Drug-eluting stent

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An example of a drug-eluting stent. This is the TAXUS™ Express²™ Paclitaxel-Eluting Coronary Stent System, which releases paclitaxel.

In cardiology, a drug-eluting stent is a stent (a scaffold) placed into narrowed, diseased coronary arteries that slowly releases a drug to block cell proliferation. This prevents scar-tissue–like growth that, together with clots (thrombus), could otherwise block the stented artery.

Heart attacks, or myocardial infarctions, are major causes of death and disability; they result when a portion of heart muscle dies from inadequate blood flow. This typically occurs at sites where coronary arteries are already narrowed and damaged. Fat and cholesterol deposition as well as inflammation in the arterial wall cause injury; excessive tissue growth and additional cholesterol deposition occur, and clots form. These narrowings are prone to being suddenly blocked, or a piece may break off and block a smaller branch downstream (embolism). If blood flow can be restored early enough, permanent damage can be prevented, and pre-emptive manipulation can prevent heart attacks from occurring in the first place.

Coronary artery stents, typically a metal framework, can be placed inside the artery to help keep it open. However, as the stent is a foreign object (not native to the body), it incites an immune response. This may cause scar tissue (cell proliferation) to rapidly grow over the stent. In addition, there is a strong tendency for clots to form at the site where the stent damages the arterial wall. Since platelets are involved in the clotting process, patients must take antiplatelet therapy afterwards, usually clopidogrel for six months and aspirin indefinitely.^[1] However, the antiplatelet therapy may be insufficient to fully prevent clots; these and the cell proliferation may cause the standard (“bare-metal”) stents to become blocked. Drug-eluting stents were designed to lessen this problem; by releasing an antiproliferative drug (drugs typically used against cancer or as immunosuppressants), they can help avoid this in-stent restenosis (re-narrowing).

Drug-eluting stents have been shown to be superior to traditional stents ("bare-metal stents") in reducing short-term complications. Their long term effectiveness compared traditional stents or coronary bypass grafting is under scrutiny by the FDA.^[2]

[edit] Structure

Drug-eluting stents consist of three parts. The stent itself is an expandable framework, usually metal. Added to this is a drug to prevent the artery from being re-occluded, or blocked. These typically have been drugs already in use as anti-cancer drugs or drugs that suppress the immune system, although new drugs are being developed specifically for drug-eluting stents. Finally, there must be a carrier which slowly releases the drug over months. The carrier is typically a polymer, although phosphorylcholine or ceramics are also being researched.^[3] Different carriers release the loaded drug at different rates.

[edit] Placement

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

[edit] Current devices

Currently, two models of drug-eluting stents are used. Both drugs currently in use were previously developed for other purposes; their use to prevent in-stent proliferation is relatively new.

The first successful type releases sirolimus (rapamycin), a powerful immunosuppressive and antiproliferative drug. Sirolimus is primarily used as an immunosuppressant 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 thereby blocking the cell cycle at the G₁→S transition.^[4] A sirolimus-eluting stent is produced by Cordis Corporation (Johnson & Johnson), and marketed under the name Cypher. This stent is made of stainless steel and uses a polymer as the carrier.^[5]

A second model uses paclitaxel, another antiproliferative drug; it is primarily used against various forms of cancer. Derived from the yew tree, paclitaxel binds to and stabilizes microtubules. Without the dynamic framework provided by these components of the cytoskeleton, the cell cannot undergo mitosis and so is arrested at the M stage.^[6] The paclitaxel-eluting stent produced by Boston Scientific is marketed under the name Taxus. Like the Cypher stent, the Taxus stent is made of stainless steel and uses a polymer as drug carrier.^[7]

[edit] History

Diagram of stent placement. In A, the catheter is inserted across the lesion. In B, the balloon is inflated, expanding the stent and compressing the plaque. In C, the catheter and deflated balloon have been removed. Before-and-after cross sections of the artery show the results of the stent placement.

The first procedural method to treat blocked coronary arteries was a type of open-heart surgery called coronary artery bypass graft (CABG) surgery, which uses a section of vein or artery from elsewhere in the body to bypass the diseased vessel. In 1977, Andreas Grüntzig introduced percutaneous transluminal coronary angioplasty (PTCA), in which a catheter was introduced through a peripheral artery and a balloon expanded to compress and crack the obstructive plaque.^[8]

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.^[9] PTCA could only be used on limited scenarios, and the vessels had a high rate (30–40% in six months) of restenosis; additionally, 3% required emergency bypass surgery.^[9] Dotter and Judkins had suggested using prosthetic devices inside arteries to maintain blood flow (in arteries of the leg) in 1964,^[10] and in 1986, Puel and Sigwart implanted the first stent in humans.^[3] Several trials in the 1990s showed the superiority of stent placement to simple balloon angioplasty, and stent placement became increasingly prevalent, reaching 84% of percutaneous interventions (those done via needle-puncture rather than incision) by 1999.^[3]

Initial difficulties included blood clotting and occluding the stent in the hours or days after placement.^[9] Coating the stent with biologically inert substances like platinum or gold did not help.^[3] Eventually, using high balloon pressures to tightly fix the stent against the vessel and administering aspirin and (usually) clopidogrel as anticoagulants were established; these changes eliminated most of the difficulty with in-stent thrombosis.^{[3], [9]}

Difficulties still remained, however, with the formation of scar tissue inside the stent (in-stent neointimal hyperplasia) and clotting problems not addressed by the antiplatelet drug regimen. The stent itself was a logical choice for delivering medication. The slow release of drugs from the stent spares the patient the inconvenience of taking yet another medication, and prevents the danger of the patient forgetting to take or losing interest in taking the medicine. But more importantly, a stent that releases a drug can deliver high concentrations directly to the target region, analogous to placing a medicated cream on a skin problem or taking an inhaler to help the lungs or airways. Taking the medication orally or intravenously would require much higher doses to ensure a sufficient concentration at the target; this could cause unacceptable side effects or patient injury.

The first successful trials were of sirolimus-eluting stents. A successful trial in 2002 led to approval of the Cypher stent in Europe, followed by FDA approval in the U.S. in 2003.^[3] Soon thereafter, a series of trials of paclitaxel-eluting stents led to FDA approval of the Taxus stent in 2004.^[7]

[edit] Uses

There has been considerable research showing the benefits of coronary stents. Data specifically on drug-eluting stents are less abundant, though where studied, they have usually been shown to be superior to bare-metal stents, and in some cases, may be used for lesions for which surgery was previously the only option. Drug-eluting stents are used both for restoring blood flow immediately after a heart attack and also electively for improving blood flow in a compromised vessel. Only certain types of blockages are amenable to stent placement, though drug-eluting stents may be successful in lesions for which bare-metal stents were insufficient. Drug-eluting stents are used to reopen grafts from prior CABG surgery that have themselves become blocked, and also can be used in cases of in-stent restenosis in prior stents.^[3]

[edit] Current research

Research focuses on establishing the roles for drug-eluting stents and for developing new types of stents. Different materials for all three components—the scaffolding, the carrier, and the drug—are being actively investigated.

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.^[11] 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^[12] and paclitaxel^[13] 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.^[14] 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^[3], also uses phosphorylcholine to carry the zotarolimus, and was approved for use in Europe in 2005.

Clinical trials are currently examining two stents carrying everolimus,^[3] an immunosuppressant that like sirolimus is used to prevent organ rejection.^[4] Guidant, which has the exclusive license to use everolimus in drug-eluting stents, is the manufacturer of both stents. This Guidant business has subsequently been sold to Abbott Labs.^[15] The Champion stent uses a bioabsorbable polylactic acid carrier on a stainless steel stent.^{[16], [17]} In contrast, its Xience stent uses a durable (non-bioabsorbable) polymer on a cobalt stent.^[18]

Coronary Bypass Surgery versus Percutaneous Coronary Intervention The rapid developments in both surgical and percutaneous techniques have been such that the choice of the optimum revascularisation strategy is changing, often without an established evidence base; this is particularly true in complex conditions including patients with three-vessel and left main stem anatomy. The widespread use of drug eluting stents has resulted in a significant reduction in patients referred for CABG although published data favours the surgical approach in this high-risk group. The SYNTAX Trial [1]aims to explore the interface between treatment with coronary bypass grafting and PCI in patients with three-vessel and left main stem disease, comparing coronary bypass grafting using contemporary techniques and PCI using drug eluting TAXUS stents.

Recently, research has revealed that drug eluting stents are associated with a 5 fold higher risk for late thrombosis compared to bare metal stents. Although this risk is still small, fatality results in one-third of patients who develop late thrombosis.^[19]

[edit] Complications and controversy

In the last several years, drug-eluting stent use has become increasingly popular, both in place of surgery and for lesions not severe enough for surgery. Placing stents is not without risk, however, and the recent development of the drug-eluting stents means that long-term data, especially in comparison to traditional bare-metal stents, are not available. As enthusiasm for the new devices abates, there is some concern about overzealous use of stents in general.

As with all cardiac catheterization, there are several risks. Patients may exhibit severe allergic response to the contrast agents used to visualize the coronary arteries, and occasionally, the peripheral entry artery fails to properly heal after the catheter is removed, causing a collection of blood called a hematoma. Rarely, a coronary artery can be perforated while the catheter is advanced or during stent placement.^[9]

Finally, stent occlusion can occur. Thrombosis may occur during the procedure, in the following days, or much later. Stents cause damage to the vessel wall, and, as foreign objects, they provoke inflammation and clot formation. And tissue proliferation in the stent can cause the vessel to narrow again. Patients with stents (but 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 cause a clot to form;^[9] aspirin must be taken for life.^[3] Drug-eluting stents have been shown to have significantly lower rates of in-stent proliferation compared to bare-metal stents. However, some studies suggest that the proliferation may be merely delayed; when the drug has been completely eluted, proliferation may occur.^[3] The magnitude and significance of this effect is unclear. Rarely, a type of allergic reaction to the drug may occur; episodes of fatality have been reported.^[20]

Nevertheless, coronary stents, and drug-eluting stents in particular, have revolutionized the treatment of coronary heart disease, and new techniques and materials that may ameliorate these problems are being studied. Bioabsorble or biodegradable polymer or stent may help avoid the inflammation and other side effects of long-term foreign objects. Different carriers affect the rate of release of drug, and different antiproliferative drugs may have different clinical effects.^[3] 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.^[21] Such use remains investigational.

[edit] References

[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.  (journal review article, subscription required)

[edit] External links

Wikimedia Commons has media related to:

Stent

• Drug-Eluting Stents — Angioplasty.Org