP IIb/IIIa inhibitors, such as abciximab, combined with stenting has been investigated in several clinical trials. In the Evaluation of IIb/IIIa Platelet Inhibitor for STENTing (EPISTENT) trial, combined treatment with stenting and abciximab was associated with a significant reduction in death, myocardial infarction (MI), and target vessel revascularization at 6 months in patients with diabetes.16
DES trials Several studies have been published or are still ongoing that evaluate DES with respect to their release kinetics, effective dosage, safety in clinical practice, and benefit: Paclitaxel-eluting stent (TAXUS) I,17 II,18 III, IV; European EvaLUation of PacliTaxel Eluting Stent (ELUTES)19; DELIVER; Asian paclitaxel-eluting stent clinical trial (ASPECT)20; Study to compare restenosis rate between QueST and QuaDDS-QP2 (SCORE); PATENCY (paclitaxel); Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions (RAVEL)21; SIRIUS22 (sirolimus); the SIRIUS trial in Canada (C-SIRIUS); the SIRIUS trial in Europe (E-SIRIUS); Actinomycin eluting stent improves outcomes by reducing neointimal hyperplasia (ACTION); Endovascular investigation determining the safety of a new tacrolimus-eluting stent graft (EVIDENT); Preliminary safety evaluation of nanoporous tacrolimus-eluting stents (PRESENT). Much of the data from the partly completed and ongoing DES studies are only available as conference presentations or via specialist websites. Indeed, the rapidity with which data are being generated outpaces traditional publication methods to the extent that an American College of Cardiology Expert Consensus Panel (ACC Expert Consensus Panel, 1998 #1716) stated, “The rapid evolution of stent design, deployment approaches, and adjunctive therapy have led to changes in clinical practice patterns that precede rigidly controlled supporting scientific data.” Therefore it is difficult to encompass the full breadth of these studies. Nevertheless, it is valuable to examine several of the pivotal studies. The randomized TAXUS I safety trial17 (NIRx, paclitaxel coated, Boston Scientific Corp, Boston, Mass) demonstrated beneficial reduction of restenosis at 6-months follow-up (0% vs 11%) and was not associated with thrombotic events or other untoward complications. In TAXUS II,18 patients had 10-mm– long lesions (15% had diabetes) and the reference ves-
Leon and Bakhai S15
sel size was 2.75 mm. This randomized trial compared the effect of slow release and moderate release paclitaxel on an encapsulated polymer matrix over a commercially available stent. The primary end point was an intravascular ultrasound reduction in neointima, and results showed a dramatic reduction in neointimal hyperplasia and percentage volume obstruction with either slow or moderate release compared with control, and a dramatic reduction in the stented segment of restenosis from 19% in controls to 2.3% or 4.7% in the 2 release formulations. The First-In-Man (FIM) study23 was a small pilot trial involving 45 patients treated with sirolimus-eluting stents with de novo coronary lesions ⬍18 mm in length and a vessel diameter of 3.0 to 3.5 mm. Follow-up at 24 months revealed 0% in-stent restenosis and minimal neointimal hyperplasia. There was no subacute or late stent thrombosis. Two patients required another PTCA after 1 year due to new progression at a site outside the previously stented segment. This study, although focusing on simple lesions, importantly demonstrated few late adverse events, suggesting acceptable durability of the initial excellent procedural results. The landmark RAVEL trial21 was a randomized, double-blind trial involving 238 patients at 19 centers across Europe and Latin America. The trial compared a bare metal stent with a sirolimus-eluting stent (Bx VELOCITY stent). The reference vessel size was 2.65 mm and the lesion length was ⬍10 mm. At 6-months follow-up, the restenosis rate of the treated group was zero, with an event-free survival of 96.5%. This was the first large-scale stent study to document sustained evidence of minimal restenosis, no deaths, and lack of need for reintervention (ie, no further angioplasty or bypass is required). These first clinical results were striking and are a precursor to a new era in interventional cardiology with minimal restenosis. The SIRIUS trial22 used the same sirolimus-eluting stent but with somewhat more complex patients than the RAVEL trial; longer lesions and more patients with diabetes were included (25% of the participants in the trial). It was a blinded, randomized trial of ⬎1000 patients with angiographic and intravascular ultrasound follow-up. GP IIb/IIIa inhibitors were used in 60% of patients at the discretion of the investigators. There was no difference in clinical outcome when a GP IIb/ IIIa inhibitor was used, but interestingly, investigators used them in those patients with more complex anatomic scenarios or with periprocedural complications. There was a 90% rate of reduction in neointimal hyperplasia as assessed by intravascular ultrasound. The rate of reduction ranged from 75% to 91% in restenosis depending on whether the entire vessel was analyzed or just the part surrounding the stent, resulting in an improvement in all clinical parameters including target
American Heart Journal October 2003
S16 Leon and Bakhai
lesion revascularization, target vessel revascularization, and target vessel failure. Subgroup analyses (eg, sex, diabetes, left anterior descending [LAD]/non-LAD, small or large vessels, and short or long lesions) also showed improvement in subsequent restenosis when compared with controls. It is also important to appreciate that not all DES trials have been positive. Several trials have been relatively unsuccessful and the DES systems used in these studies are no longer being evaluated. Trials related to actinomycin (ACTION) and the taxol derivative, 7-hexanolytaxol (SCORE), have been discontinued: the former because of an inability to reduce restenosis, and the latter due to high rates of early and late stent thrombosis leading to increased adverse cardiac events. The randomized, multicenter SCORE24 trial (Quanam stent, paclitaxel coated) enrolled 266 patients at 17 sites. At 6-months follow-up, a reduction in in-stent restenosis of 83% was achieved using the DES (6.4% DES vs 36.9 % control group) and attributed to a significant decrease in intimal proliferation. Unfortunately, due to both frequent stent thrombosis and sidebranch occlusions, the reported 30-day major adverse coronary events rate was 10.2% and the trial was not continued further.
Diabetes and DES Diabetes represents a major and growing health problem. Around 25% of those with diabetes also have heart disease, and almost two thirds of deaths in patients with diabetes are caused by heart disease. Patients with diabetes experience far more restenosis after angioplasty and stenting, and they may stand to benefit dramatically from DES. Several previous and future DES clinical trials have included patients with diabetes. SIRIUS, RAVEL, and TAXUS II have all demonstrated dramatic reduction in patients with diabetes after deployment of sirolimus and paclitaxel eluting stents. The FREEDOM trial and CARDia trials25 are designed to address the most difficult patient subgroup: patients with diabetes with multivessel coronary disease. Current data suggest that surgery is the preferred treatment for these patients. The FREEDOM trial will randomize approximately 2600 patients to either sirolimus-coated DES with mandated abciximab use or coronary artery bypass graft (CABG), with the primary end point being 5-year mortality with many interim secondary end points. One hundred centers in North America will participate and the trial will begin in late 2003 or early 2004. Patients with diabetes with multivessel disease are being recruited to the British CARDia study. They will be randomized to either CABG or PCI with sirolimus-coated stents and abciximab. (CARDia patients randomized to PCI also receive abciximab.) These studies will help us to determine whether similar rates of MACE, including
mortality, can be achieved over a prolonged period with DES compared to CABG in patients with diabetes, and whether DES will span the current gap in outcomes between standard stents and CABG.
The future of PCI The availability of DES heralds a shift to interventional therapies in the treatment of more complex patients who are at higher risk of restenosis. Based on the results of recent trials, it is expected that surgical revascularization may diminish in frequency by as much as 30% in the next several years. Much will depend on available resources in different parts of the world; for example, medical treatment would be more appropriate in a third world setting. Early diagnosis and risk stratification is a good alternative therapeutic approach in resource-constrained environments. DES are poised to become the core technology for interventional vascular therapy. All previous high-risk restenosis scenarios, including patients with diabetes, will be challenged with the emphasis shifting to advanced operator-driven intervention—advanced PCI of ultra-complex patients and lesions. This will involve treatment with DES for ostial lesions, bifurcations, saphenous grafts, small vessels, diffuse disease, left main disease, total occlusions, and multivessel disease. A 70% to 80% penetration of DES for interventional coronary procedures in the United States is expected by the end of 2003. Factors that could stunt the growth in DES use include increased complications such as stent thrombosis and cost. Subacute stent thrombosis contributed to almost half the MI and death in the ARTS trial,26 which compared multivessel stenting with surgery in 1200 patients. However, only ⬃10% of stented patients in the ARTS and the Stent or Surgery (SOS) trial received GP IIb/IIIa inhibitors, in contrast to the 60% to 70% of PCI cases today. The combination approach of DES and GP IIb/IIIa inhibitors is therefore likely to be a formidable combination in the future to reduce complications and improve safety in the high-risk patient cohorts. An important consideration for any new technology is cost. The current list price for the CYPHER sirolimus-eluting stent in the United States is $3195. With volume discounts to many centers, the average selling price will be somewhat reduced. Thus, when compared with an average sales price of $1000 for a nonDES, the incremental cost of each DES is expected to be $1500 to $2000. It will be even more expensive if this is combined with a GP IIb/IIIa inhibitor. It is estimated that the annual worldwide market for coronary stents, including DES, may grow to $5 billion by 2005. This increased expenditure is therefore an important consideration before widespread adoption of the new
American Heart Journal Volume 146, Number 4
technology occurs. To address this issue, several formal health economic evaluations are under way. These evaluations investigate the cost-effectiveness of DES and are eagerly awaited.27,28 Such reports are critical to appreciate whether the long-term benefits of this new, costly technology are justified.
References 1. Gru¨ntzig AR, Senning A, Siegenthaler WE. Nonoperative dilation of coronary artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:61– 8. 2. Serruys PW, de Jaere P, Kiemeneij et al. A comparison of balloonexpandable stent implementation with balloon angioplasty in the treatment of coronary artery disease: Benestent study group. N Engl J Med 1994;331:489 –95. 3. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease: Stent Restenosis Study investigators. N Engl J Med 1994;331:496 –501. 4. Schatz PW, Baim DS, Leon, M, et al. Clinical experiences with the Palmaz-Schatz coronary stent: initial results of a multicenter study. Circulation 1991;83:148 – 61. 5. de Jaegere PP, de Feyter PJ, van der Giessen WJ, et al. Endovascular stents: preliminary clinical results and future developments. Clin Cardiol 1993;16:369 –78. 6. Rubartelli P, Niccoli L, Verna E, et al. Stent implantation versus balloon angioplasty in chronic coronary occlusions: results from the GISSOC trial. J Am Coll Cardiol 1998;32:90 – 6. 7. Dauerman HL, Higgins PJ, Sparano AM, et al. Mechanical debulking versus balloon angioplasty for the treatment of true bifurcation lesions. J Am Coll Cardiol 1998;32:1845–52. 8. Kobayashi Y, de Gregorio J, Reimers B. The length of the stented segment is an independent predictor of restenosis. J Am Coll Cardiol 1998;31:366A. 9. de Feyter PJ, Kay P, Disco C, et al. Reference chart derived from post-stent implantation intravascular ultrasound predictors of 6-months expected restenosis on quantitative coronary angiography. Circulation 1999;100:1777– 83. 10. Ahn YK, Jeong MH, Kim JW, et al. Preventive effects of the heparin-coated stent on restenosis in the porcine model. Catheter Cardiovasc Interv 1999;48:324 –30. 11. Lincoff A, Furst J, Ellis S, et al. Sustained local delivery of dexamethasone by a novel intravascular eluting stent to prevent restenosis in the porcine coronary injury model. J Am Coll Cardiol 1997;29:808 –16. 12. Sollott SJ, Cheng L, Pauly RR, et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. J Clin Invest 1995;95:1869 –76. 13. Heldman AW, Cheng L, Jenkins GM, et al. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation 2001;103:2289 –95.
Leon and Bakhai S17
14. Axel DI, Kunert W, Goggelmann C, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 1997;96:636 – 45. 15. Vella JP, Sayegh MH. Maintenance pharmacological immunosuppressive strategies in renal transplantation. Postgrad Med J 1997; 73:386. 16. Marso SP, Lincoff AM, Ellis SG, et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT diabetic substudy. Circulation 1999;100:2477– 84. 17. Grube E, Silber SM, Hauptmann KE. TAXUS I: prospective, randomized, double-blind comparison of NIRxTM stents coated with paclitaxel in a polymer carrier in de novo coronary lesions compared with uncoated controls [abstract]. Circulation 2001;104: II463. 18. Clinical Follow-Up of the TAXUS II Paclitaxel-Eluting Stent Study [abstract]. The 52nd Annual Scientific Sessions of the American College of Cardiology 2002;31–3. 19. Chevalier B, de Scheerder I, Gershlick A, et al. Effect of restenosis with pacllitaxel eluting stent: factors associated with inhibition in the ELUTES clinical study [abstract]. J Am Coll Cardiol 2002;39: 59A. 20. Van Es RF, Jonker JJ, Verheeugt FW, et al. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomized controlled trial. Lancet 2002;360:109 –13. 21. Morice MC, Serruys PW, Sousa JE, et al. Randomized study with the sirolimus-coated Bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions: a randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346:1773– 80. 22. Leon MB, Moses JW. Presented at: Presentations in Euro PCR 2002 Conference; May, 2002; Paris, France. 23. Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation 2001; 104:2007–11. 24. Grube E, Hauptmann K, Colombo A, et al. SCORE trial safety results: despite efficacy, late stent thrombosis with the QuaDDS-QP2 stent [abstract]. J Am Coll Cardiol 2002;39:38A. 25. CARDia. Coronary artery revascularisation in diabetes trial. Available at: http://www.cardia.org.UK. Accessed: September 29, 2003. 26. The ARTS investigators. The ARTS: background, goals and methods. Int Cardiovasc Intervent 1999;2:41–50. 27. Greenberg D, Bakhai A, Cohen DJ. Do the benefits of new technology outweigh the costs? The case of drug-eluting stents. Am J Drug Deliv 2003;1:1–12. 28. Cohen DJ, Bakhai A, Shi C, et al. Cost-effectiveness of sirolimus drug-eluting stents for the treatment of complex coronary stenoses: results from the randomized SIRIUS trial. J Am Coll Cardiol 2003; 41:32A.
Background Although coronary stenting has improved the results of coronary interventions compared to coronary angioplasty alone, in-stent restenosis remains a significant limitation of this procedure. Drug-eluting stents with or without glycoprotein IIb/IIIa inhibitor therapy represent an additional advance in the evolution of this strategy. Methods
We review the currently available trials comparing studies of non-drug– eluting and drug-eluting stents using sirolimus and paclitaxel agents and their derivatives.
Results Ten studies are available that compare drug-eluting to traditional non-drug– eluting stents. A variety of antiplatelet regimes have been used. The majority of these studies are in the process of being published. No head-to-head studies comparing different drug-eluting stents are available. Conclusions
Drug-eluting stents using sirolimus and paclitaxel in combination with enhanced antiplatelet strategies represent an important advantage over non-drug– eluting stents for the reduction of in-stent restenosis. The rate at which drug-eluting stents are adapted into widespread practice depends heavily on whether they are safe, efficacious, and costeffective in various clinical settings. (Am Heart J 2003;146:S13–7.)
Since Andreas Gru ¨ ntzig implemented the first catheter-based technique for treating symptomatic coronary stenoses 25 years ago,1 the goal of interventionists has been to make this procedure safe, durable, and complication free, with consistent results applicable to treatment of a wide range of patients and, ultimately, to eliminate restenosis, the Achilles heel of coronary angioplasty. The introduction of intracoronary stents as an adjunct to coronary angioplasty has considerably improved results. Stenting reduces restenosis in large vessels with a diameter ⬎3 mm and yields better longterm results than conventional percutaneous transluminal coronary angioplasty (PTCA) alone. In-stent restenosis remains the main limitation of stenting technology predominantly due to neointimal proliferation. As a result, additional approaches—such as brachytherapy and molecular genetics techniques— have been investigated to eliminate this complication; however, to date, no therapies have been shown to eliminate restenosis.
From the aCardiovascular Research Foundation, Lennox Hill Hospital, New York, NY, and bSt Mary’s NHS Trust, London, United Kingdom. Reprint requests: Martin B Leon, MD, Director and CEO, Cardiovascular Research Foundation, Lennox Hill Hospital, 130 77th Street, New York, NY 10012. E-mail: [email protected] © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/j.ahj.2003.09.004
Problems associated with percutaneous intervention Stents are deployed in ⬃80% of interventions today, either after balloon angioplasty2,3 or simultaneously with balloon angioplasty (direct stenting). Direct stenting trials have, on the whole, shown similar clinical results to the traditional predilation and subsequent stenting approach. However, direct stenting trials have the additional benefit of reducing radiation exposure and resource use in carefully selected lesion types. A drawback of currently available stents is that they are metallic and therefore have thrombogenic properties that need to be overcome using anticoagulation therapy.4 Such therapy exposes the patient to an increased risk of major bleeding complications and may prolong hospital stay.5 Stent thrombogenecity is an important precursor to neointimal hyperplasia, which leads to in-stent restenosis. In-stent restenosis occurs in approximately 15% to 20% of patients within 6 to 9 months. Initially, routine stent usage was shown to reduce the rate of repeat revascularizations in patients with intermediate and large vessels with focal lesions compared with balloon angioplasty alone. However, improvements in stent technology have led to more complex anatomy being tackled, including small vessels, chronic total occlusions,6 bifurcations,7 diffuse disease,8 and challenging patients (eg, patients with diabetes mellitus or those presenting with acute myocardial infarction). The use of stents in more complex
American Heart Journal October 2003
S14 Leon and Bakhai
Table I. Factors leading to higher rates of stent thrombosis Physiologic
Clinical
Procedural
Small vessels
Patients with acute myocardial infarction Raised platelet count Hypercoagulability disorders
Flow-limiting coronary dissections postprocedure Need for multiple stents at target site Inadequate stent deployment/vessel apposition Use of brachytherapy resulting in damaged vessel left uncovered by stenting
Long target lesions Multiple vessel procedures Pre-existing thrombus at target site
Diabetes mellitus
interventions has led to an increase in stent thrombosis. The variables that may increase the chance of stent thrombosis are shown in Table I.9
In-stent restenosis Compared with coronary balloon angioplasty, stents reduce the need for repeat intervention by preventing vessel elastic recoil and negative remodeling by acting as scaffolds for the vessel. However, stent expansion with or without predilation can cause stretch injury to the vessel endothelium, internal elastic lamina, and media resulting in activation of stress-induced protein kinases, leading to thrombus formation and platelet activation. Important inflammatory changes stimulate the production of growth factors and cytokines, which activate receptors on the smooth muscle cell surface. A variety of signal transduction mechanisms also activate and accelerate the cell cycle. There is a proliferation of smooth muscle cells, production of matrix, and migration of these cells predominantly from the medial layer to the inner vessel layer (intima), although they may migrate through the struts of the stent to form a layer within the lumen of the stent. The resulting abnormal neointimal cells express proinflammatory molecules (including cytokines, chemokines, and adhesion molecules) that further trigger a cascade of events that lead to proliferative neointimal disease and eventually stent stenosis. Using a variety of approaches, studies have clearly demonstrated that blockade of smooth muscle cell proliferation results in preservation of normal vessel phenotype and function, thus reducing the occurrence of neointimal hyperplasia and stent failure.
Drug-eluting stents Drug-eluting stents (DES) are the latest in a long line of interventions devised to overcome the problem of in-stent restenosis. Many different drug classes may be
considered for use in DES, for example, agents that are anti-inflammatory or immunomodulators, antiproliferative agents, drugs which affect migration and extracellular matrix production, and drugs that promote healing and re-endothelialization. A DES is coated with a substance (carrier vehicle or polymer) that is designed to control the release of a drug into the surrounding vessel wall. The intention of this time-release process is to decelerate the growth of unwanted cells (restenosis) and allow the vessel to heal or endothelialize. Some new DES designs use pores or wells, with or without polymers, to act as the carrier vehicle. Although many drugs have been considered for DES,10,11 currently, the main drugs used are paclitaxel, sirolimus, and their derivative agents. Dexamethasone, because of its anti-inflammatory properties, has also been used in recent studies.
Paclitaxel and its derivatives Paclitaxel (Taxol) was the first stent-based antiproliferative agent under clinical investigation to provide profound inhibition of neointimal thickening, depending on delivery duration and dosage. Paclitaxel and related drugs are used as cancer chemotherapeutic agents; their principal mechanism of action is inhibition of microtubule disassembly. Investigators have found that paclitaxel inhibits smooth muscle cell proliferation and migration in vitro and in vivo in balloon injured rat arteries.12 Paclitaxel has also been shown to prevent neointimal hyperplasia in stented pig coronary and rabbit iliac arteries.13,14
Sirolimus and its derivatives Sirolimus (formerly known as rapamycin) is a macrolide antibiotic with immunosuppressant properties. It is also an inhibitor of smooth muscle cell proliferation and migration. It inhibits smooth muscle cell proliferation by binding to its receptor, the FK506 binding protein (FKBP12), and thereby blocking cell cycle progression by preventing the downregulation of the cell division kinase (CDK) inhibitor p27kip1. Deletion of p27kip1 confers resistance to sirolimus, while overexpression of p27kip1 using gene transfer techniques inhibits neointimal hyperplasia. It is of note that the related immunosuppressant drug tacrolimus15 also binds to FKBP12 but does not inhibit smooth muscle cell proliferation and migration. Other sirolimus analogs such as ABT-578 and everolimus have similar FKBP binding properties and are also potent antiproliferative and immunosuppressive agents.
Glycoprotein IIb/IIIa inhibitors As platelet activation and aggregation after trauma to the endothelium serve as a catalyst for thrombin gener-
American Heart Journal Volume 146, Number 4
ation, the platelet is an attractive target for therapies directed at reducing thrombotic complications during percutaneous coronary intervention (PCI). The platelet glycoprotein (GP) IIb/IIIa inhibitors block the final common pathway of platelet activation and aggregation. The effect of GP IIb/IIIa inhibitors, such as abciximab, combined with stenting has been investigated in several clinical trials. In the Evaluation of IIb/IIIa Platelet Inhibitor for STENTing (EPISTENT) trial, combined treatment with stenting and abciximab was associated with a significant reduction in death, myocardial infarction (MI), and target vessel revascularization at 6 months in patients with diabetes.16
DES trials Several studies have been published or are still ongoing that evaluate DES with respect to their release kinetics, effective dosage, safety in clinical practice, and benefit: Paclitaxel-eluting stent (TAXUS) I,17 II,18 III, IV; European EvaLUation of PacliTaxel Eluting Stent (ELUTES)19; DELIVER; Asian paclitaxel-eluting stent clinical trial (ASPECT)20; Study to compare restenosis rate between QueST and QuaDDS-QP2 (SCORE); PATENCY (paclitaxel); Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions (RAVEL)21; SIRIUS22 (sirolimus); the SIRIUS trial in Canada (C-SIRIUS); the SIRIUS trial in Europe (E-SIRIUS); Actinomycin eluting stent improves outcomes by reducing neointimal hyperplasia (ACTION); Endovascular investigation determining the safety of a new tacrolimus-eluting stent graft (EVIDENT); Preliminary safety evaluation of nanoporous tacrolimus-eluting stents (PRESENT). Much of the data from the partly completed and ongoing DES studies are only available as conference presentations or via specialist websites. Indeed, the rapidity with which data are being generated outpaces traditional publication methods to the extent that an American College of Cardiology Expert Consensus Panel (ACC Expert Consensus Panel, 1998 #1716) stated, “The rapid evolution of stent design, deployment approaches, and adjunctive therapy have led to changes in clinical practice patterns that precede rigidly controlled supporting scientific data.” Therefore it is difficult to encompass the full breadth of these studies. Nevertheless, it is valuable to examine several of the pivotal studies. The randomized TAXUS I safety trial17 (NIRx, paclitaxel coated, Boston Scientific Corp, Boston, Mass) demonstrated beneficial reduction of restenosis at 6-months follow-up (0% vs 11%) and was not associated with thrombotic events or other untoward complications. In TAXUS II,18 patients had 10-mm– long lesions (15% had diabetes) and the reference ves-
Leon and Bakhai S15
sel size was 2.75 mm. This randomized trial compared the effect of slow release and moderate release paclitaxel on an encapsulated polymer matrix over a commercially available stent. The primary end point was an intravascular ultrasound reduction in neointima, and results showed a dramatic reduction in neointimal hyperplasia and percentage volume obstruction with either slow or moderate release compared with control, and a dramatic reduction in the stented segment of restenosis from 19% in controls to 2.3% or 4.7% in the 2 release formulations. The First-In-Man (FIM) study23 was a small pilot trial involving 45 patients treated with sirolimus-eluting stents with de novo coronary lesions ⬍18 mm in length and a vessel diameter of 3.0 to 3.5 mm. Follow-up at 24 months revealed 0% in-stent restenosis and minimal neointimal hyperplasia. There was no subacute or late stent thrombosis. Two patients required another PTCA after 1 year due to new progression at a site outside the previously stented segment. This study, although focusing on simple lesions, importantly demonstrated few late adverse events, suggesting acceptable durability of the initial excellent procedural results. The landmark RAVEL trial21 was a randomized, double-blind trial involving 238 patients at 19 centers across Europe and Latin America. The trial compared a bare metal stent with a sirolimus-eluting stent (Bx VELOCITY stent). The reference vessel size was 2.65 mm and the lesion length was ⬍10 mm. At 6-months follow-up, the restenosis rate of the treated group was zero, with an event-free survival of 96.5%. This was the first large-scale stent study to document sustained evidence of minimal restenosis, no deaths, and lack of need for reintervention (ie, no further angioplasty or bypass is required). These first clinical results were striking and are a precursor to a new era in interventional cardiology with minimal restenosis. The SIRIUS trial22 used the same sirolimus-eluting stent but with somewhat more complex patients than the RAVEL trial; longer lesions and more patients with diabetes were included (25% of the participants in the trial). It was a blinded, randomized trial of ⬎1000 patients with angiographic and intravascular ultrasound follow-up. GP IIb/IIIa inhibitors were used in 60% of patients at the discretion of the investigators. There was no difference in clinical outcome when a GP IIb/ IIIa inhibitor was used, but interestingly, investigators used them in those patients with more complex anatomic scenarios or with periprocedural complications. There was a 90% rate of reduction in neointimal hyperplasia as assessed by intravascular ultrasound. The rate of reduction ranged from 75% to 91% in restenosis depending on whether the entire vessel was analyzed or just the part surrounding the stent, resulting in an improvement in all clinical parameters including target
American Heart Journal October 2003
S16 Leon and Bakhai
lesion revascularization, target vessel revascularization, and target vessel failure. Subgroup analyses (eg, sex, diabetes, left anterior descending [LAD]/non-LAD, small or large vessels, and short or long lesions) also showed improvement in subsequent restenosis when compared with controls. It is also important to appreciate that not all DES trials have been positive. Several trials have been relatively unsuccessful and the DES systems used in these studies are no longer being evaluated. Trials related to actinomycin (ACTION) and the taxol derivative, 7-hexanolytaxol (SCORE), have been discontinued: the former because of an inability to reduce restenosis, and the latter due to high rates of early and late stent thrombosis leading to increased adverse cardiac events. The randomized, multicenter SCORE24 trial (Quanam stent, paclitaxel coated) enrolled 266 patients at 17 sites. At 6-months follow-up, a reduction in in-stent restenosis of 83% was achieved using the DES (6.4% DES vs 36.9 % control group) and attributed to a significant decrease in intimal proliferation. Unfortunately, due to both frequent stent thrombosis and sidebranch occlusions, the reported 30-day major adverse coronary events rate was 10.2% and the trial was not continued further.
Diabetes and DES Diabetes represents a major and growing health problem. Around 25% of those with diabetes also have heart disease, and almost two thirds of deaths in patients with diabetes are caused by heart disease. Patients with diabetes experience far more restenosis after angioplasty and stenting, and they may stand to benefit dramatically from DES. Several previous and future DES clinical trials have included patients with diabetes. SIRIUS, RAVEL, and TAXUS II have all demonstrated dramatic reduction in patients with diabetes after deployment of sirolimus and paclitaxel eluting stents. The FREEDOM trial and CARDia trials25 are designed to address the most difficult patient subgroup: patients with diabetes with multivessel coronary disease. Current data suggest that surgery is the preferred treatment for these patients. The FREEDOM trial will randomize approximately 2600 patients to either sirolimus-coated DES with mandated abciximab use or coronary artery bypass graft (CABG), with the primary end point being 5-year mortality with many interim secondary end points. One hundred centers in North America will participate and the trial will begin in late 2003 or early 2004. Patients with diabetes with multivessel disease are being recruited to the British CARDia study. They will be randomized to either CABG or PCI with sirolimus-coated stents and abciximab. (CARDia patients randomized to PCI also receive abciximab.) These studies will help us to determine whether similar rates of MACE, including
mortality, can be achieved over a prolonged period with DES compared to CABG in patients with diabetes, and whether DES will span the current gap in outcomes between standard stents and CABG.
The future of PCI The availability of DES heralds a shift to interventional therapies in the treatment of more complex patients who are at higher risk of restenosis. Based on the results of recent trials, it is expected that surgical revascularization may diminish in frequency by as much as 30% in the next several years. Much will depend on available resources in different parts of the world; for example, medical treatment would be more appropriate in a third world setting. Early diagnosis and risk stratification is a good alternative therapeutic approach in resource-constrained environments. DES are poised to become the core technology for interventional vascular therapy. All previous high-risk restenosis scenarios, including patients with diabetes, will be challenged with the emphasis shifting to advanced operator-driven intervention—advanced PCI of ultra-complex patients and lesions. This will involve treatment with DES for ostial lesions, bifurcations, saphenous grafts, small vessels, diffuse disease, left main disease, total occlusions, and multivessel disease. A 70% to 80% penetration of DES for interventional coronary procedures in the United States is expected by the end of 2003. Factors that could stunt the growth in DES use include increased complications such as stent thrombosis and cost. Subacute stent thrombosis contributed to almost half the MI and death in the ARTS trial,26 which compared multivessel stenting with surgery in 1200 patients. However, only ⬃10% of stented patients in the ARTS and the Stent or Surgery (SOS) trial received GP IIb/IIIa inhibitors, in contrast to the 60% to 70% of PCI cases today. The combination approach of DES and GP IIb/IIIa inhibitors is therefore likely to be a formidable combination in the future to reduce complications and improve safety in the high-risk patient cohorts. An important consideration for any new technology is cost. The current list price for the CYPHER sirolimus-eluting stent in the United States is $3195. With volume discounts to many centers, the average selling price will be somewhat reduced. Thus, when compared with an average sales price of $1000 for a nonDES, the incremental cost of each DES is expected to be $1500 to $2000. It will be even more expensive if this is combined with a GP IIb/IIIa inhibitor. It is estimated that the annual worldwide market for coronary stents, including DES, may grow to $5 billion by 2005. This increased expenditure is therefore an important consideration before widespread adoption of the new
American Heart Journal Volume 146, Number 4
technology occurs. To address this issue, several formal health economic evaluations are under way. These evaluations investigate the cost-effectiveness of DES and are eagerly awaited.27,28 Such reports are critical to appreciate whether the long-term benefits of this new, costly technology are justified.
References 1. Gru¨ntzig AR, Senning A, Siegenthaler WE. Nonoperative dilation of coronary artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:61– 8. 2. Serruys PW, de Jaere P, Kiemeneij et al. A comparison of balloonexpandable stent implementation with balloon angioplasty in the treatment of coronary artery disease: Benestent study group. N Engl J Med 1994;331:489 –95. 3. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease: Stent Restenosis Study investigators. N Engl J Med 1994;331:496 –501. 4. Schatz PW, Baim DS, Leon, M, et al. Clinical experiences with the Palmaz-Schatz coronary stent: initial results of a multicenter study. Circulation 1991;83:148 – 61. 5. de Jaegere PP, de Feyter PJ, van der Giessen WJ, et al. Endovascular stents: preliminary clinical results and future developments. Clin Cardiol 1993;16:369 –78. 6. Rubartelli P, Niccoli L, Verna E, et al. Stent implantation versus balloon angioplasty in chronic coronary occlusions: results from the GISSOC trial. J Am Coll Cardiol 1998;32:90 – 6. 7. Dauerman HL, Higgins PJ, Sparano AM, et al. Mechanical debulking versus balloon angioplasty for the treatment of true bifurcation lesions. J Am Coll Cardiol 1998;32:1845–52. 8. Kobayashi Y, de Gregorio J, Reimers B. The length of the stented segment is an independent predictor of restenosis. J Am Coll Cardiol 1998;31:366A. 9. de Feyter PJ, Kay P, Disco C, et al. Reference chart derived from post-stent implantation intravascular ultrasound predictors of 6-months expected restenosis on quantitative coronary angiography. Circulation 1999;100:1777– 83. 10. Ahn YK, Jeong MH, Kim JW, et al. Preventive effects of the heparin-coated stent on restenosis in the porcine model. Catheter Cardiovasc Interv 1999;48:324 –30. 11. Lincoff A, Furst J, Ellis S, et al. Sustained local delivery of dexamethasone by a novel intravascular eluting stent to prevent restenosis in the porcine coronary injury model. J Am Coll Cardiol 1997;29:808 –16. 12. Sollott SJ, Cheng L, Pauly RR, et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. J Clin Invest 1995;95:1869 –76. 13. Heldman AW, Cheng L, Jenkins GM, et al. Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Circulation 2001;103:2289 –95.
Leon and Bakhai S17
14. Axel DI, Kunert W, Goggelmann C, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 1997;96:636 – 45. 15. Vella JP, Sayegh MH. Maintenance pharmacological immunosuppressive strategies in renal transplantation. Postgrad Med J 1997; 73:386. 16. Marso SP, Lincoff AM, Ellis SG, et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT diabetic substudy. Circulation 1999;100:2477– 84. 17. Grube E, Silber SM, Hauptmann KE. TAXUS I: prospective, randomized, double-blind comparison of NIRxTM stents coated with paclitaxel in a polymer carrier in de novo coronary lesions compared with uncoated controls [abstract]. Circulation 2001;104: II463. 18. Clinical Follow-Up of the TAXUS II Paclitaxel-Eluting Stent Study [abstract]. The 52nd Annual Scientific Sessions of the American College of Cardiology 2002;31–3. 19. Chevalier B, de Scheerder I, Gershlick A, et al. Effect of restenosis with pacllitaxel eluting stent: factors associated with inhibition in the ELUTES clinical study [abstract]. J Am Coll Cardiol 2002;39: 59A. 20. Van Es RF, Jonker JJ, Verheeugt FW, et al. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomized controlled trial. Lancet 2002;360:109 –13. 21. Morice MC, Serruys PW, Sousa JE, et al. Randomized study with the sirolimus-coated Bx velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions: a randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346:1773– 80. 22. Leon MB, Moses JW. Presented at: Presentations in Euro PCR 2002 Conference; May, 2002; Paris, France. 23. Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: one-year angiographic and intravascular ultrasound follow-up. Circulation 2001; 104:2007–11. 24. Grube E, Hauptmann K, Colombo A, et al. SCORE trial safety results: despite efficacy, late stent thrombosis with the QuaDDS-QP2 stent [abstract]. J Am Coll Cardiol 2002;39:38A. 25. CARDia. Coronary artery revascularisation in diabetes trial. Available at: http://www.cardia.org.UK. Accessed: September 29, 2003. 26. The ARTS investigators. The ARTS: background, goals and methods. Int Cardiovasc Intervent 1999;2:41–50. 27. Greenberg D, Bakhai A, Cohen DJ. Do the benefits of new technology outweigh the costs? The case of drug-eluting stents. Am J Drug Deliv 2003;1:1–12. 28. Cohen DJ, Bakhai A, Shi C, et al. Cost-effectiveness of sirolimus drug-eluting stents for the treatment of complex coronary stenoses: results from the randomized SIRIUS trial. J Am Coll Cardiol 2003; 41:32A.