Sara Ariotti, Marco Valgimigli (Swiss Cardiovascular Center Bern, Inselspital, Bern University Hospital, Switzerland) and others report in JACC: Cardiovascular Interventions that a zotarolimus-eluting stent (Endeavor Sprint, Medtronic) provides superior safety and efficacy compared with a bare metal stent in patients at high risk of bleeding. Ariotti and Valgimigli talk to Cardiovascular News about the implications of these findings for the future use of bare metal stents.
In your study, how did you define “high bleeding risk”?
Objective criteria to define the “high bleeding risk status” are not currently available nor is a standardised algorithm to select high bleeding risk patients and compare outcomes among different studies. However, multiple bleeding risk scores or single individual risk factors have previously been reported.1–3
We used these available data to identify the most common high bleeding risk factors and we found six main criteria applied in the ZEUS (Zotarolimus-eluting Endeavor Sprint stent in uncertain drug-eluting stent candidates) study to define our “high bleeding risk” subpopulation (Ariotti et al’s study was a substudy of the ZEUS study): age >80 years; clinical indication to oral anticoagulant therapy; history of bleeding; bleeding diathesis; known anaemia; and need for chronic therapy with steroids or non-steroidal anti-inflammatory drugs (NSAID).
Typically, what proportions of patients are at high bleeding risk?
In our study, age >80 years and clinical indication to oral anticoagulant therapy were the two most represented high bleeding risk criteria (reported in approximately 89% of high bleeding risk patients, alone or combined with one or more of the other high bleeding risk factors). Data from the CathPCI registry4 reported a percentage of patients 80 years of age or older, treated between 2010 and 2011, of 12.3%, while the CRUSADE registry5 showed that one in every 20 stented patients also had atrial fibrillation or another indication for oral anticoagulant therapy. If we consider the progressive increase of the mean age of the western population and the not negligible percentage of patients with a history of bleeding, a bleeding diathesis, or patients who needs long-term steroid or NSAID therapy, the result is that patients at high bleeding risk represent a sizable portion of patients undergoing PCI—at least the 30% of all-comers population.
Why is the use of drug-eluting stents controversial in these patients?
Current European6 and American7 guidelines recommend a minimum course of dual antiplatelet therapy (DAPT) after drug-eluting stent implantation of three or 12 months, respectively, while one month could be enough after bare metal stent implantation. As a consequence, the use of drug-eluting stents instead of bare metal stents remains controversial in high bleeding risk patients because the need for long-term DAPT poses safety concerns. These concerns were confirmed also in a recent European Survey,8 in which six of 10 (576 of 946) participants preferred bare metal stents whereas only one out of 20 (44 of 946) responders vouched for the value of new-generation drug-eluting stents for high bleeding risk patients.
Why might second-generation stents provide advantages in high bleeding risk patients?
After appearance in clinical practice, bare metal stents were noted to be associated with a significant occurrence of restenosis and, consequently, of target vessel revascularisation. Compared with bare metal stents, first-generation, drug-eluting stents have consistently been shown to reduce restenosis rate, and accordingly, the risk of target vessel failure. However, the first generation drug-eluting stents raised safety concerns because related to a higher incidence of late or very late stent thrombosis after early discontinuation of DAPT, which brought the concept “the longer, the better” with respect to the dual antiplatelet duration. Actually, the recommended DAPT regimen after first-generation drug-eluting stent implantation, to restore safety at the same level of bare metal stents, was 12 months, independently of clinical presentation type. With respect to the first-generation drug-eluting stents, new-generation devices maintained all benefits in terms of restenosis rate but with a significant reduction of late and very late stent thrombosis, which allowed shortening the DAPT duration after newer drug-eluting stent implantation without safety concerns.
High bleeding risk patients were showed to be at the same time at high ischaemic risk, due to a consistent overlap among ischaemic and bleeding risk factors. For this reason, in the high bleeding risk population, the new-generation drug-eluting stents are superior to bare metal stents because they may reduce restenosis rate and, consequently, target vessel revascularisation and stent-related myocardial infarction. Moreover, last-generation devices are superior to the first-generation drug-eluting stents because the reduced rate of late and very late stent thrombosis allows decreasing the duration of DAPT without safety concerns, and this represents a definite advantage in patients at high risk of bleeding events.
What were the key findings of your study?
- The criteria used to define the high bleeding risk population really conferred a high risk of bleeding events. Actually, the high bleeding risk population showed a higher risk of bleeding, consistently across all assessed bleeding scales and proportionally greater depending on the number of high bleeding criteria simultaneously fulfilled, as compared with no high bleeding risk population.
- Patients at high bleeding risk were, at the same time, at higher ischaemic risk as compared with no high bleeding patients, mainly driven by higher death and myocardial infarction rate. Also the stent thrombosis was almost three-fold greater in high bleeding as compared with no high bleeding risk patients. This finding confirms the presence of an overlap among bleeding and ischaemic risk criteria and highlights the challenge to identify a safe and effective antithrombotic therapy in this patient population in clinical practice.
- In particular, our study demonstrated that the use of the Endeavor Sprint stent, a hydrophilic polymer-based second-generation device, followed by a very short DAPT duration (30 days), in high bleeding risk patients with stable or unstable coronary artery disease, provides superior efficacy and safety as compared with conventional bare metal stent under the same 30-day DAPT regimen.
- Notwithstanding the protocol-mandated DAPT duration was 30 days independently of stent type, patients who underwent a bare metal stent implantation had a significantly longer cumulative DAPT duration as compared with patients treated with Endeavor Sprint, mainly driven by a higher rate of target vessel revascularisation in the former group. The evidence of a trend towards a high rate of bleeding events in bare metal stents arm reflected the prolonged duration of DAPT in these patients.
Do you think we will reach a point when drug-eluting stents will be used for all patients, whatever their bleeding risks are, and bare metal stents will no longer be used?
The LEADERS-FREE trial,9 which compared the BioFreedom biolimus A9 drug-coated stent with a very similar bare metal stent followed by a one-month DAPT regimen in high bleeding risk patients, showed a superiority of the drug-coated stent in terms of primary safety and efficacy endpoints. Our study demonstrated the same findings in patients at high bleeding risk treated with the Endeavor Sprint stent. If further studies will extend these results to other available permanent or bioresorbable drug-eluting stents, the bare metal stents will not be longer used or their use may restrict to selected patient populations (ie. patients with low life expectancy) for economic reasons.
How would you recommend managing a patient at high risk of bleeding?
To date, recent findings showed a significant improvement in safety and efficacy outcomes in high bleeding risk patients after Endeavor Sprint or biolimus drug-coated stent implantation, followed by a very short DAPT regimen (30 days), as compared with bare metal stents. Until extension of these study results to the other new-generation drug-eluting stents, three could be the treatment options for high bleeding risk patients requiring PCI:
- Treat patients with one of the investigated drug-eluting stents (taking into account that Endeavor Sprint is not currently available in clinical practice), instead of bare metal stents, in order to obtain the benefits derived from drug-eluting technology but using a shorter than currently recommended DAPT without safety concerns.
- Treat patients with other available new-generation drug-eluting stents. In this case, is important to remember that the safety of a shorter than currently recommended DAPT regimen has not been yet demonstrated and the three-month duration DAPT should be preferred until further evidence will be available.
- If an investigated drug-eluting stent is not available and the patients’ bleeding risk exceeds the ischaemic risk, the use of a bare metal stent followed by a 30-day DAPT should be considered.
- Subherwal et al. Circulation 2009; 119(14): 1873–82.
- Mehran et al. Journal of the American College of Cardiology 2010; 55(23): 2556–66.
- Lip et al. Journal of the American College of Cardiology 2011; 57(2): 173–80.
- Dehmer et al. Journal of the American College of Cardiology 2012; 60(20): 2017–31.
- Wang et al. American Heart Journal 2008; 155(2): 361–68.
- Windecker et al. European Heart Journal 2014; 35(37): 2541–19.
- Levine et al. Journal of the American College of Cardiology 2011; 58(24): e44–122.
- Valgimigli et al. EuroIntervention 2015; 11(1): 68–74.
- Urban et al. The New England Journal of Medicine 2015; 373(21): 2038–47.