One-Month Dual Antiplatelet Therapy Followed by P2Y₁₂ Inhibitor Monotherapy After Biodegradable Polymer Drug-Eluting Stent Implantation　― The REIWA Region-Wide Registry ―

Abstract

Background: The safety and feasibility of using 1-month dual antiplatelet therapy (DAPT) followed by P2Y₁₂ inhibitor monotherapy for patients after percutaneous coronary intervention (PCI) with thin-strut biodegradable polymer drug-eluting stents (BP-DES) in daily clinical practice remain uncertain.

Methods and Results: The REIWA region-wide registry is a prospective study conducted in 1 PCI center and 9 local hospitals in northern Japan. A total of 1,202 patients who successfully underwent final PCI using BP-DES (Synergy: n=400; Ultimaster: n=401; Orsiro: n=401), were enrolled in the registry, and received 1-month DAPT followed by P2Y₁₂ inhibitor (prasugrel 3.75 mg/day or clopidogrel 75 mg/day) monotherapy. The primary endpoint was a composite of cardiovascular and bleeding events at 12 months, including cardiovascular death, myocardial infarction (MI), definite stent thrombosis (ST), ischemic or hemorrhagic stroke, and Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding. Based on the results of a previous study, we set the performance goal at 5.0%. Over the 1-year follow-up, the primary endpoint occurred in 3.08% of patients, which was lower than the predefined performance goal (P_{non-inferiority}<0.0001). Notably, definite ST occurred in only 1 patient (0.08%) within 1 year (at 258 days). No differences were observed in the primary endpoint between stent types.

Conclusions: The REIWA region-wide registry suggests that 1-month DAPT followed by P2Y₁₂ inhibitor monotherapy is safe and feasible for Japanese patients with BP-DES.

For patients with high bleeding risk (HBR), the efficacy of short (3-month) dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) using a current-generation drug-eluting stent (DES) has been established; therefore, recent guidelines recommend short DAPT in cases without anticoagulant treatment.^1,2 Moreover, the ONYX ONE trial demonstrated the safety and feasibility of 1-month DAPT after implantation of the Resolute durable polymer DES (DP-DES).³ Thus, very short (1- to 2-month) DAPT following DP-DES implantation appears to be sufficient to prevent early thrombotic events in patients with HBR. However, because the STOPDAPT-2 trial demonstrated the safety and feasibility of very short DAPT following Xience DP-DES for all-comer patients,⁴ it remains contentious whether 1-month DAPT is suitable for non-HBR patients and those with acute coronary syndrome (ACS), which is associated with a higher thrombotic risk after DES implantation than for chronic coronary syndrome (CCS).⁵ Furthermore, studies investigating whether aspirin or P2Y₁₂ inhibitors should be continued after the early de-escalation of DAPT are currently underway.^4,6,7

Editorial p 885

Recently, thin-strut biodegradable polymer DES (BP-DES), which have a low incidence of device-oriented adverse events comparable to the Xience DP-DES,^8–10 have become widely used in patients with coronary artery disease. In addition, recent studies using pathological materials and optical coherence tomography images have demonstrated that BP-DES exhibits excellent and comparable early strut coverage on thrombotic lesions with greater neointimal maturity and reduced inflammation compared with DP-BES.^11,12 Based on the similar vascular healing performance and clinical evidence of BP-DES and DP-DES, we hypothesized that the use of P2Y₁₂ inhibitor monotherapy after 1-month of DAPT in daily practice could also be appropriate for patients treated with BP-DES. To confirm this hypothesis, this study evaluated the safety and feasibility of P2Y₁₂ inhibitor monotherapy with 1-month DAPT after BP-DES implantation in patients with and without HBR.

Methods

Study Design and Study Population

REIWA is a prospective multicenter region-wide registry study conducted at 1 PCI center (Iwate Medical University Hospital) and 9 local hospitals in or near Iwate Prefecture (Supplementary Figure 1). The rationale and design of the study have been described previously.¹³ This study was registered with the UMIN Clinical Trials Registry (UMIN000037321) and conducted in accordance with the Declaration of Helsinki.

Patients who underwent successful PCI with a novel thin-strut BP-DES, which included the Synergy everolimus-eluting stent (S-EES; Boston Scientific, Marlborough, MA, USA), Ultimaster sirolimus-eluting stent (U-SES; Terumo Corporation, Tokyo, Japan), and the Orsiro sirolimus-eluting stent (O-SES; Biotronik, Bülach, Switzerland), for the treatment of ACS or CCS were screened at each of the participating hospitals. If these patients could tolerate the 1-month DAPT, they were registered for this study after providing written informed consent. The key exclusion criteria were as follows: (1) patients undergoing planned revascularization for residual lesions; (2) a need for oral anticoagulation; (3) a need for antiplatelet therapy other than aspirin and P2Y₁₂ inhibitors; and (4) a life expectancy of <24 months. When patients had multiple-vessel disease in which each vessel was suitable for PCI, only the final procedure was added to this registry. Clinical endpoints were evaluated in all registered patients at 1 month (30–59 days) and 12 months (335–395 days) after the final PCI procedure.

Procedure and Antiplatelet Therapy

In this registry, the choice of stent type was left to the discretion of the attending physician. When multiple stenting procedures were performed, in most cases the same type of stent was used for all lesions. A lesion with an overlapping stent was considered a single target lesion. When multiple lesions were treated without an overlapping stent, the target lesion was determined as the lesion with the most severe stenosis. To assess overall and lesion characteristics, qualitative and quantitative coronary angiography (QCA) was performed on 150 patients (50 patients per BP-DES) who were randomly selected at the time of enrolment. A blinded independent reviewer from the Iwate Cardiovascular Core Laboratory (Iwate, Japan) analyzed the data using an offline QCA system (QAngio XA version 7.3; Medis Medical Imaging System BV, Leiden, Netherlands). The target lesion, defined as the entire segment containing the implanted stent and the 5-mm proximal and distal regions adjacent to the stent, was analyzed using a standardized technique.

In this study, the decision to use clopidogrel or prasugrel was left to discretion of the attending physicians. Patients who had not been taking aspirin or P2Y₁₂ inhibitors were administered a Japanese loading dose of these drugs before PCI, specifically aspirin 200 mg with clopidogrel 300 mg or prasugrel 20 mg. Until the 1-month follow-up, all patients received the Japanese standard dose of DAPT, which was aspirin 81–100 mg/day with clopidogrel 75 mg/day or prasugrel 3.75 mg/day. Subsequently, aspirin treatment was stopped at the 1-month follow-up and P2Y₁₂ inhibitor monotherapy with clopidogrel 75 mg/day or prasugrel 3.75 mg/day was continued until the 12-month follow-up. If new-onset atrial fibrillation, venous thromboembolism, or left ventricular thrombus is found after de-escalation of DAPT, oral anticoagulants are acceptable based on risk stratification.

Study Endpoints

The primary endpoint of this study was the same as that used in the STOPDAPT-2 trial, namely a composite of cardiovascular death, myocardial infarction (MI), definite stent thrombosis (ST), ischemic or hemorrhagic stroke, and Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding.⁴ Secondary endpoints were: (1) a cardiovascular endpoint (composite of cardiovascular death, MI, definite ST, or ischemic or hemorrhagic stroke); and (2) a bleeding endpoint (major or minor TIMI bleeding). MI and ST were defined according to the Academic Research Consortium criteria.¹⁴ In addition, we assessed the incidence of all-cause death, probable ST, clinically driven target lesion revascularization (TLR), device-oriented cardiovascular events (DoCE), including cardiac death, target vessel MI, clinically driven TLR, ischemic and hemorrhagic stroke, Bleeding Academic Research Consortium (BARC) Type 3 or 5 bleeding,¹⁵ BARC Type 2 bleeding, and gastrointestinal bleeding. In the stratified analysis of patients with and without HBR, we used both the Japanese and Academic Research Consortium (ARC) HBR definitions.^2,16

Statistical Analysis

Because the clinical outcomes of the use of BP-DES were similar to those of DP-DES,^8–10 we assumed that the clinical outcomes of the 12-month DAPT in the REIWA cohort were similar to those found for the 12-month DAPT group in the STOPDAPT-2 trial. To verify our hypothesis, we compared the REIWA 1-month DAPT cohort with a hypothetical 12-month cohort calculated from the clinical results of the 12-month DAPT reported in the STOPDAPT-2 trial. In the STOPDAPT-2 trial, the primary endpoint rate of 12-month DAPT after DP-DES implantation was 3.7% per year.⁴ However, because this event rate may have been underestimated owing to the exclusion of patients with comorbidities or complex lesions, we considered the extra margin of this event rate because the real-world registry was most likely to include patients with comorbidities or complex lesions. Therefore, we set the performance goal at 5.0% to determine the safety and feasibility of 1-month DAPT following P2Y₁₂ inhibitor monotherapy after BP-DES implantation. In the present study, we established a non-inferiority margin of 1.5%. Assuming a 3% loss to follow-up, an evaluable sample size of 1,143 patients was provided, with a statistical power exceeding 80%. Therefore, 1,200 patients were included to evaluate the safety and feasibility of BP-DES in the REIWA DAPT regimen.

Statistical analyses were performed using SPSS version 21 (SPSS Inc., Chicago, IL, USA). Because most of the continuous values were not normally distributed, all data are presented as the median with interquartile range (IQR) or as numbers and percentages. One-year cumulative outcomes were estimated using the Kaplan-Meier method. For intergroup comparisons, categorical data were analyzed using the Chi-squared or Fisher’s exact test, as appropriate. Median values were compared between groups using the Mann-Whitney U test or Kruskal-Wallis test, as appropriate. Time-to-event analyses were performed by using the log-rank method. Differences were considered statistically significant at P<0.05.

Results

Baseline Patient and Medication Characteristics

Between July 2019 and July 2022, 2,182 patients who successfully underwent BP-DES implantation were prospectively enrolled from 10 participating hospitals. Of these patients, 496 were excluded from this registry at the physician’s discretion, and 484 patients met the exclusion criteria (Figure 1). Finally, 1,202 patients (55.1%) were assessed for primary and secondary endpoints, with slightly different enrolment periods for each stent group (Supplementary Figure 2).

Figure 1.

Study flowchart. BP-DES, thin-strut biodegradable polymer drug-eluting stent; PCI, percutaneous coronary intervention.

Baseline patient characteristics are presented in Table 1. The median age was 69 years old and 29.5% of patients were aged ≥75 years. More than 70% of patients were men and had hypertension and hypercholesterolemia, and 43% of patients were registered at the time of ACS. Of 685 patients with CCS, 145 underwent PCI for non-culprit lesions of recent ACS. Of all patients, 46.0% and 35.8% met Japanese HBR and ARC-HBR criteria, respectively. Regarding the duration of DAPT, 98.1% of patients had discontinued aspirin at 60 days, although 85.6% of patients were on DAPT at 30 days (Supplementary Figure 3). In this study, the rates of prasugrel and clopidogrel use were 70% and 30%, respectively. Antiulcer drugs, including proton pump inhibitors (PPIs), potassium-competitive acid blockers, and histamine H₂ receptor antagonists, were used in 91.8% of patients. Although the type of stent was selected according at the operator’s discretion, there was no difference in patient background among the 3 types of BP-DES (Supplementary Table 1).

Table 1.

Baseline Patient Characteristics (n=1,202)

Patient characteristics
Age (years)	69 [61–77]
Age ≥75 years	355 (29.5)
Male sex	930 (77.4)
Medical history
Hypertension	938 (78.2)
Hypercholesterolemia	860 (71.5)
Diabetes	501 (41.7)
Current smoker	293 (24.4)
Previous MI	254 (21.1)
Previous stroke	113 (9.4)
Previous PCI (before screening for this study)	211 (17.6)
Previous CABG	12 (1.0)
Heart failure	110 (9.2)
Peripheral vascular disease	37 (3.1)
Renal deficiency (eGFR <30 mL/min/1.73 m2)	71 (5.9)
Dialysis	42 (3.5)
Japanese HBRA	554 (46.0)
ARC-HBR	430 (35.8)
Clinical presentation
ACS	517 (43.0)
STEMI	266 (22.1)
NSTEMI	143 (11.9)
Unstable angina	108 (9.0)
CCS	685 (57.0)
Culprit lesion of CCS	540 (44.9)
Non-culprit lesion of recent MI	145 (12.1)
Medication at registration
Aspirin	1,202 (100)
P2Y12 inhibitors
Prasugrel	836 (69.6)
Clopidogrel	366 (30.4)
Statin	1,100 (91.5)
Antiulcer drugs	1,103 (91.8)
PPI or P-CAB	1,061 (88.3)
H2 blocker	36 (3.0)
β-blocker	669 (55.7)

Values are presented as n (%) or as the median [interquartile range]. ^AJapanese definition of high bleeding risk (HBR) as per Nakamura et al.² ACS, acute coronary syndrome; ARC, Academic Research Consortium; CABG, coronary artery bypass graft surgery; CCS, chronic coronary syndrome; H₂ blocker, histamine H₂ receptor antagonists; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; P-CAB, potassium-competitive acid blocker; PPI, proton pump inhibitor; STEMI, ST-elevation myocardial infarction.

Procedural Characteristics

In this study, more than half the target lesions treated were in the left descending artery, and left main coronary artery (LMCA) disease was treated in 2.4% of patients (Table 2). As is common practice in Japan, almost all patients (99.8%) underwent PCI under intravascular imaging guidance. Because stent selection was at the physician’s discretion with consideration of product features, there were some differences in procedural characteristics among the BP-DESs (Supplementary Table 2). Briefly, U-SES was more frequently used for LMCA disease or bifurcation lesions, and less frequently used for small vessels. In addition, O-SES was more frequently used for small vessels, CCS, or staged PCI, and less frequently used for ACS and emergency PCI. Compared with these BP-DESs, the S-EES was used without bias, except in cases of right coronary artery disease. Regarding the angiographic findings from 150 randomly selected patients, there were no significant differences in pre- and post-QCA findings among the 3 groups (Table 3). However, the location of the target lesion and the severity of coronary calcium differed among the 3 BP-DES types. In addition, a numerically higher prevalence of bifurcation was observed in the U-SES group, and a smaller post-PCI minimum lumen diameter was found in the O-SES group.

Table 2.

Procedural Characteristics (n=1,202)

Target lesion location
LMCA	29 (2.4)
LAD	685 (57.0)
LCX	202 (16.8)
RCA	286 (23.8)
Lesion morphology
ACS-causing culprit lesions	517 (43.0)
Sable lesion	685 (57.0)
CTO	27 (2.2)
BifurcationA	261 (21.7)
LMCA bifurcation stenting	55 (4.6)
Urgent PCI	470 (39.1)
Staged PCI	692 (57.6)
Total no. stents implanted
1	1,012 (84.2)
≥2	190 (15.8)
Intravascular imaging	1,200 (99.8)
IVUS	1,135 (94.4)
OCT/OFDI	78 (6.5)
Stent diameter (mm)	3.0 [2.75–3.5]
Use of ≤2.5-mm stent in target lesion	304 (25.3)
Total stent length (mm)	28 [20–38]

Values are presented as n (%) or as the median [interquartile range]. ^ALesions that have a side branch of ≥1.5 mm by visual on-site assessment. CTO, chronic total occlusion; IVUS, intravascular ultrasound; LAD, left anterior descending artery; LCX, left circumflex artery; LMCA, left main coronary artery; OCT, optical coherence tomography; OFDI, optical frequency domain imaging; RCA, right coronary artery. Other abbreviations as in Table 1.

Table 3.

Angiographic Findings in 150 Randomly Selected Patients

	Total (n=150)	S-EES (n=50)	U-SES (n=50)	O-SES (n=50)	P value
Target vessel location					0.04
LMCA	9 (6)	0 (0)	7 (14)	2 (4)
LAD	83 (55)	25 (50)	29 (58)	29 (58)
LCX	29 (19)	14 (28)	6 (12)	9 (18)
RCA	29 (19)	11 (22)	8 (16)	10 (20)
Bifurcation	39 (26)	10 (20)	19 (38)	10 (20)	0.06
Total occlusion	10 (7)	5 (10)	2 (4)	3 (6)	0.47
Severe calcification	6 (4)	0 (0)	5 (10)	1 (2)	0.03
Preprocedural TIMI flow grade 3	99 (66)	35 (70)	32 (64)	32 (64)	0.77
Preprocedural QCA
Reference vessel diameter (mm)	2.48 [2.11–2.97]	2.50 [2.12–2.82]	2.50 [2.11–2.97]	2.45 [2.04–3.14]	0.93
Minimum lumen diameter (mm)	1.11 [0.70–1.41]	1.10 [0.69–1.48]	1.18 [0.66–1.49]	1.08 [0.75–1.35]	0.75
Diameter stenosis (%)	56.4 [40.7–71.8]	54.6 [38.5–74.5]	55.5 [39.4–73.3]	58.2 [46.7–71.3]	0.63
Postprocedural TIMI flow grade 3	144 (96)	49 (98)	48 (96)	47 (94)	0.59
Post-procedural QCA
Minimum luminal diameter (mm)	2.31 [1.89–2.64]	2.30 [1.98–2.76]	2.40 [1.89–2.68]	2.19 [1.86–2.62]	0.38
Diameter stenosis (%)	16.4 [12.2–21.1]	16.6 [11.0–21.1]	16.9 [13.1–21.8]	15.9 [12.1–19.9]	0.65
Acute gain (mm)	1.14 [0.70–1.73]	1.12 [0.63–1.86]	1.17 [0.81–1.68]	1.12 [0.70–1.69]	0.95

Unless indicated otherwise, values are presented as n (%) or the median [interquartile range]. O-SES, Orsiro sirolimus-eluting stent; QCA, quantitative coronary angiography; S-EES, Synergy everolimus-eluting stent; TIMI, Thrombolysis in Myocardial Infarction; U-SES, Ultimaster sirolimus-eluting stent. Other abbreviations as in Table 2.

One-Year Clinical Outcomes

During the 1-year follow-up period, the primary endpoint was observed in 3.08% of patients (Table 4). The higher bound of the 95% confidence interval of this incidence was 4.26%, which was lower than the predefined performance goal of 5.0% (P_{non-inferiority}<0.0001; Figure 2). In addition, the incidence of secondary cardiovascular and bleeding endpoints was 2.25% and 1.08%, respectively, and these events gradually increased over time (Figure 3). Notably, definite ST occurred in only 1 (0.08%) patient at 258 days. There was no difference in the primary endpoint between the stent types (Supplementary Figure 4). Similar rates of cardiovascular and bleeding events, including clinically driven TLR and DoCE, were observed in each BP-DES group (Supplementary Table 3).

Table 4.

Clinical Outcomes at 1 Year (n=1,202)

Primary endpoint	37 (3.08)
Cardiovascular death	16 (1.33)
Myocardial infarction	9 (0.75)
Definite stent thrombosis	1 (0.08)
Stroke (ischemic or hemorrhagic)	6 (0.50)
TIMI major bleeding	10 (0.83)
TIMI minor bleeding	3 (0.25)
Secondary endpoints
Cardiovascular endpoint	27 (2.25)
Bleeding endpoint (TIMI major or minor bleeding)	13 (1.08)
Exploratory endpoints
All-cause death	22 (1.83)
Probable stent thrombosis	1 (0.08)
Clinically driven TLR	9 (0.75)
DoCE	27 (2.25)
Ischemic stroke	4 (0.33)
Hemorrhagic stroke	2 (0.17)
BARC Type 3 or 5 bleeding	13 (1.08)
BARC Type 2 bleeding	7 (0.58)
Any gastrointestinal bleeding	8 (0.67)

Values are presented as n (%). BARC, Bleeding Academic Research Consortium; DoCE, device-oriented cardiovascular events; TIMI, Thrombolysis in Myocardial Infarction; TLR, target lesion revascularization.

Figure 2.

The primary endpoint compared with the predefined performance goal. The rate of the primary endpoint in the REIWA registry was 3.08% with a one-sided higher 95% confidence interval (CI) of 4.26%, which was lower than the predefined performance goal of 5.00% (P_{non-inferiority}<0.0001).

Figure 3.

Kaplan-Meier curves for the 1-year incidence of primary and secondary endpoints. The incidence rates of the primary endpoint (a composite of cardiovascular death, myocardial infarction [MI], definite stent thrombosis [ST], ischemic or hemorrhagic stroke, and major or minor Thrombolysis in Myocardial Infarction [TIMI] bleeding), the cardiovascular endpoint (a composite of cardiovascular death, MI, definite ST, or ischemic or hemorrhagic stroke), and the bleeding endpoint (major or minor TIMI bleeding) at 1 year were 3.08%, 2.16%, and 1.08%, respectively. PCI, percutaneous coronary intervention.

In the stratified analysis, HBR patients had higher incidences of the primary endpoint, cardiovascular endpoint, and cardiovascular death than non-HBR patients. However, there was no statistically significant difference in the incidence of the bleeding endpoint between the HBR and non-HBR groups (Supplementary Figure 5). Even in patients with ARC-HBR, the incidence of both TIMI major or minor bleeding events and BARC 3 or 5 bleeding events was less than 4%, with each category at 1.63%. Regarding the incidence of each endpoint between ACS and CCS patients, there were no statistically significant differences, although some numerical differences were observed (Supplementary Figure 6A). In addition, patients treated with clopidogrel had a slightly higher (albeit non-significant) incidence of the primary endpoint, cardiovascular endpoint, and cardiovascular death than those treated with prasugrel (Supplementary Figure 6B).

Discussion

In this region-wide registry study, we assessed the safety and feasibility of 1-month DAPT followed by P2Y₁₂ inhibitor monotherapy in patients after BP-DES implantation. The main findings were as follows:

1. The primary endpoint occurred in 3.08% of patients, and the upper bound of the 95% confidence interval was 4.26%, which was lower than the predefined performance goal.

2. The incidence of the cardiovascular endpoint, including clinically driven TLR and DoCE, was similar among the different types of BP-DES.

3. The incidence of the bleeding endpoint was <2% per year, even in HBR patients, whereas HBR patients had higher incidences of cardiovascular endpoints and cardiovascular death than non-HBR patients.

4. The 1-year incidence of definite and probable ST was very low, at only 0.08% each.

This study highlights that 1-month DAPT followed by P2Y₁₂ inhibitor monotherapy is safe and feasible, even for patients undergoing BP-DES implantation. Furthermore, the findings from the REIWA registry suggest similar clinical outcomes of very short DAPT among each BP-DES type, although the study is statistically underpowered. Considering the findings from present and previous relevant studies,^3,4,17–23 very short DAPT sessions may be considered as first-line therapy for patients following implantation of any type of current-generation DES.

Focusing on the secondary cardiovascular endpoint, including cardiovascular death, MI, definite ST, and stroke, the findings from the REIWA registry demonstrate a relatively low incidence compared with previous studies. Notably, definite and probable ST occurred in only in 2 (0.17%) patients over the course of 1 year, and late ST was observed only in 1 (0.08%) patient between 30 and 365 days, which is lower than in the previous 1-month DAPT studies (Table 5). This can be attributed to several factors. First, intravascular imaging guidance, which is known to reduce the risk of target vessel failure through stent optimization,²⁴ led to excellent clinical outcomes. Second, P2Y₁₂ inhibitor monotherapy, which reduces thrombotic and bleeding events more effectively than aspirin monotherapy in patients 1 year after PCI,⁶ is also effective in patients 1 month after PCI. Third, this study exclusively included patients from the Japanese population, which has a lower thrombotic risk than White and Black populations.²⁵ Although there several factors contributed to the low rate of cardiovascular events in REIWA, this study suggests that BP-DESs have excellent antithrombotic performance, even in patients undergoing very short DAPT.

Table 5.

Data of 1-Year Definite or Probable Stent Thrombosis Rates From 1-Month DAPT Studies

Study	Area	Type of stent	Population	ACS (%)	SAPT regimen	ST rate (%)
						1-month DAPT	12-month DAPT
LEADERS FREE (2015)16	Europe	BES	HBR pts	41.5	ASA	1.97	N/A
GLASSY (GROVAL LEADERS adjudication substudy) (2019)18	Worldwide	BES	All-comers	51.1	Ticagrelor	0.87	1.21
STOPDAPT-2 (2020)4	Japan	CoCr-EES	All-comers	37.7	Clopidogrel	0.27	0.07
ONIX ONE (2020)3	Europe and Asia	R-ZES	HBR pts	52.8	ASA or P2Y12-I	1.32	N/A
One-month DAPT (2021)19	South Korea	BES	Non-complex PCI	38.1	ASA	0.73	0.79B
MASTER DAPT (2021)20	Worldwide	U-SES	HBR pts	49.1	ASA or P2Y12-I	0.64C	0.36C
Xience 28A (2021)21	Worldwide	CoCr-EES	HBR pts	34.1	ASA	0.3D	N/A
STOPDAPT-2 ACS (2022)22	Japan	CoCr-EES	ACS	100	Clopidogrel	0.49	0.19
POEMA (2022)23	Italy	PtCr-EES	HBR pts	40.6	ASA	0.90	N/A
REIWAA (2024)	Japan	BP-DES	All-comers	43.0	Clopidogrel or low-dose prasugrel	0.17	N/A

^ARegistry study; the remaining studies are randomized control trials. ^BThis group was treated with 6- to 12-month dual antiplatelet therapy (DAPT). ^CThe study period was from 1 to 12 months after stenting. ^DThis value was calculated using matched data to Xience 90. ASA, aspirin; BES, biolimus A9-eluting drug-coated stent; BP-DES, thin strut biodegradable polymer drug-eluting stent; CoCr-EES, cobalt chromium everolimus-eluting stent; HBR pts, high bleeding risk patients; N/A, not available; P2Y₁₂-I, P2Y₁₂ inhibitors; PtCr-EES, platinum chromium everolimus-eluting stent; R-ZES, Resolute zotarolimus-eluting stent; SAPT, single antiplatelet therapy; ST, stent thrombosis; U-SES, Ultimaster sirolimus-eluting stent. Other abbreviations as in Table 1.

Focusing on the difference in baseline procedural characteristics among each type of BP-DES, it should be noted that the type of stent was chosen on the basis of the type of lesion; specifically, S-EES were primarily used for LCX diseases, U-SES were primarily used for bifurcation lesions, and O-SES were primarily used for stable lesions in small vessels. Considering the features of each product (i.e., U-SES is the most expandable BP-DES with the largest opening cells,²⁶ S-EES has excellent flexibility and conformability,²⁷ and O-SES is the thinnest BP-DES²⁸ and has lower TLR rates in small vessels²⁹), intentional selection of BP-DES based on the type of lesion may also be related to the excellent clinical outcomes even after very short DAPT.

Recently, the STOPDAPT-3 trial using the Xience DP-DES demonstrated that the aspirin-free strategy failed to reduce major bleeding compared with the DAPT strategy and demonstrated a numerically small but statistically higher incidence of ST within 1 month after PCI.³⁰ Therefore, for patients after current-generation DES implantation, it is suggested that 1-month DAPT remains the shortest recommended DAPT strategy and reducing the duration of DAPT to 1 month should be sufficient to reduce the incidence of bleeding events. However, it has never been established whether a very short duration of DAPT is suitable for patients with a high thrombotic risk, such as those with ACS or diabetes. REIWA also demonstrated that the ACS group had a numerically higher rate of cardiovascular events than the CCS group. The TICO trial, which compared ticagrelor monotherapy following 3-month DAPT with ticagrelor-based 12-month DAPT, demonstrated the feasibility of 3-month DAPT in patients with ACS after O-SES implantation.³¹ However, the STOPDAPT-2 ACS trial which had the same endpoints as STOPDAPT-2 and REIWA, failed to establish the non-inferiority of 1-month DAPT over 12-month DAPT in terms of net clinical benefit.²² Considering that prolonged (12 months) DAPT after second-generation DES implantation is associated with higher bleeding and similar thrombotic event rates compared with 1- to 3-month DAPT followed by P2Y₁₂ inhibitor monotherapy,³² guideline-recommended durations (3–12 months) of DAPT may still be optimal after current DES implantation for some ACS patients without HBR. Therefore, further investigations are needed to determine the optimal duration of DAPT for patients with ACS after current-generation DES implantation. Recently, all-comer studies conducted in East Asia demonstrated that patients undergoing 1–3 months of DAPT after BP-DES implantation had a remarkably low incidence of bleeding events and relatively lower cardiovascular event rates.^4,22,33,34 If the cardiovascular event rates in patients receiving 1-month DAPT followed by P2Y₁₂ monotherapy (REIWA DAPT regimen) were consistently low across all countries and significantly lower than those in the prolonged DAPT group, this DAPT regimen could potentially be considered in daily practice for all patients with coronary artery disease.

This study also highlighted that the 1-year incidence of bleeding events was very low even in patients with HBR. The incidence of BARC 3 or 5 bleeding was 1.08%, which was comparable to that reported in other 1-month DAPT studies.^{3,4,17,18,20–22} Originally, ARC-HBR is defined as a BARC 3 or 5 bleeding risk of ≥4% at 1 year or a risk of an intracranial hemorrhage of ≥1% at 1 year.¹⁶ However, within the REIWA cohort, ARC-HBR criteria were no longer a predictor of BARC 3 or 5 bleeding risk of ≥4%. If this is a universal finding for patients with DES, the HBR criteria may be updated for patients receiving 1-month of DAPT. Recently, the HOST-EXAM trial demonstrated that clopidogrel monotherapy for maintenance treatment was associated with a significantly lower incidence of cardiovascular events, hemorrhagic stroke, and gastrointestinal bleeding than aspirin monotherapy.⁶ Focusing on 1-month DAPT studies, the 1-year rates of hemorrhagic stroke in studies assessing P2Y₁₂ monotherapy were lower than in studies assessing aspirin monotherapy.^4,19,22,23 Considering the low bleeding event rate in the REIWA registry, discontinuation of aspirin at 1 month may have contributed to the reduction in major bleeding events. However, in the 5-year results of the STOPDAPT-2 trial, the reduction in bleeding events by clopidogrel monotherapy between 1 and 5 years after Xience DP-DES implantation was less distinct when compared with aspirin monotherapy.⁷ Thus, the effect of early P2Y₁₂ monotherapy on clinical outcomes remains controversial in patients with DES.

Another potential reason for the low bleeding event rate in the REIWA group could be the exclusion of patients receiving oral anticoagulants. Because oral anticoagulation is one of the major criteria for ARC-HBR and is closely related to bleeding events,¹⁶ it is possible that the incidence of bleeding events may have been somewhat underestimated in the REIWA registry.

At the time of early follow-up, physicians should consider which antiplatelet agent should be stopped, aspirin or the P2Y₁₂ inhibitor. In particular, safety and cost are important factors in determining lifelong antiplatelet treatment for secondary prevention of coronary events. A recent meta-analysis assessing secondary prevention demonstrated that long-term (2 years) cardiovascular and any gastrointestinal bleeding rates during P2Y₁₂ inhibitor monotherapy were lower than those during aspirin monotherapy.³⁵ Based on these results, there seems to be no reason to choose aspirin monotherapy at the time of de-escalation of DAPT, except for economic reasons. However, only ticagrelor or clopidogrel was used for P2Y₁₂ inhibitor monotherapy in the studies included in the meta-analysis, and clinical data on secondary prevention has never been compared between a reduced dose of prasugrel and aspirin monotherapy. In addition, the 5-year results of the STOPDAPT-2 trial and HOST-EXAM extended study suggested that the aggressive use of PPIs reduced bleeding risk associated with aspirin to a lower level compared with clopidogrel monotherapy.^7,36 Therefore, even though the safety of early discontinuation of aspirin after 1-month DAPT has been demonstrated in this study, long-term clinical outcomes of reduced dose prasugrel monotherapy for secondary prevention should be compared to those of combination aspirin and PPI therapy to support the benefit of P2Y₁₂ inhibitor monotherapy for secondary prevention.

Study Limitations

This study has some limitations. First, it was a single-arm registry study, and therefore lacked a control group. To establish strong evidence, especially for patients without HBR, a randomized control trial comparing 1-month and prolonged DAPT groups may be preferable. Second, because we used 3 types of stents and 2 types of P2Y₁₂ inhibitor, there was bias in the selection of stents and medications. Third, this study only included patients who successfully underwent PCI; therefore, the incidences of periprocedural cardiac death, MI, and bleeding may have been underestimated. Fourth, the dose of prasugrel administered in Japan is lower than that administered in the US and Europe. Therefore, the reduced dose may have had an impact on clinical outcomes, especially bleeding events. Finally, this study included only Japanese individuals who have a lower thrombotic risk and higher bleeding risk than White and Black individuals.²⁵ A worldwide study may be necessary to eliminate the potential confounding factors related to racial differences.

Conclusions

The REIWA region-wide registry using 3 types of BP-DESs revealed that the 1-year incidence of either cardiovascular or bleeding events was very low in Japanese patients undergoing 1-month DAPT followed by P2Y₁₂ inhibitor monotherapy. This DAPT regimen could be a therapeutic option for patients with HBR or non-HBR to minimize the risk of cardiovascular and bleeding events following BP-DES implantation.

Acknowledgments

The authors thank Kanako Omiya, Yumiko Okuyama, and Kayoko Fujiwara for their editorial assistance.

Sources of Funding

None.

Disclosures

M.I. has received lecture honoraria from Boston Scientific Japan, Daiichi-Sankyo, Japan Lifeline, and Terumo Corporation. T. Ishisone has received lecture honoraria from Boston Scientific Japan, Daiichi-Sankyo, Japan Lifeline, and OrbusNeich. T. Itoh has received lecture honoraria from Daiichi-Sankyo. Y. Morino has received unrestricted research grants from Boston Scientific Japan, Japan Lifeline, and Terumo Corporation; and lecture honoraria from Boston Scientific Japan, Daiichi-Sankyo, and Terumo Corporation). Y. Morino is a member of Circulation Journal’s Editorial Team. None of the remaining authors declare any conflicts of interest.

IRB Information

This study was approved by Iwate Medical University (IRB Committee reference no. MH2019-042).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0091

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