**Title**
Prothrombin complex concentrate in major bleeding patients under DOACs; Off label or standard of care? An updated systematic review and meta-analysis.
**Review question(s)**
What is the safety and effectiveness of prothrombin complex concentrate use in patients under DOACs presenting with major bleeding?
**Searches**
This will be an update of a meta-analysis on the effectiveness and safety profile of PCC use in bleeding patients under DOACs by Piran et al. published in January 20191. Their literature review included studies until September 2018 including a total of 340 patients. In the following years more and more centers have been publishing their experience via small or moderate size retrospective cohort studies. We found that the total amount of these patients may even over-double the number of pooled patients initially published.
We will search Medline (via PubMed), Scopus, the Cochrane Library and Web of science in alignment with the search strategy of Piran et al. limiting the search from 1/1/2018 to 6/19/2020. To complement our search, all references from selected studies will be retrieved and manually reviewed according to the snowball effect. We will search for unpublished abstracts in major congresses. Articles in languages other than English will be excluded.
**Types of studies to be included**
Case series studies, case control studies, prospective and retrospective cohort studies, RCTs
**Condition or domain being studied**
Direct oral anticoagulants (DOACs) are used by the majority of physicians gaining more ground every day as Studies have shown that non Vitamin K anticoagulants are non-inferior compared to warfarin in preventing stroke and systemic embolism2.
There are cases were they have proven to demonstrate a safer profile than their older predecessors3. Their market launching without physiologically targeted reversal agent remained until recently a critical safety concern for practicing clinicians and prescribes. Andexanet alfa, a targeted factor Xa was recently approved, but at high cost4. PCC being the cheaper off label alternative is expected to remain in prescribers options. The rationale for this off-label use is based on the fact that factors II, V, VII and X would produce excess thrombin and pro-thrombotic complexes to counterbalance the effect of Xa inhibitors1.
Unfortunately, no randomized clinical trials have been published to examine the effectiveness and safety of PCC in off label off target indications. Therefore, many centers have been publishing their own clinical experience in predominantly retrospective cohort studies focusing on the haemostatic effectiveness and safety outcomes of the off label intervention5.
**Participants/Population**
Inclusion criteria
1) Adult patients (18 years old)
2) Patients under DOACs (apixaban, betrixaban, edoxaban, rivaroxaban)
3) Patients with major bleeding (including intra-abdominal, GI bleeding, ICH, intramuscular bleeding)
Exclusion criteria
1) Narrative review articles, editorials and case reports
2) Experimental in vitro or ex vitro studies, animal studies
3) Patients with major bleeding while receiving dabigatran
4) Patients requiring DOAC reversal for reason other than major bleeding (e.g. emergent surgery)
**Intervention(s), exposure(s)**
PCC administration.
**Comparator(s), control**
No control.
**Outcomes**
Main Outcome: Effectiveness of major bleeding management (either according to the International Society on Thrombosis and Haemostasis (ISTH) definitions for major bleeding management , or to each study’s definition of hemostasis achievement
Additional Outcomes: Mortality up to 30 days after PCC administration, thromboembolic event incidence (deep venous thrombosis and/or pulmonary embolism, stroke, myocardial infarction) up to 30 days after PCC administration
**Data extraction (selection and coding)**
Database search results will be imported into Covidence for title/abstract and full-text screening, as well as data extraction. After duplication removal, two reviewers (IM and IF) will independently screen titles and/or abstracts and then full texts for eligible studies; any conflict will be resolved between the two reviewers by consensus. All reasons for exclusion will be reported.
Our systematic review and restrictive meta-analysis will be performed in respect to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Two reviewers (IM and IF) will independently extract data on a predefined Microsoft Excel spreadsheet. A pilot test will be performed before initiation to ensure coherence between the two review authors. Any disagreement will be resolved by consensus. Authors will be contacted for missing data relevant to the analysis.
**Risk of bias (quality) assessment**
Risk of bias will be assessed by using the ROBINS-I (“Risk Of Bias In Non-randomised Studies of Interventions”) tool and/or the Joanna Briggs Institute critical appraisal checklist for case series as appropriate, after the full text revision of studies and prior to data extraction. We will perform a sensitivity analysis excluding studies with low quality. The certainty of body of evidence will be assessed using the GRADE approach.
**Strategy for data synthesis**
Given the absence of a control group, a pooled proportion estimate will be generated for each of the main and additional outcomes. Given heterogeneity across studies, a random effects model will be used. We will assess study to study variation using the chi-square test of heterogeneity. The I2 index will be used to quantify inconsistency across studies and values >50% will be described as moderate. Publication bias will be visualized with a funnel plot and should the final pool of studies be more than 10, the Egger’s test will be performed.
**Analysis of subgroups or subsets**
Subgroup analysis based on the type of haemorrhage, high or low dosing of PCC and a standardised dosing of FFP/cryoprecipitate will be pursued but not limited to.
**Type and method of review**
Blood and immune system; Cardiovascular; Intervention; Systematic review; Meta-analysis;
**Named contact**
Ioannis.Milioglou2@UHhospitals.org
**Review team**
Ioannis Milioglou
Ioannis Farmakis
Mandy Neudecker
Ismini Kourouni
**Organizational affiliation(s)**
University Hospitals Cleveland Medical Center
MetroHealth Cleveland Medical Center
Aristotle University of Thessaloniki
**Country**
USA, Greece
**Anticipated or actual start date**
June 2020
**Anticipated completion date**
December 2020
**Last search date**
19/06/2020
**Funding sources/sponsors**
None
**Conflicts of interest**
None
**References**
1. Piran, S. et al. Management of direct factor Xa inhibitor – related major bleeding with prothrombin complex concentrate : a meta-analysis. 3, (2019).
2. Tromeur, C. et al. Novel Anticoagulant Treatment for Pulmonary Embolism with Direct Oral Anticoagulants Phase 3 Trials and Clinical Practice. (2018).
3. Steiner, T., Weitz, J. I. & Veltkamp, R. in the Era of Reversal Agents. 1432–1437 (2017). doi:10.1161/STROKEAHA.116.013343
4. Lawrence, J. H. et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. 1326–1335 (2019). doi:10.1056/NEJMoa1814051
5. Barra, M. E. et al. Evaluation of andexanet alfa and four-factor prothrombin complex concentrate ( 4F-PCC ) for reversal of rivaroxaban- and apixaban-associated intracranial hemorrhages. 1–11 (2020). doi:10.1111/jth.14838
