Results announced at the 2006 ESC meeting in Barcelona questioned the long-term safety of drug eluting stents (DES) and sparked intense discussion.
The dark side of this debate was an unjustified alarm when results were presented in the general press which created unnecessary anxiety among the thousands of patients who have already received stents. Since the data supporting the main meta-analysis which created this concern proved to be not scientifically sound, we must regret the lack of a more balanced data presentation and critical review which could have prevented needless discomfort and suffering.
The positive side of this debate has been that existing randomised trials and registries have been intensely scrutinised and plans have been made for more adequately powered trials with results applicable to the majority of patients treated for coronary artery disease.
The European Society of Cardiology, represented by a former Past-President, Professor Marten Simoons, Thoraxcentre, Rotterdam, NL, in cooperation with the European Association of Percutaneous Cardiovascular Interventions, represented by its Chairman Professor William Wijns, Aalst, Belgium, organised a Consensus Conference in Nice where data form late follow-up of trials and registries was reviewed. On September 27 and 28, 2007, key opinion leaders in clinical and interventional cardiology and representatives from industry and regulatory bodies gathered at the European Heart House with studies and registries presenting data on restenosis , re-intervention, late stent thrombosis, myocardial infarction, mortality of DES compared with bare metal stents (BMS). Results showed two divergent trends difficult to reconciliate. Late stent thrombosis, developing > one year after stent implantation, was exceedingly rare with BMS but was present in approx. 0.1-0.2% per year in the simple lesions and patients randomized in clinical trials and reached percentages as high as 0.5-0.6% per year when all-comers were followed up closely in centres with high average complexity of interventions performed. The existing data shows this trend to be persistent for the first three-four years after implantation. Paradoxically, this increased rate of late thrombosis does not translate into an increase in mortality or incidence of myocardial infarction despite the fact that late thromboses are associated in more than 2/3 of cases with these catastrophic events. The most likely explanation is that the evidence that restenosis and reinterventions are not as benign as the opponents of DES indicated, with restenosis presenting as acute coronary syndromes in 20% of cases, often inducing periprocedural complications at the time of retreatment with surgery or angioplasty.
Meta-analyses of randomized trials with more than 5,000 patients followed up at four-five years and some of the early registries of all-comers indicated that BMS and DES have similar mortality and incidence of myocardial infarction, with a large advantage of DES on need for reinterventions. More recent registries involving a majority of complex lesions and patients that did not qualify for the classical randomized trials went further and suggested a benefit of DES in terms of late events.
We still have limited data from dedicated trials addressing the long-term safety and efficacy of DES in high-risk subgroups like diabetics, and patients with ST and non ST segment elevation MI or complex lesions (bifurcations, long lesions) but registry data and small scale studies suggest the benefit in terms of new revascularisation and late events can be greater in these high risk situations.
Existing data indicate that there are important differences between the various types of stents, with dissimilar mechanical and pharmacological properties and subsequent differences in clinical outcome. Ongoing large scale trials with second and third generation DES have been powered and have extended their follow-up long enough to support claims of reduced thrombogenicity of these devices. During the conference, there was consensus among regulatory bodies, investigators and the Industry that future randomized controlled trials pre-registration should strive to include all-comers and should be followed by large-scale all-comer registries to assess both the benefits and late complications. Initial approval might be based on assessment of restenosis (angiography, IVUS) or neointima formation and stent coverage (OCT, endothelial function studies) including one-year clinical follow up but these data should be followed by the assessment of death, MI and stent thrombosis over longer follow-up (at yearly intervals up to three to five years).
In order to define indications, cost-effectiveness analyses are essential but careful interpretation is needed when analyzing specific patient subsets derived from clinical trials which might not reflect real world clinical practice. The only regulatory body which issued a specific recommendation (the National Institute of Cost-Effectiveness, NICE from the UK) issued a statement in 2007 suggesting that DES would be cost-effective in the majority of patients undergoing percutaneous coronary intervention at a price premium around €400 above the price of comparable BMS. Despite this remaining a controversial issue, it is interesting to note that the price differential between DES and BMS has already fallen below this threshold in almost all European countries.