Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding

Abstract

Summary This retrospective study investigated the efficacy and safety of prothrombin complex concentrates (PCCs) for management of major bleeding events (MBE) in 344 patients receiving the anticoagulants rivaroxaban, apixaban or warfarin during the period January 2016 to April 2018. Median (range) PCC dose was 2000 units (1000–4500). Intracranial haemorrhage (ICH) was the most common indication (137/344, 39·8%) for PCC use followed by gastrointestinal bleeding (93/344, 27%). ICH patients more frequently received rivaroxaban (62·5%) or apixaban (52·5%) compared to warfarin (34·5%), P = 0·002; and visceral bleeding patients received warfarin more frequently (24·2%) than rivaroxaban (5%) or apixaban (10%), P = 0·003. Median rivaroxaban and apixaban levels were 230 ng/ml (47–759) and 159 ng/ml (45–255). Median International Normalised Ratio pre‐ and post‐PCC in patients on warfarin were 3·4 (1·9–15·4) and 1·2 (1·0–1·9). Blood products use was the same between groups. Thirty‐day mortality and re‐bleeding rates in patients with ICH were 35% (P = 0·50) and 18% (P = 0·90) with no differences between the groups. Thrombosis occurred in 4·1% patients within 30 days with no difference between groups. Two of 91 (2·2%) patients with ICH only (both on warfarin) had ischaemic strokes within 30 days post‐PCC. In conclusion, there was no difference in the safety (thrombosis) or efficacy (30‐day mortality, re‐bleeding) in use of PCC for MBE in patients on warfarin, rivaroxaban or apixaban.

Andexanet versus prothrombin complex concentrates: Differences in reversal of factor Xa inhibitors in in vitro thrombin generation

“…Moreover, thrombin generation was not normalized in most cases with 4F‐PCCs until the inhibitors had been substantially cleared, 21 a finding consistent with the present study showing that 4F‐PCCs did not normalize TF‐TG unless FXa inhibitor levels were <35‐75 ng/mL (Table 2; Figure 5). Regarding bleeding patients on FXa inhibitors, several observational studies have reported on the use of 4F‐PCCs but have shown inconsistent efficacy results 24‐27 . In the light of the current study, the data in these four major reports are difficult to interpret because anti‐FXa levels were measured in only 122 of 361 (34%) patients taking apixaban and rivaroxaban spanning these four PCC studies.…”

“…Of note, this is the only study of the four that had consistent serial imaging of ICH, similar to the mandatory CTs required in ANNEXA‐4. The other three studies reported a benefit of PCCs in patients with major bleeding on rivaroxaban or apixaban with overall hemostatic efficacies of 69% (84 patients, Majeed et al 24 ), 65% (66 patients, Schulman et al 25 ), and 74% (80 patients, Arachchillage et al 27 ). In these three studies, one can estimate that ~25% or more of the patients were in the lower ranges of anticoagulation, similar to that seen in ANNEXA‐4 for patients with anti‐FXa levels <75 ng/mL.…”

“…Factor replacement therapies, such as four‐factor prothrombin complex concentrates (4F‐PCCs), are approved for reversal of anticoagulation with vitamin K antagonists (VKA; eg, warfarin) and serve to replace factors VII (FVII), IX (FIX), X (FX), and II (FII) rendered functionally deficient by the anticoagulant 11 . Although 4F‐PCCs have been studied for FXa inhibitor reversal in nonclinical in vitro/ex vivo assays, 12‐14 animal models, 15 healthy volunteers, 16‐23 and observational clinical studies in patients taking FXa inhibitors, 24‐27 the effectiveness and clinical benefit of 4F‐PCCs on hemostatic efficacy and reversal of key biomarkers are mixed, 7,28‐31 and their potential mechanism of action has not been critically elucidated. There have been no controlled studies evaluating the effectiveness of 4F‐PCCs for reversal of FXa inhibitor–mediated bleeding (or anticoagulation), and they are not approved for this indication.…”

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

“…On the full-text review, 14 case series met inclusion criteria for this systematic review without exclusions. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] An additional nine case series available as abstracts only were included in the sensitivity analysis only. [32][33][34][35][36][37][38][39][40] Characteristics of case series The impact factor of journals in which case series were published ranged from 0.0420 to 16.562 (median, 2.873) (online supplemental eTable 1).…”

Prothrombin Complex Concentrate in Liver Transplant Surgery: Correction of Therapeutic Anticoagulation and the Coagulopathy of End-Stage Liver Disease: Case Series

“…Thromboembolic events were statistically similar across the groups at 2.5-5.1%. There was no difference in transfusion of other products among the three groups (Arachchillage et al, 2019). Arachchillage also retrospectively evaluated patients undergoing cardiac surgery whose anticoagulation therapy was treated with PCC or FFP and found among the PCC group significantly less cardiac failure related to circulatory overload; no difference was reported in 30 days mortality, kidney injury, or thrombotic events.…”