Clinical outcomes of patients treated using very short duration dual antiplatelet therapy after implantation of biodegradable‑polymer drug‑eluting stents: rationale and design of a prospective multicenter REIWA registry
Masaru Ishida · Fumiaki Takahashi · Iwao Goto · Masanobu Niiyama · Hidenori Saitoh · Tsubasa Sakamoto · Yuko Maegawa · Takuya Osaki · Osamu Nishiyama · Hiroshi Endo · Ryohei Sakamoto · Tsuyoshi Kojima · Yorihiko Koeda · Takumi Kimura · Tomonori Itoh · Yoshihiro Morino · REIWA investigators
1 Division of Cardiology, Department of Internal Medicine, Iwate Medical University, 2-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate 020-3695, Japan
2 Division of Medical Engineering, Department of Information Science, Iwate Medical University, Yahaba-cho, Iwate, Japan
3 Department of Cardiology, Hachinohe Red Cross Hospital, Hachinohe, Japan
4 Department of Cardiology, Iwate Prefectural Chubu Hospital, Kitakami, Japan
5 Department of Cardiology, Iwate Prefectural Ofunato Hospital, Ofunato, Japan
6 Department of Cardiology, Iwate Prefectural Miyako Hospital, Miyako, Japan
7 Department of Cardiology, Iwate Prefectural Kuji Hospital, Kuji, Japan
8 Department of Cardiology, Iwate Prefectural Ninohe Hospital, Ninohe, Japan
9 Department of Cardiology, Iwate Prefectural Iwai Hospital, Ichinoseki, Japan
10 Department of Cardiology, Nakadori General Hospital, Akita, Japan
11 Department of Cardiology, Morioka Red Cross Hospital, Morioka, Japan
Abstract
Several studies have demonstrated the safety and feasibility of short (3–6 months) and very short duration (< 2 months) dual antiplatelet therapy (DAPT) in patients with a durable-polymer drug-eluting stent (DP-DES). However, the clinical impor- tance of using very short duration DAPT has yet to be established in patients with a biodegradable polymer drug-eluting stent (BP-DES). The aim of this REIWA registry (multicenter and prospective registry; investigation of clinical outcomes of patients treated with short duration dual antiplatelet therapy after implantation of biodresorbable-polymer drug-eluting stent: a multicenter, prospective registry from Iwate medical university affiliated hospitals) is to determine the safety and feasibility of using 1-month DAPT followed by P2Y12 inhibitor monotherapy in patients after BP-DES implantation. This study is an observational, prospective, multicenter registry encompassing the entire local medical region of Iwate Prefecture (northern area of mainland Japan). A total of 1200 patients who underwent successful PCI with a novel thin strut BP-DES (Synergy, Ultimaster or Orsiro) and are considered to be appropriate patients for very short DAPT, are registered and sub- sequently administered 1-month DAPT followed by P2Y12 inhibitor monotherapy (clopidogrel 75 mg/day or prasugrel3.75 mg/day). The primary endpoint was a composite of cardiovascular and bleeding events, which included cardiovascular death, spontaneous myocardial infarction, definite stent thrombosis, ischemic or hemorrhagic stroke, or TIMI major or minor bleeding at 12 months. The REIWA registry (UMIN000037321) will demonstrate both the safety and feasibility of using 1-month DAPT in patients with BP-DES. Furthermore, results of this study will also be able to provide supportive evidence for P2Y12 inhibitor monotherapy after 1-month DAPT following BP-DES implantation.
Introduction
For patients undergoing percutaneous coronary interven- tion (PCI), neither the efficacy of very short duration dual antiplatelet therapy (DAPT) nor the strategy for the de- escalation of DAPT has yet to be established. Since more than half of thrombotic events, including stent thrombo- sis, have occurred within 3 months after contemporary PCI [1–3], current guidelines recommend the use of a short DAPT (at least 3 months) to reduce the risk for stent thrombosis when patients are implanted with a drug-elut- ing stent (DES) [4–6]. However, recent randomized trials using new generation DES have reported that the use of a very short duration (< 2 months) of DAPT was associated with a lower risk of bleeding without increasing the throm- botic risk [7, 8]. Therefore, the use of 1-month DAPT fol- lowing the current generation DES implantations has the potential to become a safe and feasible treatment, even in patients without any high bleeding risk (HBR).
P2Y12 inhibitor monotherapy following a shorter dura- tion of DAPT is another option for de-escalation of DAPT. Results from the CAPRIE trial showed that patients on clopidogrel monotherapy for atherosclerotic risks had a relatively low incidence of ischemic events, including myocardial infarction, stroke or vascular death, as com- pared to aspirin monotherapy [9]. In addition, the STOP- DAPT-2 trial, which used Xience durable polymer DES (DP-DES), exhibited a low incidence of thrombotic and bleeding events in patients treated with the P2Y12 inhibi- tor following the 1-month DAPT that was given after thecurrent DES implantation [7]. Based on this evidence, the administration of the P2Y12 inhibitor monotherapy fol- lowing a shorter DAPT may result in better anti-throm- botic effects as compared to the aspirin monotherapy that is used following a shorter DAPT, in addition to poten- tially reducing the bleeding risk that is associated with prolonged DAPT.
Recently, thin strut biodegradable polymer DES (BP- DES), which has a low incidence of device-oriented adverse events comparable to the Xience DP-DES [10–12], has become widely used in patients with coronary artery dis- ease (CAD). Similar to STOPDAPT-2, P2Y12 inhibitor monotherapy following the use of 1-month DAPT after BP- DES implantation may result in favorable clinical outcomes. Therefore, we created the REIWA registry (multicenter and prospective registry; investigation of clinical outcomes of patients treated with short duration dual antiplatelet therapy after implantation of biodresorbable-polymer drug-eluting stent: a multicenter, prospective registry from Iwate medical university affiliated hospitals) to determine the safety and feasibility of using the STOPDAPT-2-like DAPT regimen (P2Y12 inhibitor monotherapy following 1-month DAPT) after BP-DES implantation.
Methods
Study design and study population
REIWA is an observational, prospective, multicenter reg- istry that was started at 10 sites in the northern area ofmainland Japan (Fig. 1). This study has been registered with the UMIN Clinical Trial Registry (UMIN000037321), and was designed to enroll up to 1200 patients with BP- DES. This study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan.
All CAD patients who underwent successful PCI with novel thin strut BP-DES, which included the Synergy everolimus-eluting stent (Boston Scientific, Marlbor- ough, Massachusetts), Ultimaster sirolimus-eluting stent (Terumo Corporation, Tokyo, Japan) or Orsiro siroli- mus-eluting stent (Biotronik, Bülach, Switzerland), are screened at each of the participating hospitals. Patients that are considered to be tolerable for 1-month DAPT will be registered for this study after providing informed con- sent. Key exclusion criteria include, (1) patients having planned revascularization for residual lesion, (2) need for oral anticoagulation, (3) need for antiplatelet therapy other than aspirin and P2Y12 inhibitors, (4) known intolerance to P2Y12 inhibitors, (5) history of stent thrombosis, (6) life expectancy < 24 months, (7) woman of childbearing potential and (8) history of bioresorbable scaffold implan- tation within the last 3 years (Table 1). Patients with any clinical presentations such as acute myocardial infarction (AMI), unstable angina (UA) or stable CAD are included in the REIWA registry, with the clinical data from these subjects. Fourth Universal Definition is used for the diag- nosis of AMI [13]. UA is defined according to the Braun- wald classification of UA [14]. Other presentations are classified as stable CAD, which includes stable angina or asymptomatic CAD. When patients have multiple vesseldisease for which each vessel is appropriate for PCI, only the final procedure is added to this registry.
Antiplatelet regimens and follow‑up
The clinical endpoints are evaluated in all registered patients at 1 month (30–59 days) and 12 months (335–394 days) after the PCI procedure for the target lesion. Patients are then given the DAPT until the 1-month follow-up, with the stand- ard dose that is currently used in Japan administered at the discretion of the attending physician (aspirin 81–200 mg/ day with clopidogrel 75 mg/day or aspirin 81–200 mg/day with prasugrel 3.75 mg/day). Subsequently, the STOPDAPT- 2-like DAPT regimen is started. For this procedure, the aspirin treatment is stopped at the 1-month follow-up, after which the P2Y12 inhibitor monotherapy with clopidogrel 75 mg/day or prasugrel 3.75 mg/day is then continued until the 12-month follow-up (Fig. 2). For patients with a HBR [15], a reduced dose of P2Y12 inhibitor (clopidogrel 50 mg/ day or prasugrel 2.5 mg/day) is considered acceptable dur- ing the study period. When new onset atrial fibrillation, venous thromboembolism, or left ventricular thrombus is found after the de-escalation of DAPT, oral anticoagulants are acceptable for use based on the risk stratification.
Study endpoints
In the REIWA registry, all clinical endpoints are the same as those that were used for the STOPDAPT-2 trial. The pri- mary endpoint of this study is a composite of the cardio- vascular and bleeding events, which include cardiovascular death, spontaneous myocardial infarction (MI), definite stent thrombosis, ischemic or hemorrhagic stroke, or thrombolysisin myocardial infarction (TIMI) major or minor bleeding (Table 2) [16]. The primary secondary endpoints are (1) the cardiovascular endpoint (a composite of cardiovascular death, MI, definite stent thrombosis, or ischemic or hemor- rhagic stroke) and (2) the bleeding endpoint (TIMI major or minor bleeding). Spontaneous MI and stent thrombosis are defined by the Academic Research Consortium criteria [17]. Other prespecified secondary endpoints are as follows; all-cause death, death due to cardiovascular cause, spon- taneous MI, definite stent thrombosis, definite or probablestent thrombosis, ischemic or hemorrhagic stroke, TIMI major bleeding, TIMI minor bleeding, Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding [18], BARC type 5 bleeding, BARC type 3 bleeding, Global Use of Strategies to Open Occluded Arteries (GUSTO) mod- erate or severe bleeding [19], GUSTO severe bleeding, GUSTO moderate bleeding, gastrointestinal bleeding, any coronary revascularization, target lesion revascularization (TLR), clinically driven TLR, non-target lesion revascular- ization, coronary artery bypass graft surgery, a composite of death or MI, a composite of cardiovascular death or MI, and major adverse cardiac events (a composite of cardiac death, MI, and clinically driven TLR).
Quantitative coronary angiography
To assess overall and each lesion characteristics, quali- tative and quantitative coronary angiographies (QCA) will be assessed in 150 patients (50 patients per each BP- DES) who are randomly selected at the time of enrollment. An independent reviewer from the Iwate Cardiovascular Core Laboratory (ICAL; Iwate, Japan) will be responsible for analyzing the new data using an offline QCA system (QAngio XA version 7.3, Medis Medical Imaging System BV, Leiden, the Netherlands). The target lesion, which is defined as the entire segment involving the implanted stent and the 5 mm proximal and distal edges adjacent to the stent, will be analyzed using a standard technique. A lesion with an overlapping stent is regarded as a single target lesion. If multiple lesions are treated without an overlap- ping stent, the lesion having the most severe stenosis will be defined as the target lesion.
Safety monitoring
An independent evaluation committee will perform the safety monitoring throughout the study period, and will decide when to stop enrollment if a serious problem is found during the evaluation of the first 300 patients.
Sample size calculation
The REIWA registry is single-arm prospective observational study designed to determine the safety and feasibility of BP-DES in conjunction with 1-month DAPT. This registry is based on the STOPDAPT-2 trial, which used DP-DES. Since the clinical evidence for BP-DES is similar to that for DP-DES [10–12], we hypothesize that the clinical out- comes of the 12-month DAPT in the REIWA cohort will be similar to that found for the 12-month DAPT group in the STOPDAPT-2 trial. To determine our hypothesis that STOP- DAPT-2-like DAPT regimen is non-inferior to 12-month DAPT even after BP-DES implantation, we are going to try and compare the REIWA cohort that includes the 1-month DAPT with a hypothetical 12-month cohort, which will be calculated from the clinical results of the 12-month DAPT reported in the STOPDAPT-2 trial.
In the STOPDAPT-2 trial, the event rate of the primary endpoint for the 12-month DAPT following the DP-DES implantation was 3.7% per year [7]. However, as this event, rate might have been underestimated due to the exclusion of patients with comorbidity or complex lesion, the extra margin of this event rate will perhaps need to be considered in an all-comer registry study. Thus, based on the currently available data, we hypothesized that the event rate for the primary endpoint for the 12-month DAPT following the BP- DES implantation would be 5.0%. A non-inferiority margin of 1.5% was selected for the current trial. Assuming a 3% loss to follow-up, an evaluable sample size of 1143 patients would yield more than 80% power. Thus, we assumed that a total of 1200 patients would be a reasonable number for determining the safety and feasibility of BP-DES in a STOP- DAPT-2-like DAPT regimen.
Discussion
Most of the reported short DAPT trials have enrolled CAD patients with a HBR and then tried to shorten the duration of DAPT down to 3 months. Although the GLOBAL LEAD- ERS sub-analysis and STOPDAPT-2 have already shown a benefit when using 1-month DAPT for general CAD patients, there were differences noted between both studies for the implanted stent, DAPT regimen, and the countries that were involved in these studies [7, 8]. Therefore, the feasibility of using a very short (< 2 months) DAPT has yetto be established for general CAD patients. Recent trials using current generation DES demonstrated the non-inferi- ority of 3-month DAPT compared to 12-month DAPT for CAD patients regardless of the HBR [20–23]. In addition, the ONYX ONE trial demonstrated that the use of 1-month DAPT following Resolute Onyx DP-DES implantation was both safe and effective for HBR patients, as well being pol- ymer-free drug-coated stents, which were superior to the reported results for the bare-metal stent used for 1-month DAPT [24]. Based on this evidence and the results from the STOPDAPT-2 trial, the current study will hopefully provide additional safety and feasibility data for the 1-month DAPT procedure in patients either with or without HBR.
Recent studies have also demonstrated that the use of BP-DESs resulted in a large amount of healing even for the results analyzed for the early follow-up period. An obser- vational study that used optical coherence tomography found that the uncovered strut rate after Ultimaster BP-DES implantation was 15% at 1 month and 13% at 2 months, respectively [25]. Considering that more than 30% of the uncovered strut rate is related to stent thrombosis after DES implantation [26], it can be potentially expected that this BP- DES could lead to the de-escalation of DAPT at 1–2 months. Similarly, it has been reported that the Synergy BP-DES showed a faster endothelization as compared to the Nobori BP-DES and Resolute Integrity DP-DES in an animal model [27]. Furthermore, another experimental study demonstrated that the vascular healing following Orsiro BP-DES implanta- tion was relatively fast as compared to that observed follow- ing Cypher first-generation DES or PROMUS element DP- DES implantation [28]. Thus, the use of both the Synergy and Orsiro BP-DES may lead to earlier vascular healing as compared to the DP-DES, as well as the Ultimaster BP-DES. Although P2Y12 inhibitor monotherapy following DAPT has yet to be established for CAD patients with DES, sev- eral trials have demonstrated the feasibility of this treatment. Indeed, the use of ticagrelor monotherapy following short duration DAPT is currently being viewed as a therapeutic option for HBR patients when using the current genera- tion DES [29, 30]. The SMART-CHOICE trial, which had slightly similar treatment characteristics to that for STOP- DAPT-2 (usage of clopidogrel and Xience DP-DES were more than 70% and 30%, respectively), recently showed the feasibility of using P2Y12 inhibitor monotherapy follow- ing 3-month DAPT in Korean patients with DP- or BP-DES as compared to the 12-month DAPT [22]. However, except for the STOPDAPT-2 trial, clopidogrel or prasugrel mono- therapy following DAPT has been poorly investigated and thus, the use remains controversial for general CAD patientswith DES.
For the current registry, sub-analyses will be performed in the clinically relevant sub-group with stratification according to the patient’s characteristics (age, sex, clinicalpresentation, well-known coronary risk factors, thrombotic or bleeding risk factors) or procedural characteristics (type of stent, access site, target vessel, total number of implanted stents, total stent length). For assessment of the thrombotic or bleeding risk, already known risk scores, such as the PARIS thrombotic/bleeding risk score and the CREDO- Kyoto thrombotic/bleeding risk score will be used [31, 32]. In addition to primary and secondary endpoints, device- oriented cardiac events (DoCE) including cardiac death, target vessel MI and TLR will also be compared between each BP-DES group. Even though there will probably be a low statistical power for the evaluation of the DoCE or for the other differences in the device features, this exploratory data will be of importance with regard to the design of future randomized-control trials, which will aim to investigate the efficacy of BP-DES when using a very short DAPT and/or P2Y12 inhibitor monotherapy.
Conclusion
The REIWA registry, which encompasses the entire local medical region of the northern area of Japan, will be one of the most important real-world observational studies for patients with thin strut BP-DES for the purpose of evaluating both the safety and feasibility of 1-month DAPT. In addition, this study will hopefully provide supportive evidence for the utilization of the P2Y12 inhibitor monotherapy following the use of 1-month DAPT after BP-DES implantation.
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