At the 2018 Transcatheter Cardiovascular Therapeutics (TCT) meeting (21–25 September, San Diego, USA), David Kandzari (Piedmont Heart Institute, Atlanta, USA) presented the two-year results of the BIOFLOW V study. These indicate that Orsiro (Biotronik) was associated with a significantly lower rate of target lesion failure than was Xience (Abbott). However, five-year data from the BIOSCIENCE study, which was presented at the 2018 European Society of Cardiology (ESC) Congress (25–29 August, Munich, Germany), show no significant difference in the rate of target lesion failure between these two devices. In this interview with Cardiovascular News, Kandzari discusses all of the available data for Orsiro and whether it does provide superior outcomes to Xience.
Overall, what were the key findings of the BIOFLOW V study?
BIOFLOW V was designed as a pivotal to inform approval of Orsiro in the USA with an overview by the FDA. It compared Orsiro, a sirolimus-eluting stent with a biodegradable polymer, with Xience (an everolimus-eluting stent with a permanent polymer). Historically, Xience has been the benchmark for comparison for drug-eluting stents.
Prior to BIOFLOW, no study has shown a superiority for a stent compared with Xience. But in BIOFLOW V, at one year, we demonstrated a significant difference in target lesion failure with the Orsiro stent and we also showed a significant difference in myocardial infarction that favoured Orsiro. So when reviewing the two-year data, the question was whether we would continue to see a difference in these outcomes with Orsiro and whether new differences might emerge. Not only did the differences in target lesion failure and myocardial infarction persist between Orsiro and Xience at two years, but we also observed significant differences in target lesion revascularisation and late and very late stent thrombosis that favoured the Orsiro stent. Therefore, with Orsiro, we saw persistent and emerging differences compared with Xience—an unprecedented result.
Why do you think no significant differences in target lesion failure were observed between Orsiro and Xience in the BIOSCIENCE study?
It is hard to compare data from two different trials. BIOFLOW V was a multicentre, international pivotal trial whereas BIOSCIENCE was an all-comers study of patients enrolled at selected centres in Switzerland. Not only did the study populations differ, but there were very important differences in methodology between the two trials. For example, being a pivotal trial, BIOFLOW V had detailed endpoint definitions and ascertainment, for example, periprocedural biomarker assessments for periprocedural myocardial infarction—but the use of such assessments and definitions were not consistent with BIOSCIENCE.
Furthermore, BIOSCIENCE had some unique findings such as a higher of all-cause mortality rate and an older population than seen in other large, comparative drug-eluting stent trials. Orsiro was associated with a significantly higher rate of all-cause mortality than was Xience in the BIOSCIENCE trial, which most if not all people in the interventional cardiology community see as a chance finding.
If Orsiro is associated with superior outcomes to Xience, why do you think that would be?
The biodegradable polymer of Orsiro may confer a late safety advantage as the polymer dissolves and returns the stent to a phenotype of a bare metal stent—meaning that there is no polymer substrate for persistence of inflammation or neointimal hyperplasia. We may see this advantage as follow-up data beyond two years begin to emerge. Importantly, however, the biodegradable polymer of the Orsiro stent does not completely disappear until at least two years after stent implantation. Therefore, I do not think that the biodegradable polymer is the exclusive reason that differences are pbserved compared with the Xience stent.
Instead, a more likely potential reason for the differences in outcomes between Orsiro and Xience is that Orsiro is an ultrathin strut stent whereas Xience is a thin strut stent. For Orsiro stents that are 3mm diameter or less, Orsiro has a strut thickness of 60µm while Xience has a strut thickness of 81µm. In a recent meta-analysis that compared “ultrathin” strut stents (included Orsiro) with “thin” strut stents, there seemed to be a consistent finding of lower ischaemic events—such as myocardial infarction and stent thrombosis—with the ultrathin stents. Ultrathin stents may be a new focus for us as we think about new stent designs and development.
If thinner struts do explain the difference in outcomes between Xience and Orsiro in BIOFLOW, why were there no significant differences (in target vessel failure) between Orsiro and Resolute Onyx (Medtronic) in the recent BIONYX study given that the Resolute Onyx has a similar strut thickness to Xience?
Again, we have to keep in mind we are comparing data across different trials and that limits any definite conclusions. The BIONYX was a large comparative study showing noninferiority of the Onyx stent with the Orsiro stent regarding target vessel failure. It is noteworthy that the investigators selected Orsiro as the benchmark comparator stent. It is also noteworhy, however, that the BIONYX trial investigators also performed the BIORESORT trial. This trial showed that at one year, there were no significant differences between Orsiro, Resolute Integrity, and the everolimus-eluting, biodegradable polymer stent Synergy (Boston Scientific). However, the two-year data (presented at the 2018 EuroPCR meeting) showed a significant difference in target lesion failure and target lesion revascularisation that favoured the Orsiro stent. Therefore, it will be interesting to see the two-year findings of BIONYX continue to show no significant differences between Orsiro and Resolute Onyx.
BIONYX also showed that Resolute Onyx was associated with a significantly lower rate of definite or probable stent thrombosis. Why do you think this was?
The presenter of that study acknowledged that that event rates were low for both stents—0.7% for Orsiro and 0.1% for Resolute Onyx. The extremely low rate of stent thrombosis for Resolute Onyx was surprising because it is not consistent with previous studies of Resolute nor is it consistent with any finding for a drug-eluting stent in such a broad, unselected patient population. It is a very favourable result but it may be more of a chance finding.
Given the good outcomes we have seen with current generation drug-eluting stents, we reached a plateau in terms of improving safety and efficacy with the latest generation stents?
In the past three to five years, I think there has been an impression in the community that we had met a plateau with regard to drug-eluting stent safety and efficacy. But, BIOFLOW V changed that paradigm as it showed that there was still the opportunity for incremental benefit with newer stents.
One of the key issues, however, is that we need to reset our expectations with regard to when, how and what potential differences we will see between drug-eluting stents as they continue to evolve and develop. By that, I mean that we may not necessarily observe differences at the traditional one-year time point; we may need longer durations of follow-up. Alternatively, differences may appear earlier than one year, such as periprocedural myocardial infarction (significantly reduced with Orsiro vs. Xience). The other issue is that the differences observed may not be the more traditional or expected endpoints such as target lesion revascularisation. In BIOFlOW V, for example, we observed differences between Orsiro and Xience in endpoints such as target vessel myocardial infarction and stent thrombosis, findings which have been a consistent finding with ultrathin struts.
Do you think, based on the available evidence, that Orsiro is now the gold-standard stent?
That would be my opinion but I am certainly not the only one to have that opinion. The investigators of BIORESORT and BIONYX, for example, have now established Orsiro as a new standard of comparison in the design of their trials.