What is the clinical evidence from this study?

Study design: Observational. Population: Major bleeding or requiring urgent surgical intervention (n=1381). Intervention: 4-factor prothrombin complex concentrate (4F-PCC). Primary outcome: Incidence of thromboembolic events (TEEs).

What does this research mean for the field?

In Japanese patients experiencing major bleeding or requiring urgent surgery, 4-factor prothrombin complex concentrate is effective and associated with a low (1.5%) incidence of thromboembolic events. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

February 6, 2024Open Access

Real-World Safety and Effectiveness of a 4-Factor Prothrombin Complex Concentrate in Japanese Patients Experiencing Major Bleeding: A Post-marketing Surveillance Study

MYMasahiro YasakaOhkawara Neurosurgical Hospital MSMichiyasu SuzukiYamaguchi University SKShigeki KushimotoTohoku University

Key Result

In Japanese patients experiencing major bleeding or requiring urgent surgery, 4-factor prothrombin complex concentrate was effective and associated with a 1.5% incidence of thromboembolic events.

Study Design

Type

Observational (n=1,381)

Multicenter

Yes

Structured PICO

Population

1,381 Japanese patients experiencing major hemorrhage or requiring expeditious surgical intervention who received 4-factor prothrombin complex concentrate for the first time. 1,271 (92%) received a vitamin K antagonist. 58% were aged ≥ 75 years, 49% manifested atrial fibrillation, 17% presented with valvular heart disease, and 6% exhibited venous thromboembolism.

Intervention

4-factor prothrombin complex concentrate (4F-PCC) administered at the discretion of the attending physician based on INR and body weight (mean dose 28 IU/kg).

Outcome

Incidence of thromboembolic events (TEEs) at 4 weeks follow-up.safety

In a real-world Japanese cohort, 4-factor prothrombin complex concentrate effectively reversed anticoagulation in patients with major bleeding or requiring urgent surgery, with a low 1.5% incidence of thromboembolic events.

Limitations

Single-cohort design prevented comparisons with conventional therapy
Possible misclassifications of events and hemostatic effectiveness due to lack of an independent adjudication committee
Variable dose of 4F-PCC and time of INR measurement because data originated from daily medical practice
Relative risk estimates or absolute incidence rates cannot be confirmed as completely unbiased

Abstract

INTRODUCTION: Limited data are available regarding the safety and effectiveness of 4-factor prothrombin complex concentrate (4F-PCC) in patients experiencing major hemorrhage or requiring expeditious surgical intervention, both globally and within Japan. METHODS: We executed a prospective, observational post-marketing surveillance study of patients receiving 4F-PCC for the first time between September 19, 2017 and August 15, 2018 in Japan. Patients were subjected to a comprehensive follow-up for a duration of 4 weeks. RESULTS: Of 1381 eligible patients, 1271 (92%) received a vitamin K antagonist. Among these, 58% were aged ≥ 75 years, 49% manifested atrial fibrillation, 17% presented with valvular heart disease, and 6% exhibited venous thromboembolism. The median (range) international normalized ratio was 2.67 (0.96-27.11) at baseline and 1.21 (0.45-6.61) at first measurement post-administration of 4F-PCC. The most common reason for 4F-PCC administration was intracranial hemorrhage (59.6%), followed by gastrointestinal bleeding (6.6%). Hemostatic effectiveness was achieved in 85.8% of patients. The incidences of adverse drug reactions (ADRs) and serious ADRs were 3.9% and 2.8%, respectively. Thromboembolic events (TEEs) occurred in 20 (1.5%) patients, with a mean onset of 10 days. The majority of TEEs were classified as nervous system disorders (55%). At the time of TEE, only 13% of patients resumed anticoagulant therapy. CONCLUSION: The incidence of TEEs following treatment with 4F-PCC did not surpass those observed in phase 3 trials. No novel safety signals were identified. The safety and effectiveness of 4F-PCC in Japanese real-world practice were in harmony with the observations of prior studies.

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