London, UK - One of the three galvanizing drug-eluting-stent (DES) studies of the World Congress of Cardiology 2006 (WCC 2006)—dubbed the Bern-Rotterdam analysis in the debate that ensued—has now been published in the February 24, 2007 issue of the Lancet [1]. The study, which examined late stent thrombosis rates (>30 days poststenting) between April 2002 and December 2005 in the SIRTAX and Post-SIRTAX registries in Bern and the RESEARCH and T-SEARCH registries in Rotterdam, found a cumulative incidence of angiographically documented stent thrombosis at three years of 2.9%.

Dr Peter Wenaweser (University Hospital, Bern, Switzerland) presented the results during the WCC 2006 meeting in Barcelona; Dr Joost Daemen (Erasmus Medical Center, Rotterdam, the Netherlands) is first author on the paper.

As previously reported by heartwire, the finding from the analysis that proved to be the flash point for the debate that followed was that the risk of stent thrombosis did not appear to decline with time but to occur steadily, at a constant rate of 0.6% per year out to three years after stent implantation.

"The results of the present study suggest that late stent thrombosis with drug-eluting stents occurs more frequently than expected and that rates increase steadily during long-term follow-up. The sustained occurrence over a long-term period might be explained in part by the delayed healing response after implantation of drug-eluting stents, as indicated by delayed reendothelialization and hypersensitivity reactions to the antiproliferative drugs or, more probably, to the synthetic polymers."

In an accompanying Comment, Drs Philip Urban and Edoardo De Benedetti (La Tour Hospital, Geneva, Switzerland) address the question of why the stent thrombosis rates in Daemen et al's study are higher than rates reported in other studies, including recent meta-analyses of the randomized trials that led to the approval of the two stents in the first place [2].

For one, they note, the form of treatment offered to patients at the sites included in the analysis represent "one extreme," with DES being used as the default stent in all patients, including those presenting with ACS (59% of patients).

Total length of stented segments and number of stents used per patient were both higher in the Bern-Rotterdam study (36 mm and two stents per patient, respectively) than in the pivotal SES and PES trials, in which mean stent length was 22 mm for both trials and mean number of stents per patient was 1.4 in the SIRIUS trial and 1.1 in TAXUS IV.

Overall, Urban and De Benedetti are upbeat, citing several reasons. For one, they argue, "better or safer options do not necessarily exist today."

Moreover, the natural history of coronary artery disease, even in the setting of optimal secondary-prevention measures, "remains a greater threat to patients than do the potential events related to the stented segment of coronary artery," they suggest.

To heartwire, Urban explained that, in his opinion, the unanswered questions about DES break down into two separate issues. The first, he stated, is clinical decision making with current-generation DES: "Who needs one, who can do without . . . and who has a contraindication to one," based on anticipated poor compliance with the dual antiplatelet regimen.

The second issue is how to improve upon current DES technology "to decrease and hopefully eliminate the very real problem of stent thrombosis and also the need for prolonged antiplatelet treatment," he said.

While ongoing randomized controlled trials comparing different DES, or DES with CABG, may answer some questions, the stent-thrombosis issue may ultimately be resolved by newer drugs, polymers, or resorbable stents, Urban and De Benedetti conclude.

But for the time being, Urban confirmed to heartwire that he does, indeed, "remain optimistic about the future of DES."

"The data that have become available recently—although some disagreement persists—suggest that the overall risk of mortality and MI is probably no different for DES and bare-metal stents, even if late stent thrombosis does appear to be more of a problem with DES," he said.

The registry data from Bern and Rotterdam reflect higher stent-thrombosis rates than seen elsewhere, but they also reflect a higher-risk patient population, Urban observed, a group that other studies, as well as the FDA advisory panel, acknowledge to be at increased risk of adverse events, including stent thrombosis.

"All stakes are bound to be higher in such patients," Urban pointed out. "Focusing only on stent thrombosis is a little like judging a powerful antibiotic only on the allergic reactions it induces."