Quality evaluation of case series describing four-factor prothrombin complex concentrate in oral factor Xa inhibitor-associated bleeding: a systematic review

Abstract

IntroductionAs oral factor Xa (oFXa) inhibitor use has increased, so has publication of case series describing related bleeding managed with four-factor prothrombin complex concentrate (4F-PCC).ObjectiveThis review aimed to identify case series describing 4F-PCC management of oFXa inhibitor-related bleeding and appraise their methodological and reporting quality.DesignWe searched Medline and EMBASE (1 January 2011 to 31 May 2020) to identify series of ≥10 patients with oFXa inhibitor-related major bleeding given off-label 4F-PCC. Case series were evaluated using a validated tool adapted for this topic. The tool addressed patient selection, bleed/outcome ascertainment, causal/temporal association and reporting.ResultsWe identified 14 case series. None had ≥100 patients (range=13–84), three were prospective, two detailed appropriate inclusion criteria and four noted consecutive inclusion. While 12 series provided clear/appropriate methods for diagnosis of intracranial haemorrhage (ICH); none did so for extracranial bleeds and it was not clear whether bleeding was adjudicated in any. Haemostatic effectiveness, thrombosis and mortality were together evaluated in 12 series, but only seven used validated methods to evaluate/diagnosis haemostasis in ICH, six in gastrointestinal bleeds, five in other bleeds and three in thrombosis. Independent adjudication of haemostasis (n=1) and thrombosis (n=2) was infrequent. Thirty-day follow-up for mortality and thrombosis was noted in five and seven series. Anticoagulation measurement/levels in at least some patients were conveyed in three series. Few series provided data on anticoagulant agent/dose (n=4), time from anticoagulant (n=4), time-to-reversal (n=7), baseline (n=7) or change (n=0) in neurologic function.ConclusionsAlthough many case series describe off-label use of 4F-PCC for oFXa inhibitor-related bleeding, methodological flaws and/or poor reporting necessitates caution in interpretation.

Eastern Association for the Surgery of Trauma Multicenter Trial: Comparison of pre-injury antithrombotic use and reversal strategies among severe traumatic brain injury patients

“…It is worth noting that, in most studies evaluating PCC use among ICH in patients taking Xa inhibitors, the mortality rate is consis-tently around 20%. [18][19][20][21][22] In this study, overall mortality in Xa inhibitor patients was 5.2% and 13.2% in the severe TBI subset, which is more in line with Kobayashi et al 6 (7% and 12%, respectively). Enthusiasm around the approval of Andexanet, a specific reversal agent for Xa inhibitors is tempered by questions of improved clinical outcomes.…”

“…In addition, radiologic hematoma volume was used as the marker for efficacy, limiting translation to clinically important outcomes. It is worth noting that, in most studies evaluating PCC use among ICH in patients taking Xa inhibitors, the mortality rate is consistently around 20% 18–22 . In this study, overall mortality in Xa inhibitor patients was 5.2% and 13.2% in the severe TBI subset, which is more in line with Kobayashi et al 6 (7% and 12%, respectively).…”

“…There is a paucity of high-quality data with reversal of these agents. Costa and colleagues 18 reviewed available information from case series using PCC for Xa inhibitor reversal, which is often used off-label from its approved use. Given the retrospective, noncontrolled methodologies and the heterogeneous nature of this body of literature, it is difficult to derive effectiveness and safety.…”

American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period

“…However, the mortality results were not adjusted for confounding, and the comparator group's death rate is unknown. Several systematic reviews (33)(34)(35) have reported mainly on low-quality, single-arm cohort studies.…”

Management of Coagulopathy in Bleeding Patients

“…Overall, there is significant heterogeneity in reporting standards, methodology, and outcomes across these small, retrospective studies; therefore, these results should be interpreted with caution [ 70 ]. In a recent meta-analysis of 22 studies of FXa inhibitor-associated bleeding treatment, the overall rate of good to excellent haemostatic control with 4F-PCC was 76% [ 71 ].…”