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 Cardiovascular Devices & Drugs, 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 CD&D, "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 Thomson Reuters 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 manufacturers the devices.

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 CD&D.

"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 favor 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 crossovers 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 (Minneapolis) 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," states the report, adding "the results of the large E-Five registry and the 8,800 patients randomized PROTECT trial are eagerly awaited."

Tougher rules, better data, price cuts

The reputation of drug-eluting stents (DES) has been severely SCAAR-ed, and the ESC report seeks to heal that wound with a thorough scrutiny of hundreds of clinical studies.

It was the Swedes who started what ESC has termed a "firestorm" over the efficacy of DES with the presentation at the 2006 ESC Congress of the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), which suggested higher mortality among patients receiving the drug-coated stents compared to those with bare-metal stents.

Worldwide use of DES went into a sharp decline since the 2006 ESC congress with sales following the curve falling from a peak of $5.1 billion in 2005 to $3.9 billion last year, according to Thomson Reuters Research and Markets.

In response, ESC created the Task Force on Drug Eluting Safety. Unexpectedly, the task force went beyond clinical concerns over DES to attack cost-effectiveness and regulatory issues as well in its report.

Where the recommendations over clinical criteria in the report remain tattered and scarred, the ESC Task Force is clear, conclusive and even controversial in its directives regarding reimbursement and regulation.

Due to the relative ease of receiving a CE mark for stents with a requirement only to demonstrate safety, as opposed to the American FDA requirements to demonstrate both safety and efficacy, Europe became the battleground for Stent Wars, an escalating competition that has seen spending and marketing muscle on a scale usually associated with blockbuster drugs rather than medical devices.

Noting there were 19 stents commercially available to European cardiologists at the time of the ESC Forum, compared to just two in the U.S. in 2007, the final report from the ESC meeting calls into question the entire regulatory process as well as challenging the methodology of myriad clinical trials.

The report cites a review by the German Society of Cardiology of data from 76 randomized controlled trials supporting those DES receiving the CE mark which concluded that "only three, or at best five, out of the 19 CE-marked DES had adequate clinical documentation supporting their use."

In its most strongly worded recommendation the ESC Forum Report says, "The European Commission is asked to initiate the development of a unified guidance document for assessment of DES," and encourages the EU to consult with the FDA in drawing up its standards.

Going further, the ESC Task Force recommends that European market access should be based on efficacy, suggesting that initial approval might be based on assessment of restenosis or neointimal formation using one-year clinical follow-up.

The ESC group then calls for mandatory annual assessments of adverse events for a given stent stretching out to five years.

The ESC Forum Report also draws a bead on clinical trial design, not only calling for standardization but specifically spelling out some elements and in some cases the precise terminology to be used.

ESC set the tone for future clinical studies with its own SYNTAX trial presented at the organization's annual congress in September 2008.

Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) was a large-scale investigation with 62 European heart centers and 23 centers in the U.S. participating that featured both a randomized clinical trial component and a separate registry component.

SYNTAX, sponsored by Boston Scientific, compared interventional stenting of arteries with traditional coronary bypass surgery, with the endpoint being major adverse cardiac events at one year.

Significantly, in designing its own study, the cardiologists insisted on their preference for the real-world "all-comers" design where the study includes all patients who have severe cardiac disease and does not set highly selective criteria for patient exclusion, which characterizes clinical trials designed by manufacturers.

In the ESC Forum report, the voice of this experience can be heard in the recommendation that clinical trials "should strive to include all-comers, which should be followed by large-scale all-comer registries to assess both the benefits and late complications."

Tightening further the standards for clinical trials, the report states flatly, "randomized trials are required to assess the benefit, cost-effectiveness, and optimal dose and duration of long-term (dual) anti-platelet therapy," and that "currently, the preferred design for prospective trials seems to be a 2 x 2 factorial design that incorporates a double randomization to device and anti-platelet regimen."

Data from clinical trials and registries should be in the public domain for independent analyses, insist the authors.

Yes to DES, but at what price?

The premium price of DES compared with BMS have led to multiple cost-effectiveness studies and the ESC Task Force notes that in contrast to clinical concerns, the findings of the cost-benefit analyses are consistent, "indicating that DES are not cost-effective at the current price levels for most patients undergoing PCI for stable angina, while the use of DES can be cost-effective in a subset of patients at high risk for restenosis."

The cardiologists move quickly through this issue, and conclude simply by calling for a price cut saying that the cost of the stent is a key factor in the equation of balancing benefits against risk.

The Task Force follows the evolution over five years of the cost analyses and findings of the British technology assessment agency, the National Institute for Clinical Excellence (NICE), and surprisingly, delivers a wholehearted endorsement not only of the analysis but the reimbursement schedule set for practitioners in the UK's National Health Service, even citing the price in pounds Sterling.

"DES would be cost-effective in the majority of patients undergoing PCI at a price premium around 450 ( 300) above the price of comparable BMS, or less," states the report.

For new market entrants, the cardiologists are equally sharp in setting benchmarks, saying, "The incremental cost-effectiveness ratio will be heavily influenced by the costs of both the new and old technologies. The more successful the new technology, the more rapidly and further the price of the old technology is likely to fall. This may reduce the relative cost-effectiveness of the new technology, unless its price is similarly reduced."

"There is a price to pay for using DES," said an author of the ESC report, said Kristensen, who noted that he uses drug-coated stents for "easily more than half of my patients, so clearly I see advantages."

The hot issue now among interventional cardiologists he said has moved to the anti-clotting therapies that are an essential companion treatment to the implantation of the device.

"The sharpest discussion right now is just how long this therapy needs to be used," Kristensen said.

"The problem of giving these patients these drugs for the rest of their lives is not just the high cost but the risk of combinations with other drugs, such as aspirin, that can cause bleeding, sometimes serious cerebral bleeding," he said.

"We simply have no data to show if it is a good idea to continue these therapies beyond the first year and there is a desperate need for more study in this area," Kristensen said.