PARIS — The reputation of drug-eluting stents (DES) has been severely SCAAR-ed, and a new report from the European Society of Cardiology (ESC; Sophia Antipolis, France) 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 (BMS).
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 the Thomson Reuters agency Research and Markets.
In response, ESC created the Task Force on Drug Eluting Safety that after a long delay responded to the challenges to DES safety and efficacy with its report to be published in the upcoming edition of the European Heart Journal that became available online this week (Medical Device Daily, Dec. 11, 2008).
In an unexpected move, 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 Food & Drug Administration 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 (MDD, Sept. 3, 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 (Natick, Massachusetts), 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 1450 ( 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, Steen Kristensen, MD, of Aarhus University Hospital (Skejby, Denmark), who said 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," said Kristensen.
"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.