Rapid and reliable reversal of the INR in warfarin anticoagulated patients who experience a critical bleed, trauma, or the need for emergent surgery is necessary to provide effective care during these critical events. Pre-reversal INR, the dose of PCC administered, adjunct therapies such as vitamin K and FFP, and the composition of coagulation factors in PCC products can all be factors to consider when evaluating PCC products’ ability to reverse INR. While several small, single-center research comparisons of PCC3 and PCC4 have been published, a large, randomized comparison of the efficacy and safety of these products has not been done. Whether there is a difference in the ability of PCC3 or PCC4 to effectively and safely reverse INR is unknown.
This systematic review and meta-analysis of studies comparing PCC3 and PCC4 for emergent warfarin reversal found the odds of reversal of INR to defined goal INR was more likely with PCC4, and there was little difference in the odds of experiencing a TE or hospital mortality. Patients who received PCC4 for EWR had more than three times the odds of achieving goal INR than patients who received PCC3. There was little difference in the odds of TE or hospital mortality.
This is the first systematic review and meta-analysis of directly comparing PCC3 and PCC4 safety and effectiveness for EWR. A previous systematic review without meta-analysis investigated decreasing the INR to ≤ 1.5 within one hour of PCC administration in PCC4 and PCC3, but no direct comparisons between the treatments had been published at the time of their publication [19]. They included eight studies investigating PCC3, ten for PCC4, and found PCC4 was more effective than PCC3 in decreasing the INR to ≤ 1.5.
Several possible considerations are underlying the findings. First, the compositional differences in the PCC products, specifically concerning the amount of factor VII. Given the INR is most sensitive to factor VII, a lack of replacement of this factor could account for the comparative weaker response to INR lowering with PCC3. Second, PCC4 products were studied in clinical trials for use in warfarin reversal using a predefined weight and INR-based dosing strategy, whereas PCC3 products have been prescribed off label and with no dosing recommendations, thus leading to prescribing based on unvalidated dosing strategies. Therefore, hospital treatment protocols tend to follow manufacturer dosing guidance for PCC4 whereas PCC3 protocols vary between providers and hospital systems. Third, there is little overlap in the use of PCC3 and PCC4 in the studies. Most institutions treated patients with PCC3 products, the only available products available in the US before the approval of a PCC4 product, and then switched to PCC4 once it became available. As such, there may be a temporal effect in the overall OR that cannot be ruled out.
Studies comparing PCC3 to PCC4 outside of the setting of EWR have similar results. Zeeshan et al. found faster correction of INR with PCC4 compared to PCC3 in a propensity-score-matched analysis of patients treated for coagulopathy of trauma (PCC4: n = 125, 365 minutes vs. PCC4: n = 125, 428 minutes, p < 0.01), fewer units of FFP transfused (6 units vs. 8 units, p < 0.03) [53]. Also, the incidence of TE and mortality were similar between the PCC groups. Although their study excluded patients who were receiving preinjury warfarin anticoagulants and other anticoagulants, the findings suggest the increased effectiveness and reduction of FFP use may be due to the role that factor VII plays in the coagulation cascade. Regardless of prior warfarin treatment, the administration of PCC4 with a higher factor VII concentration leads to faster correction of the INR.
While the focus of this current study investigates non-activated PCC3 and PCC4 products, other blood factor products, not included in this analysis, have been used as hemostatic agents alone or in combination with PCC3, vitamin K, and FFP. Factor eight (VIII) inhibitor bypassing activity (FEIBA®), an activated PCC (aPCC) product, contains mainly non-activated factors II, IX, and X and activated factor VII [12]. Coagulation factor VII activated (NovoSeven® RT) is a single coagulation factor product [13]. These products are approved by the US Food and Drug Administration (FDA) for indications to control and prevent bleeding in hemophilia A and B [12,13]. Factor VIIa has been used alone and in combination with PCC3 to compensate for the low amount of factor VII [14,15]. Activated PCC has been used off-label for EWR [54]. Given the differing composition of these products as containing active factor VII and that guidelines do not currently recommend these products for EWR, we chose to not include these products in our analysis.
Thromboembolic events are a concern with PCC products given patients treated with warfarin have underlying TE predisposition. Hypothetically, the increased concentration of factor VII in PCC4 should increase the risk of TE compared to PCC3. However, this review found no evidence of this difference between PCC4 and PCC3. The risk of TE could be offset with the anticoagulant proteins (protein C, protein S, antithrombin, and heparin) in PCC4 compared to PCC3.
The clinical implications of our findings serve to reinforce current recommended guidelines; in most cases, PCC4 has surpassed PCC3 for EWR in the US with FFP as a second-line agent. In a recent survey of 281 critical care and emergency medicine pharmacists, 92.9% reported the use of PCC4 for warfarin reversal. However, only 58.7% of them reported the use of the labeled weight-based dosing strategy for this indication. Of those not following the FDA-labeled dose, 30.6% used a fixed-dose regimen, commonly 1500 units once [55]. Since the safety profile is similar between PCC treatments, PCC3 could be used as an alternative for PCC4 when it is unavailable, as long as the treating clinicians account for the decreased effectiveness associated with reversing INR to goal with PCC3. Guidelines for the management of warfarin-induced intracerebral hemorrhage recommend PCC3 or PCC4 as valid treatment options [2,7].
There are several limitations to study findings associated with a meta-analysis of observational studies. Selection of a preferred PCC product in the US has been driven by product availability (only PCC3 products before 2013) and FDA approval (PCC4 after 2013) of PCC4 after clinical trial results demonstrating efficacy over FFP. While both PCC3 and PCC4 products continue to be available for clinicians to prescribe for EWR, clinical evaluation of the effectiveness and safety comparing PCC4 and PCC3 products has not been the guiding principle for their clinical use.
None of the studies included in this systematic review and meta-analysis were randomized controlled trials, which would limit bias in PCC treatment effect findings by design, and where all patients would follow the same protocol. An inherent difficulty with retrospective cohort analysis is few study level variables or factors are the same for all patients. In the critical care setting, an RCT study design is difficult to implement. So, a reasonable alternative given the constraints is to retrieve electronic health records collected during clinical care to estimate the difference in effectiveness and safety between PCC3 and PCC4 treatment protocols.
Answering clinical questions is limited by the variety of reporting methods authors chose. For example, change in INR after PCC administration is an outcome of interest to clinicians as a direct measure of treatment effect. However, there is no reliable method to combine these two measures of central tendency into a meta-analytic model without introducing bias [38,56]. Additionally, there is an inherent difficulty in estimating the treatment effect on INR reduction attributed to one treatment when several concomitant therapies which also reduce INR are given. There is no way to determine the effect of any one of these factors with the variability at which they happen during clinical care with an observational, retrospective study design.
An additional limitation is the heterogeneity of the studies included in the analysis, resulting from the various treatment protocols, the patient populations, and study variations in the literature. Despite these limitations, this research has added understanding of the effectiveness and safety profiles of PCC products used during clinical care.