Abstract
Background:
PRASFIT-Practice II is a postmarketing observational study conducted in 4,155 Japanese patients with ischemic heart disease (IHD) who received long-term prasugrel. The data were used to assess the utility of Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria.
Methods and Results:
Patients in PRASFIT-practice II were clinically followed for 2 years. The primary endpoint was the cumulative incidence of major adverse cardiovascular events (MACE) and Thrombolysis in Myocardial Infarction (TIMI) major/minor bleeding. Patients were divided into 2 groups based on ARC-HBR criteria (HBR (40.1% of patients) and non-HBR (59.9%)) and the effect of HBR on the primary endpoint was assessed. The median duration of dual antiplatelet therapy with prasugrel was 391.0 days. At 2 years, the cumulative incidence of MACE was 3.3%, and of TIMI major/minor bleeding was 2.7%. At 1 year, MACE and TIMI major/minor bleeding in the HBR group (4.0% and 3.4%, respectively) were higher than that in the non-HBR group (1.3% for both). Landmark analysis at 3 months and 1 year showed that the higher risk of MACE or TIMI major/minor bleeding in the HBR group persisted through 2 years.
Conclusions:
The results of this study confirmed the safety and effectiveness of long-term treatment with prasugrel, and demonstrated that the ARC-HBR criteria for bleeding risk are applicable in Japanese IHD patients treated with prasugrel.
Patients who undergo percutaneous coronary intervention (PCI) are at an increased risk of cardiovascular events,1
so current guidelines recommend treatment with dual antiplatelet therapy (DAPT) with aspirin and a P2Y12
inhibitor for at least 6–12 months after the procedure.2–5
However, clinical studies conducted after the introduction of second-generation drug-eluting stents (DES) have suggested a link between bleeding events and death, which has led to a recent focus on reducing the risk of bleeding complications and prompted researchers to investigate the feasibility of shorter duration of DAPT followed by P2Y12
inhibitor monotherapy after PCI.6,7
The GLOBAL LEADERS and STOPDAPT-2 studies both showed that 1 month of DAPT followed by 11 months of P2Y12
inhibitor monotherapy was at least as effective as 12 months of DAPT for preventing adverse cardiovascular events after PCI with a new-generation DES.6,7
Reflecting recent evidence, the Japanese Circulation Society 2018 Acute coronary syndrome (ACS) treatment guidelines recommend shortening DAPT duration to under 3 months in patients with high bleeding risk (HBR).2
Current US and European guidelines also recommend shortening DAPT duration to 3–6 months to minimize bleeding complications in HBR patients.4,5
The increased focus on bleeding events has also led to the establishment of a universal consensus document from the Academic Research Consortium for HBR (ARC-HBR) initiative defining HBR criteria for patients undergoing PCI.8
Although this definition will further facilitate the individualization of DAPT after PCI, the applicability of the ARC-HBR criteria for this purpose in Japanese patients has not been fully assessed. Specifically, there is a lack of data on prasugrel-containing DAPT in Japanese HBR patients. PRASFIT-Practice II is a postmarketing observational study that collected long-term real-world data from >4,000 patients with ischemic heart disease (IHD) who received prasugrel at the dose approved in Japan (loading dose of 20 mg followed by maintenance dose of 3.75 mg/day). Safety and efficacy results from a 3-month interim analysis and 1-year follow-up of PRASFIT-Practice II have been published previously.9,10
Here, we report the final analysis of the large-scale observational PRASFIT-Practice II study with 2 years of follow-up data. We used these data to evaluate the predictive power of the ARC-HBR criteria in patients receiving prasugrel. This is the first completed long-term observational study of the approved Japanese dose of prasugrel when used in real-world practice.
Methods
Study Design and Patients
This postmarketing observational study (clinical trial registration no. UMIN000018003) was conducted in Japan in accordance with the Good Postmarketing Study Practice regulations (Ministry of Health, Labour and Welfare Ordinance no. 171, December 2004). Details of the study design have been described elsewhere.9,10
Briefly, the study enrolled patients with IHD who required PCI and were started on long-term prasugrel treatment. To be eligible, patients needed to undergo PCI within 30 days of starting prasugrel. All patients provided written informed consent for participating in the study.
The study was conducted between June 1, 2015 and May 31, 2018, to include an observation period of at least 2 years from the start of prasugrel in all patients, regardless of whether they completed or discontinued treatment. Prasugrel was prescribed at the discretion of the treating physician and in accordance with the Japanese package insert.11
Physicians completed case report forms (CRFs) for each patient at 3, 12 and 24 months after enrollment, which recorded information on prasugrel treatment, clinical events, use of other medications (including antiplatelet or anticoagulant drugs), cardiovascular events, adverse events (AEs; including bleeding), and vital signs/laboratory data.
Application of ARC-HBR Criteria
To assess the feasibility of the ARC-HBR criteria in predicting major bleeding in Japanese patients, a slightly modified version was applied to this cohort. The major and minor ARC-HBR criteria that were used in this study are listed in
Supplementary Table 1. As per the proposed ARC-HBR definition,8
if 1 major criterion or 2 minor criteria were met, the patient was classified as HBR. All other patients were grouped together as non-HBR. A history of intracranial hemorrhage (ICH) or ischemic stroke was a major criterion, although the prevalence of prior ischemic stroke was low. Anemia and CKD were classified as major or minor criterion according to laboratory data. Patients with no laboratory data (i.e., hemoglobin and creatinine levels) were therefore excluded from the analysis.
Study Variables
The key study variables were cardiovascular events and bleeding AEs.9,10,12
Major adverse cardiovascular events (MACE) were defined as a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal ischemic stroke and stent thrombosis. All cardiovascular events were assessed by an independent event-monitoring committee and the incidence of MACE was aggregated. As well as MACE and each individual component of this endpoint, data were collected on the incidence of all-cause death, non-cardiovascular death, readmission due to angina pectoris, non-ischemic stroke, and revascularization. All bleeding AEs that were not related to coronary artery bypass grafting were recorded and classified as Thrombolysis in Myocardial Infarction (TIMI) major bleeding, TIMI minor bleeding, clinically relevant bleeding, or other.12
AEs and adverse drug reactions were classified according to MedDRA/J version 22.0.
Statistical Analysis
Patient characteristics were summarized as frequency for categorical variables, and mean and standard deviation (SD) for continuous variables. The on-treatment analysis period was defined as the period from the start to 14 days after completion of prasugrel treatment, and the intention-to-treat (ITT) analysis period as the time between the start of prasugrel treatment and the last date of the 24-month observation when each patient’s CRF was collected. Both the on-treatment and ITT analysis periods were limited to 780 days after the start of prasugrel treatment. If either period was longer than 780 days based on these definitions, then only the first 780 days were used in the statistical analysis. For all analyses, a period of 30 days was counted as 1 month, 360 days as 1 year, and 720 days as 2 years. DAPT was defined in the analysis as taking prasugrel and aspirin at the same time. The Kaplan-Meier method was used to estimate adherence to DAPT, as well as the cumulative incidence of MACE and bleeding AEs during treatment in the overall population and the HBR and non-HBR groups. Landmark analysis of TIMI major or minor bleeding and MACE was performed at 90 days and 360 days in the HBR and non-HBR groups.
All statistical analyses were conducted using SAS software version 9.2 (SAS Institute Inc.; Cary, NC, USA). Two-sided statistical significance was defined by an α level of <0.05, unless stated otherwise.
Results
Patients
CRFs were available for 4,270 patients and, after the exclusion of those who withdrew consent or had protocol violations, evaluable data were available for 4,155 patients (Supplementary Figure). The median duration of observation was 740.0 days, and the median duration of treatment with DAPT was 391.0 days.
The median age of patients was 69 years (range 24–95 years; 76.5% male) and 31.1% were aged ≥75 years (Table 1). Patients had ACS (57.1%) or non-ACS IHD (42.9%). The main indications for prasugrel were stable angina pectoris (36.8%), STEMI (32.1%) and unstable angina pectoris (17.6%). Excluding 485 patients with missing laboratory data, the HBR group comprised 1,472 patients (40.1%) and the non-HBR group comprised 2,198 patients (59.9%). Aside from the ARC-HBR criteria, the HBR group contained higher proportions of females, and patients with low body weight, peripheral arterial disease or non-ACS IHD compared with the non-HBR group.
Table 1.
Patient Baseline Demographics and Clinical Characteristics
| |
All patients
(N=4,155) |
HBR
(N=1,472) |
Non-HBR
(N=2,198) |
| Males, n (%) |
3,179 (76.5) |
1,028 (69.8) |
1,777 (80.8) |
| Age, years |
| Median (range) |
69 (24–95) |
76 (35–95) |
65 (24–92) |
| ≥75 years, n (%) |
1,292 (31.1) |
890 (60.5) |
270 (12.3) |
| ≥80 years, n (%) |
659 (15.9) |
483 (32.8) |
108 (4.9) |
| Weight, kg |
| ≤50 kg, n (%) |
561 (13.5) |
301 (20.4) |
206 (9.4) |
| Medical history and complications, n (%) |
| Prior MI |
366 (8.8) |
145 (9.9) |
169 (7.7) |
| Prior ischemic stroke |
215 (5.2) |
215 (14.6) |
0 (0.0) |
| Prior PCI |
596 (14.3) |
258 (17.5) |
260 (11.8) |
| Atrial fibrillation |
279 (6.7) |
279 (19.0) |
0 (0.0) |
| Heart failure |
179 (4.3) |
107 (7.3) |
58 (2.6) |
| Anemia |
164 (3.9) |
139 (9.4) |
18 (0.8) |
| PAD |
298 (7.2) |
179 (12.2) |
96 (4.4) |
| Renal disease |
394 (9.5) |
300 (20.4) |
62 (2.8) |
| Risk factors, n (%) |
| Hypertension |
3,010 (72.4) |
1,136 (77.2) |
1,544 (70.2) |
| Dyslipidemia |
2,864 (68.9) |
954 (64.8) |
1,586 (72.2) |
| Diabetes mellitus |
1,654 (39.8) |
641 (43.5) |
836 (38.0) |
| Diagnosis, n (%) |
| ACS |
2,374 (57.1) |
754 (51.2) |
1,431 (65.1) |
| STEMI |
1,333 (32.1) |
410 (27.9) |
833 (37.9) |
| NSTEMI |
311 (7.5) |
102 (6.9) |
187 (8.5) |
| Unstable angina pectoris |
730 (17.6) |
242 (16.4) |
411 (18.7) |
| Non-ACS |
1,781 (42.9) |
718 (48.8) |
767 (34.9) |
| Stable angina pectoris |
1,530 (36.8) |
606 (41.2) |
657 (29.9) |
| Old MI |
159 (3.8) |
63 (4.3) |
75 (3.4) |
| Other |
92 (2.2) |
49 (3.3) |
35 (1.6) |
| DES stent, n (%) |
3,871 (93.2) |
1,352 (91.8) |
2,058 (93.6) |
| PCI puncture site, n (%) |
| Brachial |
183 (4.4) |
69 (4.7) |
80 (3.6) |
| Radial |
2,809 (67.6) |
952 (64.7) |
1,510 (68.7) |
| Femoral |
1,155 (27.8) |
448 (30.4) |
604 (27.5) |
| Treatment dose of prasugrel* |
| 2.5 mg |
23 (0.6) |
14 (1.0) |
8 (0.4) |
| 3.75 mg |
4,127 (99.3) |
1,458 (99.0) |
2,187 (99.6) |
*Maintenance dose. ACS, acute coronary syndrome; DES, drug-eluting stent; DOAC, direct oral anticoagulant; MI, myocardial infarction; NSTEMI, non-ST segment elevation myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; STEMI, ST segment elevation myocardial infarction.
The median duration of treatment with DAPT was 391 days, and 27.8% of patients continued to receive DAPT after day 720 (Figure 1A). Among patients who completed DAPT within 360 days, there tended to be higher proportions of females, patients aged ≥80 years, and of patients with low body weight or atrial fibrillation. Following discontinuation of DAPT, 2,189 patients received antiplatelet monotherapy, mainly with aspirin (1,776 patients); monotherapy with prasugrel or clopidogrel was administered to 321 and 92 patients, respectively.
DAPT prescription at 360 days was slightly lower in the HBR group (54.4%) than in the non-HBR group (63.2%;
Figure 1B). After DAPT, monotherapy in the HBR group was mainly with aspirin (622 patients), followed by prasugrel (143 patients) and clopidogrel (48 patients).
Cardiovascular Events
The cumulative incidence of cardiovascular events at 720 days after the start of prasugrel administration (ITT analysis) was 3.3% (95% confidence interval [CI] 2.8–3.9%) for MACE, 1.5% (95% CI 1.2–2.0%) for cardiovascular death and 0.2% (95% CI 0.1–0.5%) for stent thrombosis (Figure 2). The annual rate of MACE was 1.7% in both the on-treatment and ITT analysis (Supplementary Table 2).
Bleeding AEs
The cumulative incidence of bleeding AEs at 720 days after the start of treatment (ITT) was 7.0% (95% CI 6.3–7.9%) for all bleeding AEs and 2.7% (95% CI 2.2–3.2%) for TIMI major or minor bleeding (Figure 3). The annual rates of all bleeding AEs and TIMI major or minor bleeding were 3.9% and 1.4%, respectively, in the ITT analysis, and 4.9% and 1.7%, respectively, in the on-treatment analysis (Supplementary Table 3).
Cardiovascular Events and Bleeding AEs According to ARC-HBR Criteria
Subgroup analyses using ARC-HBR criteria showed that long-term use of anticoagulants, anemia (hemoglobin <11 g/dL), renal disease (estimated glomerular filtration rate(eGFR) <30 mL/min/1.73 m2), liver cirrhosis, malignancy, age (≥75 years) and long-term concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids was associated with an incidence of TIMI major or minor bleeding of ≥4% at 360 days or an incidence of ICH of ≥1% at 360 days (Figure 4).
The cumulative incidence of TIMI major or minor bleeding and that of MACE in the HBR group and non-HBR groups are shown in
Figure 5A,B. At 360 days, both the incidence of TIMI major or minor bleeding and MACE were higher in the HBR group compared with the non-HBR group (Figure 5A,B).
Landmark Analysis
At 90 and 360 days, landmark analysis demonstrated that both the cumulative incidence of TIMI major or minor bleeding and MACE was highest in the HBR group (Figure 5C,D), the difference being most pronounced at 360 days. Between days 0 and 90, days 91 and 360 and days 361 and 720, the cumulative incidence of MACE in the HBR group was 1.5%, 2.6% and 1.8%, respectively (Figure 5C), and the cumulative incidence of TIMI major or minor bleeding was 1.7%, 1.7% and 1.1%, respectively (Figure 5D). Because both MACE and TIMI major or minor bleeding occurred most frequently in the HBR group at 360 days, the relationship between bleeding AEs and MACE was also investigated. In the HBR group, the incidence of MACE within 360 days in patients with and without bleeding AEs was 9.0% and 3.4%, respectively (Table 2).
Table 2.
Incidence of MACE Within 360 Days in Patients With and Without Bleeding AEs in the HBR Group
| |
Incidence of MACE within
360 days, n (%) |
| HBR group (N=1,472) |
| Presence of bleeding AEs (N=133) |
12* (9.0) |
| Absence of bleeding AEs (N=1,339) |
45 (3.4) |
*9 patients developed MACE (cardiovascular death) as the outcome of bleeding AEs (cerebral hemorrhage); 2 patients developed MACE ≥30 days after bleeding AEs; and 1 patient developed bleeding AEs after MACE. AEs, adverse events; HBR, high bleeding risk; MACE, major adverse cardiovascular event.
Discussion
The primary aim of this observational real-world study was to assess the long-term incidence of cardiovascular events and bleeding AEs in Japanese patients with IHD who received prasugrel. The main findings were as follows: (1) the 2-year cumulative incidence of MACE was 3.3% and that of TIMI major or minor bleeding was 2.7%; (2) the prevalence of HBR patients according to ARC-HBR criteria was 40.1%, and HBR was associated with higher risk of both bleeding AEs and MACE; and (3) in HBR patients, the higher risk of bleeding AEs and MACE was observed through 2 years and especially during the first year.
Our MACE and TIMI major or minor bleeding data were comparable to those obtained in the pivotal PRASFIT-ACS and PRASFIT-Elective trials,13,14
on which Japanese approval of prasugrel was based. In the PENDULUM registry of contemporary PCI outcomes, 1-year MACE and major bleeding rates were 4.4% and 2.8%, respectively.15
Thus, for both events, the outcomes in the current study were slightly better than those reported in the PENDULUM registry. This may be simply because of differences in the respective patient populations, as this study was conducted just after the approval of prasugrel. Given that the PENDULUM registry included patients treated with prasugrel and clopidogrel,15
our results indicate that prasugrel, administered at the locally approved dose (a loading dose of 20 mg, followed by maintenance dose of 3.75 mg/day) is effective in the long-term treatment of Japanese patients with IHD. These results are also expected to translate to patients with IHD in other Asian countries, where prasugrel will be marketed at the same dose as in Japan.
In the present cohort, the prevalence of HBR (40.1%) was similar to that in the CREDO-KYOTO registry (43%)16
and higher than that in the STOPDAPT-2 study (35.0%),17
both of which enrolled Japanese patients. Because STOPDAPT-2 was a randomized controlled trial rather than a real-world study, and each of the ARC-HBR criteria was not fully applied in these cohorts, it can be estimated that at least 40% of patients undergoing PCI in Japan have HBR, which suggests that evaluation of HBR could be clinically important for Japanese patients undergoing PCI. In our analysis, long-term use of anticoagulant therapy, anemia (hemoglobin <11 mg/dL), renal disease (eGFR <30 mL/min/1.73 m2), liver cirrhosis, malignancy, age ≥75 years and long-term concomitant use of NSAIDs or steroids were all associated with an incidence of TIMI major or minor bleeding ≥4% or ICH ≥1%. This finding suggests that most major and some minor (age and use of NSAIDs or steroids) ARC-HBR criteria are applicable to Japanese patients. A platelet count of <100×109/L, which is a major ARC-HBR criterion,8
was not associated with TIMI major or minor bleeding or ICH. However, the small number of patients with a platelet count <100×109/L limited our ability to conclude whether this ARC-HBR criterion is applicable to Japanese patients. The influence of ischemic stroke on bleeding risk was probably underestimated in the current study because a history of ischemic stroke (unspecified onset or severity), rather than the official ARC-HBR criterion of moderate or severe ischemic stroke within the past 6 months was classified as a major HBR criterion. This may suggest that the timing of stroke is an important determinant of bleeding risk.
It has been proposed that East Asian patients with ACS tend to have HBR and a different ischemia/bleeding tradeoff to Caucasians.13,18
In fact, a relatively low dose of prasugrel has been recommended for Japanese patients because of their potentially increased bleeding risk.12,13
The ability of the ARC-HBR criteria to predict bleeding AEs during use of the approved Japanese dose of prasugrel needs to be confirmed. In our study, the cumulative incidence of TIMI major or minor bleeding at 1 year was highest in the HBR group (3.4% vs. 1.3% in the non-HBR group), suggesting that discrimination of the bleeding risk based on ARC-HBR criteria is applicable for daily use of prasugrel. This observation is consistent with the post-hoc analysis of the all-comers CREDO-KYOTO registry of Japanese PCI patients, in which the cumulative incidence of Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO) moderate or severe bleeding AEs at 1 year was 10.4% in ARC-HBR patients compared with 3.4% in non-HBR patients.16
Several reasons can be given to explain the difference in the incidence of bleeding AEs between our study and the CREDO-KYOTO registry analysis, including the definition of bleeding (TIMI major or minor vs. GUSTO moderate or severe), and differences in enrolled patients, DAPT drugs (prasugrel in our study vs. clopidogrel or ticlopidine in the CREDO-Kyoto registry analysis) and PCI procedure. The current study was basically an all-comers registry and prasugrel dosing was tailored to Japanese patients, but the possibility of selection bias, such as exclusion of patients with extremely high bleeding risk, cannot be discounted. Important PCI procedural differences might be related to when the studies were conducted (June 2015 to May 2018 for our study vs. January 2005 to December 2007 for the CREDO-Kyoto registry analysis). In our study, patients generally received a second-generation DES via a radial approach. In contrast, in patients enrolled in the CREDO-KYOTO registry, PCI was generally performed using a bare-metal stent or first-generation DES via a femoral approach. Collectively, based on the results of our study and the ARC-HBR analysis of the CREDO-Kyoto registry, we may conclude that application of the ARC-HBR criteria consistently identified patients with HBR irrespective of the different regimens utilized during the 2 study eras.
We observed that the higher risk of bleeding AEs and MACE in the HBR than in the non-HBR group was consistent over 2 years, especially up to 1 year after PCI. In the HBR group, the incidence of MACE within 1 year was highest in patients with bleeding AEs (9.0% vs. 3.4% in patients without bleeding), suggesting an association between bleeding AEs and MACE. The fact that the difference between the HBR and non-HBR groups began at 3 months suggests that the risk–benefit balance of DAPT should be considered before PCI. In addition, in line with the guidelines, this observation suggests that within 1 year may be an important time to review the termination or continuation of DAPT.2–5
After 1 year, the difference between the HBR and non-HBR groups became smaller, which may reflect the natural history of IHD19
and the diminishing effect of DAPT on bleeding (DAPT prescription <30% at 2 years).
The difference in DAPT prescription between the HBR and non-HBR groups was quite small, suggesting that physicians tended not to consider the balance between risk and benefit of DAPT in real-world practice. Studies have demonstrated a strong relationship between nonfatal bleeding and death.20
These findings strongly suggest that strategies to prevent bleeding AEs may improve prognosis. The prescription of appropriate DAPT tailored according to bleeding risk (e.g., using a reduced dose such as prasugrel 2.5 mg) may reduce the incidence of bleeding AEs and MACE, thereby improving clinical outcomes after PCI.
Study Limitations
There are a number to note. Firstly, because the use of the ARC-HBR criteria was not prespecified, some of the required information was not collected and the criteria had to be modified. Furthermore, in the ARC-HBR definition, bleeding was assessed using the BARC criteria, whereas in this study, bleeding AEs were assessed using the TIMI criteria. Additionally, this was an observational real-world study and therefore the risk of bias was higher than that of a randomized controlled trial. In addition, further hypothesis-generating research is needed to further strengthen the therapeutic strategy of antiplatelet therapy because decisions regarding the duration of DAPT and subsequent monotherapy were made by each patient’s physician in this observational study.
Conclusions
We confirmed the safety and effectiveness of long-term treatment with prasugrel, administered at the dose approved in Japan. Furthermore, the study showed that the ARC-HBR criteria for bleeding AEs are applicable to Japanese patients with IHD receiving prasugrel. In order to obtain a net clinical benefit with prasugrel, we suggest that assessment and consideration of each patient’s bleeding risk is required for appropriate DAPT planning.
Acknowledgments
We thank all the investigators, staff and patients who contributed to this postmarketing observational study. We also thank Catherine Rees and Georgii Filatov of Springer Healthcare Communications who wrote the outline and first draft of this manuscript. This medical writing assistance was funded by Daiichi Sankyo Co., Ltd.
No funds from a non-profit organization or government were received.
Disclosures
This study was sponsored by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). M. Nakamura received remuneration and research funding from Daiichi Sankyo Co., Ltd; T. Kitazono received remuneration and scholarship fund/donation from Daiichi Sankyo Co., Ltd; K. Kozuma received remuneration from Daiichi Sankyo Co., Ltd; T. Sekine, S. Nakamura, K. Shiosakai, A. Tanabe and T. Iizuka are employees of Daiichi Sankyo Co., Ltd. T. Kitazono is a member of
Circulation Journal
’ Editorial Team.
Data Availability
The anonymized participant data will not be shared.
Research Ethics / IRB Information
The study was conducted by Daiichi Sankyo Co., Ltd. (Tokyo, Japan) in accordance with the Good Postmarketing Study Practice standards specified by the Ministry of Health, Labour and Welfare in Japan. The study protocol was approved by the In-House Committee of Daiichi Sankyo Co., Ltd, and by the Ministry of Health, Labour and Welfare of Japan, which was approved on November 15, 2014 (approval ID: EFT013-041).
All patients provided written informed consent for participating in the study.
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-0253
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