Abstract
Introduction
We previously conducted a prospective, observational post-marketing surveillance study to assess the safety and effectiveness of four-factor prothrombin complex concentrate (4F-PCC) for rapid vitamin K antagonist (VKA) reversal in Japanese patients.
Methods
This subgroup analysis compared the safety, especially thromboembolic events (TEEs), and effectiveness of 4F-PCC by stratifying patients into two subgroups according to baseline international normalized ratio (INR) levels with < 2.0 and ≥ 2.0.
Results
Of 1271 eligible patients, 215 (17.9%) had INR < 2.0 and 987 (82.1%) had INR ≥ 2.0. Overall baseline characteristics were similar between groups; age (74.0 years vs 74.0 years), body mass index (22.1 kg/m2 vs 21.9 kg/m2), ratio of inpatients (90.2% vs 88.7%), manifested atrial fibrillation (46.0% vs 48.8%). Median INRs at baseline were 1.72 (minimum 0.92, maximum 1.99) in the INR < 2.0 group and 2.95 (2.00, 27.11) in the INR ≥ 2.0 group. The most common reason for 4F-PCC administration was intracranial hemorrhage (67.0% vs 59.5%), and lesser gastrointestinal bleeding (0.9% vs 7.5%). After 4F-PCC administration (average doses 24.5 IU/kg [INR < 2.0 group] and 29.2 IU/kg [INR ≥ 2.0 group]), INRs were significantly reduced to 1.21 (− 28%) and 1.31 (− 68%), respectively, and resulted in hemostasis in a similarly rapid manner. The incidences of adverse drug reactions were 3.7% in each group. TEEs occurred in 4 (1.9%) patients in the INR < 2.0 group and 11 (1.1%) patients in the INR ≥ 2.0 group and were predominantly composed of stroke, while similar rates (67.0% vs 62.9%) of bleeding events post-anticoagulant resumption were observed between groups.
Conclusion
This study supports the favorable tolerability and efficacy of 4F-PCC regardless of baseline INR (< 2.0 or ≥ 2.0), with a prompt reduction of INR and substantial hemostatic effectiveness in the real-world setting for patients requiring urgent VKA reversal, although no indicated 4F-PCC dose for VKA reversal exists for INR < 2.0 to date.
Keywords: Anticoagulants, Bleeding, International normalized ratio, Intracranial hemorrhage, Japan, Prothrombin complex concentrate, Vitamin K antagonist
Key Summary Points
| Why carry out this study? |
| No study has extensively assessed the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) in patients with international normalized ratio (INR) < 2.0. |
| To compare the safety and effectiveness of 4F-PCC based on INR < 2.0 and ≥ 2.0, we conducted a subgroup analysis of a previously published prospective, observational post-marketing surveillance study. |
| What was learned from the study? |
| The study revealed that the safety and effectiveness of 4F-PCC in Japanese patients were consistent between INR < 2.0 and ≥ 2.0, although no indicated 4F-PCC dose for vitamin K antagonist (VKA) reversal exists for INR < 2.0 to date. |
| The results of this study support the use of 4F-PCC in patients with INR < 2.0 for rapid VKA reversal in real-world clinical practice. |
Introduction
Vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) demonstrate a favorable benefit–risk profile for managing thrombotic events (TEEs). However, there is a risk of precipitating or worsening acute major bleeding, resulting in significant morbidity and mortality [1–6]. VKA therapy increases the risk of bleeding with events typically being minor but potentially life-threatening [7, 8]. A global review of VKA-treated atrial fibrillation (AF) found an annual major hemorrhage rate of 1.3–7.2% and an annual intracranial hemorrhage (ICH) rate of 0.1–2.5% [9]. ICH represents a significant contributor to both mortality and morbidity in these patients [10, 11]. Prompt reversal of VKA effects is crucial for managing acute hemorrhage, necessitating cessation of antithrombotic agents, especially in cases of ICH [12, 13].
Administration of 4-factor prothrombin complex concentrate (4F-PCC) is recommended for fast and reliable reversal [12, 14–16]. Owing to its capacity to administer 2000 IU in 80 mL, 4F-PCC is suitable for promptly correcting the international normalized ratio (INR) [17]. Phase 3 trials with 4F-PCC demonstrated effective hemostasis and a significant reduction in INR with 4F-PCC [18–20]. The 3.8% incidence rate of TEEs observed in global phase 3 trials was not negligible, indicating the need for continued monitoring, especially among Japanese patients. Therefore, we conducted a prospective, observational post-marketing surveillance (PMS) study of Japanese patients receiving 4F-PCC [21]. The data revealed that the incidence of TEEs (1.5%) was numerically lower than that seen in global phase 3 trials [18–20].
The dosage of 4F-PCC is determined on the basis of the INR ranges, with 25 IU/kg (maximum 2500 IU) for INR ≥ 2.0 and < 4.0, 35 IU/kg (maximum 3500 IU) for INR ≥ 4.0 and ≤ 6.0, and 50 IU/kg (maximum 5000 IU) for INR > 6.0. Japanese guidelines recommend maintaining an optimal INR range of 1.6–2.6 under warfarin treatment for patients aged 70 and older, whereas the optimal range for those under 70 is generally an INR of 2–3, based on evidence from Japanese registries [12, 22–24]. However, to date, no extensive study has assessed the safety and effectiveness of 4F-PCC globally or in Japan including patients with INR < 2.0.
Here, we report the results of a subgroup analysis of the PMS study which compared the incidence of TEEs with 4F-PCC in patients with baseline INR < 2.0 and ≥ 2.0.
Methods
Study Design and Patients
This study represents the second analysis of the PMS study [21], which involved patients with major bleeding or those requiring urgent surgical intervention, and subsequently given 4F-PCC with a follow-up period for 4 weeks. The dosage of 4F-PCC was based on the Japanese label recommendations, which vary according to patient INR ranges: 25 IU/kg (up to 2500 IU) for INR ≥ 2.0 and < 4.0, 35 IU/kg (up to 3500 IU) for INR ≥ 4.0 and ≤ 6.0, and 50 IU/kg (up to 5000 IU) for INR > 6.0. There are no established dosage guidelines for 4F-PCC in cases where INR levels are < 2.0. The dose of 4F-PCC was decided by the attending physician.
The study was carried out in compliance with the Declaration of Helsinki (1964 and its subsequent amendments). It also adhered to the principles outlined in the Japanese Good Postmarketing Study Practice (GPSP) regulations. The protocol was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) and by the ethics committees. All participating patients provided comprehensive, written informed consent. All Japanese sites that administered 4F-PCC post-approval participated in the study.
Study Endpoints
Patients were stratified into the following subgroups based on baseline INR < 2.0 and ≥ 2. The study’s primary endpoint was the incidence of TEEs. Secondary endpoints included the incidence of ADRs. Hemostatic effectiveness was assessed at the physician’s discretion and graded by the attending physician as absent, present, or unknown.
The timing of anticoagulant therapy resumption and the specific drug used upon recommencement were also examined. Day 1 was defined as the day 4F-PCC was administered.
Statistical Analyses
Continuous effectiveness variables were succinctly summarized using descriptive statistics, including the number of patients, mean, and standard deviation (SD). A paired t test was utilized to analyze the change in INR from baseline to administration. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Japan).
Results
Patient Disposition
A total of 482 centers engaged in this investigative survey. Of 1973 registered patients eligible for the PMS study, 1387 provided informed consent, and case report forms were not collected from 6 patients. Thereby, 1381 patients were analyzed for safety and effectiveness. Of these, 1271 (92.0%) patients received a VKA (Fig. 1). INR measurements were obtained before initial administration of 4F-PCC in 1202 patients, of which 215 (17.9%) had INR < 2.0 group and 987 (82.1%) had INR ≥ 2.0.
Fig. 1.
Patient disposition and analysis sets. INR international normalized ratio, VKA vitamin K antagonist
Patient Characteristics at Baseline
The patient characteristics of overall cohort have been previously published [20]. There were 119 male patients and 96 female patients in the INR < 2.0 group, and 617 male patients and 370 female patients in the INR ≥ 2.0 group. For most baseline variables, age (74.0 vs 74.0 years), body mass index (22.1 kg/m2 vs 21.9 kg/m2), and the ratio of inpatients (90.2% vs 88.7%) were similar between both groups (Table 1). Notably, the proportion of elderly patients was high in both groups, with those aged ≥ 80 years accounting for 39.5% in the INR < 2.0 group and 40.3% in the INR > 2.0 group.
Table 1.
Baseline patient characteristics
| INR < 2.0 (n = 215) | INR ≥ 2.0 (n = 987) | |
|---|---|---|
| Sex, male, n (%) | 119 (55.3) | 617 (62.5) |
| Sex, female, n (%) | 96 (44.7) | 370 (37.5) |
| Age, years, mean (SD) | 74.0 ± 13.5 | 74.0 ± 14.2 |
| Age group, years, n (%) | ||
| < 10 | 0 (0.0%) | 4 (0.4%) |
| 10–15 | 0 (0.0%) | 5 (0.5%) |
| 16–19 | 2 (0.9%) | 5 (0.5%) |
| 20–29 | 3 (1.4%) | 6 (0.6%) |
| 30–39 | 0 (0.0%) | 10 (1.0%) |
| 40–49 | 4 (1.9%) | 24 (2.4%) |
| 50–59 | 15 (7.0%) | 60 (6.1%) |
| 60–69 | 42 (19.5%) | 164 (16.6%) |
| 70–79 | 64 (29.8%) | 310 (31.4%) |
| 80–89 | 70 (32.6%) | 338 (34.3%) |
| ≥ 90 | 15 (7.0%) | 60 (6.1%) |
| Body weight, kg, mean (SD) | 56.1 ± 13.0 | 56.0 ± 13.0 |
| BMI, mean (SD) | 22.1 (4.1) | 21.9 (3.9) |
| Inpatient, mean (SD) | 194 (90.2%) | 875 (88.7%) |
| Outpatient, mean (SD) | 20 (9.3%) | 106 (10.7%) |
| Baseline INR, mean (minimum, maximum) | 1.72 (0.92, 1.99) | 2.95 (2.00, 27.11) |
| Distribution of baseline INR, n (%) | ||
| < 1.6 | 78 (36.3) | 0 |
| 1.6 to < 2.0 | 137 (63.7) | 0 |
| 2.0 to < 4.0 | 0 | 705 (71.4) |
| 4.0–6.0 | 0 | 137 (13.9) |
| 6.01 to < 10.0 | 0 | 89 (9.0) |
| ≥ 10 | 0 | 56 (5.7) |
| Reason for the utilization of VKA, n (%) | ||
| AF | 99 (46.0) | 482 (48.8) |
| Valvular heart disease | 46 (21.4) | 157 (15.9) |
| Cerebral infarction | 6 (2.8) | 96 (9.7) |
| VTE | 18 (8.4) | 56 (5.7) |
| Ischemic heart disease | 10 (4.7) | 41 (4.2) |
| Ventricular assist device | 6 (2.8) | 37 (3.7) |
| Heart failure | 5 (2.3) | 20 (2.0) |
| Arrhythmia except AF | 4 (1.9) | 14 (1.4) |
| PAD | 3 (1.4) | 15 (1.5) |
| Intracardiac thrombus | 2 (0.9) | 10 (1.0) |
| Aortic aneurysm/dissection | 3 (1.4) | 9 (0.9) |
| Pacemaker | 1 (0.5) | 4 (0.4) |
| Ventricular aneurysm | 1 (0.5) | 3 (0.3) |
| Dialysis | 1 (0.5) | 2 (0.2) |
| Other | 7 (3.3) | 27 (2.7) |
| Not available | 17 (7.9) | 80 (8.1) |
AF atrial fibrillation, BMI body mass index, INR international normalized ratio, PAD peripheral arterial disease, SD standard deviation, VKA vitamin K antagonist, VTE venous thromboembolism
This study identified nine pediatric patients (under 15 years), all of whom had an INR ≥ 2.0, and there were no pediatric patients with an INR < 2.0.
The average INR values (minimum, maximum) were 1.72 (0.92, 1.99) in the INR < 2.0 group and 2.95 (2.00, 27.11) in the INR ≥ 2.0 group. Of the INR < 2.0 group, 36.3% had an INR of < 1.6.
Both groups showed a comparable ranking of reasons for VKA use, with AF (46.0% vs 48.8%; INR < 2.0 vs ≥ 2.0) as the leading cause and valvular heart disease (21.4% vs 15.9%) as the second most frequent.
Dose of 4F-PCC
The average doses of 4F-PCC were 24.5 IU/kg (INR < 2.0 group) and 29.2 IU/kg (INR ≥ 2.0 group) (Table 2).
Table 2.
Summary of 4F-PCC administration
| INR < 2.0 (n = 215) | INR ≥ 2.0 (n = 987) | |
|---|---|---|
| Dose of 4F-PCC, IU/kg, mean (SD) | 24.5 ± 7.1 | 29.2 ± 9.5 |
| Distribution of dose of 4F-PCC, n (%) | ||
| < 10 | 4 (1.9) | 5 (0.5) |
| 10 to < 15 | 10 (4.7) | 14 (1.4) |
| 15 to < 20 | 26 (12.1) | 51 (5.2) |
| 20 to < 25 | 67 (31.2) | 240 (24.3) |
| 25 to < 35 | 94 (43.7) | 465 (47.1) |
| 35 to < 50 | 9 (4.2) | 144 (14.6) |
| ≥ 50 | 4 (1.9) | 62 (6.3) |
| Reasons for the administration of 4F-PCC, n (%) | ||
| Acute major bleeding | ||
| Intracranial hemorrhage (ICH) | 144 (67.0) | 587 (59.5) |
| Non-traumatic ICH (except for subarachnoid hemorrhage) | 59 (27.4) | 293 (29.7) |
| Traumatic ICH (except for chronic subdural hematoma) | 43 (20.0) | 169 (17.1) |
| Subarachnoid hemorrhage | 20 (9.3) | 89 (9.0) |
| Chronic subdural hematoma | 13 (6.0) | 16 (1.6) |
| Other | 2 (0.9) | 4 (0.4) |
| Unclassifiable | 7 (3.3) | 16 (1.6) |
| GI bleeding | 2 (0.9) | 74 (7.5) |
| Other bleeding | 33 (15.3) | 151 (15.3) |
| Urgent surgery/invasive procedure | ||
| Abdominal surgery/intervention | 12 (5.6) | 56 (5.7) |
| Cardiovascular surgery/intervention | 16 (7.4) | 44 (4.5) |
| Orthopedic surgery | 2 (0.9) | 16 (1.6) |
| Neurological surgery/intervention | 2 (0.9) | 6 (0.6) |
| Other surgery/intervention | 2 (0.9) | 27 (2.7) |
| INR overextension (prolonged) | 0 | 13 (1.3) |
| Unknown | 2 (0.9) | 13 (1.3) |
| Concomitant vitamin K, n (%) | 154 (71.6) | 716 (72.5) |
| Blood transfusion or blood product use, n (%) | 106 (49.3) | 395 (40.0) |
4F-PCC 4-factor prothrombin complex concentrate, GI gastrointestinal, ICH intracranial hemorrhage, INR international normalized ratio, SD standard deviation
The distribution of dose of 4F-PCC was also similar between both groups in the INR < 2.0 and ≥ 2.0. The most commonly used dose ranges were 25–35 IU/kg, followed by 20–25 IU/kg. The use of < 20 IU/kg was more frequent in the INR < 2.0 group at 18.6% compared to 7.1% in the INR ≥ 2.0 group.
Reason for Administration of 4F-PCC
Both INR < 2.0 and ≥ 2.0 groups showed a comparable ranking of reasons for the administration of 4F-PCC, with ICH (67.0% vs 59.5%), inclusive of non-traumatic ICH (27.4% vs 29.7%), and traumatic ICH (20.0% vs 17.1%) as the leading causes, followed by abdominal and cardiovascular surgery/intervention (5.6% and 7.4% vs 5.7% and 4.5%) (Table 2). Gastrointestinal (GI) bleeding was more frequent in the INR ≥ 2.0 group (7.5%) compared to the INR < 2.0 group (0.9%). Additionally, INR prolongation was observed in 13 cases (1.3%) in the INR ≥ 2.0 group but not in the INR < 2.0 group.
The rates of concomitant vitamin K and blood transfusion were similar between both groups (71.6% and 49.3% vs 72.5% and 40.0%), with over 99% of the Vitamin K being administered intravenously.
Effectiveness
The hemostatic effectiveness showed similar achievement between both INR < 2.0 and ≥ 2.0 groups (82.3% and 86.7%). Treatment with 4F-PCC significantly reduced INR (p < 0.001); median (minimum, maximum) INRs at baseline and post-administration were 1.75 (0.96, 1.99) and 1.18 (0.45, 2.30), respectively, in the INR < 2.0 group (Fig. 2a) and 2.98 (2.00, 27.11) and 1.22 (0.89, 6.61), respectively, in the INR ≥ 2.0 group (Fig. 2b). At post-administration, the percentage of patients achieving INR ≤ 1.3 was 78.9% in the INR < 2.0 group and 64.8% in the INR ≥ 2.0 group.
Fig. 2.
INR before and after initial administration of 4F-PCC. Baseline (before initial administration of 4F-PCC) INR < 2.0 (a), INR ≥ 2.0 (b). INR between before and after initial administration of 4F-PCC was analyzed using a paired t test. INR prothrombin time—international normalized ratio, 4F-PCC four prothrombin complex concentrate
Resumption of Anticoagulant Therapy
The proportion of anticoagulant resumption after ICH was lower than after any bleeding, indicating a similar pattern in both groups: 61.8% vs 67.0% in INR < 2 group; 56.3% vs 62.9% in INR ≥ 2.0 group (Table 3). The date to resume anticoagulation varied across both groups and regardless of the type of bleeding events.
Table 3.
Summary of anticoagulant therapy resumption
| INR < 2.0 | INR ≥ 2.0 | |
|---|---|---|
| Any bleeding, n | 215 | 987 |
| Resumption of anticoagulant therapy, n (%) | 144 (67.0) | 621 (62.9) |
| Date of the resumption, n (%) | ||
| 1–3 days | 36 (16.7) | 162 (16.4) |
| 4–7 days | 38 (17.7) | 179 (18.1) |
| 8–14 days | 41 (19.1) | 162 (16.4) |
| > 14 days | 28 (13.0) | 117 (11.9) |
| ICH, n | 144 | 587 |
| Resumption of anticoagulant therapy, n (%) | 89 (61.8) | 331 (56.3) |
| Date of the resumption, n (%) | ||
| 1–3 days | 16 (11.1) | 57 (9.7) |
| 4–7 days | 23 (16.0) | 97 (16.5) |
| 8–14 days | 28 (19.4) | 93 (15.8) |
| > 14 days | 21 (14.6) | 84 (14.3) |
ICH intracranial hemorrhage, INR international normalized ratio
Safety and Characteristics of TEE
The reporting rate of ADR was similar in both groups. In the INR < 2.0 group, there was one case (0.5%) of shock and four cases of TEE (1.9%). Conversely, in the INR ≥ 2.0 group, there were 11 instances of TEE (1.1%) (Table 4).
Table 4.
Incidence of ADRs
| INR < 2.0 (n = 215) | INR ≥ 2.0 (n = 987) | |
|---|---|---|
| Any ADRs, n (%) | 8 (3.7) | 37 (3.7) |
| Assessing priority survey items, n (%) | ||
| Anaphylaxis | 0 | 0 |
| Shock | 1 (0.5) | 0 |
| TEE (contains duplicates) | 4 (1.9) | 11 (1.1) |
| Stroke | 3 (1.4) | 11 (1.1) |
| Intracardiac thrombus | 0 | 1 (0.1) |
| Deep vein thrombosis | 1 (0.5) | 2 (0.2) |
| Pulmonary embolism | 0 | 1 (0.1) |
| Arterial embolism | 0 | 5 (0.5) |
| Renal infarction | 0 | 1 (0.1) |
ADR adverse drug reaction, INR international normalized ratio, TEE thromboembolic events
The characteristics of the TEEs are also presented in Table 4. The majority of TEEs were stroke, with 3 out of 4 cases occurring in the INR < 2 group and all 11 cases in the INR ≥ 2 group. Among other TEE events, there was one case of deep vein thrombosis in the INR < 2 group, while in the INR ≥ 2 group, there were also five cases of intracardiac thrombus, and one case each of pulmonary embolism, arterial embolism, and renal infarction, some of which overlapped with reports of stroke.
Upon investigating the details of the four cases of TEEs in the INR < 2.0 group revealed that three cases had a baseline INR < 1.6. Additionally, all four cases received ≥ 20 IU/kg, while no TEEs occurred in patients given < 20 IU/kg. Furthermore, in two of the four cases, anticoagulant therapy had not been resumed, and in one case, it was resumed after 16 days.
Discussion
The current study is a subgroup analysis of the data derived from a prospective, observational PMS study in Japanese patients receiving 4F-PCC for urgent VKA reversal [21]. By collecting information regarding 1202 patients for 4F-PCC therapy and baseline INR values, we identified 215 (17.9%) patients with the INR < 2.0, while no indicated 4F-PCC dose for VKA reversal exists for INR < 2.0. To date, this study represents the largest investigation globally and within Japan regarding the safety and effectiveness of 4F-PCC treatment. The findings of this real-world study highlight the hemostatic effectiveness and safety of 4F-PCC, especially in terms of TEE, even in patients with INR < 2.0, a population for whom no data are available from phase 3 trials [18–20, 25]. This analysis demonstrated consistent efficacy and safety of 4F-PCC regardless of baseline INR values. Intriguingly, around 20% of patients in the INR < 2.0 group received a reduced 4F-PCC dose of < 20 IU/kg.
The recommended dose of 4F-PCC for patients who require urgent VKA reversal is based on INR at baseline with INR > 2.0 derived from data in phase 3 trials [18–20, 25]. However, there have been reports of major bleeding events occurring in patients with an INR < 2.0. The concern is particularly acute in cases of ICH, especially among Japanese individuals, as a result of their increased risk of bleeding [26–28]. Indeed, Japanese guidelines for AF management recommend treatment with warfarin to achieve a target INR of 1.6 to 2.6 in patients with nonvalvular AF who are age 70 years or older, and INR of 2 to 3 in those younger than age 70 years, based on data in a Japanese nationwide registry [12, 22–24]. Notably, the present study revealed that approximately 70% of all patients needing 4F-PCC treatment were ≥ 70 years old, regardless of baseline INR. Furthermore, approximately half of patients were receiving VKA for reasons other than AF, and the assessment of INR in this population has been poorly examined previously. Thus, evidence of warfarin reversal via 4F-PCC in patients with INR < 2.0 is greatly needed.
While there is no indication for INR < 2 to date, Sarode et al. [29] investigated 4F-PCC dosing strategies for the population using pharmacometrics modeling utilizing data from phase 3 trials. They reported that doses of 20 IU/kg and 15 IU/kg were required to achieve 50% of factor X activity in over 80% of patients 30 min after 4F-PCC administration at INR levels of 1.9 and 1.6, respectively. Small studies from US groups also suggested the usefulness of administering 15–25 IU/kg of 4F-PCC for INR < 2.0 [30, 31]. In the current study, all four cases received ≥ 20 IU/kg, while no TEEs occurred in patients given < 20 IU/kg.
Even though over 80% of patients in the group with INR < 2.0 were using doses higher than the recommended doses from previous simulation analysis, they showed comparable overall safety and effectiveness with those in the INR ≥ 2.0 group. Since the timing of INR measurements differs from earlier studies, making a precise comparison is challenging. Even more importantly, in the real-world setting, most physicians generally appeared to be treating patients without particular concern for the dose adjustments of 4F-PCC by baseline INR values, whereas there was a slight variation in the frequency of < 20 IU/kg use. On the basis of the present data, there appear to be no major issues with outcomes.
The mean INR reductions from baseline to post-administration of 4F-PCC were 1.75 to 1.18 in the INR < 2.0 group (− 28%) and 2.98 to 1.22 in the INR ≥ 2.0 group (− 68%). While the magnitude of the reduction from baseline in the INR < 2.0 group is not exceptionally large, it could still be considered a clinically meaningful reduction. Indeed, this study showed that INR ≤ 1.3 was achieved in 78.9% of patients in the INR < 2.0 group and 64.8% of patients in the INR ≥ 2.0 group, i.e., comparable or higher than those observed in global phase 3 trials (62.2% [19], 55% [20]).
In this study, most patients were given 4F-PCC for ICH, with minimal usage for GI bleeding, whereas global phase 3 trials predominantly featured patients with GI bleeding [18–20]. This is believed to be due to the elevated risk of ICH among patients with Asian ethnicity [26–28]. Interestingly, this pattern remained consistent across both INR < 2.0 and INR ≥ 2.0 groups, whereas US guidelines recommend an INR target < 1.4 in patients only with VKA-associated ICH [32]. The INR < 2.0 group exhibited a more pronounced lesser GI bleeding.
The occurrence of TEE was four cases (1.9%) in the INR < 2.0 group and 11 cases (1.1%) in the INR ≥ 2.0 group, with a similar incidence rate. Most TEEs in both groups were stroke. Of note, approximately 30% of TEEs in both groups manifested 8 days or more after 4F-PCC administration. It should be noted that most TEEs occurred in patients who were not receiving anticoagulant therapy at the time of the event. Indeed, according to the detailed investigation on the four cases of TEEs in the INR < 2.0 group, anticoagulant therapy was not resumed in two out of the four cases, and in one case, it was resumed after 16 days. Thus, the occurrence of TEEs appears to be strongly associated with the delay in anticoagulant therapy. Japanese guidelines state that if hemostasis is confirmed and there is an indication for anticoagulant resumption, anticoagulant therapy should be restarted as soon as possible [12]. The data indicated varying timings for resuming anticoagulation therapy, which might result from the attending physician carefully considering the timing of the resumption individually on the basis of the patient’s condition. Alternatively, it could suggest an incomplete understanding of the importance of promptly resuming anticoagulant therapy.
This regulatory-mandated PMS is an observational study and therefore it has inherent limitations. First, the single-cohort design did not allow for comparisons with conventional therapy. Second, potential misclassifications of events cannot be ruled out, as these were assessed by treating physicians and not verified by an independent adjudication committee. Third, the variability in 4F-PCC dosing and the timing of INR measurements, especially after 4F-PCC administration, arose from routine medical practice. Finally, relative risk estimates or absolute incidence rates may not be entirely free from bias.
Conclusion
This large-scale prospective, observational study highlighted the favorable tolerability and efficacy of 4F-PCC, irrespective of whether baseline INR < 2.0 or ≥ 2.0, with a rapid reduction of INR and significant hemostatic efficacy in the real-world setting for patients needing urgent VKA reversal.
Acknowledgements
We thank Masashi Nakayama, a former employee of CSL Behring K.K., for conceptualization and the acquisition of data.
Medical Writing/Editorial Assistance
Mark Snape of inScience Communications (Springer Healthcare, Springer Nature Japan K.K.) conducted a native English check, funded by CSL Behring K.K.
Author Contributions
Masahiro Yasaka: data interpretation. Fumihiko Shimizu: study design, data acquisition, data analysis. Ayako Kiyonaga: data analysis, data interpretation. Yuki Niwa: data analysis, data interpretation. Naoki Terasaka: data interpretation, writing the manuscript.
Funding
This research and the journal’s Rapid Service Fee were funded by CSL Behring K.K. Study design, data collection, analysis, and interpretation, and the decision to submit the article for publication were also supported by CSL Behring K.K.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of Interest
Fumihiko Shimizu, Ayako Kiyonaga, Yuki Niwa and Naoki Terasaka are full-time employees of CSL Behring. Masahiro Yasaka has received lecture, advisory, and travel fees from AstraZeneca, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Bayer, Daiichi Sankyo, and CSL Behring, as well as scholarship funds or nonrestricted grants from Nippon Boehringer Ingelheim.
Ethical Approval
The study was carried out in compliance with the Declaration of Helsinki (1964 and its subsequent amendments). It also adhered to the principles outlined in the Japanese Good Postmarketing Study Practice (GPSP) regulations. The protocol was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) and by the ethics committees. All participating patients provided comprehensive, written informed consent. All Japanese sites that administered 4F-PCC post-approval participated in the study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.