Newer-Generation DES With Abbreviated DAPT Bests BMS in Patients at High Risk for Bleeding

As the evidence continues to mount that bare-metal stents may be going the way of the horse and buggy, an analysis of patients at high risk for bleeding suggests that even in this challenging group, a drug-eluting stent that releases its drug rapidly and requires only a 1-month course of dual antiplatelet therapy (DAPT) may result in fewer adverse events and lower stent thrombosis risk. 

In the past, patients at high bleeding risk have largely been excluded from major trials comparing stent types, say lead author Sara Ariotti, MD (Bern University Hospital, Switzerland; Erasmus Medical Center, Rotterdam, the Netherlands), and colleagues.

Two years ago, the same researchers reported primary results from the ZEUS trial, which enrolled 1,606 patients considered unlikely candidates for DES because of either high bleeding risk (51.6%), high thrombotic risk (17.7%), or low restenosis risk (58.6%; some had more than one risk factor). Patients were randomized to implantation with either a BMS (n = 804) or the Endeavor zotarolimus-eluting stent (Medtronic; n = 802), a hydrophilic polymer-based second-generation device that elutes the drug within 15 days of implantation.

Overall, the ZES followed by an individualized course of DAPT was associated with a lower risk of MACE at 1 year, driven by reductions in TVR, MI, and definite/probable stent thrombosis. Among the three high-risk groups, those with high bleeding risk had the lowest DAPT duration, averaging just 30 days compared with 174 days for those with high thrombotic risk or low restenosis risk.

Less MACE, MI, TVR, and Stent Thrombosis Seen

This time around, Ariotti and colleagues along with senior author Marco Valgimigli, MD, PhD (Erasmus Medical Center), dove deeper into the data, looking at a prespecified analysis consisting of the 828 ZEUS patients who met clinical or biochemical criteria for high bleeding risk (advanced age, indication for oral anticoagulants or other pro-hemorrhagic medications, history of bleeding requiring medical attention or hospitalization, and known anemia).

Similar to the main ZEUS results, patients at high bleeding risk who received the ZES had fewer incidents of MACE (primary endpoint) at 12 months compared with those given BMS, a difference driven by less MI and TVR. ZES-treated patients also were less likely to develop definite or probable stent thrombosis. Rates of bleeding, however, were similar regardless of device used. The only exception was a trend towards less bleeding (BARC 2, 3, or 5 events) in the ZES group.

Rates of all events, including stent thrombosis, were higher for the high-bleeding-risk patients as a group than for patients who did not meet the risk criteria.

According to Ariotti et al, the lower risk of MI or stent thrombosis with ZES versus BMS, despite a similarly short DAPT duration for both, is consistent with “mounting evidence” that lower in-stent intimal hyperplasia may carry not only greater efficacy in the form of lower TVR risk, but also improved safety in the form of less stent thrombosis or stent-related MIs.

More Perception Than Reality?

The ZEUS study addresses “one of the last remaining clinical settings in which BMS are still commonly used yet unstudied,” notes David E. Kandzari, MD (Piedmont Heart Institute, Atlanta, GA), in an accompanying editorial. These latest data, he observes, “add to an emerging evidence base that challenges existing standards and brands the utility of BMS more a misperception than a reality.”

Kandzari also suggests that BMS may have, in a sense, been held to a lower standard than DES, providing “a false reassurance” that guideline-recommended 1-month DAPT in combination with a BMS protects against stent thrombosis and restenosis. Recent studies, including the PRODIGY trial, have documented higher rates of MACE and definite/probable stent thrombosis through 2 years with BMS compared with newer-generation DES, he notes. Similarly, the DAPT Study showed a greater incidence of stent thrombosis through 33 months for BMS compared with DES, he adds.

As to whether the advantage the efficacy of the Endeavor ZES can be extrapolated to include other newer-generation DES, Kandzari says that is “speculative,” but he notes that the most recent guidelines from the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery advise less than 6 months of DAPT following DES in patients with bleeding risk based on data from Endeavor ZES studies.

Since the ZEUS trial was published, however, another contender has arisen from the LEADERS FREE trial, he observes. In that trial, the BioFreedom drug-coated stent (Biosensors International), a polymer-free drug-coated stent that transfers biolimus A9 and requires only 1 month of DAPT, also bested BMS in high-risk PCI patients.

Taken together, Kandzari concludes that the ZEUS and LEADERS FREE data “further challenge the clinical purpose of BMS in [high-bleeding-risk] patients.” 

David J. Cohen, MD (Saint Luke's Mid America Heart Institute, Kansas City, MO), noted in an email to TCTMD that the original design of ZEUS was somewhat confusing to understand because of the three distinct but combined populations. Separating out those with high bleeding risk as was done in this analysis, he said, “helps to clarify the benefit of the zotarolimus-eluting Endeavor stent in a specific and well-characterized population that we all struggle to deal with every day.”

Although the ZEUS and LEADERS FREE data could defend a position that BMS are neither safer nor more efficacious (with respect to restenosis and TLR) than the DES that were studied, Cohen said, it is important to remember “that these are very specific drug-eluting stents with unique properties that may make them well-suited to the high-bleeding-risk patients.” Additionally, beyond it being unclear if the results can be generalized to the DES platforms currently in widespread use, neither the BioFreedom nor the Endeavor stent is currently marketed in the United States, he noted. “Therefore, it appears that for the time being, we still may have a need for bare-metal stents in the US.”

Sources:  
1. Ariotti S, Adamo M, Costa F, et al. Is bare-metal stent implantation still justifiable in high bleeding risk patients undergoing percutaneous coronary intervention? a pre-specified analysis from the ZEUS trial. J Am Coll Cardiol Intv. 2016;9:426-436.
2. Kandzari DE. Can’t bare it any longer. J Am Coll Cardiol Intv. 2016;9:438-439. 

Disclosures:

• The ZEUS study was cofunded by an unrestricted research grant from Medtronic to Consorzio Ferrara Ricerche. 
• Ariotti and Valgimigli report no relevant conflicts of interest. 
• Kandzari reports research/grant support from Abbott Vascular, Biotronik, Boston Scientific Corporation, Medinol, and Medtronic CardioVascular; and consulting honoraria from Boston Scientific Corporation and Medtronic CardioVascular.
• Cohen reports relationships with multiple drug and device companies.

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