Freedom from long DAPT signals the demise of the bare-metal stent: Table 1

This editorial refers to ‘Biolimus-A9 polymer-free coated stent in high bleeding risk patients with acute coronary syndrome: a Leaders Free ACS sub-study’†, by C.K. Naber et al., on page 961. Last year, the Leaders Free trial report was perceived in the interventional cardiology community as one of the most clinically relevant studies in recent history.1 The study clearly addressed a high bleeding risk (HBR) population including patients with 13 pre-defined clinical criteria at age ≥75 years or those with co-morbidities such as renal failure and oral anticoagulation therapy. The HBR patients undergoing percutaneous coronary intervention (PCI) also possess thrombo-ischaemic risks of stent thrombosis and future atherothrombotic events, which used to pose a clinical dilemma for physicians in the choice of stent type and antithrombotic regimens for HBR patients: a drug-eluting stent (DES) and relatively long dual antiplatelet therapy (DAPT) with additional bleeding risk and decreased ischaemic risk vs. bare-metal stent (BMS) and short DAPT with increased ischaemic (restenotic) risk and less additional bleeding risk.2 The Leaders Free study with 2466 patients provided a solution to the dilemma, demonstrating that the specific biolimus A9-eluting polymer-free stent (BA9-DCS) with a 1-month DAPT was safer and more efficacious than the BMS with the same DAPT regimen, with similar rates of bleeding events. Of note, the subgroup analysis showed that in patients presenting with acute coronary syndrome (ACS), the treatment effects of the two devices were different. In this issue of the journal, Naber and colleagues provided further insights into the ACS population from the Leaders Free trials.3 In 659 HBR patients presenting with ACS at entry (BA9-DCS, 330; BM, 329), treatment with BA9-DCS and 1-month DAPT was superior to BMS with the same DAPT duration in terms of the composite endpoint of cardiac death, myocardial infarction (MI), or stent thrombosis. Notably, the individual rates of cardiac death and MI were significantly lower in the BA9-DCS arm than in the BMS arm, while Bleeding Academic Research Consortium (BARC) bleedings were similar between the two arms. The individual categorization of third definition clearly showed that BMS is thrombotic; Type 4b (MI related to stent thrombosis) and 4c (MI related to restenosis) were reported as 2.52% and 1.66%, respectively, in the BMS arm. The results are, by nature of the substudy, to be cautiously interpreted. However, the substudy demonstrated that the BMS is no longer the sole choice of device for the ACS-HBR population. The design and interpretation of stent and DAPT studies are generally complex (Table 1) due to the following: (i) the potential number of combinations of stent type with DAPT regimens are numerous and the evidence cannot always be extrapolated from one device to the other; (ii) the trade-off between bleeding and ischaemic risk exists and two types of events cannot be equally weighted considering the clinical impact from patient perspectives, although bleeding events also have an impact on mortality. In the Leaders Free trial, 1-month use of DAPT in both arms made the interpretation of the study straightforward. One-month DAPT with BMS is the safest approach in terms of bleeding and is regarded as a reference of minimal bleeding. In the DES arm, 1-month DAPT was justified by the use of a polymer-free BA9-DCS stent, which was considered to become BMS-like after fast elution of BA9 in 1 month. In the HBR-ACS substudy, the bleeding risk of both arms was similar, as expected. Stent type and antiplatelet regimen in trials A, aspirin; C, clopidogrel; CI-TLR, clinically indicated target lesion revascularization; CVA, cerebrovascular accident; D, death; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; E-, Endeavor; MACCE, major adverse cardiac and cerebrovascular events; MB, major bleeding; MI, myocardial infarction; NCT, ClinicalTrials.gov numbers; P, purasugrel; PES, paclitaxel-eluting stent; P2Y12i, P2Y12 inhibitor; SES, sirolimus-sluting stent; ST, stent thrombosis; Ti, ticlopidine; TVR, target vessel revascularization; UR, urgent revascularization; ZES, zotarolimus-eluting stent. Additional references (a–n) are given in the Supplementary material online. The study design of ongoing trials was obtained from https://clinicaltrials.gov/, as accessed on 30 May 2016. Stent type and antiplatelet regimen in trials A, aspirin; C, clopidogrel; CI-TLR, clinically indicated target lesion revascularization; CVA, cerebrovascular accident; D, death; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; E-, Endeavor; MACCE, major adverse cardiac and cerebrovascular events; MB, major bleeding; MI, myocardial infarction; NCT, ClinicalTrials.gov numbers; P, purasugrel; PES, paclitaxel-eluting stent; P2Y12i, P2Y12 inhibitor; SES, sirolimus-sluting stent; ST, stent thrombosis; Ti, ticlopidine; TVR, target vessel revascularization; UR, urgent revascularization; ZES, zotarolimus-eluting stent. Additional references (a–n) are given in the Supplementary material online. The study design of ongoing trials was obtained from https://clinicaltrials.gov/, as accessed on 30 May 2016. The pronounced preference of BA9-DCS over BMS in the ACS subpopulation is theoretically related to the BA9 (biolimus). The lipophilicity of biolimus is the highest amongst the currently available limus drug-eluting stents.4,5 In ACS, the coronary lesion presumably has a large lipid burden; therefore, the high lipophilicity of biolimus may facilitate the rapid distribution of drug with potentiated local effect. The favourable results of a biolimus-eluting stent in the population with ST-segment elevation myocardial infarction (STEMI) were also observed in the Leaders trial and COMFORTABLE AMI trials,6,7 in which, instead of a polymer-free stent, a biolimus-eluting biodegradable polymer stent (BES) was used. In the randomized Leaders trial comparing BES and a sirolimus-eluting stent (SES) in 1700 patients, the heterogeneity of the treatment effect in favour of BES over SES was observed in the STEMI population. In the randomized COMFORTABLE AMI trial enrolling 1161 patients, the stainless steel stent eluting BA19-9 from a biodegradable polymer coating (BES) showed a significantly lower rate of major adverse cardiac events, driven by a lower risk of target vessel MI and ischaemia-driven target lesion revascularization, compared with a BMS.7 The question therefore remains of whether there is a difference between the two devices (polymer-free vs. biodegradable polymer) when used with short DAPT. Theoretically, BES takes 6–9 months to accomplish complete degradation of the polymer, while BA9-DCS becomes ‘bare metal’-like after 1 month with a burst elution of biolimus. The concept of a biodegradable polymer BES with 1-month DAPT followed by ticagrelor monotherapy is currently being tested in the Global Leaders trial.8 What is open to debate is whether the observed favourable clinical results of BA9-DCS are transferrable to other stents with a 1-month DAPT regimen especially in the HBR population. Retrospective studies showed indirect evidence that DAPT after implantation of the RESOLUTE zotarolimus-eluting stent (ZES) and Xience everolimus-eluting stent (EES) could be discontinued safely at 1 month in a low risk population. Many commercially available new-generation DES have a CE mark labelling indicating potential shortening of DAPT to 1 month according to clinical needs. These new stents eluting sirolimus, zotarolimus, and everolimus should therefore be investigated with shortened DAPT in high bleeding patients. Whenever different DAPT durations are used, it would be important to design a study that enables the interpretation of the trade-off between bleeding and an ischaemic event. The other remaining point at issue is the clinical safety and efficacy of BA9-DCS in a broader population in comparison with the other DES. The current European guidelines indicate 3–6 months DAPT after DES in non-ST elevation ACS patients deemed at high bleeding risk as a IIb class A recommendation, based on four studies (RESET, OPTIMIZE, EXCELLENT, and ISAR-SAFE).9 The RESET and OPTIMIZE trials are exclusively using the Endeavour zotarolimus-eluting stent (E-ZES). More recently, Ariotti et al. demonstrated that in the pre-specified high-bleeding population of the ZEUS study, the 1-year occurrence of MI, stent thrombosis, and repeat target vessel revascularization was significantly lower in the E-ZES arm than in the BMS arm.10 This publication might further support in general the usage of DES with a short duration of DAPT. Caution should, however, be observed knowing the E-ZES is no longer commercially available and is fundamentally different from the other currently available second-generation stents. E-ZES was considered to be more close to a BMS, with rapid coverage due to a relatively high neointima compared with first-generation DES.11 The current Leaders Free substudy provides one of the first pieces of evidence to support a new DES with a 1-month DAPT in HBR-ACS. The frequency of the specific population—PCI patients at HBR presenting with ACS—in daily clinical practice is perceived to be considerable, but is still unknown. In an European all-comer PCI registry, ∼15% of patients fulfilled the most dominant HBR criteria in the Leaders Free study: age ≥75 years.12 In a Japanese registry, the frequency is higher (∼30%).13 In the Leaders and Resolute all-comer drug-eluting stent studies, 18% and 17% of patients were older than 75 years, respectively.6,14 When combining a HBR criterion of renal failure and prior intracranial bleeding/stroke with the age criterion, approximately 20% patients are estimated to fulfil at least one of the two bleeding criteria. Among those, approximately half of the population presented with ACS. In summary, in these all-comer trials, at least ∼10% of the population are characterized as HBR-ACS according to the Leaders Free criteria. However, this could underestimate the size of the HBR-ACS population in real clinical practice. Patients with planned surgery within 6 months are, for example, excluded from these ‘all-comer’ studies. More HBR-ACS patients could exist outside the context of clinical studies. The guideline recommendation of shortened DAPT for the ACS-HBR population is still based more on indirect evidence for the current generation DES and it is certain that the current ACS-HBR study will influence the clinical decisions of practising cardiologists. The message is very clear that in the specific ACS-HBR population, the BA9-DCS with 1-month DAPT is superior to BMS. For practitioners, it is more important to have one established regimen for a specific risk population rather than having to choose the stent type and antithrombotic regimen influenced by inferential evidence among numerous combinations of stent types and APT regimens. This study defines the end for BMS even in the ACS-HBR population where BMS are still commonly used. Conflict of interest: none declared.