PARIS – A report from the European Society of Cardiology (ESC; Sophia Antipolis, France) responding to repeated challenges over the safety and efficacy of drug-eluting stents (DES) finds that while there is a short-term benefit over bare-metal stents (BMS) for the drug-coated version, there remains a continuing concern that DES presents an "excess risk of late stent thrombosis."

Long-awaited and long-delayed, the final report from the ESC Task Force On Drug Eluting Safety also takes on issues of cost-effectiveness and regulatory oversight for DES with an endorsement of the controversial pricing scheme developed by the UK's National Institute for Clinical Excellence (NICE) and a recommendation calling for the intervention of the European Commission to set tighter standards for approval of new stents.

The report was released in the online version of the European Heart Journal in early December and will appear in the upcoming print edition.

Significantly, despite six years of clinical experience and dozens of high-profile studies, there is not a ringing endorsement of DES over the simpler and less-costly bare-metal version.

Instead the report's authors hope the next-generation technology will fulfill the promise, saying, "The current conclusions regarding the safety and efficacy of DES should not divert the attention from the importance to continue development of less- or non-thrombogenic stents."

Explaining the 14-month lapse between the meeting and the publication of the report William Wijns, MD, president of the European Association for Percutaneous Cardiovascular Interventions (EAPCI, also Sophia Antipolis) and a lead author of the report, said, "It was essential to make sure that its content is considered acceptable by all stakeholders"

The final report "reflects the consensus, or lack thereof, between the profession, the industry and the representatives of regulatory bodies," he told Medical Device Daily, adding that he believes the result is "quite rewarding and the content of the document remains very relevant."

Another author, Steen Kristensen, a cardiologist at Aarhus University Hospital (Skejby, Denmark), told MDD, "The firestorm started in 2006 is now settling and while it seems there is a slight increase of risk with DES long-term, there is no doubt that these stents decrease restenosis for up to 12 months."

"With DES, we have a device that is useful for a lot of patients, but balancing the risks is what this report addresses," he said.

The ESC Task Force on Drug Eluting Safety was created in the wake of controversial findings presented at the society's annual congress in 2006 that set off widespread concern about whether the much-heralded stents introduced in 2002 actually were causing blood clots.

Worldwide sales of DES have been in a sharp decline since the 2006 ESC congress, falling from a peak of $5.1 billion in 2005 to $3.9 billion last year, according to the Thomson Reuters agency Research and Markets.

Manufacturers, and the cardiologists who implant the stents, have been scrambling ever since as a cascade of registries and studies, including those sponsored by stent makers, have continued to reveal mixed or mitigated results for DES in light of the promised potential and the premium price tag attached to the therapy.

The key moment in the task force's effort was the two-day Forum on Drug Eluting Stents held in September, 2007 at the European Heart House near Nice, France, that gathered all stakeholders to the DES controversy, including a prestigious international panel of practitioners, representatives of both European and America regulators, and the multi-national giants who manufacture the devices (A 'Who's Who' of cardiology studied DES concerns, page 9).

Yet the ESC Forum Report struggles to draw a clear conclusion about the clinical safety and efficacy of DES precisely because, despite the dozens of studies launched to defend the qualities of DES, data is neither consistent nor consistent and reliable data is not available.

"I see no need for raising again the level of adrenalin," said Wijns, who leads the Cardiovascular Center at Onze-Lieve-Vrouwziekenhuis Hospital (Aalst, Belgium).

"We now understand better the delicate balance between the unquestionable efficacy of DES and the small incremental late safety hazard," he said. "The key message is that the net result is no overall excess risk of death or infarction.

"The field is in strong evolutionary mode and some of the newer-generation DES seem to be successful in addressing the shortcomings of the first-generation devices that have to be considered as prototypes with all the limitations that go with a first attempt," he said during his conversation with MDD.

"Whether better, more biocompatible polymers or the use of bioerodable polymers will be the best buy remains to be seen," he said. "The good news is that both approaches are very encouraging."

In the short term, a compilation of study results and registries of patients indicates that when DES is compared with BMS as an initial treatment strategy, the drug-eluting version is associated with lower subsequent revascularization rates, according to the ESC report.

The report adds that at early stages "the overall relative safety and efficacy of DES compared with BMS appears to be consistent across different groups of patients, albeit at various levels of absolute benefit and risk."

But data from studies indicate a worrisome trend for the longer term where DES poses "an excess risk of late stent thrombosis."

"The apparent early benefit [of DES] is lost by an excess of subsequent events," states the report that goes on to cite "a pattern of lower initial and increased late mortality rates," of adverse events.

Fortunately for the manufacturers, the regulators who approved the devices and the cardiologists who implant them, the study states cautiously that to this point, this risk "does not seem to impact on the occurrence of hard clinical endpoints like death and myocardial infarction up to four years."

Still, DES is not out of the woods with the focus turning to late stage results.

"If the trend of an early benefit with some DES, with a later excess of death and MI as observed in some studies would persist, long-term outcome beyond five years might gradually favour some types of BMS," says the report, adding quickly, "This is, of course, highly speculative. Nevertheless, it is desirable that the investigators will continue to provide such very long-term follow-up data."

The report also cautions that despite industry claims to the contrary, "the long-term safety and efficacy of DES in high-risk patient subsets such as diabetics and patients presenting with myocardial infarction remains to be established."

The problem in searching for more conclusive data is the studies themselves, according to the report's authors.

"Interpretation of long-term follow-up data is hampered by cross-overs and mixed DES and BMS use, patients who receive first one type of stent and another type of stent at a later point in time, for example, for in-stent restenosis," according to the authors.

There are also important differences between various types of stents, the report notes, with dissimilar mechanical and pharmacological properties and subsequent differences in clinical outcome.

While the reports authors struggle to draw conclusions that could lead to guidance on the use of DES, the evidence seems to point to the leading incumbents, the sirolimus-eluting (SES) Cypher from Cordis (Miami Lakes, Florida) and the paclitaxel-eluting (PES) Taxus from Boston Scientific (Natick, Massachusetts), being fading stars.

The ESC report notes two- and three-year follow-up of the ENDEAVOR trials for the new zotarolimus-eluting stent from Medtronic (Mineapolis) shows "remarkably low rates" of stent thrombosis and "significantly lower cardiac death and MI rates" up to three years.

"It is possible that this zotarolimus-eluting stent has a better safety profile than SES or PES," says the report, adding "the results of the large E-Five registry and the 8,800 patients randomized PROTECT trial are eagerly awaited."