The drug class of oral anticoagulants consists of vitamin K antagonists or non-vitamin K antagonists.
Non-vitamin K antagonist oral anticoagulants (NOAC) have gained increasing popularity in recent years [
5‐
7]. In at least three Cochrane reviews, NOACs showed non-inferiority compared with warfarin [
7‐
10]. A network meta-analysis claimed superiority of NOAC over warfarin, when adding together the net benefits of protection of embolic events and less bleeding in patients with atrial fibrillation [
6].
Two general classes of NOAC exist: direct thrombin (factor IIa) inhibitors (e.g. dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, betrixaban, and edoxaban). Now, factor XI inhibitors are on the way – and we expect larger trials on these soon [
11,
12]. The direct thrombin inhibitor dabigatran functions by competitive inhibition of the active site on the thrombin molecule [
13]. The factor Xa inhibitors inhibit the coagulation cascade by competitively binding to the active site of factor Xa [
13].
Haemorrhagic complications
When patients on oral anticoagulants present with critical bleeding, the ability to reverse the iatrogenic coagulopathy in the acute hospital setting is important. Studies have shown that patients with vitamin K antagonists-associated intracerebral haemorrhage suffer larger admission haematoma volumes and have a greater tendency to undergo post-admission haematoma expansion compared to patients not treated with oral anticoagulants [
14‐
17]. Post-admission haematoma expansion is consistently linked to neurological deterioration and poor functional outcome [
18‐
21] and hence an important mediator in the association between anticoagulation treatment and poor outcome in intracerebral haemorrhage patients. A fast and efficient method to reverse the coagulopathy is warranted, if such a methods exists,as the probability of haematoma expansion is linked directly to the time spend before reversal of the coagulopathy is achieved [
22].
Meta-analysis of randomised clinical trials investigating NOAC versus vitamin K antagonists for various thrombotic indications finds the risk of bleeding episodes significantly lower among patients treated with NOAC (pooled odds ratio 0.36 (95% CI 0.15 to 0.84)) [
23]. This notion is supported by a recent network meta-analysis for several of the individual NOACs [
6]. Patients treated with NOAC have in small observational studies been found to present with smaller intracerebral haematomas on admission compared to patients pre-treated with warfarin [
24‐
27], however, haematoma expansion seems to happen almost as frequently [
28,
29]. It is possible that these observational studies could suffer from confounding by indication and that temporal changes in treatment-guidelines could skew the results in favour of NOAC. A meta-analysis of randomised clinical trial data has not been able to show a difference in clinical outcome of patients suffering intracerebral haemorrhage, while being treated with NOAC compared with vitamin K antagonists [
30].
Reversal strategies (experimental interventions)
Different reversal strategies have been suggested and employed in the clinical setting, when treating vitamin K antagonists associated bleeding: stopping the vitamin K antagonist therapy, administration of phytomenadion (vitamin K), administration of fresh frozen plasma, or administration of prothrombin complex concentrate [
31,
32]. Simply stopping the therapy with vitamin K antagonists will cause normalisation of the coagulation cascade over the course of days dependent on especially the weekly warfarin dose and the baseline international normalised ratio [
33,
34]. The normalisation of the coagulation cascade is a function of the half-life of warfarin (approximately 35 to 45 h) and the synthesis of coagulation factors in the liver [
34]. Phytomenadion as monotherapy has in both observational studies and randomised trials been shown effective in controlling excessive anticoagulantion (excessively raced INR) in non-critically bleeding patients [
35‐
37], but to our knowledge, it has never been tested as monotherapy in critically bleeding patients. In randomised clinical trials, it has never been shown that factor replacement with either fresh frozen plasma or prothrombin complex concentrate is superior in terms of limiting morbidity and mortality to simply stopping the vitamin K antagonist therapy or administering phytomenadion alone. Guidelines have, however, consistently recommended using either fresh frozen plasma or prothrombin complex concentrate in addition to stopping the therapy, when treating critically bleeding patients treated with vitamin K antagonists, as replacement of the coagulation factors is deemed necessary in order to achieve an effective haemostasis [
38,
39]. Many sources do recommend combining the administration of coagulation factors with phytomenadion, when treating critically bleeding patients on vitamin K antagonists. This is due to an observed re-increase in INR after 12 to 24 h in patients treated with coagulation factor replacement alone [
40]. For a long time, one of the most commonly accepted reversal strategies used, when patients suffered serious haemorrhagic complications to vitamin K antagonists therapy, has been the administration of fresh frozen plasma collected from healthy donors [
38]. Fresh frozen plasma replaces the coagulation factors that have been pharmacologically depleted from the vitamin K antagonists treated patients’ coagulation cascade. However, rapid administration of fresh frozen plasma might be hampered by blood type matching, maximal acceptable administration pace, and possible complications related to fluid overload [
41].
During recent years, the use of prothrombin complex concentrate has come into use in critically bleeding patients. Prothrombin complex concentrate contains a collection of either three coagulation factors (II, IX, and X) or four coagulation factors (II, VII, IX, and X) in a concentration approximately 25 times higher than normal plasma [
31]. Prothrombin complex concentrate might be a more attractive alternative compared with fresh frozen plasma. Prothombin complex concentrate does not require blood type matching, a lower volume is required making the risk of fluid overload smaller, and the risk of infections might be lower as prothrombin complex concentrate undergoes viral inactivation procedures [
31,
42]. Observational [
43‐
48] and randomised [
49‐
51] evidence indicates that prothrombin complex concentrate might reverse the raised INR quicker compared to fresh frozen plasma. This can possibly be translated into a lower morbidity and mortality in patients treated with prothrombin complex concentrate.
In NOAC-treated patients, one of the most persistent concerns to clinicians has been the lack of an effective technique allowing a swift reversal of the iatrogenic coagulopathy in case of critical bleeding episodes. Eerenberg et al. [
52] showed that a relatively effective biochemical reversal of the coagulopathy inflicted on healthy volunteers by pre-treatment with the factor Xa inhibitor rivaroxaban was possible by administrating prothrombin complex concentrate. Healthy volunteers pre-treated with dabigatran did, however, not obtain the same reversal effect. Boehringer Ingelheim (Germany) has released a monoclonal antibody fragment—idarucizumab—which has been shown effective at normalising the utilised coagulation assay (diluted thrombin time and ecarin clotting time) in critically bleeding patients pre-treated with dabigatran [
53,
54]. Idarucizumab is now marketed and can be used in clinical practice.
Other biological antidotes proposed are andexanet alfa (Portola Pharmaceuticals, CA, USA) and ciraparantag (Perosphere, CT, USA) [
55]. Andexanet alfa has been shown effective in normalising the utilised coagulation assay (chromogenic anti-factor Xa assay) in critically bleeding patients pre-treated with factor Xa inhibitors [
56] even though some rebound of the anticoagulating effect seems to happen after end-of-infusion [
56,
57]. Andexanet alfa has recently been approved by the United States Food and Drug Administration (media release, May 2018,
http://www.portola.com). Ciraparantag (PER977) is a synthetic molecule that binds factor Xa inhibitors, direct thrombin inhibitors, and unfractionated as well as low molecular weight heparins [
55]. Even though not proven effective in a critically bleeding patient population, ciraparantag has been shown effective in normalising the utilised coagulation assay (whole blood clotting time) in healthy volunteers pre-treated with endoxaban [
58]. In addition to reversal of NOAC using biological antidotes, a trial is currently being conducted aiming at investigating, if tranexamic acid can limit haematoma growth in patients, who develop intracerebral haemorrhage while being treated with NOAC—the TICH-NOAC trial (NCT02866838, November 2017).
To our knowledge, neither prothrombin complex concentrate, idarucizumab nor andexanet alfa have been shown effective on patient-relevant outcomes in treating NOAC-related critical bleeding. However, guidelines recommend the use of prothrombin complex concentrate in patients suffering intracerebral haemorrhage pre-treated with factor Xa inhibitors and idarucizumab in patients pre-treated with dabigatran [
39].
Another important aspect to consider when administering factor replacement (fresh frozen plasma or prothrombin complex concentrate) or when using other measures to reverse anticoagulation treatment is the risk of inducing thromboembolic events. Patient populations being treated with anticoagulants are likely at an increased risk of thromboembolic complication due to the indication of anticoagulation treatment (atrial fibrillation, mechanical heart valves, etc.). By discontinuing the anticoagulation treatment, it is likely that we expose the patients to an increased risk of thromboembolic events. Moreover, the risk of thromboembolic events can presumably be aggravated even further by administration of factor replacement [
59], especially if high-dose regimens are used [
60].
Why is it important to do this review?
It is essential to establish, if the apparent effect of prothrombin complex concentrate in reversing vitamin K antagonists and NOAC induced coagulopathy translates into changes in functional outcome or mortality. In addition, a synthesis of the randomised clinical trials might allow us to assess the safety profile of the different treatment options directly. A Cochrane review from 2015 [
61] assessed the comparison of prothrombin complex concentrate with fresh frozen plasma. However, this review did not specifically assess the effects of prothrombin complex concentrate versus fresh frozen plasma in the subgroup of patients with intracranial haemorrhage. This complication is especially dreaded. Moreover, a preliminary search has also identified new trials since the last update of this review [
51]. Another systematic review published in 2017 conducted by Brekelman et al. [
62] focused on four-factor prothrombin complex concentrate and did mostly include observational studies. The systematic literature search conducted by the authors ended in August 2015 before publication of the INR normalisation in patients with coumarin-related intracranial haemorrhages trial (INCH trial) [
51]. The present systematic review aims at forming the basis for evidence-based guideline recommendations for treatment of oral anticoagulant-associated critical bleeding using prothrombin complex concentrate taking bias risks (systematic errors), play of chance (random errors), and certainty of the findings into consideration.