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Effect of Prothrombin Complex Concentrate (PCC) for Warfarin Anticoagulation Reversal

Effect of Prothrombin complex concentrate (PCC) for Warfarin Anticoagulation reversal in patients undergoing urgent neurosurgical procedures.
Background:
Surgeons are constantly confronted with the urgent neurosurgical patients on anticoagulants drug therapy. Management of these group of patients is strenuous and complex. In such neurosurgical procedures there is higher risk of thrombotic and cardiovascular events due to discontinuation of Anticoagulants (Warfarin – VKA, Novel Oral Anticoagulants – NOACs). At the same time, continuation of this Anti-thrombotic drugs highly increases the risk of bleeding leading to life-threatening scenario’s during peri-operative procedures [1].
To maintain the balance during neurosurgeries and reversal of Warfarin is achieved with the help of Prothrombin concentrate complex (PCC) and Fresh Frozen Plasma (FFP). Fresh Frozen Plasma is prepared from whole blood donations and consist of both pro-coagulant and anticoagulant protein. FFP is also administered in combination with PCC to substitute the factor VII deficiency. There are several adverse events possible with FFP which include allergic reactions, transfusion related acute lung injury[2], transfusion transmitted diseases`[3-5], transfusion associated circulatory overload and thromboembolic events. Preparation of PCC is done from pooled plasma. It can be categorized in 3F-PCC (coagulation factor II, IX, and X) and 4F-PCC (coagulation factors II, VII, IX, and X. Moreover,4F-PCC consist of higher concentration of natural coagulants (Protein S and C) along with small amount of heparin. Few benefits of PCC administration are faster administration, No ABO compatibility, reduced volume resulting in lower risk of volume overload. Disadvantages of PCC are expensive, inadequate availability, and absence of factor VII. Along with this, there is an increased risk of thromboembolic events with PCC administration.[6]
Rationale:
There were several meta-analyses, systematic reviews, and other studies, addressing the effect of PCC with faster reversal of warfarin against FPP, correction of INR, variability of PCC dose was reported but there is insufficiency of well-established result, according to our knowledge for the patients undergoing urgent neurosurgical procedures.
However, In the systematic review and meta-analysis we will be gathering all information from RCTs and observational studies to perform analyses between PCC and FFP in the patients who are in urgent need of neurosurgery or neurosurgical procedures.
Description of the condition:
Bleeding is one of the common and complex complication for patients on Warfarin therapy. This is related to higher International Normalization values (INR). There are also other risk factors which includes elderly patients (age), significant bleeding history and different comorbidities suffered by patients.[7]The risk of bleeding depends largely on the type of surgery, location and extent of the surgery. Based on this, Neurosurgical operations are categorized in High risk group for increased incidence of bleeding. INR value for neurosurgery is preferred to be below 1.2 due to the longer wash out period.[8]
Description of the intervention:
Patients who require urgent neurological procedures and regularly use anticoagulants should be administered some drugs that can reverse the anticoagulation effect to prevent bleeding during or after the procedure. Warfarin and other anticoagulants reversal can be achieved by multiple ways. For warfarin, administration of vit K in combination with coagulation factor replacement with FFP or PCC. FFP is prepared from Blood donations and contains both pro-coagulant and anticoagulant proteins. PCC have 25% more concentration of factors which decreases the volume of administration.[9]
The recommended dose for warfarin is 25-50 units/kg. Although, there are studies available presenting nomograph for PCC dose according to body weight, initial INR and desired INR available.[10] Almost 80-90% of patients receiving PCC achieves the reduction in INR in first 15 mins. For high INR values a small additional dose of PCC is administered again. Apart from being expensive, risk factors like shock, carcinoma and cardiomyopathy are observed.[11]
Hypothesis:

  • Fresh Frozen plasma (FFP) and Prothrombin complex concentrate (PCC) are equally effective in reversal of anticoagulation effect of Warfarin in patients need urgent neurological procedure.
  • Fresh Frozen plasma (FFP) and Prothrombin complex concentrate (PCC) are equal in safety in reversal of anticoagulation effect of Warfarin in patients need urgent neurological procedure.

Objectives:

  • The aim of this pairwise meta-analysis is to evaluate the effectiveness and safety of Prothrombin complex concentrate (PCC) versus Fresh Frozen plasma (FFP) in reversal of anticoagulation effect of Warfarin in patients needing urgent neurological procedure.

Methods:
The study will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for reporting of systematic reviews incorporating meta-analyses of health care interventions.[12]
Inclusion criteria:

  • We will include Randomized Clinical Trials (RCT’s) and observational studies (cohort, case-control, and case series)
  • Population: 18 year or older requiring urgent neurosurgical procedure and are on Warfarin therapy.
  • Intervention and Control:  Comparison between PCC and FFP in reversal of anticoagulation effect of Warfarin in patients need urgent neurological procedure.
  • Outcomes: Case mortality, Volume over load, Faster INR reduction, Thromboembolic events will be examined.

 
Exclusion Criteria:

  • We will restrict the language to English any other language articles will be excluded.
  • We will exclude article if they have any other anticoagulant reversal agents (Idarucizumab and Andexanet Alfa)

Types of interventions

  • We will include RCT’S, prospective cohort, retrospective cohort, and case controls that compared PCC to FFP in reversal of anticoagulation effect of Warfarin in patients need urgent neurological procedures.

Types of outcome measures:
Primary outcomes
The primary outcome will be all cause mortality at 30 days. We selected 30 days because beyond this period deaths are more likely to be associated with causes that are unrelated to anticoagulation reversal.
Secondary outcomes.

  • Volume overload
  • Thromboembolic event
  • Hemostasis
  • Faster INR reduction
  • Length of Stay
  • Proportion of patients who achieved INR correction and red blood cell (RBC) transfusion.

Search methods for identification of studies:
We will conduct electronic search the following databases to detect relevant articles:

  • Cochrane Central Register for Controlled Trials (CENTRAL)
  • MEDLINE accessed via PubMed
  • Embase
  • Clinical trials.gov

We will be excluding duplicate articles and additional bibliographies of publications will be hand search to identify potentially relevant articles. Publication period will not be restricted.
Search Terms:
Search terms: PubMed
(“Neurosurgery”[Mesh]OR Neurosurger*[tw] OR “Neurosurgical Procedures”[Mesh] OR Neurosurgical Procedure[tw] OR Neurologic Surgical Procedure*[tw] OR Brain Tissue Grafting*[tw] OR Brain tissue transplantation* [tw] OR Cerebral Decortication*[tw] OR Cerebral Cortex Decortication* [tw] OR Hemispherectomy[tw] OR Cerebrospinal Fluid Shunt [tw] OR Ventriculoperitoneal Shunt* [tw] OR Ventriculo peritoneal Shunt [tw] OR Ventriculostom*[tw] OR Ventriculocisternostomy[tw] OR Denervation*[tw] OR Neurectom*[tw] OR Axotom*[tw] OR Cordotom*[tw] OR Chordotom* [tw] OR Autonomic Nerve Block*[tw] OR Sphenopalatine Ganglion Block*[tw] OR Pterygopalatine Ganglion Block*[tw] OR Rhizotom*[tw] OR Nerve Transfer*[tw] OR Neurotization*[tw] OR Hypophysectom*[tw] OR Neuroendoscop*[tw] OR Foraminotom*[tw] OR laminectomy*[tw] OR laminotom*[tw] OR laminoplast*[tw] OR laminaplast*[tw] OR Microvascular Decompression[tw] OR Psychosurger*[tw] OR lobotom*[tw] OR Gyrectom*[tw] OR Leukotom*[tw] OR Leucotom*[tw] OR Topectom*[tw] OR Stereotaxic Technique* [tw] OR “Brain Injuries, Traumatic”[Mesh] OR Traumatic Brain Injur*[tw] OR TBI[tw] OR Brain Trauma* [tw] OR subdural hematoma*[tw] OR intracerebral hematoma*[tw] OR subarachnoid hemorrhage[tw] OR intracranial bleed*[tw] OR Craniotom*[tw] OR Craniectomie*[tw] OR Trephining[tw] OR Trephination[tw] OR Trepanation[tw] OR Trepanning[tw] OR “Intracranial Aneurysm”[Mesh] OR Brain Aneurysm*[tw] OR Cerebral aneurysm*[tw] OR Intracranial Aneurysm*[tw] OR burr hole*[tw] OR burr-hole*[tw] OR aneurysm clip*[tw] OR External ventricular drainage[tw] OR “Spine”[Mesh] OR Vertebral Column[tw] OR Spinal Column[tw] OR “Spinal Fractures”[Mesh] OR Spinal Fracture[tw] OR “Spinal Injuries”[Mesh] OR Spinal Injury[tw] OR               “Spinal Neoplasms”[Mesh] OR Spinal Neoplasm[tw])
AND
(prothrombin complex concentrate*[tw])
Hits: 98
“Intracranial Hemorrhages”[Mesh] OR Intracranial Hemorrhage*[tw] OR Brain Hemorrhage*[tw] OR
Search Terms: Embase
(exp Neurosurgery/ OR Neurosurger*.tw. OR exp Neurosurgical Procedures/ OR Neurosurgical Procedure.tw. OR Neurologic Surgical Procedure*.tw. OR Brain Tissue Grafting*.tw. OR Brain tissue transplantation*.tw. OR Cerebral Decortication*.tw. OR Cerebral Cortex Decortication*.tw. OR Hemispherectomy.tw. OR Cerebrospinal Fluid Shunt.tw. OR Ventriculoperitoneal Shunt*.tw. OR Ventriculo peritoneal Shunt.tw. OR Ventriculostom*.tw. OR Ventriculocisternostomy.tw. OR Denervation*.tw. OR Neurectom*.tw. OR Axotom*.tw. OR Cordotom*.tw. OR Chordotom*.tw. OR Autonomic Nerve Block*.tw. OR Sphenopalatine Ganglion Block*.tw. OR Pterygopalatine Ganglion Block*.tw. OR Rhizotom*.tw. OR Nerve Transfer*.tw. OR Neurotization*.tw. OR Hypophysectom*.tw. OR Neuroendoscop*.tw. OR Foraminotom*.tw. OR laminectomy*.tw. OR laminotom*.tw. OR laminoplast*.tw. OR laminaplast*.tw. OR Microvascular Decompression.tw. OR Psychosurger*.tw. OR lobotom*.tw. OR Gyrectom*.tw. OR Leukotom*.tw. OR Leucotom*.tw. OR Topectom*.tw. OR Stereotaxic Technique*.tw. OR exp Brain Injuries, Traumatic/ OR Traumatic Brain Injur*.tw. OR TBI.tw. OR Brain Trauma*.tw. OR subdural hematoma*.tw. OR intracerebral hematoma*.tw. OR subarachnoid hemorrhage.tw. OR intracranial bleed*.tw. OR exp craniotomy/ OR Craniotom*.tw. OR Craniectomie*.tw. OR Trephining.tw. OR Trephination.tw. OR Trepanation.tw. OR Trepanning.tw. OR exp Intracranial Aneurysm/ OR Brain Aneurysm*.tw. OR Cerebral aneurysm.tw. OR Intracranial Aneurysm*.tw. OR burr hole*.tw. OR burr-hole*.tw. OR aneurysm clip*.tw. OR External ventricular drainage.tw. OR spine/ OR exp spine surgery/ OR Vertebral Column.tw. OR Spinal Column.tw. OR exp Spinal Fractures/ OR Spinal Fracture.tw. OR exp Spinal Injuries/ OR Spinal Injury.tw. OR exp Spinal Neoplasms/ OR Spinal Neoplasm.tw.)
AND
(prothrombin complex concentrate*.tw.) OR exp prothrombin complex concentrate/
Hits: 387
Search Terms: Cochrane
MeSH descriptor: [Neurosurgery] explode all trees
OR
MeSH descriptor: [Neurosurgical Procedures] explode all trees
OR
MeSH descriptor: [Brain Injuries, Traumatic] explode all trees
OR
MeSH descriptor: [Intracranial Aneurysm] explode all trees
OR
MeSH descriptor: [Craniotomy] explode all trees
OR
(Neurosurger* OR Neurosurgical Procedure OR Neurologic Surgical Procedure* OR Brain Tissue Grafting* OR Brain tissue transplantation* OR Cerebral Decortication* OR Cerebral Cortex Decortication* OR Hemispherectomy OR Cerebrospinal Fluid Shunt OR Ventriculoperitoneal Shunt* OR Ventriculo peritoneal Shunt OR Ventriculostom* OR Ventriculocisternostomy OR Denervation* OR Neurectom* OR Axotom* OR Cordotom* OR Chordotom* OR Autonomic Nerve Block* OR Sphenopalatine Ganglion Block* OR Pterygopalatine Ganglion Block* OR Rhizotom* OR Nerve Transfer* OR Neurotization* OR Hypophysectom* OR Neuroendoscop* OR Foraminotom* OR laminectomy* OR laminotom* OR laminoplast* OR laminaplast* OR Microvascular Decompression OR Psychosurger* OR lobotom* OR Gyrectom* OR Leukotom* OR Leucotom* OR Topectom* OR Stereotaxic Technique* OR Traumatic Brain Injur* OR TBI OR Brain Trauma* OR subdural hematoma* OR intracerebral hematoma* OR subarachnoid hemorrhage OR intracranial bleed* OR Craniotom* OR Craniectomie* OR Trephining OR Trephination OR Trepanation OR Trepanning OR Brain Aneurysm* OR Cerebral aneurysm OR Intracranial Aneurysm* OR burr hole* OR aneurysm clip* OR External ventricular drainage OR ):ti,ab,kw
AND
(prothrombin complex concentrate*):ti,ab,kw
Hits: 13
 
Total: 477
 
Appendixes of key words here.
PCC – Prothrombin Complex Concentrate
4F – PCC – 4 Factor Prothrombin Complex Concentrate
3F – PCC – 3 Factor Prothrombin Complex Concentrate
FFP – Fresh Frozen Plasma
RCT – Randomized Control Trials
INR – International Normalization Ratio
Data collection and analysis:
Selection of studies:
Two authors () will independently and in duplicate examine each title and abstract determined in the research to exclude irrelevant studies.
The two authors then will examine full text articles to identify eligibility. We will discuss any disagreement with a third author.
We will include studies (RCT’S and observational) that investigated adult patients (18 years or more) who presented with for urgent neurological surgery and need anticoagulation reversal urgently. We will select studies that compare PCC (either 3F or 4F PCC).
Data extraction and management:
Two authors () will independently extract the data from published and unpublished reports using a standardized form.
The following information will be extracted and recorded: first author, year of publication, inclusion criteria, study design, mean or median age of participants, sex, indications for anticoagulant therapy, bleeding site, type of surgery (procedure), type and dose of PCC, dose of FFP and duration of follow-up. Discrepancies between the reviewers resolved by consensus or a third reviewer.
Assessment of risk of bias in included studies:
Randomized control studies:

  • Two review authors () will assess the risk of bias using the ’risk of bias tool for RCT’S described in the Cochrane Handbook for Systematic Reviews of Interventions. [13]
  • We will assess the risk of bias by using the six evidence-based domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective outcome reporting (reporting bias).
  • For each risk of bias domain, the authors will assign either ’low risk of bias’, ’high risk of bias or ’unclear risk of bias.
  • The blinding domain will be assessed at the outcome level, regarding blinding for objective outcomes and for subjective outcomes.
  •  For blinding of participants and care providers, studies will be considered at ’low risk’ if blinding was assured or if the outcome was unlikely to be influenced by the lack of blinding (mortality rate); and studies will be considered at ’high risk’ for subjective outcomes if blinding was lacking.
  • For blinding of outcomes assessors, studies will be considered at ’low risk’ if blinding was assured or for an objective outcome. If an independent Clinical Endpoint Adjudication Committee assessed subjective outcomes, studies will be considered at ’low risk’ and at ’high risk’ otherwise.

Observational studies:
We will use Newcastle scale to evaluate the risk of bias in included observational studies.

  •      Two review authors () will assess the risk of bias using the Newcastle-Ottawa Scale.
  •      The risk of bias will be assessed on the bases of six domains (Sequence generation, Allocation concealment, Blinding of participants, personnel and outcome assessors, Incomplete outcome data, selective outcome reporting and other sources of bias.)

Risk of bias will be categorized among.

  •      lower risk – plausible bias unlikely to seriously alter the result
  • Unclear risk of bias – Bias that raise some doubt about the results
  •      High risk of bias – bias that seriously risk the confidence of result.
  •      All the three bias will be examined within a study as well as across the study. [14]

 
Publication bias Precautions:
Publication bias will be assessed by visual inspection of the funnel plot and formal testing for Funnel plot asymmetry, using Begg’s test and Egger’s test at a significance level of p value < 0.05.
Summary Statistics for Outcome Measures:
For each outcome, we will calculate summary estimates of treatment effects (with 95% CI) for each comparison.
For time-to- event endpoints we will report Hazard Ratios (HR’s).
When time-to-event data are unavailable from trial reports, we will reconstruct individual survival patient data from published Kaplan-Meier curves or Cox-proportional statistical methodologies and we will estimate hazard ratios or relative risk, respectively.

  • For dichotomous outcomes (objective response and toxicity), we will use odds ratios (OR).
  • For continuous outcomes, mean differences (MD) will be showed for measures using the same scale, and standardized mean differences (SMD) will be showed for measures that used different scales

Assessment of heterogeneity:
We will assess statistical heterogeneity among studies by analyzing the forest plot and using the chi-square test (p<0.1 will considered significant). We will also calculate the I-square statistics.
This test will describe the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error. Values of I-square ranges from 0 to 100. Here, 0 means no heterogeneity and 100 means considerable heterogeneity.
For our review we will categorize I-square values into the following:

  • 0% to 29%, heterogeneity might not be important
  • 30% to 49%, represents moderate heterogeneity
  • 50% to 74%, substantial heterogeneity and
  • 75% to 100%, considerable heterogeneity.

Statistical analysis:
We will conduct the pair-wise meta-analysis using Fixed effect and Random effect models to account for heterogeneity between and within the studies to obtain weighted average of effect estimate. Individuals study results will be pooled together statistically to identify pooled estimate for average intervention.
In case of significant heterogeneity, we will conduct sub-group analysis and meta-regression to explore the sources of heterogeneity.2 We will use Stata Statistical Software for pairwise meta-analysis (Version 15.1; StataCorp, College Station, Texas, USA)
Reference:
1. Douketis, J.D., et al., Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012. 141(2, Supplement): p. e326S-e350S.
2. Jones, L.M., et al., TRALI following fresh frozen plasma resuscitation from burn shock. Burns, 2017. 43(2): p. 397-402.
3. Nelson, K.E., et al., Transmission of retroviruses from seronegative donors by transfusion during cardiac surgery: A multicenter study of hiv-1 and htlv-i/ii infections. Annals of Internal Medicine, 1992. 117(7): p. 554-559.
4. Pomper, G.J., Y. Wu, and E.L. Snyder, Risks of transfusion-transmitted infections: 2003. Curr Opin Hematol, 2003. 10(6): p. 412-8.
5. Selik, R.M., J.W. Ward, and J.W. Buehler, Trends in transfusion-associated acquired immune deficiency syndrome in the United States, 1982 through 1991. Transfusion, 1993. 33(11): p. 890-3.
6. Goodnough, L.T., A reappraisal of plasma, prothrombin complex concentrates, and recombinant factor VIIa in patient blood management. Crit Care Clin, 2012. 28(3): p. 413-26, vi-vii.
7. Tran, H.A., S.D. Chunilal, and H. Tran, An update of consensus guidelines for warfarin reversal. Med J Aust, 2014. 200(2): p. 82.
8. White, R.H., et al., Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med, 1995. 122(1): p. 40-2.
9. Schulman, S. and N.R. Bijsterveld, Anticoagulants and their reversal. Transfus Med Rev, 2007. 21(1): p. 37-48.
10. Makris, M. and H.G. Watson, The management of coumarin-induced over-anticoagulation Annotation. Br J Haematol, 2001. 114(2): p. 271-80.
11. Pindur, G. and S. Morsdorf, The use of prothrombin complex concentrates in the treatment of hemorrhages induced by oral anticoagulation. Thromb Res, 1999. 95(4 Suppl 1): p. S57-61.
12. Hutton, B., et al., The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med, 2015. 162(11): p. 777-84.
13. Long, L., et al., Exercise-based cardiac rehabilitation for adults with stable angina. Cochrane Database Syst Rev, 2018. 2: p. Cd012786.
14. <Newcastle Ottawa scale.pdf>.



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