aPCC versus 4F-PCC for warfarin reversal

Reversal of warfarin-associated major haemorrhage: activated prothrombin complex concentrate versus 4-factor prothrombin complex concentrate

Peksa GD, Mokszycki RK, Rech MA, Maynard B, Panos NG, Sweis RT, DeMott JM. Thromb Haemost 2020 Feb;120(2):207-215. DOI: 10.1055/s-0039-3400958.

• Some centres preferentially use aPCC over 4F-PCC for a variety potential reasons including cost or to maintain a narrow medication
• This study assessed the efficacy of a low-dose aPCC regimen versus a variable-dose 4F-PCC regimen for VKA reversal in patients with warfarin-associated major
• In patients with warfarin-associated major haemorrhage, 4F-PCC is associated with a greater achievement of INR ≤1.5 than aPCC.

The vitamin K antagonist (VKA) warfarin is a commonly prescribed oral anticoagulant. However, usage of warfarin is associated major haemorrhage occurring at a rate of 1.7 to 3.4% in routine clinical practice. This must be treated through anticoagulation reversal by correcting international normalized ratio (INR) values.

Four-factor prothrombin complex concentrate (4F-PCC) is currently an attractive option for warfarin reversal due to its the ease of reconstitution, low administration volumes, and lack of blood-type matching. However, activated prothrombin complex concentrate (aPCC) is still used by some centres for a variety of potential reasons, including cost or to maintain a narrow medication formulary.

While 4F-PCC and aPCC do contain similar factor concentrates (II, VII, IX, and X), they differ by containing nonactivated versus activated factor VII and by their dosing regimens.

Recently, the American College of Cardiology suggested that various 4F-PCC dosing strategies can be used as treatment options for VKA reversal (Tomaselli et al., 2017). However, low-dose regimens of aPCC have the potential to be similarly efficacious for VKA reversal while reducing the risk of adverse events such as thromboembolism (Wójcik et al., 2009; Stewart et al., 2013; Rowe et al., 2016).

This study aimed to compare the efficacy of a low-dose aPCC regimen against a variable-dose 4F-PCC regimen for VKA reversal in patients with warfarin-associated major haemorrhage.

How do 4F-PCC and aPCC compare in VKA reversal?

Of the 342 patients who met the inclusion criteria of this study, 237 patients were given aPCC and 105 were given 4F-PCC. Following a 1:1 propensity score matching, two groups of 86 patients were formed. The primary endpoint was achievement of INR 1.5 at the post-treatment INR sampling.

Secondary endpoints included thrombotic events and mortality.

In the unmatched cohort, the target INR (1.5) was reached in a higher proportion of patients in the 4F-PCC group than the aPCC group (aPCC = 151 [63.7%] vs. 4PCC = 92 [87.6%]; 95% CI –32.7% to – 15.1%).

Furthermore,

• The aPCC group had more repeat doses (aPCC = 42 [17.7%] 4PCC = 2 [1.9%]; difference 1⁄4 15.8%, 95% CI 10.3–21.3%)
• Groups differed in the site of major haemorrhage; 4F-PCC predominantly had intracranial haemorrhages (aPCC = 133 [56.1%] vs. 4PCC = 88 [83.8%]; 95% CI –37.2% to –18.2%)
• Concomitant therapies between unmatched groups also differed; the 4F-PCC group used more vitamin K, FFP and platelets and the aPCC group used more packed red blood cells.

In the matched cohort, patients achieved the target INR at a higher rate in the 4F-PCC group than the aPCC group (aPCC = 61 [70.9%] vs. 4PCC = 76 [88.4%]; 95% CI –29.2% to –5.7%). Both groups however had comparable in-hospital thrombotic events and mortality.

This differs from a previous study that failed to find a difference between a low-dose aPCC and a variable-dose 4PCC in achieving a target INR of <1.4. This was an unmatched study, however, that was limited with a smaller sample size and imbalanced pre-treatment INR values between groups (Rowe et al., 2018).

Figure 1: Median INR values before and after treatment with aPCC and 4F-PCC in the matched cohort of patients. 4F-PCC, 4-factor prothrombin complex concentrate; aPCC, activated prothrombin complex concentrate.

Comparisons of the matched groups also showed,

• The aPCC group required more repeat doses (aPCC = 14 [16.3%] 4PCC = 2 [2.3%]; 95% CI 5.5–22.4%)
• The site of bleed between groups did not differ, although both groups had predominantly intracranial haemorrhages (aPCC = 65 [75.6%] 4PCC = 70 [80.4%])
• There was no difference between groups in concomitant therapies
• Mortality, thrombotic events, hospital length of stay, and haemoglobin/platelets at measured time points did not differ between the groups.

The results of this study suggest that 4F-PCC is associated with greater achievement of INR 1.5 compared with aPCC with comparable thrombotic events and mortality.

There were however limitations such as the retrospective design, underpowered sample size, uncontrolled timing of blood draws for INR values and uncontrolled FFP administration. Validating scoring criteria were also not used to assess the severity of haemorrhages and safety outcomes were limited to index admission data.

Further studies will be needed to confirm these results and determine an optimal dosing strategy to maximise both efficacy and safety.

References

Rowe AS, Mahbubani PS, Bucklin MH, Clark CT, Hamilton LA. Activated Prothrombin Complex Concentrate versus Plasma for Reversal of Warfarin-Associated Hemorrhage. Pharmacotherapy. 2016;36(11):1132–1137.

Rowe AS, Dietrich SK, Phillips JW, Foster KE, Canter JR. Activated prothrombin complex concentrate versus 4-factor prothrombin complex concentrate for vitamin K-antagonist reversal. Crit Care Med. 2018;46(6):943–948.

Stewart WS, Pettit H. Experiences with an activated 4-factor prothrombin complex concentrate (FEIBA) for reversal of warfarin-related bleeding. Am J Emerg Med. 2013;31(8):1251–1254.

Tomaselli GF, Mahaffey KW, Cuker A, Dobesh PP, Doherty JU, Eikelboom JW, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042–3067.

Wójcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med. 2009;2(4):217–225.