Friday, May 29, 2009

Drug Delivery: STENTS


The Stent Revolution

Drug-eluting devices grow in popularity, and research looks at how to expand their application

Drug-eluting stents, a significant innovation for preventing coronary artery restenosis, have revolutionized interventional cardiology. A broad range of disciplines have made major contributions to the design and development of these ingenious devices.

In interventional cardiology, physicians use minimally invasive techniques to treat cardiac abnormalities. The most common of these procedures involves the treatment of coronary artery disease. Using these techniques, coronary arteries that are narrowed or contain obstructions are opened with balloon catheters. The procedure entails a small incision in the upper portion of the leg or the arm while the patient is under light sedation; this relieves the patient of a blockage that could cause chest pain (angina) or a heart attack.1

The concept of the stent grew directly out of interventional cardiologists' experience with angioplasty balloons between 1977 and 1987. Sometimes balloon dilation weakened the wall of the coronary artery. In a small percentage of cases, although the artery had been opened using a balloon, it would collapse after the balloon was deflated-sometimes after the patient had been moved to the recovery room. The only option for this patient was emergency bypass graft surgery.2

Structure

A drug-eluting stent consists of an expandable framework, usually metal. Added to this is a drug that will prevent the artery from being blocked. Typically, the drugs used to coat the stent were designed to fight cancer or suppress the immune system, although new drugs are being developed specifically for drug-eluting stents.3

The outer aspect of a standard coronary stent is coated with a thin carrier containing medication that can prevent the formation of scar tissue at the site of coronary intervention. The carrier is typically a polymer, although phosphorylcholine and ceramics are also being researched. Different carriers release the loaded drug at varying rates.4

The currently available stent is coated with a medication known as sirolimus. Sirolimus is often used to prevent rejection following organ transplantation. These stents have been shown to decrease the chance of restenosis dramatically. Additionally, drug-eluting stents have been found to be superior in the management of many of the conditions traditionally treated using bare-metal stents. They have been highly successful at treating coronary heart disease and offer significant advantages over other therapies such as surgery. In the few years since their approval by the Food and Drug Administration (FDA) in 2003, drug-eluting stents have become one of the dominant interventions used to prevent and treat heart attacks.5

Placement

The stent, in its collapsed form, is loaded onto a balloon at the end of a catheter with a guide wire. The device is introduced through a peripheral artery, usually at the groin through one of the femoral arteries. It is threaded toward the heart.6

In the aorta, just prior to entering the heart, the appropriate coronary artery is entered. The balloon is then inflated, cracking and compressing the plaque and expanding the stent. The balloon may be inflated and deflated several times. The balloon and catheter are then withdrawn, leaving the stent, which will release its drug over the next several months.7

The procedure is monitored via the real-time angiogram, although some cardiologists also use more detailed information using intravascular ultra-sound imaging.8 The patient must take, in addition to aspirin, an anti-clotting or antiplatelet drug, such as clopidogrel or ticlopidine (known by the brand names Plavix and Ticlid) for six or more months after the stenting. The medication prevents the blood from reacting to the new device by thickening and clogging up the newly expanded artery (thrombosis).9 Ideally, a smooth, thin layer of endothelial cells (the inner lining of the blood vessel) grows over the stent during this period, incorporating the device into the artery and reducing the tendency for clotting.10

Current Devices

Drug-eluting stents are the subject of many disputes, legal and otherwise, which were labeled "Stent Wars" some time ago.11These devices have been adopted so quickly that they have doubled the world market for stents to $5 billion annually.

Various biodegradable stent frameworks are in the early phases of investigation. Metal provokes inflammation, scarring, and clotting, but biodegradable or bioabsorbable stents could prevent some of these effects.

It's easy to understand the flurry of activity by competing manufacturers.12 Only two drug-eluting stents-the Cordis Cypher sirolimus-eluting stent and the Boston Scientific Taxus paclitaxel-eluting stent system-have received FDA approval for sale in the United States (the Cypher in April 2003; the Taxus in March 2004).

In addition, Medtronic's Endeavor stent, which uses ABT-578, a drug made by Abbott, was approved in Europe in April 2005. Abbott had its own stent, ZoMaxx, in clinical trials but canceled its development in fall 2006, opting instead to market its Xience stent, co-acquired as part of the Boston Scientific/Guidant/Abbott merger agreement.13-14

Boston Scientific has launched its second-generation Taxus Liberte stent in Europe and will market the Xience stent under the brand name Promus.15 Taxus and Cypher have shown significant reduction of restenosis both in clinical trials and in the field. Both stents have also shown dramatic reduction in rein-terventions in diabetics, who are highly susceptible to restenosis.16-17

The first successful type of stent releases sirolimus (rapamycin), a powerful immunosuppressive and antiproliferative drug. Sirolimus is primarily used to prevent organ transplant rejection produced by the bacterium Streptomyces hygroscopicus; it binds to the immunophilin FKBP-12. The resulting complex inhibits the mammalian target of rapamycin (mTOR), which has several effects, including preventing the cell from duplicating its genetic material and, as a result, blocking the cell cycle at the G1?S transition.18-19

New Studies

Current research focuses on establishing the roles of drug-eluting stents and developing new types. Different materials for the scaffolding, the carrier, and the drug are under investigation.20-21

In place of the stainless steel currently used in stents, various biodegradable frameworks are in the early phases of investigation. Metal provokes inflammation, scarring, and thrombosis (clotting); it is hoped that biodegradable or bioabsorbable stents could prevent some of these effects.22 A magnesium alloy-based stent has been tested in animals, though there is currently no carrier for drug elution.23

One promising biodegradable framework is made from poly-L-lactide, a polymer of a derivative of L-lactic acid.24 One of these stents, the IgakiTamai device, has been studied in pigs; tranilast and paclitaxel have been used as the eluted drugs.25 Several other anti-proliferative drugs are under investigation in human clinical trials.26 In general, these are analogs of sirolimus and, like sirolimus, they block the action of mTOR.27

Abbott has developed zotarolimus, designed for use in stents with phosphorylcholine as a carrier.28 ZoMaxx is a zotarolimus-eluting, stainless steel, tantalum-based stent; a modified phosphorylcholine slowly releases the zotarolimus.29 Zotarolimus has been licensed to Medtronic, which is researching its effectiveness in a drug-eluting stent of its own.30 Medtronic's Endeavor stent, a cobalt alloy, also uses phosphorylcholine to carry zotarolimus and was approved for use in Europe in 2005.31

Clinical trials are examining two stents carrying everolimus, an immunosuppressant that is, like sirolimus, used to prevent organ rejection.32 Guidant, which has the exclusive license to use everolimus in drug-eluting stents, makes both devices.33 The Champion stent uses a bioabsorbable polylactic acid carrier on a stainless steel stent. In contrast, Guidant's Xience stent uses a durable (non-bioabsorbable) polymer on a cobalt stent.34

Complication, Controversy

In the past several years, use of drug-eluting stents has become increasingly popular in place of surgery and for lesions not severe enough for surgery. Placing stents does not occur without risk, however, and the recent development of drug-eluting stents means long-term data-especially in comparison to traditional bare-metal stents-are not available.

There is some concern about the overzealous use of stents in general. As with all cardiac catheterization, there are risks.35-36 Patients may exhibit severe allergic response to the contrast agents used to visualize the coronary arteries. Occasionally the peripheral entry artery fails to heal properly after the catheter is removed, causing a collection of blood called a hematoma.37 Rarely, a coronary artery can be perforated while the catheter is advanced or during stent placement. Also, the stent can become occluded.

Thrombosis can occur during the procedure, in the following days, or much later.38 Stents damage the vessel wall, and-as foreign objects-provoke inflammation and clots.39 Tissue proliferation in the stent can cause the vessel to narrow again. Patients with stents (though not those undergoing isolated balloon angioplasty) must remain on an antiplatelet drug like clopidogrel for at least three to six months; discontinuing it, even for a short time, can allow a clot to form. Further, aspirin must be taken for life.40

Drug-eluting stents have been shown to have significantly lower rates of instent proliferation compared with bare-metal stents. Some studies suggest the proliferation may merely be delayed, however; when the drug has been completely eluted, proliferation may occur.41 The magnitude and significance of this effect is unclear.

A rare type of allergic reaction to the drug may occur; fatalities have been reported. Nevertheless, coronary stents, and drug-eluting stents in particular, have revolutionized the treatment of coronary heart disease.

New techniques and materials that may ameliorate these problems are being studied. Bioabsorbable or biodegradable polymer stents may help avoid inflammation and other side effects of long-term foreign objects. Different carriers affect the rate of drug release, and different antiproliferative drugs may have distinct clinical effects. The success of drug-eluting stents in coronary disease has prompted investigation of their use in other narrowed arteries, such as the carotid arteries leading to the brain. Such use remains investigational. �

Dr. Jayvadan is associate professor and chief, Pharmaceutics Department, Shree S.K. Patel College of Pharmaceutical Education and Research, Gujarat, India. E-mail him at . Priyal is an assistant professor at the same institution.

REFERENCES

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18. Lansky AJ, Popma JJ, Columbo A. Follow-up angiographic comparison of the low dose vs high dose phosphorous-32 radioactive isostent: results from expanded IRIS and Milan Dose A studies. J Am Coll Cardiol. 1999;33:Suppl 17A.

19. 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(23):1773-1780.

20. Grube E, Hauptmann K, Colombo A, et al. SCORE trial interim safety results: despite efficacy, late stent thrombosis with the QuaDDSQP2 stent. J Am Coll Cardiol. 2002;39(5):38A.

21. Liistro F, Colombo A. Late acute thrombosis after paclitaxel eluting stent implantation. Heart. 2001;86(3):262-264.

22. Virmani R, Kolodgie FD, Farb A, et al. Drug eluting stents: are human and animal studies comparable? Heart. 2003;89(2):133-138.

23. U.S. Food and Drug Administration. CYPHER sirolimus-eluting coronary stent on RAPTOR over-the-wire delivery system or RAPTORRAIL rapid exchange delivery system-P020026. Rockville, Md.: U.S. Food and Drug Administration; April 24, 2003.

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38. Sigwart U, Puel J, Mirkovitch V, et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty. N Engl J Med. 1987;316(12):701-706.

39. 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(8):496-501.

40. Rankin JM, Spinelli JJ, Carere RG, et al. Improved clinical outcome after widespread use of coronary-artery stenting in Canada. N Engl J Med. 1999;341(26):1957-1965.

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