Drug Eluting Stents Playing Role of Blood Traffic Cop After Angioplasty

The stent market in the United States in 2002 was approximately $1.36 billion. Introduction of drug-eluting stents this year is expected to expand the market to $2.6 billion, and it is anticipated to reach almost $4 billion by 2004.

In the first decade of use of coronary balloon angioplasty (1977-87), cardiologists were faced with a dilemma. In a small percentage of cases, the artery would collapse after the balloon was deflated, sometimes after the patient had been moved to recovery. The only option available was emergency bypass graft surgery. Another problem was that about 30 percent of all coronary arteries started to close again after balloon angioplasty.

Enter the Stent
By the mid-1980s, new devices were being designed that aimed to provide more durability and safety. One such device was the stent, and the first to be approved for use in the United States was the Palmaz-Schatz, made by Johnson & Johnson/Cordis.

The bare metal stent, now used in approximately 80 percent of all percutaneous coronary interventions, is mounted on a balloon after angioplasty and opened once inside the coronary artery. Although stents virtually eliminated many abrupt artery closure complications, epidemiological data shows that 20-25 percent of coronary stents will restenose.

Stents reduce the frequency of in-stent restenosis in relatively large coronary vessels; but when they are used in smaller, more tortuous vessels with more complex lesions and longer lengths, restenosis rates increase greatly.

Implanting stents induces arterial injury and foreign body reactions that cause acute and chronic vessel wall inflammation. Interventional cardiologists discovered that restenosis is not a recurrence of coronary artery disease, but rather the body’s response to the “controlled injury” of angioplasty, characterized by growth of smooth muscle cells comparable to a scar forming over an injury. Oral anticoagulants, anti-inflammatories and anti-proliferative drugs have not prevented restenosis.

Due to poor understanding of the pathophysiology of restenosis, it has not been simple to choose the right drug. However, researchers discovered they could use the body’s circulatory system to deliver pharmacological therapy, using the metal stent as the vehicle, thereby interrupting the biological process that caused restenosis.

Revolutionary Technology
Drug-coated stents give off drugs that help halt cell development, allowing the vessel to heal. In clinical trials, they have shown much lower rates of restenosis. The leading contenders are sirolimus- and paclitaxel-coated stents.

Revolutionary technologies emerged in 2002, with the immunosuppressant drug sirolimus used on the Cypher� stent from Johnson & Johnson/Cordis. Sirolimus is a synthetic drug approved by the FDA as an oral immunosuppressive agent used to prevent organ transplant rejection. It dramatically increases local vessel wall concentrations, while allowing control over release kinetics.

The SIRIUS trial has shown extremely positive results, with 8-month follow-up recently reporting an in-stent restenosis rate of only 3.2 percent, a 91 percent reduction over the control group.

“The final results of the 1,100-patient SIRIUS trial provided the power of important conclusions on many critical subgroup populations,” stated Martin B. Leon, MD, principal investigator of the SIRIUS clinical trial. “In summary, the Cypher stent has overwhelming and consistent treatment effects (improvement compared with control bare stents) in all populations tested, including diabetics, LAD lesions, small vessels and long lesions.”

In April 2003, the U.S. Food and Drug Administration (FDA) approved the Cypher stent for use in the United States. The FDA required Cordis to conduct a 2,000-patient post-approval study and continue to evaluate patients from ongoing clinical trials to assess the long-term safety and effectiveness of the Cypher stent, and to look for rare adverse events that may result from its use.

A second large clinical trial is the TAXUS II, which uses Boston Scientific’s stent coated with a polymer eluting the chemotherapy agent paclitaxel. This trial showed a restenosis rate of 2.3 percent and 4.3 percent for the slow and moderate release cohorts, respectively. Paclitaxel has also been used in the Cook ELUTES trial and the Guidant DELIVER trial, both reporting similar results.

Drug-Eluting Stent Design
Drug-eluting stent systems encompass three components: design, pharmacologic agent and drug carrier vehicle. All three have an impact on clinical outcomes. No matter the type of drug used, the therapeutic benefit vs. the local vascular toxicity must be considered.

Concerns remain over unresolved issues related to the drug, stent, type of lesion and deployment. Interactions between the components bring the potential for complications, and are still a matter of trial and error. Factors comprising an optimal drug-eluting stent system include:

excellent delivery;

good scaffolding properties;

low restenosis rates;

MRI friendly, nonferromagnetic;

improved drug loading patterns;

pharmacokinetic diversity;

high deliverability; and

biodegradable properties.

Rapid Advances
A survey conducted by JP Morgan Securities Inc. in October 2002 that involved interventional cardiologists in the United States suggested rapid adoption of drug-eluting stents in the United States. Responses from 140 interventional cardiologists, who perform approximately 30,600 angioplasties annually, suggested that once Medicare reimbursement was in place in the second quarter of 2003, two-thirds of all stents would be drug-eluting, with the expectation rising to 77 percent in the third quarter.

Barry M. Cohen, MD, a New Jersey cardiologist, states in his book, Coronary Heart Disease: A Guide to Diagnosis and Treatment, “by reducing the risk of re-narrowing with these and other techniques that are being developed, not only will fewer patients require a return visit to the cath lab, fewer patients may ultimately need bypass surgery.”

David W. McAllister, DO, interventional cardiologist at Iowa Heart Center, also believes that the use of drug-eluting stents could decrease the number of bypass surgeries.

Obstacles Remain
However, obstacles remain in expanding the use of drug-eluting stents:

Cost – While bare metal stents cost an average of $1,000 each, drug-eluting stents are coming to market at a cost of approximately $2,750. Though the reimbursement for a procedure utilizing drug-eluting stents is $1,700 higher than for bare metal stents for patients without myocardial infarction and $2,000 for those with myocardial infarction, the incremental cost of the new device is estimated at $2,600-$3,000 per procedure.

Harold L. Dauerman, MD, director of the cardiac catheterization laboratory at Fletcher Allen Healthcare and associate professor of medicine at the University of Vermont, thinks the cost will not be prohibitive in the United States, but will be in other regions of the world. For instance, Europeans have drug-eluting stents available but rarely use them due to cost constraints.

More Data – So far, trials to date have put forth only limited information on certain subsets of patients associated with higher risks of re-intervention. This suggests that more data needs to be evaluated before these new stents become the standard intervention with subsets of higher-risk patients.

Although recent data is impressive, the technology is still new, and therefore there is no long-term safety or efficacy data. Though most interventional cardiologists consider drug-eluting stents revolutionary, they will be eagerly awaiting future data.

Shelf Life – Questions have been raised as to how long a drug-eluting stent (specifically sirolimus) should be kept in stock in catheterization labs.

William Gray, MD, a cardiologist at Swedish Medical Center in Seattle, said it is too early to uncover problems with this type of stent; deployment is likely to be important, but results with the SIRIUS trial were good. He added there are theoretical concerns regarding the amount of calcium in a lesion and the possibility of disrupting the polymer coating and/or reduced drug elution to target tissue, but a trial in Europe demonstrated effectiveness with sirolimus in this kind of calcified lesion.

With regard to complications, Dr. Gray included the formation of aneurysms, late restenosis, late thrombosis and systemic drug effects with multiple stents. So far, none of these have become an issue.

Still, medical science seems to be on the verge of showing that drug-eluting stents have the impetus to be revolutionary in the treatment of coronary artery disease, the most common cause of mortality in the Western world.

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