Review ArticleSystematic review: 3-factor versus 4-factor prothrombin complex concentrate for warfarin reversal: Does it matter?
Introduction
Prothrombin complex concentrates (PCC), also known as factor IX complex concentrates, are commonly used to reverse the effects of vitamin-K antagonists (VKA) in patients with bleeding and those requiring invasive procedures or surgery. All PCCs contain the vitamin K-dependent coagulation factors II, IX and X, with variable amounts of factor VII. Products are categorized as either 3-factor or 4-factor PCCs based on the relative factor VII content. Some formulations also contain protein C, protein S, protein Z, antithrombin III, and/or heparin. PCCs offer several advantages over fresh frozen plasma (FFP) including faster normalization of the international normalized ratio (INR), smaller infusion volume, rapid administration, and no requirement for ABO blood-type matching. All PCC products are derived from pooled plasma and carry the possible risk of virus transmission, although the risk is considered very low due to improved methods of virus inactivation.
International guideline statements recommend the use of PCCs when rapid reversal of anticoagulation is indicated in patients with major bleeding due to VKA use [1], [2], [3], [4], [5] Numerous studies have found that PCCs rapidly normalize the INR to a value of less than 1.5, typically within 10–30 minutes [6] However, many of these studies utilized 4-factor PCC formulations that are not available in many countries and some experts specifically recommend 4-factor PCCs for VKA-associated major bleeding, although this recommendation is based mostly on observational data [5]
Recently the effectiveness of 3-factor PCCs have been questioned due to subtherapeutic (or no) factor VII, which may affect the ability to reverse the INR [7] A study by Holland et al. reported the use of 25 (low dose) or 50 (high dose) IU/kg of a 3-factor PCC (Profilnine-SD) in 40 patients with baseline INR > 5.0 and either bleeding or high-risk of bleeding [8] Patients with intracerebral hemorrhage (ICH) were excluded and the most common site of bleeding was gastrointestinal. The primary endpoint was INR less than 3.0 within 24 hours of PCC administration. Only 55% and 43% of patients in the low dose and high dose groups achieved the primary endpoint. Limitations of this study include the retrospective design and very low use of intravenous vitamin K, which may have impacted INR correction since the effect of PCC may be transient while vitamin K invokes a sustained rise in clotting factor concentrations. To our knowledge, there are no published studies comparing the effectiveness of 3-factor and 4-factor PCCs for reversal of anticoagulation. The purpose of this systematic review is to compare the effectiveness of 3-factor to 4-factor PCCs in normalizing the INR to ≤ 1.5 in patients with an acquired coagulopathy due to VKA use.
Section snippets
Materials and methods
The systematic review was performed utilizing the methodology from the PRISMA Statement and no specific protocol or registry was used [9]
Study characteristics
A total of 18 articles were included in the systematic review. Fig. 1 shows the results of the literature search. The most common exclusion from the abstract screening procedure was PCC studies involving hemophilia patients. After reading the full text of the 60 remaining articles, an additional 42 articles were excluded, mostly because patients did not receive PCC or PT/INR was not done at baseline and repeated within one hour of PCC administration.
Characteristics of included studies are shown
Discussion
Results from 18 studies including 654 patients show that 4-factor PCCs are more effective than 3-factor PCCs in decreasing the INR to ≤ 1.5 within one hour of administration. This may have important clinical implications for patients with life-threatening bleeding, such as ICH, since scientific guidelines recommend correcting the INR as rapidly as possible. Further, hematoma expansion, a factor associated with poor outcomes in ICH [21] may be limited by immediate INR correction [22] These
Conclusion
Although the lack of comparative studies make it difficult to make a clinical recommendation for any specific PCC product in patients with emergent bleeding, based on our findings it appears reasonable to recommend reassessment of INR within 30–60 minutes after PCC administration. As other authors recommend for an inadequate response to PCC, we suggest replacing clotting factors by an additional mode (i.e. small doses of either rFVIIa or FFP) when using 3-factor PCCs, and repeating the dose when
Conflict of interest statement
Stacy A. Voils – no conflicts to disclose.
Brian Baird - no conflicts to disclose.
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