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Continuing Medical Education
from Clinical Update, Spring 2004
Drug-eluting Stents: The Final Answer to Restenosis?
Robert J. Applegate, M.D., FACC, FASCI, FAHA
Section of Cardiology, Department of Internal Medicine
This Continuing Medical Education activity is sponsored by Wake Forest University School of Medicine.
Educational Objectives: 1) Discuss the pathophysiology and clinical manifestations of coronary artery
restenosis; 2) Describe the mechanism of benefit of drug eluting stents and outcomes associated with their use in
patients with coronary artery disease; 3) Identify patients who would benefit from this therapy.
Abstract: Re-narrowing at the angioplasty site, or restenosis, occurs in as many as 50% of patients following
percutaneous transluminal coronary angioplasty. Recently, the development of localized drug delivery using
drug-eluting stents has markedly reduced the incidence of restenosis. The safety profile of the drug-eluting stents
is comparable to that of bare-metal stents in clinical trials reported to date, but only limited data are available
about long-term safety of this powerful therapy, which costs about three times more than bare-metal stents.
Introduction
Andreas Gruentzig performed the first percutaneous transluminal coronary angioplasty (PTCA) in humans in
1977(1) and launched an exciting and innovative therapy for treating patients with coronary artery disease.
Despite technological improvements in balloon angioplasty, re-narrowing at the angioplasty site, or restenosis,
occurs in up to 30% to 50% of patients following PTCA. The development of coronary stenting reduced the
incidence of restenosis after PTCA. However, restenosis of stents themselves occurs in approximately 20% to
40% of patients and remains a significant limitation of this approach. While numerous drug and mechanical
interventions have been used in an attempt to minimize or eliminate restenosis, only limited success has been
observed with these approaches. Recently, the development of localized drug delivery using stents, or drugeluting stents, has markedly reduced the incidence of restenosis. With this new technology, a new era in the
percutaneous management of patients with coronary artery disease has emerged. The phenomenon of restenosis
as well as the clinical benefit arising from the use of drug-eluting stents will be reviewed in this article.
Pathophysiology of Restenosis
Restenosis of the coronary artery following PTCA reflects the interaction of a cascade of molecular and cellular
events occurring within the vessel wall. PTCA induces localized injury to the vessel wall, which leads to the
release of vasoactive, thrombogenic, and mitogenic factors that result in processes causing re-narrowing at the
injured site. Three distinct processes can be identified that contribute to the restenosis process: elastic recoil,
arterial remodeling and neointimal hyperplasia. The ability to predict the extent and severity of the restenotic
process has been a vexing one. It appears that a combination of patient, lesion, procedural and post-procedural
characteristics all contribute to the development of restenosis after coronary angioplasty. Diabetes mellitus and
chronic renal insufficiency appear to be the two most dominant clinical factors that predispose patients to
restenosis. A host of lesion characteristics, including long lesions, chronic total occlusions, bifurcation disease,
small caliber vessels and disease in a saphenous vein graft all are associated with higher rates of restenosis.
Finally, a larger post-procedural minimum lumen diameter substantially reduces the risk of restenosis and has
led to the concept that “bigger is better”(2).
Restenosis Therapies
Mechanical devices designed to provide a larger lumen at the completion of the procedure, and pharmacologic
therapies designed to inhibit the neointimal proliferation have both been used to reduce restenosis. Debulking
procedures, such as directional coronary atherectomy, rotational atherectomy and laser angioplasty,
unfortunately have not been associated with clear-cut reduction in the incidence of restenosis. Coronary artery
stents(3), however, have reduced the restenosis rate following coronary angioplasty by approximately 50%(4;5).
Unfortunately, in-stent restenosis occurs in 20% to 40% of patients. While studies evaluating the effectiveness of
pharmacologic agents to reduce restenosis in animal models often were encouraging, use of the same drugs in
patients to reduce restenosis has been almost universally disappointing. Several factors likely contribute to the
disparity between the results in animal models and humans, but the predominant opinion is that systemic therapy
does not provide a high enough concentration of drug at the injured site in the coronary artery to affect cell
proliferation. Nonetheless, the apparent ability of a wide variety of chemotherapeutic agents to inhibit the
neointimal hyperplastic process in animals paved the way for the concept that if drugs could be administered at a
high enough concentration locally in the coronary artery of humans, then the restenotic process may be inhibited
by local drug delivery.
Drug-Eluting Stents
A drug-eluting stent has three elements, all of which have an important effect on vascular injury and restenosis:
the metallic stent, a drug-carrier vehicle or coating, and a pharmacologic agent that interferes with local
neointimal proliferation(6;7). Current drug-eluting stent systems utilize commercially available stent designs and
balloon delivery systems, although newer stent platforms that are designed specifically for drug elution are being
evaluated. Stent coatings include biocompatible polymers such as phosphorylcholine, and depot release coatings
such as nanoporous ceramic(8). The pharmacologic agents used to interfere with local neointimal formation can
be classified as antiproliferative, anti-inflammatory or immune modulating, anti-migratory, antithrombotic and
pro-healing agents(6;7). Rapamycin, which is the pharmacologic agent used in the recently released CYPHER
stent (Cordis Corporation) interferes with cell proliferation early in the cell cycle (G1 phase arrest) and is
considered to be a cytostatic agent. There is currently a great deal of active research into evaluating different and
novel pharmacologic agents which also may limit neointimal proliferation.
Clinical Outcomes of Drug-eluting Stents
Clinical outcomes studies comparing drug-eluting stents to bare-metal stents have shown dramatic reductions in
restenosis with drug elution. The first in-man experience with a sirolimus drug-eluting stent (CYPHER, Cordis
Corporation), the RAVEL trial and finally the SIRIUS multi-center United States Phase III trial have all
demonstrated a substantial reduction in angiographic restenosis (> 50% stenosis)(9-11). In-stent restenosis rates
of 0% to 3% and in-segment or vessel restenosis rates of up to only 9% were observed with the drug-eluting
stents, compared to 33% in the bare-metal stent arm. Stent thrombosis, major clinical events, and aneurysms at
the site of the stent placement were similar in the two treatment groups. These series of clinical trials led the
FDA to approve the CYPHER stent for clinical use (April, 2003)(12). Similarly, in the TAXUS II and TAXUS
IV randomized clinical trials a substantial reduction in binary restenosis in patients receiving paclitaxel drugeluting stents compared to bare-metal stents was observed at a level comparable to that seen with a sirolimus
drug-eluting stent(13;14). Because of these results the FDA has approved the paclitaxel eluting EXPRESS stent
(Boston Scientific) for clinical use (Spring 2004). These data indicate that drug-eluting stents can be used
resulting in dramatic reduction in restenosis without sacrificing the safety of bare-metal stents.
While the results of the studies evaluating the sirolimus and paclitaxel drug-eluting stents have been extremely
positive, multiple other studies have been reported demonstrating a seeming lack of efficacy of different drugeluting stents(6;7). These negative studies suggest that the ability of a drug-eluting stent platform to inhibit
neointimal proliferation is complex and requires careful and extensive testing before concluding that a drugeluting stent system will be effective in patients. Additionally, it is likely that some biologic agents, no matter
how effective when tested in animal models, will not result in an effective drug-eluting stent platform. Since the
currently available, or soon to be available, drug-eluting platforms do not entirely eliminate neointimal
proliferation, there are opportunities to develop better drug-eluting stent systems. Whether this elusive goal can
be achieved remains to be determined.
Patients were carefully selected for inclusion in the currently available drug-eluting stent trials. Thus, the benefit
of drug-eluting stent use in a broader range of patients not evaluated in clinical trials, including those with acute
myocardial infarction, saphenous vein grafts and bifurcation lesions, remains to be determined. Having said that,
one of the most significant findings from the SIRIUS trial was that drug-eluting stents were beneficial in a wide
range of lesion lengths as well as patient types. Whether the lesion treated was a short segment in a large vessel,
or a long segment in a smaller vessel, the relative reduction in restenosis rates with drug-eluting stents were
significant. Moreover, diabetic patients also received as significant a benefit from drug-eluting stents as did nondiabetic patients. Recent “real world” clinical outcomes from a consecutive group of patients with acute
coronary syndromes treated with drug-eluting stents indicate that clinical restenosis rates and safety profiles are
comparable to those achieved in the SIRIUS trial(15). These limited results suggest that the benefits observed in
the clinical trials should result in similar outcomes in a broader group of patients. Certainly, more studies and
experience will need to be reviewed before it can be unequivocally stated that the ability of drug-eluting stents to
reduce neointimal proliferation can be uniformly expected in all patient types and lesion characteristics.
Safety Profile of Drug-Eluting Stents
While the safety profile of the drug-eluting stents is comparable to that of bare-metal stents in the clinical trials
reported to date; only limited data are available about long term-safety of this powerful therapy. One concern in
particular merits mention. The incidence of subacute stent thrombosis following the recent clinical release of
drug-eluting stents has been of much interest. The FDA recently reported several hundred cases of sub-acute
stent thrombosis following use of drug-eluting stents. Because re-endothelialization of drug-eluting stents is
believed to occur at a slower rate than that of bare-metal stents, the period of risk for subacute thrombosis may
be longer than for conventional stents, and therefore the overall risk may be theoretically higher. Accordingly,
the recommendation for the duration of antiplatelet therapy following placement of a drug-eluting stent has been
extended from one month to three months. Although the number of cases of subacute stent thrombosis drew
considerable attention and concern, when viewed in context of the huge number of drug-eluting stents placed,
the actual incidence of subacute stent thrombosis appeared to be well under 1%, which is comparable to or lower
than that seen with bare-metal stents. The incidence of stent thrombosis occurring more than three to six months
after drug-eluting stent placement remains to be determined, but in small series evaluating the safety of drugeluting stents up to three years, this does not appear to be a significant problem(16).
Impact of Drug-Eluting Stents on Health Care
Since its release in April of 2003, CYPHER stent usage in the United States has increased dramatically,
benefitting patients greatly. However, drug-eluting stents cost approximately three times more than bare-metal
stents. The substantial increase in the cost of a drug-eluting stent compared to a bare-metal stent has placed
tremendous stress on the healthcare industry, particularly hospitals, which directly bear the brunt of the increased
costs. Payment reimbursement for drug-eluting stents has been increased to match the increased cost of a drugeluting stent. However, when more than one drug-eluting stent is placed, with a national standard somewhere
between 1.5 and 1.8 stents placed per patient, the full cost of using drug-eluting stents cannot be recovered under
current remuneration plans. It is hopeful that as with all new technologies, greater competition in the
marketplace will lead to price reductions and minimize the financial pressures on hospitals.
Conclusion
In conclusion, coronary angioplasty results in lumen enlargement but also localized injury initiating processes
resulting in restenosis at the angioplasty site including elastic recoil, negative arterial remodeling and neointimal
proliferation. While stents eliminate elastic recoil and negative arterial remodeling, neointimal proliferation
within the coronary stent continues to remain a significant clinical problem. Drug-eluting stents, however,
substantially reduce neointimal proliferation within a stent without sacrificing the safety profile of conventional
stents. Thus, a new and exciting therapy for patients with coronary artery disease has been launched.
References
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