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Review
. 2015 Jul 7;2015(7):CD010555.
doi: 10.1002/14651858.CD010555.pub2.

Prothrombin complex concentrate for reversal of vitamin K antagonist treatment in bleeding and non-bleeding patients

Mathias Johansen  1 , Anne Wikkelsø, Jens Lunde, Jørn Wetterslev, Arash Afshari
Affiliations
Review

Prothrombin complex concentrate for reversal of vitamin K antagonist treatment in bleeding and non-bleeding patients

Mathias Johansen et al. Cochrane Database Syst Rev. .

Abstract

Background: Treatment with vitamin K antagonists is associated with increased morbidity and mortality. Reversal therapy with prothrombin complex concentrate (PCC) is used increasingly and is recommended in the treatment of patients with bleeding complications undertaking surgical interventions, as well as patients at high risk of bleeding. Evidence is lacking regarding indication, dosing, efficacy and safety.

Objectives: We assessed the benefits and harms of PCC compared with fresh frozen plasma in the acute medical and surgical setting involving vitamin K antagonist-treated bleeding and non-bleeding patients. We investigated various outcomes and predefined subgroups and performed sensitivity analysis. We examined risks of bias and applied trial sequential analyses (TSA) to examine the level of evidence, and we prepared a 'Risk of bias' table to test the quality of the evidence.

Search methods: We searched the following databases from inception to 1 May 2013: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (Ovid SP); EMBASE (Ovid SP); International Web of Science; Latin American and Caribbean Health Sciences Literature (LILACS) (via BIREME); the Chinese Biomedical Literature Database; advanced Google and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We applied a systematic and sensitive search strategy to identify relevant randomized clinical trials and imposed no language or date restrictions. We adapted our MEDLINE search strategy for searches in all other databases. We reran the search in October 2014 and found one potential new study of interest. We added this study to a list of 'Studies awaiting classification', and we will incorporate this study into the formal review findings at the time of the review update.

Selection criteria: We included randomized controlled trials (RCTs), irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted investigators and study authors to request relevant data.

Data collection and analysis: Three review authors independently abstracted data and resolved disagreements by discussion. Our primary outcome measures were 'overall mortality longest follow-up' and 'overall 28-day mortality'. We performed subgroup analyses to assess the effects of PCC in adults in terms of various clinical and physiological outcomes. We presented pooled estimates of the effects of interventions on dichotomous outcomes as risk ratios (RRs), and on continuous outcomes as mean differences (MDs), with 95% confidence intervals (CIs). We assessed risk of bias by assessing trial methodological components and risk of random error through TSA.

Main results: We included four RCTs with a total of 453 participants and determined that none of these trials had overall low risk of bias. We found six ongoing trials from which we were unable to retrieve further data. Three trials provided data on mortality. Meta-analysis showed no statistical effect on overall mortality (RR 0.93, 95% CI 0.37 to 2.33; very low quality of evidence). We were unable to associate use of PCC with the number of complications probably related to the intervention (RR 0.92, 95% CI 0.78 to 1.09; very low quality of evidence). Lack of transfusion data and apparent differences in study design prevented review authors from finding a beneficial effect of PCC in reducing the volume of fresh frozen plasma (FFP) transfused to reverse the effect of vitamin K antagonist treatment. The number of new occurrences of transfusion of red blood cells (RBCs) did not seem to be associated with the use of PCC (RR 1.08, 95% CI 0.82 to 1.43; very low quality of evidence). Still, the included studies demonstrate the possibility of equally reversing vitamin K-induced coagulopathy using PCC without the need for transfusion of FFP. No effect on other predefined outcomes was observed.

Authors' conclusions: In the four included RCTs, use of prothrombin complex concentrate does not appear to reduce mortality or transfusion requirements but demonstrates the possibility of reversing vitamin K-induced coagulopathy without the need for transfusion of fresh frozen plasma. All included trials have high risk of bias and are underpowered to detect mortality, benefit or harm. Clinical and statistical heterogeneity is high, and definitions of clinically important outcomes such as adverse events are highly dissimilar between trials. Only weak observational evidence currently supports the use of PCC in vitamin K antagonist-treated bleeding and non-bleeding patients, and the current systematic review of RCTs does not support the routine use of PCC over FFP. Additional high-quality research is urgently needed.

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Conflict of interest statement

Mathias Johansen: no conflicts of interest.

Anne Wikkelsø: no conflicts of interest.

Jens Lunde: no conflicts of interest.

Jørn Wetterslev: I am a member of the Copenhagen Trial Unit Task Force, which develops trial sequential analysis theory and software.

Arash Afshari: no conflicts of interest.

Figures

1
1
PRISMA. We reran the search in October 2014. We found 1 study of interest (Kerebel 2013). This study was added to a list of ‘Studies awaiting classification' and will be incorporated into formal review findings at the time of the review update .
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Mortality, outcome: 1.1 Overall mortality ‐ longest follow‐up.
5
5
Forest plot of comparison: 3 Quantity of blood products transfused, outcome: 3.1 Transfusion of RBCs.
6
6
Trial sequential analysis (TSA) of PCC vs FFP on quantity of RBCs transfused from 2 trials with diversity of 18% and an anticipated mean difference in intervention effect of 125 mL. The cumulative Z‐curve breaks through the boundary for futility (non‐superiority). The analysis therefore led to rejection of an intervention effect of 125 mL based on sparse data and repetitive analyses. The TSA adjusted confidence interval on the intervention effect estimated in a random‐effects model of ‐1.83 mL is ‐123 mL to 120 mL.
7
7
Forest plot of comparison: 4 Adverse events, outcome: 4.1 Number of complications probably related to the intervention.
8
8
Trial sequential analysis (TSA) of PCC vs FFP on adverse events from 4 trials with a control event proportion of 57%, diversity of 0% and an anticipated intervention effect of 20% relative risk reduction (RRR). The cumulative Z‐curve breaks through the boundary for futility (non‐superiority). The analysis therefore led to rejection of an intervention effect of 20% RRR based on sparse data and repetitive analyses, but the intervention effect may be less than 20% RRR.
1.1
1.1. Analysis
Comparison 1 Mortality, Outcome 1 Overall mortality ‐ longest follow‐up.
2.1
2.1. Analysis
Comparison 2 Number of new occurrences of blood transfusion, Outcome 1 Number of new occurrences of RBC transfusion.
2.2
2.2. Analysis
Comparison 2 Number of new occurrences of blood transfusion, Outcome 2 Number of new occurrences of fresh frozen plasma transfusion.
3.1
3.1. Analysis
Comparison 3 Quantity of blood products transfused, Outcome 1 Transfusion of RBCs.
4.1
4.1. Analysis
Comparison 4 Adverse events, Outcome 1 Number of complications probably related to the intervention.
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References

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