Stents, by Ryan Colombo

Background

Precutaneous coronary intervention, pioneered by Dr. Gruntzig in 1977, is the most frequently performed medical procedure [1]. In the past, this was performed using balloon angioplasty. However, ballon angioplasty alone was subject to detrimental vessel closure due to dissection and restentosis [1]. The stent was developed to maintain lumen integrity.

Angioplasty and Implantation of Stent

Figure 1. Once the catheter has been maneuvered to the site of blockage [A], the balloon is inflated [B], which deploys the stent. The stent remains open upon removal of the catheter [C] Ref. [3]

In an angioplasty, imaging techniques are used to direct a balloon-tipped catheter into an artery or vein [2]. Once the site of blockage is reached, the balloon is inflated to open the vessel, deflated, and removed. A stent may be placed around this balloon, which is deployed upon balloon inflation and will maintain the opened artery [2]. This balloon can be inflated to different

Angiplasty with stenting is initiated when a nick is made at the site of insertion. A sheath is inserted into the artery, into which the catheter is inserted and guided using fluoroscopy to the blocked site. Fluroscopy converts x-rays into video images that the doctors can see [2]. A thin guide wire is used to place the balloon-tipped catheter at the blocked site. Next, the balloon is inflated, which pushes the stent against the arterial wall. The stent remains in place once the balloon is deflated [2]. Following successful deployment, the catheter is removed and bleeding is stopped using pressure. No sutures are needed, although a closure device may be needed to seal the small hole in the artery [2]. Additionally, anesthetics are not administered during this procedure [3].

Angioplasty by itself was a decent strategy for mild coronary artery disease. However, following an angioplasty, a third of patients developed progressive or refractory angina, which required invasive treatment [11]. In addition, 5% of patients developed acute vessel closure or flow-limiting dissection, and 1/5 of patients required additional procedures over the next 3 years [11]. Therefore, there was a need for a device that could maintain lumen integrity and prevent reclosure of the vessel, which led to the development of the stent.

History

1977 - First Percutaneous coronary intervention was performed Gruntzig [1]

1986 - Puel and Sigwart deployed the first coronary stent to act as a scaffold to prevent vessel closure during PTCA and vessel closure [4]

1994 - 250000 PTCA's performed each year [4]

1999 - Stenting associated with 84.2% of all PCI's [4]

2001 - Introduction of drug eluting stents [7]

2003 - Sirolimus eluting stent developed [12]

2004 - Paclitaxel eluting stent developed [13]

2007 - 90% of stents implanted in US and Europe were drug eluting [7]

2012 - Over 500,000 patients implanted with stents each year [1]

Bare Metal Stents

One of the major problems with bare metal stents is the occurrence of neointimal hyperplasia [1,5]. Neointimal hyperplasia is the growth of scar tissue within the stent due to a proliferation and migration of smooth muscle cells in response to strut-related inflammation [5]. This leads to restentosis, or a re-narrowing of the blood veseel, and requires revascularization. This has occurred in 20-30% of patients treated with bare metal stents, usually within 5-6 months after treatment [1,5,11].

Endothelial injury caused by bare metal stents can also reder vessels thromogenic [6]. The fibrinoogen layer covering the stent surface can induce platelet activation and thrombosis, which must be countered using anti-platelet medicines. Dual antiplatelet therapies typically consist of aspirin and clopidogrel and are administered for 6 - 12 months [6].

Drug Eluting Stents

Drug eluting stents are characterized by the controlled release of immunosupressive and antiproliferative agents, which act to inhibit the accumulation of smooth muscle cells [1,7]. These stents were developed to counter restenosis more so than their bare metal predecessors. They consist of three components: the metal stent, polymer coating, and eluting drug [10].

Traditionally, stents have been constructed from stainless steel [1]. New generation stents are now being fabricated from cobalt-chrome alloys, which exhibit improved radial strength with thinner struts. Radial strength is being further improved upon via the introduction of platinum-chrome stents [1]. Thinner struts are thought to result in less arterial injury, thus reducing thrombosis and restenosis.

The polymer coating on the stent enables controlled drug release. These coatings must be biocompatible in order to decrease local inflammatory reactions and thrombosis [1]. Polymers that biodegrade are currently undergoing clinical trials [1].

Drug eluting stents have been deemed more cost effective than bare metal stents, as the higher cost of these stents is offset by the reduced need for revascularization procedures.

First Generation Drug Eluting Stents

First generation DES's are characterized by the timed release of sirolimus or paclitaxel. These antiproliferative drugs reduce revascularization as a result of neointimal hyperplasia. Similar risks of death and myocardial infraction exist as compared to BMS's [1].

Sirolimus, or Rapamycin, was discovered on Easter Island as an antifungal agent [14]. Its antiproliferative properties have enabled its use in cancer therapy and transplant rejection therapy. When eluted from a stent, Sirolimus inhibits the proliferation of smooth muscle cells and leukocytes. The Cypher stent, a Sirolimus-eluting stent, is manufactured by Cordis in Miami Lakes, FL. It is covered by poly-n-butyl methacrylate and releases the drug over 30 days [15].

Paclitaxel, a compound isolated from the bark of the Pacific Yew tree, inhibits microtubule disassembly during cell replication [16]. Like Sirolimus, it is used in cancer treatments and can inhibit smooth muscle cell proliferation. Boston Scientific manufactures the Paclitaxel-eluting Taxus stent, a stent constructed from 316L stainless steel with 132 μm struts and a Transulate® polymer coating [poly(styrene-b-isobutylene-b-styrene)] [16]. Significant reductions in restenosis and revascularization have been obtained with the Taxus stent.

In 2006, the European Society of Cardiology Congress cited stents releasing paclitaxel or sirolimus as slightly increasing the risk of thrombosis [1,10]. Clinical studies of paclitaxel-eluting stents have ceased, and sirolimus-eluting stents are no longer manufactured.

Too much antiproliferation can retard or inhibit arterial wall healing, which leads to chronic inflammation [1]. One study proved that arterial wall healing was incomplete at 180 days with drug eluting stents, where as complete healing was seen with bare metal stents after 28 days [8]. Late stent thrombosis, or thrombosis occuring more than 30 days after implantation, has a 45% mortality rate [9].

Second Generation Drug Eluting Stents and the Future

New generation stents release everolimus and zotarolimus [1]. These stents are promising in that they reduce the risk of thrombosis, one of the drawbacks of their first generation counterparts. Clinical trials have demonstrated that everolimus reduces the risk of repeat revascularization, heart attack, and stent thrombosis compared to paclitaxel and sirolimus eluting stents [1]. Compared with paclitaxel, zotarolimus resuces the risk of myocardial infraction [1].

Uses

Stents are used to treat stable coronary artery disease, in which a drug-eluting stent is used in conjunction with an antiplatelett therapy [1]. Atherosclerosis, or the hardening of arteries, occurs when fat or cholesterol accumulates on the arterial walls, forming plaques. This is commonly associated with diabetes. Multivessel disease and Left Main Coronary Artery disease are also treated using stents [1].

References

[1] Stefanini G., Holmes D. Drug eluting coronary-artery stents. New Engl J Med 2013;368:254-65.

[2] http://www.radiologyinfo.org/en/info.cfm?pg=angioplasty

[3] Encylopedia Britannica

[4] Serruys PW, Kutryk MJB, Ong ATL. Coronary-artery stents. N Engl J Med 2006;354:483-95.

[5] Moliterno DJ. Healing Achilles—sirolimus versus paclitaxel. N Engl J Med 2005;353:724-6.

[6] Caramori PRA, Lima VC, Seidelin PH, et al. Long-term endothelial dysfunction after coronary stenting. J Am Coll Cardiol1999;34:1675-9.

[7] Biondi-Zoccai GG, Agostoni P, Abbate A, et al. Adjusted indirect comparison of intracoronary drug-eluting stents: evidence from a metaanalysis of randomized bare-metal-stent-controlled trials. Int J Cardiol2005;100:119-23.

[8] Tsimikas S. Drug-eluting stents and late adverse clinical outcomes: lessons learned, lessons awaited. J Am Coll Cardiol 2006;47:2112-5

[9] McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519-21

[10] Townsend JC, Rideout P, Steinberg DH. Everolimus-eluting stents in interventional cardiology

[11] Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007;356: 1503–1516.

[12] Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315–1323.

[13] Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004;350: 221–231.

[14] Vezina C, Kudelski A, Sehgal SN. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 1975;28:721–726.

[15] Sheiban I, Villata G, Bollati M, Sillano D, Lotrionte M, Biondi-Zoccai G. Next-generation drug-eluting stents in coronary artery disease: Focus on everolimus-eluting stent (Xience V). Vasc Health Risk Manag. 2008;4:31–38.

[16] 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;96:636–645.