Management of major bleeding in patients using DOACs for non-valvular Atrial Fibrillation.

Dr Alex Byrne (FY2) Kingston Hospital NHS Foundation Trust.

Introduction

Atrial fibrillation (AF) is already the most common sustained cardiac arrhythmia and its prevalence is ever increasing1. It is associated with an elevated risk of thrombotic stroke, and those patients with a CHA2DS2VASc score of 2 or above are recommended to commence anticoagulation therapy to reduce this, taking bleeding risk into account1. For the last 70 years Warfarin has been the mainstay therapy, however Direct Oral Anticoagulants (DOACs) are being increasingly used in these patients due to their rapid onset of action, short half-life, predictable pharmacokinetics and fewer food and drug interactions2.

The common DOACs used are Dabigatran which works by directly inhibiting thrombin, and Apixaban, Rivaroxaban and Edoxaban, which are all direct factor Xa inhibitors1. An NHS England report of CCGs in England between October and December 2015 found a total of 3,753,687 anticoagulant prescriptions, with 830,042 (22%) of these being for DOACs3.

For any patient taking anticoagulants it is important to assess the risk of bleeding. Ruff et al.4 undertook a meta-analysis of 71683 patients enrolled in phase 3 randomised trials comparing patients with atrial fibrillation on DOACs to those on warfarin. They concluded that although DOACS have a favourable risk-benefit profile with reductions in stroke, intracranial haemorrhage and mortality, and similar major bleeding risks to warfarin, there was an increased risk of gastrointestinal bleeding (RR 1·25,95% CI 1·01–1·55; p=0·04).

Thus with their increasing use, risk profile and unique pharmacodynamics, it is important to know how to appropriately manage individuals presenting with bleeding who are taking DOACs, particularly major and life threatening bleeding, in order to optimise care.

Major haemorrhage

Defining Major haemorrhage is the first hurdle, as there are various definitions available.

The Joint United Kingdom Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee define Major haemorrhage as either the loss of more than one blood volume within 24 hours (around 70 mL/kg, >5 litres in a 70 kg adult), 50% of total blood volume lost in less than 3 hours, bleeding in excess of 150 mL/minute, or as a pragmatic clinical based definition of bleeding which leads to a systolic blood pressure of less than 90 mmHg or a heart rate of more than 110 beats per minute5.

Whereas the International Society on Thrombosis and Haemostasis (ISTH) defines major bleeding as a fall in haemoglobin of at least 20 g/L or those requiring a transfusion of at least two units of red cells, alternatively symptomatic bleeding into a critical area or organ, such as intracranial, intraspinal, intra-ocular, retroperitoneal, intra-articular, pericardial or intramuscular with compartment syndrome6. They have also identified a subgroup of major bleeding termed ‘life-threatening bleeding’, encompassing fatal bleeding, symptomatic intracranial bleeding, a fall in haemoglobin of at least 50 g/L or those requiring a transfusion of four units of red cells6.

It does not appear that one definition is superior to another, however there is a need for a unified definition of major bleeding in order to standardize management.  It would be appropriate to consult local guidelines as to what the adopted definition is for each respective trust in order to safely manage patients.

Initial assessment and management

For any major haemorrhage, early recognition and intervention is essential, with the immediate priorities being to establish haemostasis and optimise tissue perfusion. This can be achieved evaluating bedside observations such as heart rate, blood pressure and oxygen saturation to determine patient stability, alongside a thorough history and examination in order to identify the source and cause of bleeding, and whether the patient is still actively bleeding7. Furthermore, appropriate surgical intervention, depending on the site of bleeding, may provide a definitive solution and should be considered.  Early resuscitation with fluids and oxygen is recommended as well as a review of the medications, not only to identify and discontinue the offending drugs, but also to establish when the last dose of anticoagulant was consumed, as this will tailor subsequent management7. Furthermore, establishing whether there is any hepatic or renal impairment is also important as this could prolong elimination of the drug7.

Red cell transfusion is usually necessary if 30–40% blood volume is lost5. Decisions to transfuse should not be made solely on haematocrit and haemoglobin concentrations, as these can be inaccurate in acute bleeds. Thus the full clinical context needs to be taken into account. With the transfusion of intravenous products not containing coagulation factors or platelets there is a risk of dilutional coagulopathy. Thus it is prudent to consider additional products such as fresh frozen plasma (FFP) to account for this, as well as adjuvant therapies such as tranexamic acid to prevent fibrinolysis10. There is limited research into the use of prothrombin complex concentrate and activated prothrombin complex concentrate, however these product should also be considered in situations where prompt haemostasis is needed10.

Prothrombin time (PT) and activated partial thromboplastin time (APTT) are commonly used to guide blood component replacement in standard major haemorrhage cases5. However at present there is limited data to support the use of these products in DOAC associated bleeding8. Furthermore the benefit of coagulation tests is reduced by the time delay between sampling and testing5. The role of coagulation studies is further discussed below.

Evaluation of coagulation status in patients using DOACs

Routine coagulation testing is not used for determining the anticoagulation status of patients receiving DOACs. However the EHRA 2015 updated guidelines on DOAC use in AF point out that although this is appropriate, the quantitative assessment of drug exposure and anticoagulant effect may be needed in emergency situations8. Fundamentally, before blood sampling it is important to know when the DOAC was last administered and what the estimated elimination half-life is in order to have some context in which to interpret the results8. Since there are more than one class of DOAC, recommendations on clotting assessment differ depending on the anticoagulants underlying mechanism of action.

Direct thrombin inhibitors (Dabigatran):

An activated partial thromboplastin time (aPTT) may provide a qualitative assessment of dabigatran level and activity8, however differences in aPTT reagents can produce varying results, with the test itself not detecting the level of dabigatran present  but moreso providing a broad assessment of coagulability2. Some studies have suggested that a normal aPTT could be used to exclude an anticoagulant effect, however this has not been systematically tested and there are cases where individuals have been given dabigatran and the aPTT has been normal9.

The ecarin clotting time is another way of assessing coagulation status by providing a more direct measure of dabigatran activity, and was adopted by Pollack et al.9 during their assessment of idaracizumab in reversing the effect of dabigatran9. However at present there is not a recommended safety cutoff for elevated levels, with its main use being to indicate a limited anticoagulant effect of dabigatran if levels are close to baseline10, it is also not widely available2.

Further tests that have been studied for Dabigatran include the activated clotting time which responds similarly to aPTT, and Thrombin time which is very sensitive but not clinically suitable for assessing anticoagulation status due to the doses of dabigatran being used2. Alternatively dilute thrombin time assays may provide a more accurate and reproducible means of measuring dabigatran activity, however are not widely available2.

Factor Xa inhibitors (rivaroxaban, apixaban and endoxaban):

For Rivaroxaban the prothrombin time (PT) may be used as a surrogate marker of drug presence if prolonged, however there is a limited relationship between PT and drug concentration, and a limited sensitivity for detecting low concentrations of these drugs2. Furthermore different assays can create wide variability in test results, alongside a plethora of patient co morbidities including hepatic failure and malignancy2. It should also be noted that INR is not reliable for the evaluation of factor Xa inhibitor activity due to significant result variability.

Dilute PT tests alongside Anti Factor Xa chromogenic assays may be used to assess anticoagulant levels more accurately, however these tests are also not widely available and have limited research on their clinical relevance2

Further studies are required to confirm the predictive accuracy of coagulation studies for use with DOACs. Management decisions including subsequent use of reversal agents should not routinely be made based on these investigations, but on the whole clinical picture. Additionally, consultation with a hematologist would be appropriate for advice on management of these patients in line with local policies.

Reversal agents

Reversal of anticoagulation is generally considered in patients with major bleeding who remain actively anticoagulated. However research in support of this is limited11. Potential reversal agents differ depending on the DOAC mechanism of action. These are discussed below.

Idarucizumab:

In December 2015 idarucizumab was launched in the UK with a license for use in adults treated with dabigatran etexilate when rapid reversal of its anticoagulant effects is required for emergency surgery or urgent procedures, or in life threatening or uncontrolled bleeding12. It is a humanised monoclonal antibody fragment with a very high affinity to dabigatran and is priced at £2,400 per 5g excluding VAT12.

It works by binding to dabigatran and its metabolites, preventing it from exerting its anticoagulant effect12. Its action is specific to dabigatran etexilate and so it will not reverse the action of other anticoagulants. NICE12recommend a dose of 5g given iv as 2 consecutive infusions of 2.5g/50ml over 5 to 10 minutes each or as 2 consecutive 2.5g bolus injections. Administration of a second 5g dose may be considered if there is recurrence of clinically relevant bleeding together with prolonged clotting times or if potential re-bleeding would be life threatening and prolonged clotting times are observed or patients require a second emergency surgery or urgent procedure and have prolonged clotting times.

The research backing these recommendations is from an ongoing phase III prospective cohort study (RE-VERSE AD)9. In an analysis of 90 patients Pollack et al.9 found that a 5g dose of idarucizumab reversed the anticoagulant activity of dabigatran in 88 to 98% of patients. In those suffering from life threatening bleeding median time to cessation of bleeding was 11.4 hours, although the authors note this being difficult to assess and were unable to evaluate this in 13 patients. Of note this initial analysis was unblinded and they did not have a control arm, making it somewhat difficult to assess the clinical benefit of idarucizumab. Furthermore the mortality was high with 18 deaths overall, however the causes for death varied significantly. Thrombotic events occurred in 5 patients ranging between 2 and 26 days post infusion, with none of these patients receiving antithrombotic therapy when the events occurred.

NICE recommend reviewing thrombotic risk after idaracuzimab administration, with dabigatran recommencement being advised to start no earlier than 24 hours post infusion if the patient is clinically stable, however a LMWH could be considered in the interim if required12.

The decision to treat with idaracizumab should be made on an individual basis, taking into account bleeding severity and location, additional comorbidities and risks of thromboses. It’s use should be assumed in conjuction with standard supportive measures, and caution should be used in patients with hereditary fructose intolerance due to the high amount of sorbitol contained within Idaracizumab12.

Andexanet alfa:

Andexanet alfa is an unlicensed modified human factor Xa molecule currently in development13. It acts as a decoy to bind factor Xa inhibitors rendering them unable to exert their therapeutic effects13. Furthermore it does not have procoagulant activity13. There are some phase 2 trials reported and currently there is an ongoing phase 3 trial looking at the hemostatic efficacy of andexanet alfa in patients receiving a factor Xa inhibitor and who are experiencing an acute major bleed14. The estimated primary completion date of this trial is November 202214.

Siegal et al.15 undertook two phase 2 randomized, double-blind, placebo-controlled studies of andexanet in patients receiving either 5mg of apixaban (ANNEXA-A) and rivaroxaban (ANNEXA-R). They recruited healthy older volunteers between 50 and 75 years of age who received their respective anticoagulants followed by andexanet. Andexanet was given as either a bolus or bolus plus 2 hour infusion. The primary outcome being a percent change in anti factor Xa acitivity. They found that among the apixaban-treated participants, anti–factor Xa activity was reduced by 94% in those receiving an andexanet bolus compared with 21% in the placebo group (P<0.001). In the rivaroxaban group, anti–factor Xa activity was reduced by 92% in those receiving an andexanet bolus compared with 18% in the placebo group (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. There were no serious adverse or thrombotic events were reported.

However, although the participant age was reflective of those who may suffer from AF, these individuals were healthy volunteers and the environment was well controlled, making it difficult to extrapolate the findings to a hospital population. Additional studies will be needed to determine the true efficacy and safety of andexanate, and the findings from the phase 3 trial looking at its use in acute major bleeding will be eagerly anticipated.

Other interventions to consider:

In situations where DOAC ingestion is relatively acute the use of activated charcoal at an adult dose of 30-50g could be used to reduce further absorption10. However this may play a limited role in major haemorrhage.

Alternatively, haemodialysis could be considered in patients using Dabigatran due to its significant renal clearance10, however this would need to be readily available.

Conclusions

The increasing use of DOACs to treat patients with Atrial Fibrillation will inevitably mean encountering more cases of major haemorrhage in this patient cohort. Establishing a unifying definition of Major Haemorrhage is important in order to standardize protocols for these patients. Early assessment and intervention is prudent, and clear communication and involvement of the multidisciplinary team is essential in order to optimise patient care. Current routine management with blood replacement products as well as tranexamic acid, FFP, and PCC/aPCC should be considered for all patients, alongside discussion with a haematologist and a review of local guidelines. The adoption of specific reversal agents should be chosen on a case by case basis with thrombotic risk being continually assessed throughout the post transfusion period. Continuing research into new reversal agents poses an exciting era for anticoagulation and management of major haemorrhage, with the potential for these agents to further increase the use of DOACs and improve patient outcomes. However a significant amount of research needs to be undertaken to appropriately evaluate the safety and efficacy of these drugs before their use becomes commonplace.

 

References

1.            Nice CG180. Atrial Fibrillation: Management. Available from: https://www.nice.org.uk/guidance/cg180/resources/atrial-fibrillation-management-35109805981381

[Accessed 21st August 2016]

2.            Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. European Heart Journal. 2013;34(7):489-498b.

3.            NHS England. Medicines Optimisation Dashboard May 2016.

Available from: https://www.england.nhs.uk/ourwork/pe/mo-dash/

[Accessed 21st August 2016].

4.            Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomized trials. Lancet. 2014;383(9921):955-962.

5.            Norfolk D (ed.) Handbook of Transfusion Medicine 5th Ed. Norwich:UK.TSO. 2013.p1-161.

6.            Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Journal of Thrombosis and Haemostasis. 2005;3: 692–4.

7.            Garcia D, Crowther M. Management of bleeding in patients receiving direct oral anticoagulants. UpToDate.

Available from:http://www.uptodate.com/contents/management-of-bleeding-in-patients-receiving-direct-oral-anticoagulants

[Accessed 21st August 2016].

8.            Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. Updated EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015:17(10):1467-507.

9.            Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Selke FW, Stangier J, Steiner T, Wang B, Kam CK, Weitz JI. Idarucizumab for dabigatran reversal. New England Journal of Medicine. 2015; 373: 511–20.

10.         Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Europace. 2013:15(5):625-651.

11.         Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. American Journal of Hematology. 2012;87(1):141-45.

12.           NICE Guidance esnm73. Reversal of the anticoagulant effect of dabigatran: idaracizumab. Available from: https://www.nice.org.uk/guidance/esnm73/resources/reversal-of-the-anticoagulant-effect-of-dabigatran-idarucizumab-1502681164008901

[Accessed 21st August 2016].

13.         Hu TY, Vaidya VR, Asirvatham SJ. Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa and idarucizumab. Vascular Health and Risk Management. 2016;12:35-44.

14.         ClinicalTrials.gov. A Study in Patients With Acute Major Bleeding to Evaluate the Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Direct and Indirect Oral Anticoagulants. Available from:

https://clinicaltrials.gov/ct2/show/NCT02329327

[Accessed 21st August 2016].

15.         Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, Mathur VS, Castillo J, Bronson MD, Leeds JM, Mar FA, Gold A, Crowther MA. Andexanet Alfa for the Reversal of Factor Xa inhibitor Activity. The New England Journal of Medicine. 2015;373:2413-24.

Click here to download the editorial as a PDF file