Drug-eluting stent
Encyclopedia
A drug-eluting stent is a peripheral or coronary stent
(a scaffold) placed into narrowed, diseased peripheral or 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 peripheral or coronary artery by an Interventional cardiologist or Interventional Radiologist during an angioplasty
procedure.
Drug-eluting stents in current clinical use were approved by the FDA after clinical trials showed they were statistically superior to bare-metal stent
s (BMS) for the treatment of native coronary artery narrowings, having lower rates of major adverse cardiac events (MACE) (usually defined as a composite clinical endpoint of death + myocardial infarction
+ repeat intervention because of restenosis
).
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. 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.
Dotter
and Melvin Judkins had suggested using prosthetic devices inside arteries (in the leg) to maintain blood flow after dilation as early as 1964. In 1986, Puel and Sigwart implanted the first coronary stent in a human patient. 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.)
Early difficulties with coronary stents included a risk of early thrombosis
(clotting) resulting in occlusion of the stent. Coating stainless steel stents with other substances such as platinum or gold did not eliminate this problem. 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.
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. 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. Soon thereafter, a series of trials of paclitaxel
-eluting stents led to FDA approval of the Taxus stent in 2004.
The Xience V everolimus eluting stent was approved by the FDA in July 2008 and has been available in Europe and other international markets since late 2006. It is an investigational device in Japan.
. 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.)
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."
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, with worse outcomes for the patients in both studies. More recent data suggests that off label use of both bare metal stents as well as drug eluting stents have increased risks. However, DES seemed to have similar or improved rates of death or MI compared with BMS, and consistently reduced need for target vessel revascularization (TVR). Overall, the data supports the use of DES for off-label indications.
Coronary artery bypass graft surgery is the best treatment for some patients. Differences between outcomes with stenting and with coronary bypass grafting (CABG) are a point of controversy. 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. 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.
Other studies, including the ARTS II registry, suggest that drug-eluting stenting is not inferior to coronary bypass for treatment of multivessel coronary disease. 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 (itself a randomized comparison between multivessel bare metal stenting vs. CABG.) 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.
In all comparison studies of stenting vs. bypass surgery, it is worth noting that only a small minority of patients with multivessel coronary disease have been eligible for inclusion in the studies, and that for most patients, clinical judgement by experienced operators suggests that one or the other approach is preferred.
Risks associated with cardiac catheterization
procedures include bleeding, allergic reaction to the X-ray contrast 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, though this remains highly controversial in the United States, not least because of the rare but largely unpredictable risk of coronary artery perforation. Rarely, a type of allergic reaction to the drug may occur; episodes of fatality have been reported.
formation with stents to be a problem, thus clotting suppressant agents are routinely given during placement and anti-clotting agents should be continued; the question is for how long. For drug-eluting stents (which, by design, delay formation of a new endothelium cover over the stent) that the incidence of clot formation within the stent may persist for a longer period of time, perhaps as long two to three years in a very small percentage of people. 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 formation of a new endothelial
layer over the new stent to inhibit clot formation. This lack of healing can make the stent an exposed surface on which a clot, sometimes life-threatening, 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. The presence of thrombus around the stent may in turn affect the drug-eluting performance of the stent. 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. A recent histopathology study showed that very late DES thrombosis is associated with histopathological signs of inflammation and intravascular ultrasound evidence of vessel remodeling. Compared with other causes of myocardial infarction, eosinophilic infiltrates are more common in thrombi harvested from very late DES thrombosis and correlate with the extent of stent malapposition.
Whether drug-eluting stents are at higher risk than bare-metal stents for late thrombosis is intensely debated. 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. 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.
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.
The SPIRIT II study showed the Xience V DES was better than the Taxus.
Drug-eluting stents with a biodegradable coating
In order to address the risk of late stent thrombosis, drug-eluting stents with a biodegradable coating have been developed. One such stent is the BioMatrix stent of Biosensors International
, which has been approved by European authorities in January 2008. Two year results of a large all-comers trial suggest a reduced risk of late stent thrombosis, especially after discontinuation of dual antiplatelet therapy. The Nevo stent of Cordis/J&J, also uses a biodegradable coating and is currently undergoing trials.
Drug-eluting stents consist of three parts. Stent platform, coating, and drug.
The stent itself is an expandable metal alloy framework. Many DES are based on a bare-metal stent
(BMS). The stents have elaborate mesh-like designs to allow expansion, flexibility and in some cases the ability to make/enlarge side openings for side vessels.
Cobalt chrome alloy is stronger (and more radio-opaque) than the usual 316L stainless steel so the struts can be thinner which seems to reduce the degree of restenosis
. (The L605 CoCr alloy has less nickel
than 316L stainless steel and so may cause less allergy.)
A coating, typically of a polymer
, holds and elutes (releases) the drug into the arterial wall by contact transfer.
The first few DES licenced used durable coatings, but some newer coating are designed to biodegrade after or as the drug is eluted.
Coatings are typically spray coated or dip coated. There can be one to three or more layers in the coating e.g. a base layer for adhesion, a main layer for holding the drug, and sometimes a top coat to slow down the release of the drug and extend its effect.
The drug is mainly to inhibit neointimal growth (due to proliferation of smooth muscle
cells) which would cause restenosis. Much of the neointimal hyperplasia seems to be caused by inflammation. Hence immunosuppressive and antiproliferative drugs are used. Both sirolimus and paclitaxel were previously used for other medical applications; new drugs are being evaluated for coronary stents.
Examples (approved for clinical use) :
Examples approved outside the US :
; 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
.
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, also uses phosphorylcholine to carry the zotarolimus was approved for use in Europe in 2005 is now close to U.S. FDA approval
.
Clinical trials are currently examining two stents carrying everolimus
, 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
.
The Champion stent uses a bioabsorbable polylactic acid
carrier on a stainless steel stent.
In contrast, its Xience stent uses a durable (non-bioabsorbable) polymer on a cobalt alloy stent.
One alternative to drug-eluting stents is a stent surface designed to reduce the neointimal proliferation. One such is the Genous bioengineered stent.
In place of the stainless steel (and now cobalt chrome) 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.
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
and paclitaxel
have been used as eluted drugs.
Coronary stent
A coronary stent is a tube placed in the coronary arteries that supply the heart, to keep the arteries open in the treatment of coronary heart disease. It is used in a procedure called percutaneous coronary intervention...
(a scaffold) placed into narrowed, diseased peripheral or coronary arteries that slowly releases a drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
to block cell proliferation
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
. This prevents fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
that, together with clots (thrombus
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
), could otherwise block the stented artery, a process called restenosis
Restenosis
Restenosis literally means the reoccurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and subsequently become renarrowed...
. The stent is usually placed within the peripheral or coronary artery by an Interventional cardiologist or Interventional Radiologist during an angioplasty
Angioplasty
Angioplasty is the technique of mechanically widening a narrowed or obstructed blood vessel, the latter typically being a result of atherosclerosis. An empty and collapsed balloon on a guide wire, known as a balloon catheter, is passed into the narrowed locations and then inflated to a fixed size...
procedure.
Drug-eluting stents in current clinical use were approved by the FDA after clinical trials showed they were statistically superior to bare-metal stent
Bare-metal stent
Bare-metal stent is a vascular stent without a coating . It is a mesh-like tube of thin wire. The first stents licenced for use in cardiac arteries were bare metal - often 316L stainless steel...
s (BMS) for the treatment of native coronary artery narrowings, having lower rates of major adverse cardiac events (MACE) (usually defined as a composite clinical endpoint of death + myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
+ repeat intervention because of restenosis
Restenosis
Restenosis literally means the reoccurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and subsequently become renarrowed...
).
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.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. Balloon angioplasty was generally effective and safe, but restenosis
Restenosis
Restenosis literally means the reoccurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and subsequently become renarrowed...
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.
Dotter
Charles Theodore Dotter
Charles Theodore Dotter was a US vascular radiologist who is generally credited with developing interventional radiology. Dotter, together with his trainee Dr Melvin P. Judkins, described angioplasty in 1964....
and Melvin Judkins had suggested using prosthetic devices inside arteries (in the leg) to maintain blood flow after dilation as early as 1964. In 1986, Puel and Sigwart implanted the first coronary stent in a human patient. 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
Percutaneous
In surgery, percutaneous pertains to any medical procedure where access to inner organs or other tissue is done via needle-puncture of the skin, rather than by using an "open" approach where inner organs or tissue are exposed .The percutaneous approach is commonly used in vascular procedures...
coronary interventions (i.e., those done via a catheter, and not by open-chest surgery.)
Early difficulties with coronary stents included a risk of early thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
(clotting) resulting in occlusion of the stent. Coating stainless steel stents with other substances such as platinum or gold did not eliminate this problem. High-pressure balloon expansion of the stent to ensure its full apposition to the arterial wall, combined with drug-therapy using aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and another inhibitor of platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
aggregation (usually ticlopidine
Ticlopidine
Ticlopidine is an antiplatelet drug in the thienopyridine family. Like clopidogrel, it is an adenosine diphosphate receptor inhibitor. It is used in patients in whom aspirin is not tolerated, or in whom dual antiplatelet therapy is desirable...
or clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...
) nearly eliminated this risk of early stent thrombosis.
Though it occurred less frequently than with balloon angioplasty
Angioplasty
Angioplasty is the technique of mechanically widening a narrowed or obstructed blood vessel, the latter typically being a result of atherosclerosis. An empty and collapsed balloon on a guide wire, known as a balloon catheter, is passed into the narrowed locations and then inflated to a fixed size...
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. 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
Restenosis
Restenosis literally means the reoccurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and subsequently become renarrowed...
.
The first successful trials were of sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
-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. Soon thereafter, a series of trials of paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
-eluting stents led to FDA approval of the Taxus stent in 2004.
The Xience V everolimus eluting stent was approved by the FDA in July 2008 and has been available in Europe and other international markets since late 2006. It is an investigational device in Japan.
Indications
Clinical trials have shown the benefits of coronary stenting with BMS over other methods of angioplasty, including balloon angioplasty and atherectomyAtherectomy
Atherectomy is a minimally invasive surgical method of removing, mainly, atherosclerosis from a large blood vessel within the body. Today, it is generally used to effectively treat peripheral arterial disease of the lower extremities...
. 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
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, 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
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
) causes ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
(reduced oxygen delivery to the muscle supplied by that artery.)
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; 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 AdministrationFood and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
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."
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, with worse outcomes for the patients in both studies. More recent data suggests that off label use of both bare metal stents as well as drug eluting stents have increased risks. However, DES seemed to have similar or improved rates of death or MI compared with BMS, and consistently reduced need for target vessel revascularization (TVR). Overall, the data supports the use of DES for off-label indications.
Alternatives (to stents in general)
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.Coronary artery bypass graft surgery is the best treatment for some patients. Differences between outcomes with stenting and with coronary bypass grafting (CABG) are a point of controversy. A recent study comparing the outcomes of all patients in New York
New York
New York is a state in the Northeastern region of the United States. It is the nation's third most populous state. New York is bordered by New Jersey and Pennsylvania to the south, and by Connecticut, Massachusetts and Vermont to the east...
state treated with coronary artery bypass surgery
Coronary artery bypass surgery
Coronary artery bypass surgery, also coronary artery bypass graft surgery, and colloquially heart bypass or bypass surgery is a surgical procedure performed to relieve angina and reduce the risk of death from coronary artery disease...
(CABG) or percutaneous coronary intervention
Percutaneous coronary intervention
Percutaneous coronary intervention , commonly known as coronary angioplasty or simply angioplasty, is one therapeutic procedure used to treat the stenotic coronary arteries of the heart found in coronary heart disease. These stenotic segments are due to the build up of cholesterol-laden plaques...
(PCI) demonstrated CABG was superior to PCI with DES in multivessel (two or more diseased arteries) coronary artery disease
Coronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart 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. 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.
Other studies, including the ARTS II registry, suggest that drug-eluting stenting is not inferior to coronary bypass for treatment of multivessel coronary disease. 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 (itself a randomized comparison between multivessel bare metal stenting vs. CABG.) 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.
In all comparison studies of stenting vs. bypass surgery, it is worth noting that only a small minority of patients with multivessel coronary disease have been eligible for inclusion in the studies, and that for most patients, clinical judgement by experienced operators suggests that one or the other approach is preferred.
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.Risks associated with cardiac catheterization
Cardiac catheterization
Cardiac catheterization is the insertion of a catheter into a chamber or vessel of the heart. This is done for both investigational and interventional purposes...
procedures include bleeding, allergic reaction to the X-ray contrast agents used to visualize the coronary arteries, and myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
. 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, though this remains highly controversial in the United States, not least because of the rare but largely unpredictable risk of coronary artery perforation. Rarely, a type of allergic reaction to the drug may occur; episodes of fatality have been reported.
Stent thrombosis
Although drug-eluting stents continue to represent a major medical advance for angioplasty, evidence has always shown new clot thrombosisThrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
formation with stents to be a problem, thus clotting suppressant agents are routinely given during placement and anti-clotting agents should be continued; the question is for how long. For drug-eluting stents (which, by design, delay formation of a new endothelium cover over the stent) that the incidence of clot formation within the stent may persist for a longer period of time, perhaps as long two to three years in a very small percentage of people. 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
Restenosis
Restenosis literally means the reoccurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and subsequently become renarrowed...
, are limited by the drugs released by the stent, but these drugs also limit formation of a new endothelial
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
layer over the new stent to inhibit clot formation. This lack of healing can make the stent an exposed surface on which a clot, sometimes life-threatening, can form.
Though less frequent with drug-eluting stents, neointimal proliferation can still occur in DES and cause restenosis. Stent occlusion because of thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
may occur during the procedure, in the following days, or later. The presence of thrombus around the stent may in turn affect the drug-eluting performance of the stent. Treatment with the antiplatelet drugs aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...
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. A recent histopathology study showed that very late DES thrombosis is associated with histopathological signs of inflammation and intravascular ultrasound evidence of vessel remodeling. Compared with other causes of myocardial infarction, eosinophilic infiltrates are more common in thrombi harvested from very late DES thrombosis and correlate with the extent of stent malapposition.
Whether drug-eluting stents are at higher risk than bare-metal stents for late thrombosis is intensely debated. In meta-analyses
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
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
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and sometimes death. 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
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
concluded that the mortality risk associated with drug-eluting and bare-metal stents is similar.
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.
The SPIRIT II study showed the Xience V DES was better than the Taxus.
Drug-eluting stents with a biodegradable coating
In order to address the risk of late stent thrombosis, drug-eluting stents with a biodegradable coating have been developed. One such stent is the BioMatrix stent of Biosensors International
Biosensors International
Biosensors International Group is a company that specializes in developing, manufacturing and marketing innovative medical devices for use in interventional cardiology and critical care procedures. The company was established in 1990 and was listed on the Singapore Stock Exchange in May 2005...
, which has been approved by European authorities in January 2008. Two year results of a large all-comers trial suggest a reduced risk of late stent thrombosis, especially after discontinuation of dual antiplatelet therapy. The Nevo stent of Cordis/J&J, also uses a biodegradable coating and is currently undergoing trials.
Design
Drug-eluting stents consist of three parts. Stent platform, coating, and drug.
The stent itself is an expandable metal alloy framework. Many DES are based on a bare-metal stent
Bare-metal stent
Bare-metal stent is a vascular stent without a coating . It is a mesh-like tube of thin wire. The first stents licenced for use in cardiac arteries were bare metal - often 316L stainless steel...
(BMS). The stents have elaborate mesh-like designs to allow expansion, flexibility and in some cases the ability to make/enlarge side openings for side vessels.
Cobalt chrome alloy is stronger (and more radio-opaque) than the usual 316L stainless steel so the struts can be thinner which seems to reduce the degree of restenosis
Restenosis
Restenosis literally means the reoccurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and subsequently become renarrowed...
. (The L605 CoCr alloy has less nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...
than 316L stainless steel and so may cause less allergy.)
A coating, typically of a polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
, holds and elutes (releases) the drug into the arterial wall by contact transfer.
The first few DES licenced used durable coatings, but some newer coating are designed to biodegrade after or as the drug is eluted.
Coatings are typically spray coated or dip coated. There can be one to three or more layers in the coating e.g. a base layer for adhesion, a main layer for holding the drug, and sometimes a top coat to slow down the release of the drug and extend its effect.
The drug is mainly to inhibit neointimal growth (due to proliferation of smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
cells) which would cause restenosis. Much of the neointimal hyperplasia seems to be caused by inflammation. Hence immunosuppressive and antiproliferative drugs are used. Both sirolimus and paclitaxel were previously used for other medical applications; new drugs are being evaluated for coronary stents.
Examples (approved for clinical use) :
- Cypher (J&J, Cordis ) uses a 316L stainless steel BxVelocity stent (140 µm struts) and adds a 12.6 µm 3 layer coating (2 µm Parylene C base coat, 10 µm main coat of PEVA, PBMA and sirolimusSirolimusSirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
, and a 0.6 µm top coat of PBMA). The sirolimus elutes over a period of about 30 days. - Taxus (Boston Scientific) uses a 316L stainless steel Express2 stent (132 µm struts) and adds a 16 µm single layer Translute SIBS copolymer coating containing paclitaxelPaclitaxelPaclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
which elutes over a period of about 90 days. - Endeavour (Medtronic) uses a cobalt chrome Driver stent (91 µm struts) and adds a 4.3 µm phosphorylcholinePhosphorylcholinePhosphorylcholine is a zwitterionic phospholipid found on the outer surface of red blood cell membranes. It is created by CD5+/B-1 B cells and is referred to as a non-pathogenic autoantibody.-Thrombus Resistant Stents:...
coating that includes zotarolimusZotarolimusZotarolimus is an immunosuppressant. It is a semi-synthetic derivative of rapamycin. It was designed for use in stents with phosphorylcholine as a carrier. Coronary stents reduce early complications and improve late clinical outcomes in patients needing interventional cardiology....
, on a 1 µm base coat. - Xience V (Guidant, Abbott) uses an L605 cobalt chrome ML Vision stent (81 µm struts) and adds a 7.6 µm fluropolymer multilayer coating with drug everolimusEverolimusEverolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
.
Examples approved outside the US :
- Zilver PTX (Cook Medical) Nitinol stent, no polymer, coated with paclitaxel, for use in peripheral arteries
- TaxCor (EuroCor GmbH) Highly Flexible Cobalt Chromium Stent Platform coated with fully biodegradable polymer as a carrier for Paciltaxel
- Axxion (Biosensors Int) Stainless steel stent, Synthetic Glycocalix coating with paclitaxelPaclitaxelPaclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
. - BioMatrix (Biosensors Int) S stent platform, bioabsorbable PLA coating with Biolimus A9Biolimus A9Umirolimus , is a macrocyclic lactone, a highly lipophilic derivative of sirolimus, an immunosuppressant. This drug is proprietary to Biosensors International, which uses it in its own drug-eluting stents, and licenses it to partners such as Terumo.Umirolimus inhibits T cell and smooth muscle...
drug. - ARTAX (Aachen Resonance) double helix stainless steel platform, without polymer, metal coated with paclitaxelPaclitaxelPaclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
drug.
Investigation and Alternative 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. Medtronic has developed zotarolimusZotarolimus
Zotarolimus is an immunosuppressant. It is a semi-synthetic derivative of rapamycin. It was designed for use in stents with phosphorylcholine as a carrier. Coronary stents reduce early complications and improve late clinical outcomes in patients needing interventional cardiology....
; unlike sirolimus and paclitaxel, this sirolimus analogue designed for use in stents with phosphorylcholine
Phosphorylcholine
Phosphorylcholine is a zwitterionic phospholipid found on the outer surface of red blood cell membranes. It is created by CD5+/B-1 B cells and is referred to as a non-pathogenic autoantibody.-Thrombus Resistant Stents:...
as a carrier. Their ZoMaxx stent is a zotarolimus-eluting, stainless steel and tantalum
Tantalum
Tantalum is a chemical element with the symbol Ta and atomic number 73. Previously known as tantalium, the name comes from Tantalus, a character in Greek mythology. Tantalum is a rare, hard, blue-gray, lustrous transition metal that is highly corrosion resistant. It is part of the refractory...
–based stent; a modified phosphorylcholine slowly releases the zotarolimus
.
Zotarolimus has been licensed to Medtronic
Medtronic
Medtronic, Inc. , based in suburban Minneapolis, Minnesota, is the world's largest medical technology company and is a Fortune 500 company.- History :...
which is researching the effectiveness in a drug-eluting stent of their own. Their Endeavor stent, which is a cobalt
Cobalt
Cobalt is a chemical element with symbol Co and atomic number 27. It is found naturally only in chemically combined form. The free element, produced by reductive smelting, is a hard, lustrous, silver-gray metal....
alloy, also uses phosphorylcholine to carry the zotarolimus was approved for use in Europe in 2005 is now close to U.S. FDA approval
.
Clinical trials are currently examining two stents carrying everolimus
Everolimus
Everolimus is the 40-O- derivative of sirolimus and works similarly to sirolimus as an mTOR inhibitor....
, an analog of sirolimus. Guidant
Guidant
Guidant Corporation, part of Boston Scientific and Abbott Labs, designs and manufactures artificial pacemakers, implantable defibrillators, stents, and other cardiovascular medical products. Their company headquarters is located in Indianapolis, Indiana. Their main competitors are Medtronic, St...
, 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
.
The Champion stent uses a bioabsorbable polylactic acid
Polylactic acid
Poly or polylactide is a thermoplastic aliphatic polyester derived from renewable resources, such as corn starch , tapioca products or sugarcanes...
carrier on a stainless steel stent.
In contrast, its Xience stent uses a durable (non-bioabsorbable) polymer on a cobalt alloy stent.
One alternative to drug-eluting stents is a stent surface designed to reduce the neointimal proliferation. One such is the Genous bioengineered stent.
In place of the stainless steel (and now cobalt chrome) 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
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
alloy–based stent has been tested in animals, though there is currently no carrier for drug elution.
A promising biodegradable framework is made from poly-L-lactide, a polymer of a derivative of L-lactic acid
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...
. One of these stents, the Igaki-Tamai stent, has been studied in pigs; tranilast
and paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
have been used as eluted drugs.
Further reading
(layperson overview, subscription required) (journal review article, subscription required)External links
- Drug-Eluting Stents — Angioplasty.Org Good overview and detail
- CIMIT Center For Integration of Medicine and Innovative Technology
- Cypher DES
- Image of the experimental CoStar Cobalt chrome stent
- Manu Sondhi, Amitha Jagannath & John B. Wong: A Meta-Analysis Of Randomized Controlled Trials With Coronary Drug-Eluting Stents Compared With Bare-Metal Stents: The Internet Journal of Cardiology. 2006; Volume 3, Number 2.
- Safety Profile of Drug-eluting Stents Similar to Bare-metal Stents (re G.W.Stone's presentation at TCT2006)
- TCT: Transcatheter Cardiovascular Therapeutics Meeting Coverage peer-reviewed articles from Medpage TodayMedPage TodayMedPage Today is an online medical news service for physicians and healthcare professionals and is based out of Little Falls, New Jersey. The site provides breaking medical news, professional medical analysis and continuing medical education credit for reading articles and answering a short series...
