Experts Say Warn About Stents - FDA Says No

Evelyn Pringle January 2007

What do to about the problematic over-use of drug-eluting stents has become a problem in itself. A recall is out of the question, because 3 million people in the US already have the devices implanted in their chests, according to USA today.

Drug-eluting stents (DES) are mesh tubes used in patients with heart disease to keep their arteries open following a procedures to remove blockages usually with an inflatable balloon called angioplasty.

It is believed that a majority, or likely 60%, of current DES use is off-label, meaning the stents are being implanted in patients for uses that have not been approved as safe and effective by the FDA. This off-label use, the agency says, typically involves patient and lesion subsets that are more complex than those represented in the randomized trials.

Not surprisingly, Boston Scientific and Johnson & Johnson, the two companies that sell them in the US, claim that there is no increased risk of stent thrombosis in patients implanted with the devices off-label, but that even if there is, it is probably due to their underlying health conditions. The drug-eluding stents approved for use are the Cypher and the Taxus.

On December 7-8, 2006, the FDA held a public meeting of the Circulatory System Devices Advisory Committee to: (1) provide a forum for the presentation of clinical data relevant to the issue of DES thrombosis both when DES are used according to their label and when they are used off-label in more complex patients beyond their FDA approved uses; and (2) address the appropriate duration of the use of Plavix (clopidogrel), a blood-thinning drug, with DES patients.

In the Clinical Overview for the panel, the FDA reported that recent presentations at scientific meetings have suggested a small but significant increase in the rates of: (1) death or myocardial infarction (MI); and (2) non-cardiac mortality in DES-treated patients compared to patients treated with bare metal stents.

The FDA acknowledges that although stent thrombosis detected during angiography or at autopsy is the best evidence, many patients do not undergo follow-up angiography, and autopsy rates are exceedingly low among both hospitalized and out-of-hospital patients in sudden deaths, and so counting only cases of stent thrombosis confirmed by angiography or autopsy can not provide an accurate estimate for the true rate of its occurrence.

The drug-eluding stents were developed to address the problem of restenosis, which prevents renarrowing of the artery. The relative benefits of DES compared to bare metal stents was a reduction in the composite endpoint consisting of death, MI and target vessel revascularization.

For both DES models, the FDA notes, the difference in outcome verses bare metal stents was due to a reduction in the rate of repeat revascularization, but there was no difference in the rate of death and MI between groups at 9 to 12 months after stenting.

Given the high case fatality and MI rates associated with stent thrombosis, the FDA told the advisory panel in the Overview, "it is reasonable to re-assess the risk/benefit ratio of reduced repeat revascularization rates if there is a significant increase in DES thrombosis induced death and MI."

The Overview includes a discussion of the Transcatheter Cardiovascular Therapeutics meeting in Washington, in October 2006, where Doctors Gregg Stone and Martin Leon presented meta-analyses of patient-level data from the Cypher and Taxus randomized clinical trails.

For the Taxus, the analyses found, the cumulative increase in stent thrombosis rate was 0.5% between one and four years after implantation, or approximately 0.15% per year. For the Cypher trials, the cumulative late-stent-thrombosis rate was 0.6% between one and four years, or approximately 0.2% per year.

Commenting on these meta-analyses at the meeting, Dr Stuart Pocock noted that after one year, 5 Cypher patients and no bare metal stent patients experienced late thrombosis and after one year, stent thrombosis occurred in 9 Taxus patients compared with 2 patients with bare metal stents.

The Cypher was FDA approved on April 24, 2003, and the Taxus obtained approval on March 4, 2004. As a condition of approval, both DES makers were required to conduct registry studies of at least 2,000 patients followed for 12 months.

The trials submitted for FDA approval primarily involved non-complex patients and compared the Cypher and Taxus stents to bare metal stents in patients with single-vessel disease, considered to be a low risk population.

However, according to the FDA, following these approvals, "it is estimated that a majority of DES are implanted in lesions outside of their current indications for use, such as in-stent restenosis lesions, bifurcation lesions, coronary artery bypass grafts, acute myocardial infarction, chronic total occlusions, overlapping and multiple stents per vessel and in patients with multivessel disease and chronic renal insufficiency."

The Medical Device Reporting (MDR) system is a nationwide passive surveillance system which includes both mandatory and voluntary reporting. The MDR regulations, require manufacturers to submit reports of device-related deaths or serious injuries involving a device malfunction that could cause or contribute to a death or serious injury.

However, according to the FDA, its passive surveillance system has four significant limitations: (1) under-reporting of adverse events; (2) report data are often incomplete and invalid; (3) due to device complexity and the use environment, causality cannot be determined; and (4) reports are not representative of the universe of adverse events because reporting is subject to various biases.

As a condition of FDA approval, device makers are required to submit a summary every 6
months of adverse events deemed reportable, those deemed non-reportable, and a summary of anticipated versus unanticipated events.

A few months after the Cypher was on the market, the FDA received an influx and clustering of sub-acute thrombosis reports and the FDA, together with Johnson & Johnson, issued a letter notifying physicians of these initial reports in July 2003.

In October 2003, after receiving approximately 300 reports of sub-acute thrombosis through the MDR, the FDA issued a public health notification to curtail off-label use, reminding clinicians to follow the product’s labeling, including patient selection, sizing of the stent and concomitant antiplatelet therapy

The current labeling for dual antiplatelet therapy is 3 months for Cypher and 6 months for Taxus. The FDA has recognized two major issues with duel antiplatelet therapy: (1) patient non-compliance or early discontinuation of therapy; and (2) uncertainty regarding the optimal duration of dual antiplatelet therapy is unknown, particularly with high risk patients.

Multiple studies, the FDA says, have found increased rates of DES thrombosis, MI, or mortality associated with premature discontinuation of dual anti-platelet therapy. Just this month, a study in the Journal of the American College of Cardiology, and another in the Journal of the American Medical Association, reported that risks increased when Plavix was stopped.

Experts point out that the high cost of Plavix which sells for about $4 a pill in the US, might lead to a patient's discontinuation of therapy.

However, according to the FDA, it is not even clear that extended duration of dual-antiplatelet therapy will prevent late thrombosis. For instance, in a presentation at the TCT meeting, Dr Alaide Chieffo reported that of 16 patients, among 3021 DES recipients, treated in Milan, Siegburg, and Naples, who developed late DES thrombosis, 9 had been taking Plavix.

According to the FDA, a consideration for a longer duration of therapy must also weigh the potential benefit of a reduction in thrombosis against a potential increase in the risk of major bleeding.

And experts predict that bleeding with Plavix treatment could occur in many patients. A study in the January 20, 2005, New England Journal of Medicine, found patients taking Plavix experienced more than 12 times as many ulcers bleeds as patients who received aspirin plus the heartburn pill, Nexium. The study treated 320 patients whose ulcers had healed and found that 13 of the patients taking Plavix experienced renewed ulcer bleeding while just one of the patients taking aspirin and Nexium had an ulcer bleed.

Experts also point out that Plavix is a long-lasting drug with no available antidote, meaning once a patient takes it, their platelets are out of commission for the time it takes for the body to get rid of the old platelets and make new ones which is estimated to be between 7 and 10 days. If a patient were to require immediate surgery during this time period, they point out, bleeding could become a major problem.

Critics contend that the added expense and risks associated with Plavix for people who would not ordinarily need to take the drug to begin with, are reason enough to justify a warning against the off-label use of DES.

An April 20, 2006, study in the New England Journal of Medicine, led by Dr Eric Topol and Dr Deepak Bhatt of the Cleveland Clinic, found that the combination of Plavix and aspirin not only did not help most patients with heart disease, it almost doubled the risk of death, heart attack or stroke for those with no clogged arteries but with conditions like high cholesterol or high blood pressure.

In the end, the FDA advisory panel did recommend that a warning be added to the DES labels stating that off-label use may increase the risk of thrombosis, myocardial infarction, and death, and also said that the labels should carry a recommendation that dual antiplatelet therapy with aspirin and Plavix should continue for 12 months when the stents are implanted off-label.

The panel agreed that even when implanted for approved uses, DES were associated with an increased risk of stent thrombosis, but said there was no evidence of an increased risk of death or MI.

Prior to the Bush administration's take-over of the FDA, these recommendations would have meant something because the agency almost always followed the recommendations of its advisory panels.

However, now-a-days it seems like a complete waste of tax dollars to foot the bill to haul these so-called "expert panels" to Washington because a brief look at the history over the past several yeas proves that the Bush administration's FDA will cater to the wishes of the pharmaceutical industry in nearly every instance.

And it will apparently be no different with this panel. Several members of the committee suggested that a Black Box warning should be added to the DES labels, but according to the December 8, 2006 MedPage Today, Bran Zuckerman, MD, director of the FDA's division of cardiovascular devices, "quickly quashed that suggestion."

"There will be no black box," he stated.

And moments after the hearing adjourned, MedPage reports, Daniel Schultz, MD, director of the FDA's Center for Devices and Radiological Health, said there could be no label changes that reference off-label use either.

So once again, an advisory committee has gone through the motions of trying to protect the unwitting public against Big Pharma's off-label sale of potentially lethal products and the FDA says "forget about it."