Review Article CORONARY STENTS - PAST, PRESENT AND FUTURE.

Review Article CORONARY STENTS - PAST, PRESENT AND FUTURE. VV JAIN*, S YELWATKAR**, OP GUPTA*** Introduction The advent of period of angioplasty has revolutionized the practice of interventional cardiology. After their introduction in mid 1980s there has been paradigm shift in cardiology practice making percutaneous coronary intervention (PCI) one of the most frequently performed invasive medical procedure today 1. History of Coronary Stents In 1964 Charles Theodore Dotter and Melvin P Judkins described the first angioplasty. In 1978 Andreas Gruntzig performed the first ballon angioplasty (POBA), a revolutionary and landmark treatment in cardiology. In the past 34 years since Gruntzig's ballon angioplasty, the technique of PCI has undergone tremendous growth and has surpassed coronary artery by-pass surgery(cabg).the field has seen some remarkable milestones with introduction of intracoronary stents, adjunctive antiplatelet therapy, drug-eluting stents etc 2. There was no doubt that POBA was a revolutionary treatment but came with its own drawbacks of acute vessel closure and restenosis 3. This fueled the discovery of a coronary stent. Puel and Sigwart, in 1986, deployed the first coronary stent to act as a scaffold and by 1999 4 this bare metal, self-expanding stent (BMS), known as the "Wall" stent was able to provide *Assistant Professor, **Associate Professor, *** Senior Consultant and Professor, Deptt of Medicine, MGIMS. a scaffold that prevented acute vessel closure and late constrictive recoil 5. In addition to restenosis, PTCA and BMS implantation cause exaggerated endothelial injury and inflammation, rendering both the stent and vessel highly thrombogenic. So although these initial stents were a respite to the abrupt vessel closure but there was an 18% chance of sub acute thrombotic coronary artery occlusion within 2 weeks of implantation 6 which required aggressive anticoagulant therapy. Later there were two landmark trials, BENESTENT (Belgian Netherlands Stent) trial 7 and the STRESS (Stent Restenosis Study) 8, which emphatically advocated that stenting was safe without anticoagulation therapy, with the use of dual antiplatelet therapy (DAPT) 9 and/or adequate stent deployment 10. Following these trials there was a phenomenal increase in the number of PCI performed which was approximately 84% in the year 1999. But soon it was discovered that in addition to the problem of sub acute thrombosis there was an iatrogenic problem of in-stent neointimal hyperplasia leading to stent restenosis. To tackle these problems, drug-eluting stents (DES) were introduced in 2001 as a strategy to minimize restenosis and requirement for reintervention. The DES increased the confidence of cardiologists to such an extent that the lesions that were earlier considered to be tackled only 1

Coronary stents - past, present and future. by CABG were subjected successfully to PCI with DES. The scenario changed so completely that in 2005 out of all revascularization procedures, 80-90% was with DES 11. But all things have a downside and era of DES was marked with rising safety concerns over these devices. Current status of DES The early period before the discovery of Sirolimus eluting stents was marked by overcoming challenges of delivery of Sirolimus (earlier called Rapamycin-a macrolide antibiotic, with properties of inhibition of cytokine and growth factor mediated proliferation of lymphocytes and smooth muscle cells,) either systemically or locally to prevent neointimal proliferation. But this was followed by the first human DES implant performed by J Eduardo Sausa in Sao Paulo in 1999 12. After this Sirolimus DES was commercially launched (CYPER SES) and was highly recommended by numerous large studies. The Cypher SES was initially evaluated in the pivotal RAVEL (Randomized Study With the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary Artery Lesions) study, which randomly assigned 238 patients with relatively low risk lesions to treatment with the Cypher SES or BMS as controls. At 1-year follow-up, the rate of binary stenosis was 0.0% and 26.6% for patients treated with Cypher SES and BMS, respectively 13. Following this there were numerous clinical trials which advocated the use of DES (CYPER SES) over BMS due to significant reductions in angiographic in-stent late loss, in- stent angiographic restenosis and repeat revascularization at follow up. Table 1: Indications for use of drug eluting stents 14,15. 1. "On-label" or FDA-approved use For improving coronary luminal diameter in patients with symptomatic ischemic disease due to discrete de novo lesions in native coronary arteries < 30 mm in length 2.5-3.5 mm in diameter 50% - 99% stenosis 2. "Off-label" or beyond FDA-approved use Lesion subsets Multivessel disease Left main disease Bifurcation lesions Chronic total occlusions (CTO) In-stent restenosis (ISR) Small vessels (<2.5 mm in diameter) or large vessels (>3.75 mm in diameter) Long lesions requiring multiple or overlapping stents Saphenous vein grafts (SVG) Thrombus containing lesions (acute MI) High-risk patient subsets Diabetics Renal dysfunction DES-drug-eluting stent; FDA-Food and Drug Administration; MI -myocardial infarction. The TAXUS PES was developed almost simultaneously with the SES, gaining regulatory approval 12 months later. It was critically evaluated by a number of randomized trials most of which demonstrated a significantly lower rate of late loss, angiographic binary restenosis, and repeat revascularization with PES compared with BMS that is consistent across different patient groups including those with simple lesions, STEMI, lesions in the unprotected left main stem (UPLMS), and complex lesions 1. 2

VV Jain & S Yelwatkar It was natural that SES would have been compared to PES and so it was done by many randomized trials. With respect to clinical outcomes, a meta-analysis of 16 randomized trials of SES versus PES, which included 8,695 patients and, where possible, patient level data, reported significant reductions in TLR (hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.63 to0.87, p <0.001) and ST (HR: 0.66, 95% CI: 0.46 to 0.94, p=0.02) with SES, whereas no significant differences in death (HR: 0.92, 95% CI: 0.74 to 1.13, p = 0.43), or MI (HR: 0.84, 95% CI: 0.69 to 1.03, p = 0.10) were noted at a median of 2-year follow-up 16. Second generation DES The initial coronary stents were composed of 316L stainless steel since this material is radioopaque and provides adequate radial strength to maintain arterial scaffolding with minimal acute recoil. An alternative to stainless steel is cobalt chromium (CoCr), which exhibits superior radial strength and improved radio-opacity, allowing for thinner stent struts that may reduce restenosis 17. Thinner struts can also lead to a reduction in device profile and, hence, an improvement in stent deliverability to the target lesion. The 2 second-generation DES that are currently approved by the U.S. FDA utilize CoCr, and elute "limus" drugs with the aid of more biocompatible polymers than are found on the first-generation DES. DES vs. BMS in today's real world Despite the benefits of DES, there is still a role for BMS in the management of patients with CAD. Though the recommendations promote DES more than BMS and as against the popular thinking, DES are far less used than BMS in the real world. Ultimately, the decision to implant a BMS is guided by both clinical and economic factors. We have already discussed the net clinical benefits of DES over BMS, and no discussion of stents can be completed without its economic implications. Some studies indicate that DES may be cost effective or even cost saving with specific patients, such as those who have lesions with a high risk for restenosis such as diabetic patients, long lesions, and lesions in vessels with small diameters. In the BASKET study 18, for example, DES was more effective and less expensive for vessels < 3.0 mm diameter. For vessels > 3.0 mm diameter, although the overall cost per qualityadjusted life-year gained was 39,641 ($59,392), subgroup analysis revealed that the cost per quality-adjusted life-year gained was 6,863 ($10,282) for off-label use, 3,471 ($5,200) for lesions > 24 mm in length, and 300 ($450) for patients > 65 years of age. Conversely, other studies report an incremental cost-effectiveness ratio of > 200,000 Canadian dollars per quality-adjusted life year-indicating DES is not cost effective. Nevertheless, a recent systematic review evaluated 19 different cost-effectiveness studies that mainly reported results at 1 year, and concluded that the cost effectiveness of DES was unfavorable compared with that of BMS. That was primarily because, although the use of DES was associated with a higher initial cost ( 700 [$1,060]), they did not increase life expectancy, produced only a small relative reduction in rates of repeat procedures, and led to only a short duration of improved quality of life 19. Future of coronary stenting Despite all the benefits of drug-eluting stents (DES), concerns have been raised over their long-term safety, with particular reference to 3

Coronary stents - past, present and future. stent thrombosis. In an effort to address these concerns, newer stents have been developed that include: DES with biodegradable polymers, DES that are polymer free, stents with novel coatings, and completely biodegradable stents. Many of these stents are currently undergoing pre-clinical and clinical trials; however, early results seem promising. Table 2 : Various new stents under development and trials 20. 1. Metallic DES with durable polymers. a. New polymer technology : Endeavor Resolute-zotarolimus-eluting stent (ZES) b. New antiproliferative agents: Elixir DESyne novolimus-eluting stent (NES). c. New metal stent platforms : platinum chromium Element stent platform. 2. DES with biodegradable polymers a. Sirolimus based- SUPRALIMUS stent i. EXCEL stent NEVO stent b. Biolimus A9 based i. BIOMATRIX stent i NOBORI stent XTENT custom NX stent c. Myolimus eluting stent d. Paclitaxel eluting stent i. INFINNIUM stent i JACTAX stent SYNERGY stent 3. Non-polymeric DES a. YUKON DES b. BioFreedom c. VESTAsyn Sirolimus eluting stent d. Amazonia Pax 4. Stents with novel coatings a. Catania Stent b. Titan-2 stent c. Genous Bioengineered R stent 5. Biodegradable stents a. PLLA stent- IGAKI TAMAI stent b. Abott vascular bio-reabsobable vascular scaffold(bvs) 6. Self expanding stents 7. Drug eluting ballons Conclusions : Coronary stents are an important component of percutaneous coronary revascularization. Many limitations of BMS were overcome with DES. It comes with a higher cost and is only associated with late stent thrombosis. DES has expanded the horizon of PCI which is being offered to patients with complex CAD and diabetes. There is a lot more novel DES in the developmental phases which look promising. References : 1. Garg S, Serruys PW. Coronary stents: current status. Am Coll Cardiol 2010; 56(10 Suppl): S1-42. 2. Arjomand H, Turi ZG et al. Percutaneous coronary intervention: historical perspectives, current status, and future directions. Am Heart J 2003; 146(5): 787-796. 3. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979; 301:61-8. 4. Serruys PW, Kutryk MJB, Ong ATL. Coronaryartery stents. N Engl J Med 2006; 354:483-95. 5. Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intra-vascular stents to prevent 4

VV Jain & S Yelwatkar occlusion and restenosis after transluminal angioplasty. N Engl J Med 1987; 316:701-6. 6. Roubin GS, Cannon AD, Agrawal SK, et al. Intracoronary stenting for acute and threatened closure complicating percutaneous transluminal coronary angioplasty. Circulation 1992; 85:916-27. 7. Serruys PW, de Jaegere P, Kiemeneij F, et al., for the Benestent Study Group. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331:489-95. 8. Fischman DL, Leon MB, Baim DS, et al., for the Stent Restenosis Study Investigators. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994; 331:496-501. 9. Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084-9. 10. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without anticoagulation accomplished with intravascular ultrasound guidance. Circulation 1995; 91:1676-88. 11. Jeremias A, Kirtane A. Balancing efficacy and safety of drug-eluting stents in patients undergoing percutaneous coronary intervention. Ann Intern Med 2008; 148:234-8. 12. 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 threedimensional intravascular ultrasound study. Circulation 2001; 103:192-5. 13. Morice MC, Serruys PW, Sousa JE, 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. 14. Instructions for Use: CYPHER Sirolimuseluting Coronary Stent on RAPTOR Overthe-Wire Delivery System and CYPHER Sirolimus-eluting Coronary Stent RAPTORRAIL Rapid Exchange Delivery System. Available at: http://www.fda.gov/cdrh/pdf2/ p020026c.pdf. 15. Directions for Use: TAXUS EXPRESS2 Paclitaxel-Eluting Coronary Stent System. Available at: http://www.fda.gov/cdrh/pdf3/p030025c.pdf 16. Schomig A, Dibra A, Windecker S, et al. A metaanalysis of 16 randomized trials of sirolimuseluting stents versus paclitaxel-eluting stents in patients with coronary artery disease. J Am Coll Cardiol 2007; 50:1373-80. 17. Kereiakes DJ, Cox DA, Hermiller JB, et al. Usefulness of a cobalt chromium coronary stent alloy. Am J Cardiol 2003; 92:463-6. 18. Pfisterer M, Brunner-La Rocca HP, Rickenbacher P, et al. Long-term benefit-risk balance of drug-eluting vs. bare-metal stents in daily practice: does stent diameter matter? Three-year follow-up of BASKET. Eur Heart J 2009; 30:16-24. 19. Neyt M, Van Brabandt H, Devriese S, De Laet C. Cost-effectiveness analyses of drug eluting stents versus bare metal stents: a systematic review of the literature. Health Policy 2009; 91:107-20. 20. Garg S, Serruys PW. Coronary stents: looking forward. J Am Coll Cardiol. 2010; 56(10 Suppl): S43-78. 5