Bern, Switzerland - A small Swiss study has shown that late hypersensitivity reactions likely play a major role in the pathogenesis of very late stent thrombosis in patients with drug-eluting stents (DES) [1]. Dr Stéphane Cook (University Hospital, Bern, Switzerland) and colleagues report their findings online July 20, 2009 in Circulation.
Senior author Dr Stephan Windecker (University Hospital) told heartwire: "This is a small paper explaining from a pathophysiologic standpoint a very rare clinical problem. People should not be worried, because it's a very rare adverse event and first-generation DES have been shown to be safe overall—the incidence of death or MI as compared with bare-metal stents is not increased—so there is no concern about this."
In an accompanying editorial [2], Dr William Wijns (Cardiovascular Center Aalst, Belgium) says that Cook et al "now confirm that local hypersensitivity reactions are the more likely mechanisms of very late stent thrombosis through excessive positive remodeling." Wijns told heartwire, "In retrospect, this new study explains a lot of controversies we didn't understand." Thus, the seemingly erratic pattern of very late stent thrombosis, the steady linear increase over time with no evidence of decreased event density with extended follow-up, and the weak association with discontinued dual antiplatelet therapy (in contrast to early thrombotic events) "are all consistent with the evoked mechanism of action," he says.
The work also raises a number of new questions and has implications for future research, says Wijns.
An unusual reaction explaining many mysteries
The new study looked at just 28 patients with very late stent thrombosis and 26 controls. Of the 28 patients with late stent thrombosis, 10 patients underwent both thrombus aspiration and intravascular ultrasound (IVUS). Incomplete stent apposition (ISA), also known as malapposition, and evidence of vessel remodeling were present in 73% of cases. Histopathological analysis showed much higher numbers of eosinophils in the specimens from very late DES thrombosis compared with other causes of MI—particularly with sirolimus-eluting stents—and a correlation with the extent of stent malapposition.
Windecker said: "This is an extension of work we have previously published showing an exceedingly high incidence of stent apposition in those presenting with very late stent thrombosis. What we did in this new study was correlate those findings with histopathological analysis of thrombus aspirates from living patients, and we found that the extent of vessel remodeling as diagnosed by IVUS correlated directly with the amount of eosinophilic infiltrates." An increase in eosinophils is "very unusual" he noted, and "implies a hypersensitivity reaction."
Wijns says that what Cooke et al found "in all those cases was that there was necrotizing vasculitis around the stent struts and that explains why the wall is moving away from the stent, this phenotype of malapposition." However, malapposition itself is "a moving target" he explained, "as early IVUS studies have shown it can be there from the onset and disappear, it can be present from the onset and stay as it is, or it can also be absent initially and then appear—perhaps the latter instances are the ones that are potentially related to this delayed inflammatory reaction," he observes. But whether malapposition per se is sufficient to trigger thrombosis "is unclear," he says.
Also, this study "cannot tell us exactly which component of the drug-polymer device is responsible for the late hypersensitivity reaction because, by definition, late hypersensitivity reactions can present themselves even ages after the causal agent has gone. So it's not excluded that it could be the drug [on the DES], but I think most people agree that the polymer is likely the guilty one," Wijns added.
Windecker says: "People always wondered why it is that very late stent thrombosis occurs at a steady rate, why the stents don't heal, and why the risk doesn't seem to stop after a certain period in time. Now, with these hypersensitivity reactions, we may have a partial explanation, because hypersensitivity reactions can occur at any time."
No change in advice for those affected by stent thrombosis
Wijns says there are few practical consequences of the new findings. Removal of the DES is not possible, says Windecker, so the only course of action is medical treatment, a rescue primary PCI to open the occluded stent, give appropriate antiplatelet therapy, "and hope the stent stays open," he says. "There's really not much more that you can do."
Desensitization is not an option either, Windecker explains, because "this [hypersensitivity] reaction is not IgG-mediated, which you could suppress, rather it is T-cell or eosinophil-mediated, so the only thing you could perhaps consider is local administration of steroids, but you would have to be very careful to weigh the risks of this against the benefits of therapy."
Future directions
Wijns says this work indicates that researchers looking for the optimal drug-polymer device may be wise in the future to narrow their search for constituents down to polymers and drugs that have been used extensively in humans for other indications, with known outcomes.
It is also essential that pooling of data, following the same protocol, is performed going forward in patients presenting with stent thrombosis. This is especially important in Europe, where many new DES are available, he says. Central analysis of removed thrombus, invasive imaging by IVUS or optical coherence tomography, and efforts to help identify systemic biomarkers that could predict events, or at least those patients most at risk, "should be encouraged," he notes.
"Although stent thrombosis is rare, malapposition is not an infrequent finding, seen in 8% to 13% of patients nine to 12 months after implantation of first-generation DES. Linking this phenotype to biomarker changes may help to identify patients most at risk of late stent thrombosis, perhaps the patient subset that will benefit from long-term dual antiplatelet therapy," he observes.
"Only when we have such a biomarker will we know the fraction of patients at risk of this very rare side effect, and from there the fraction who will have the event is even lower by several orders of magnitude," he commented to heartwire. "This is no reason to panic, rather the opposite," he states, "because at last we understand what the mechanism is."
Sources
- Cook S, Ladich E, Nakazawa G, et al. Correlation of intravascular ultrasound findings with Histopathological analysis of thrombus aspirates in patients with very late drug-eluting stent thrombosis. Circulation 2009; 120: 391-399.
- Wijns W. Late stent thrombosis after drug-eluting stent. Seeing is understanding. Circulation 2009; 120: 364-365.
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