Drug-eluting stent
From Wikipedia, the free encyclopedia
A drug-eluting stent is a coronary stent (a scaffold) placed into narrowed, diseased coronary arteries that slowly releases a drug to block cell proliferation. This prevents fibrosis that, together with clots (thrombus), could otherwise block the stented artery, a process called restenosis. The stent is usually placed within the coronary artery by an Interventional cardiologist.
Drug-eluting stents (DES) in current clinical use were approved by the FDA after clinical trials showed they were statistically superior to bare-metal stents (BMS) for the treatment of native coronary artery narrowings, having lower rates of major adverse cardiac events (usually defined as a composite clinical endpoint of death + myocardial infarction + repeat intervention because of restenosis.[1] [2]
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[edit] History
The first procedure to treat blocked coronary arteries was coronary artery bypass graft surgery (CABG), wherein a section of vein or artery from elsewhere in the body is used to bypass the diseased segment of coronary artery. In 1977, Andreas Grüntzig introduced percutaneous transluminal coronary angioplasty (PTCA), also called balloon angioplasty, in which a catheter was introduced through a peripheral artery and a balloon expanded to dilate the narrowed segment of artery.[3]
As equipment and techniques improved, the use of PTCA rapidly increased, and by the mid-1980s, PTCA and CABG were being performed at equivalent rates.[4] Balloon angioplasty was generally effective and safe, but restenosis was frequent, occurring in ~30–40% of cases, usually within the first year after dilation. In ~3% of balloon angioplasty cases, failure of the dilation and acute or threatened closure of the coronary artery (often because of dissection) prompted emergency CABG.[4]
Dotter and Melvin Judkins had suggested using prosthetic devices inside arteries (in the leg) to maintain blood flow after dilation as early as 1964.[5] In 1986, Puel and Sigwart implanted the first coronary stent in a human patient. [6] Several trials in the 1990s showed the superiority of stent placement over balloon angioplasty. Restenosis was reduced because the stent acted as a scaffold to hold open the dilated segment of artery; acute closure of the coronary artery (and the requirement for emergency CABG) was reduced, because the stent repaired dissections of the arterial wall. By 1999, stents were used in 84% of percutaneous coronary interventions (i.e., those done via a catheter, and not by open-chest surgery.)[6]
Early difficulties with coronary stents included a risk of early thrombosis (clotting) resulting in occlusion of the stent.[4] Coating stainless steel stents with other substances such as platinum or gold did eliminate this problem.[6] High-pressure balloon expansion of the stent to ensure its full apposition to the arterial wall, combined with drug-therapy using aspirin and another inhibitor of platelet aggregation (usually ticlopidine or clopidogrel) nearly eliminated this risk of early stent thrombosis.[6][4]
Though it occurred less frequently than with balloon angioplasty or other techniques, stents nonetheless remained vulnerable to restenosis, caused almost exclusively by neointimal tissue growth. To address this issue, developers of drug-eluting stents used the devices themselves as a tool for delivering medication directly to the arterial wall. While initial efforts were unsuccessful, it was shown in 2001 that the release (elution) of drugs with certain specific physicochemical properties from the stent can achieve high concentrations of the drug locally, directly at the target lesion, with minimal systemic side effects [7]. As currently used in clinical practice, "drug-eluting" stents refers to metal stents which elute a drug designed to limit the growth of neointimal scar tissue, thus reducing the likelihood of stent restenosis.
The first successful trials were of sirolimus-eluting stents. A clinical trial in 2002 led to approval of the sirolimus-eluting Cypher stent in Europe in 2002. After a larger pivotal trial (one designed for the purpose of achieving FDA approval), published in 2003, the device received FDA approval and was released in the U.S. in 2003.[6] Soon thereafter, a series of trials of paclitaxel-eluting stents led to FDA approval of the Taxus stent in 2004.[8]
[edit] Indications
Clinical trials have shown the benefits of coronary stenting with BMS over other methods of angioplasty, including balloon angioplasty and atherectomy. Drug-eluting stents (DES) have also been extensively studied, and are generally superior to bare-metal stents as regards Major Adverse Cardiac Events (MACE, generally defined as death, myocardial infarction, or the need for a repeat revascularization procedure.) Stents are indicated to improve the diameter of the coronary artery lumen, when narrowing (generally because of atherosclerosis) causes ischemia (reduced oxygen delivery to the muscle supplied by that artery.)
[edit] Off-label use
Drug-eluting stents also have been shown to be superior to bare-metal stents in reducing short-term complications of stenting in saphenous vein grafts [9]; however, use in these bypass grafts is an example of an "off-label" use of drug-eluting stents. That is, this application has not been sufficiently examined by the Food and Drug Administration for that agency to recommend the use. For "on-label" applications, the FDA "believes that coronary drug-eluting stents remain safe and effective when used for the FDA-approved indications. These devices have significantly reduced the need for a second surgery to treat restenosis for thousands of patients each year."[10].
As enthusiasm for the new devices abates, there is some concern about overzealous use of stents in general. Two studies found that about half of patients received stents for unapproved reasons,[11][12] with worse outcomes for the patients in both studies.
[edit] Alternatives
Medical therapy for coronary artery disease has also improved since the 1970s, and for many kinds of patients may be as successful as stenting or surgery. For those requiring PCI or surgery, medical therapy and revascularization should be viewed as complementary rather than opposing strategies.[13]
Coronary artery bypass graft surgery is the best treatment for some patients. A recent study comparing the outcomes of all patients in New York state treated with coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) demonstrated CABG was superior to PCI with DES in multivessel (two or more diseased arteries) coronary artery disease (CAD). Patients treated with CABG had lower rates of death and of death or myocardial infarction than treatment with a drug-eluting stent. Patients undergoing CABG also had lower rates of repeat revascularization.[14] The New York State registry included all patients undergoing revascularization for coronary artery disease, but was not a randomized trial, and so may have reflected other factors besides the method of coronary revascularization.
No randomized trial comparing CABG and DES has been completed, although two trials of DES versus CABG are currently enrolling patients - SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) and FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus—Optimal Management of Multivessel Disease). The registries of the nonrandomized patients screened for these trials may provide as much robust data regarding revascularization outcomes as the randomized analysis.[15]
The ARTS II registry compared a cohort of patients treated with multi-vessel stenting with DES, to the historical CABG cohort in the ARTS I trial. At three-year follow-up, major adverse cardiac events were comparable between the ARTS II DES group and the ARTS I CABG group. Re-intervention was lower in the ARTS I CABG group.[16]
[edit] Risks
Like all invasive medical procedures, implanting stents in the coronary arteries carries risk. For the newer drug-eluting stents, very-long-term results are not yet available; however, five-years after implantation sirolimus-eluting stents remained superior to bare-metal stents.[17]
Risks associated with cardiac catheterization procedures include bleeding, allergic reaction to the X-ray contast agents used to visualize the coronary arteries, and myocardial infarction. With PCI, the requirement for emergency CABG has markedly decreased since the days of balloon angioplasty, such that in some communities, coronary stenting is permitted in hospitals without on-site cardiac surgery facilities[18], though this remains highly controversial in the United States, including because of the rare but largely unpredictable risk of coronary artery perforation[4]. Rarely, a type of allergic reaction to the drug may occur; episodes of fatality have been reported.[19]
[edit] Stent thrombosis
Although drug-eluting stents were regarded as a major medical advance when they first appeared, new evidence suggests that they also put patients at risk for stent thrombosis, or the formation of a clot in the stent. A stent is a foreign object in the body, and the body responds to the stent’s presence in a variety of ways. Macrophages accumulate around the stent, and nearby smooth muscle cells proliferate. These physiological changes, which can cause restenosis, are limited by the drugs released by the stent, but these drugs also limit re-endothelialization. This lack of healing can make the stent an exposed surface on which a life-threatening clot can form.
Though less frequent with drug-eluting stents, neointimal proliferation can still occur in DES and cause restenosis. Stent occlusion because of thrombosis may occur during the procedure, in the following days, or later. Treatment with the antiplatelet drugs aspirin and clopidogrel appears to be the most important factor reducing this risk of thrombosis, and early cessation of one or both of these drugs after drug-eluting stenting markedly increases the risk of stent thrombosis and myocardial infarction.[20]
Whether drug-eluting stents are at higher risk than bare-metal stents for late thrombosis is intensely debated.[21] In meta-analyses of the sirolimus and paclitaxel-eluting stent trials, there was a small but statistically higher risk of thrombosis after the first year, compared to bare metal stents. Late stent thrombosis often causes myocardial infarction and sometimes death. [22] In other analyses, the late thrombosis risk is offset by drug-eluting stents' markedly reduced risk of restenosis and its complications including myocardial infarction. A meta-analysis concluded that the mortality risk associated with drug-eluting and bare-metal stents is similar.[23]
Comparing different drug-eluting stents Whether sirolimus or paclitaxel-eluting stents are measurably different in their outcomes is a topic of great interest, including to the marketing departments of the manufacturers themselves. Analyses favoring one or the other stent have been advanced. The differences, if any, between the two devices are small. [24]
[edit] Design
Drug-eluting stents consist of three parts. The stent itself is an expandable metal alloy framework. A coating, typically of a polymer, elutes the drug into the arterial wall by contact transfer. In the polymer is the drug, which inhibits neointimal growth. Both sirolimus and paclitaxel were previously used for other medical applications; new drugs are being evaluated for coronary stents.[6]
[edit] Investigation and Alternative drugs
In place of the stainless steel currently used in stents, various biodegradable frameworks are under early phases of investigation. Since metal, as a foreign substance, provokes inflammation, scarring, and thrombosis (clotting), it is hoped that biodegradable or bioabsorbable stents may prevent some of these effects. A magnesium alloy–based stent has been tested in animals, though there is currently no carrier for drug elution.[25] A promising biodegradable framework is made from poly-L-lactide, a polymer of a derivative of L-lactic acid. One of these stents, the Igaki-Tamai stent, has been studied in pigs; tranilast[26] and paclitaxel[27] have been used as eluted drugs.
There are also several other anti-proliferative drugs under investigation in human clinical trials. In general, these are analogues of sirolimus. Like sirolimus, these block the action of mTOR. Abbott has developed zotarolimus; unlike sirolimus and paclitaxel, this sirolimus analogue designed for use in stents with phosphorylcholine as a carrier. Their ZoMaxx stent is a zotarolimus-eluting, stainless steel and tantalum–based stent; a modified phosphorylcholine slowly releases the zotarolimus.[28] Zotarolimus has been licensed to Medtronic which is researching the effectiveness in a drug-eluting stent of their own. Their Endeavor stent, which is a cobalt alloy,[6] also uses phosphorylcholine to carry the zotarolimus was approved for use in Europe in 2005 is now close to U.S. FDA approval.[29]
Clinical trials are currently examining two stents carrying everolimus,[6] an analog of sirolimus. Guidant, which has the exclusive license to use everolimus in drug-eluting stents, is the manufacturer of both stents. The Guidant vascular business was subsequently sold to Abbott.[30] The Champion stent uses a bioabsorbable polylactic acid carrier on a stainless steel stent.[31][32] In contrast, its Xience stent uses a durable (non-bioabsorbable) polymer on a cobalt stent.[33]
[edit] References
- ^ "Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery." (2003). New England Journal of Medicine. PMID 14523139.
- ^ "One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV trial." (2004). Circulation. PMID 15078803.
- ^ Grüntzig, AR; A Senning, & WE Siegenthaler (1979-07-12). "Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty". New England Journal of Medicine 301 (2): 61–68. PMID 449946.
- ^ a b c d e Baim, Donald S. [1958] (2005). "Percutaneous Coronary Revascularization", in Dennis L. Kasper, Anthony S. Fauci, Dan L. Longo, Eugene Braunwald, Stephen L. Hauser, & J. Larry Jameson: Harrison's Principles of Internal Medicine, 16th ed., New York: McGraw-Hill, 1459–1462.
- ^ Dotter, Charles T.; & Melvin P. Judkins (1964). "Transluminal Treatment of Arteriosclerotic Obstruction". Circulation 30: 654–670. PMID 14226164. (abstract)
- ^ a b c d e f g h Serruys PW, Kutryk MJ, Ong AT (2006). "Coronary-artery stents". N. Engl. J. Med. 354 (5): 483–95. doi: . PMID 16452560.
- ^ Hwang, CW; Wu D, Edelman ER (2001). "Physiological transport forces govern drug distribution for stent-based delivery". Circulation 104: 600-605. (abstract)
- ^ New Device Approval - P030025 - TAXUS Express2 Paclitaxel-Eluting Coronary Stent System. Retrieved on 2008-02-25.
- ^ Lee MS, Shah AP, Aragon J, Jamali A, Dohad S, Kar S, Makkar RR (2005). "Drug-eluting stenting is superior to bare metal stenting in saphenous vein grafts". Catheter Cardiovasc Interv 66 (4): 507–11. doi: . PMID 16270361.
- ^ US FDA/CDRH: FDA Statement on Coronary Drug-Eluting Stents. Retrieved on 2008-02-25.
- ^ Win HK, Caldera AE, Maresh K, et al (2007). "Clinical outcomes and stent thrombosis following off-label use of drug-eluting stents". JAMA 297 (18): 2001–9. doi: . PMID 17488965.
- ^ Beohar N, Davidson CJ, Kip KE, et al (2007). "Outcomes and complications associated with off-label and untested use of drug-eluting stents". JAMA 297 (18): 1992–2000. doi: . PMID 17488964.
- ^ "Medical therapy versus coronary angioplasty in stable coronary artery disease: a critical review of the literature." (2000). J Am Coll Cardiol. PMID 17920355.
- ^ Hannan EL, Wu C, Walford G, et al (2008). "Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease". N. Engl. J. Med. 358 (4): 331–41. doi: . PMID 18216353.
- ^ Desai ND (2008). "Pitfalls assessing the role of drug-eluting stents in multivessel coronary disease". Ann. Thorac. Surg. 85 (1): 25–7. doi: . PMID 18154771.
- ^ Serruys PW, et al. (2007). "Three-year follow-up of the ARTS-II - sirolimus-eluting stents for the treatment of patients with multivessel coronary artery disease". Eurointervention (12): 450–9.
- ^ "Long-term clinical outcomes with sirolimus-eluting coronary stents: five-year results of the RAVEL trial." (2007). JACC. PMID 17903626.
- ^ Peels JO, Hautvast RW, de Swart JB, et al (2008). "Percutaneous coronary intervention without on site surgical back-up; two-years registry of a large dutch community hospital". Int. J. Cardiol.. doi: . PMID 18241941.
- ^ Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, Mihalcsik L, Tespili M, Valsecchi O, Kolodgie FD (2004). "Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious?". Circulation 109 (6): 701–5. doi: . PMID 14744976.
- ^ Iakovou I, Schmidt T, Bonizzoni E, et al (2005). "Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents". JAMA 293 (17): 2126–30. doi: . PMID 15870416.
- ^ Daemen J, Serruys PW (2007). "Drug-eluting stent update 2007: part II: Unsettled issues". Circulation 116 (8): 961–8. doi: . PMID 17709651.
- ^ Bavry AA, Kumbhani DJ, Helton TJ, Borek PP, Mood GR, Bhatt DL (2006). "Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials". Am. J. Med. 119 (12): 1056–61. doi: . PMID 17145250.
- ^ http://www.medscape.com/viewarticle/562959
- ^ Stettler C, Wandel S, Allemann S, Kastrati A, Morice MC, Schömig A, Pfisterer ME, Stone GW, Leon MB, de Lezo JS, Goy JJ, Park SJ, Sabaté M, Suttorp MJ, Kelbaek H, Spaulding C, Menichelli M, Vermeersch P, Dirksen MT, Cervinka P, Petronio AS, Nordmann AJ, Diem P, Meier B, Zwahlen M, Reichenbach S, Trelle S, Windecker S, Jüni P (2007). "Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis". Lancet 370 (9591): 937–48. doi: . PMID 17869634.
- ^ Heublein, B.; R. Rhode, V. Kaese, N. Niemeyer, W. Hartung, & A. Haverich (2003). "Biocorrosion of magnesium alloys: a new principle in cardiovascular implant technology?". Heart 89: 651–656. doi: . PMID 12748224.
- ^ Tsuji, T.; H. Tamai, K. Igaki, E. Kyo, K. Kosuga, T. Hata, T. Nakamura, S. Fujita, S. Takeda, S. Motohara, & H. Uehata (2003). "Biodegradable stents as a platform to drug loading.". International Journal of Cardiovascular Interventions 5 (1): 13–6. doi: . PMID 12623560.
- ^ Vogt, Felix; Andreas Steina, Gösta Rettemeier, Nicole Krott, Rainer Hoffmann, Jürgen vom Dahl, Anja-Katrin Bosserhoff, Walter Michaeli, Peter Hanrath, Christian Weber, & Rüdiger Blindt (2004). "Long-term assessment of a novel biodegradable paclitaxel-eluting coronary polylactide stent". European Heart Journal 25: 1330–1340. doi: . PMID 15288161.
- ^ Vascular Devices. Abbott. Retrieved on 2006-07-23.
- ^ FDA advisers OK Medtronic stent. Star Tribune. Retrieved on 2007-10-10.
- ^ Abbott Completes Acquisition of Guidant Vascular Business. Retrieved on 2007-01-12.
- ^ Grube, Eberhard; Shinjo Sonoda, Fumiaki Ikeno, Yasuhiro Honda, Saibal Kar, Charles Chan, Ulrich Gerckens, Alexandra J. Lansky, & Peter J. Fitzgerald (2004). "Six- and Twelve-Month Results From First Human Experience Using Everolimus-Eluting Stents With Bioabsorbable Polymer". Circulation 109: 2168–2171. doi: . PMID 15123533.
- ^ Guidant News Release — April 5, 2004. Guidant (2004-04-05). Retrieved on 2007-07-23.
- ^ Guidant News Release — June 22, 2005. Guidant (2005-06-22). Retrieved on 2006-07-23.
[edit] Further reading
- Fischetti, Mark (July 2006). "Vascular Stents: Expanding Use". Scientific American: 94. (layperson overview, subscription required)
- Serruys, Patrick W.; Michael J.B. Kutryk, and Andrew T.L. Ong (2006-02-02). "Coronary-Artery Stents". New England Journal of Medicine 354 (5): 483–495. doi: . PMID 16452560. (journal review article, subscription required)
[edit] External links
- Drug-Eluting Stents — Angioplasty.Org
- Drug-Eluting Stents —First in India
- CIMIT Center For Integration of Medicine and Innovative Technology
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