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Management of Hemorrhage Related to Direct Action Oral Anticoagulant Medication

Manejo das Hemorragias Relacionadas aos Anticoagulantes Orais de Ação Direta

Isabela Ramos Ali Ganem1; Luiz Claudio Behrmann Martins1; Carlos Eduardo Mendonça Tomé1,2

 

ABSTRACT:

INTRODUCTION: Direct Oral Anticoagulant - DOACs) are a new class of anticoagulant that directly inhibit the trombine (dabigatrane) or Xa factor (rivaroxabane, edoxabane and apixabane) in the coagulation cascade. These medications are being more frequently used for the treatment and prevention of thrombolytic events, mainly in patients with atrial fibrillation, in substitute to varfrine or other vitamin K antagonists (VKAs). Although the incidence of hemorrhage is higher in AVKs than in DOACs, these events may also occur in this group, even in the form of intracranial hemorrhage (ICH), with risk of death. Nowadays, DOACs indications have progressively enhanced and the availability of their specific reverse agents certainly will enhance the safety of their usage. Idarucizumab, reverse agent of dabigatrane, and alpha andexanet, reverse agent of Xa factor, have been approved by the Food and Drug Administration in the United States and ciraparantag may be approved in a near future.
OBJECTIVE: To review the literature on the manage of hemorrhage related to the use of DOACs.
METHODS: Review of literature that used articles from 1998 to 2017, from several platforms and journals.
CONCLUSION: DOACs constitute a great advance in prophylaxis and treatment of thrombolytic diseases, which presents elevated morbidymortality, and hemorrhages are the main adverse events related to their usage, being rarely necessary the immediate reverse of the anticoagulation. However, the existence of DOACs specific reverse agents enhance the safety of patients, whose anticoagulation may be rapidly reversed if necessary.

Keywords:
Atrial fibrillation; Blood coagulation; Pharmaceuticals effects.

RESUMO:

INTRODUÇÃO: Os anticoagulantes orais diretos (direct oral anticoagulant - DOACs) são uma nova classe de anticoagulantes que inibem diretamente a trombina (dabigatrana) ou o fator Xa (rivaroxabana, edoxabana e apixabana) na cascata da coagulação. Esses estão sendo cada vez mais utilizados para tratamento e prevenção de eventos tromboembólicos, principalmente em pacientes com fibrilação atrial, em substituição à varfarina ou outros antagonistas de vitamina K (AVKs). Embora a incidência de hemorragias seja maior nos AVKs do que nos DOACs, elas também podem ocorrer nesse grupo, até mesmo na forma de hemorragia intracraniana (HIC) com risco de morte. Atualmente as indicações dos DOACs vêm aumentando progressivamente, e a disponibilização de seus agentes reversores específicos certamente aumentará a segurança e, consequentemente, sua utilização. O idarucizumab, reversor da dabigatrana, e o andexanet alfa, reversor dos inibidores do fator Xa, foram aprovados pelo Food and Drug Administration (FDA) dos Estados Unidos e o ciraparantag poderá ser aprovado em um futuro próximo.
OBJETIVO: Revisar a literatura sobre o manejo da hemorragia relacionada ao uso dos DOACs.
MÉTODOS: Revisão da literatura que utilizou artigos de 1998 a 2017, de diversas plataformas e revistas.
CONCLUSÃO: Os DOACs constituem um grande avanço na profilaxia e tratamento da doença tromboembólica, que cursa com elevada morbimortalidade, e as hemorragias são os principais eventos adversos relacionados ao seu uso, sendo raramente necessária a reversão imediata da anticoagulação. No entanto, a existência dos reversores específicos dos DOAcs aumenta a segurança dos pacientes, que poderão ter sua anticoagulação revertida rapidamente, se necessário.

Palavras-chave:
Fibrilação atrial; Coagulação sanguínea; Efeitos dos fármacos.

FIGURES

Citation: Ganem IRA, Martins LCB, Tomé CEM. Management of Hemorrhage Related to Direct Action Oral Anticoagulant Medication. JBAC 32(2):89. doi:10.24207/jca.v32i2.008_PT
Received: Junho 09 2019; Accepted: Julho 01 2019
 

INTRODUCTION

Oral anticoagulation is essential for the prevention and treatment of embolism and thrombosis. Only in the United States, over six million people use oral anticoagulant medication (OACs), which could be related to higher risk of bleeding and could also echo in morbidymortality of this group1.

The incidence of diseases that require OACs have been progressively increasing and this is directly linked to the aging of the population. Atrial fibrillation (AF), the most prevalent arrhythmia in the world, presented an enhance of 13% regarding incidence in the last two decades, and age is a risk factor not only for the development of AF but also for the risk of cardio thrombolytic events. Cerebral Vascular Accident (CVA) is the main complication of FA and it is related to this arrhythmia in 20% of the cases2.

Direct Oral Anticoagulants (DOACs), represented by the direct suppressants of Xa factor (rivaroxaban, edoxaban and apixaban), and thrombin direct suppressant (dabigatran) are alternatives to the vitamin K antagonists (VKAs) for the profilaxys and treatment of thrombolytic events, greatly in part related to AF and present a series of clinical advantages when compared to VKAs, such as higher anticoagulant stability and less risk not only for intracranial hemorrhage but also bleeding5.

Regarding hemorrhage complications, due to the short half-life of these medications, in most cases only the suspension, associated to clinical support actions, may be enough to stop the bleeding. The usage of prothrombic complex4, haemodialysis and the use of activated carbon (AC) may be useful in reducing the action of DOACs; however, in cases of overdosage, massive bleeding, hemodynamic compromise or need of urgent surgical intervention, the reversion of the anticoagulant activity may be needed. To act in these more serious cases, DOACs specific reverse agents were developed, and the three main drugs are: idarucizumabe, andexanet and ciraparantag.

 

OBJECTIVE

To review the literature regarding hemorrhage management related to DOACs.

 

METHODS

This review of literature study used articles from 1998 to 2017, researched in the platforms PubMed, Medline, Cochrane Library, SciELO and UpToDate and in the scientific journals Journal of the American Medical Association, New England Journal of Medicine and Blood, using the following keywords: atrial fibrillation, anticoagulation, DOAC, alpha andexanet, idarucizumabe, ciraparantag.

 

DEVELOPMENT

Homeostasis is a normal physiological answer from the body that prevents significant blood loss after vascular damage. Coagulation cascade is a complex series of reactions that guarantees the occurrence of homeostasis (Fig. 1).

Anticoagulant system, which works in parallel to the fibrinolytic system, guarantees that the formation of the thrombus is a controlled and balanced procedure, allowing the degradation of already formed thrombus. DOACs are divided into direct inhibitors of thrombin or direct inhibitors of Xa factor, and their characteristics are presented in Table 1.

Table 1. Properties of DOACs.
  Dabigatran Rivaroxaban Apixaban Endoxaban
Actionmechanism Thrombin direct inhibitor Xa factor direct inhibitor Xa factor direct inhibitor Xa factor direct inhibitor
Time to achieveseriec level 1 to 2 h if swallowedwith food 2 to 4 h 3 to 4 h 1 to 2 h
Half-life 12 to 17 h (young people);14 to 17 h (eldery) 5 to 9 h (young people);11 to 13 h (eldery) 12 h 10 to 14 h
Dose (fanv) 150 mg twice a day 20 mg once a day 5 mg twice a day 60 mg once a day
Metabolismby cyp3a4 No Yes Yes Minimum
Elimination 80% kidney 70% liver30% kidney 30% kidney 50% kidneyl

Exetilate dabigatran is an oral pro-pharmaceutical that is converted in the liver into dabigatran, a direct, reversible, competitive inhibitor of thrombin5. There are tests of anticoagulant activity, such as the ecarin clotting time (ECT), thrombin time (TT) and partially activated thromboplastin (PATP) to detect the excessive activity of the dabigatran. TT is the most sensible in detecting low levels of dabigatran6,7.

The direct inhibitors of Xa factor (rivaroxaban, apixaban and edoxaban) directly linked themselves to the active sites of X factor in the circulation and, linked to the clot, block the interaction with its substrate. They are metabolized by the kidneys (25-35%) and liver (up to 75%) and patients with hepatic insufficiency may present this drug accumulation, but in spite of that, these medications do not seem to be toxic to the liver8.

Rivaroxaban is a direct inhibitor, reversible and competitive of the Xa factor, orally administrated. It should not be use in patients with clearance <15 mL/min, as well as in patients with important liver illness (Child-Pugh B and C with coagulopathy)9. This medication has not been tested in people under 18 years of age10.

Rivaroxaban interacts with CYP-3A4 and protein P suppressant drugs (such as ketoconazol, itraconazol, voriconazol, posaconazol and ritonavir) and its concomitant use with these drugs is not recommended11. It is not necessary to perform tests to monitor the coagulation during the treatment with rivaroxaban, except in patients that present bleeding, suspect of medication intoxication or need of emergency surgery13.

Apixaban is a direct inhibitor, reversible and competitive of Xa factor, orally administrated, needing adjust of the dose according to the creatinine clearance. It is also recommended to reduce its dose in patients that use CYP-3A4 and protein P inhibitors14.

Edoxaban is a direct inhibitor of Xa factor, selective and reversible15,16. Around 73% of the drug of the dose is eliminated unaltered in urine and faeces17,18.) The recommended dose for the prevention of Cerebral Vascular Accident in patients with AF is of 60 mg once a day, reducing to 30 mg once a day in patients with creatinine clearance between 15-50 mL/min, weight <60kg or concomitant use of any protein P inhibitor (for ex., verapamil, quinidin, eritromicin and ketoconazol)19. This medication is not recommended for patients with terminal kidney failure, creatinine clearance ,15 mL/min or under hemodialysis.

The incidence of bleeding is 2-3% a year higher in patients using DOACs, being the incidence of CVA 1-0.5%21.

 

DISCUSSION

Hemorrhage management related to the use of DOACs varies according to the gravity of the case. Light hemorrhages may be resolved only with the temporary suspension of the drug and, in the most severe cases, fluid reposition may be needed, as well as hemodynamic support, mechanical compression, surgical hemosthasis, and the use of blood derivatives. If all those measurements were not enough, one must use pro-coagulants, such as the prothrombic complex21.

Other therapies include hemodialysis, capable of removing up to 60% of the circulant dabigatrana and AC, effective in reducing the absorption of anticoagulant in the first hours after the ingestion. In the cases of overdose, massive bleeding, need to restore hemostasis by hemodynamic compromise or need of urgent surgical intervention, the reserve of the anticoagulant activity may be needed, using DOACs reverse agents21. Their indications and characteristics are presented in Table 2 and Table 3.

Table 2. Indications of the DOACs reserve agents.
Bleeding with risk of death: intracranial hemorrhage, symptomatic extradural hemorrhage or in expansion or uncontrollable hemorrhage
"Closed" bleeding or in critical organs: intraspinal, intraeye, pericardium, pulmonary, retroperitoneal or intramuscular or compartmental syndrome
More persistent bleeding in spite of al the measurement for local hemostasis or risk of recurrent bleeding
Surgery or emergency intervention in patients with risk risk of bleeding during the proceedure: neurosurgery, lumbar punction, cardiac surgery, vacular or hepathic surgery
Table 3. Properties of the specific reverse of DOACs.
  Idarucizumabe Alpha Andexanete Ciraparantag
Target Dabigratan Direct inhibitor  do fator Xa, LMWH, fondaparinux Direct inhibitor of Xa factor, low molecular weight heparin,  fondaparinux, heparin, dabigratan
Compound Human monoclonal antibody fragment Recombinant molecule derived from human Xa factor Bonding through the non-covalent hydrogen actions, diminishing the bonding to endogenous targets
Action mechanisms Afinity of bonding to dabigatran 350 times higher than the affinity of dabigratan-trombin bonding Alteration of the receptor of the Xa inhibitors with greater afinity of the bonding than "natural" Xa factor 100-400 mg intravenous administration
Dose 5 g (divided into two doses of 2.5 g intravenously adminstrated) 400-800 mg in bolus, followed by 4-8 mg/min in continuous infusion in 2h Within 10 min
Start of the action Immediate Within de 5 min Yes
Reservsion duration 12 h 1 to 2 h 24 h
Elimination Renal Indefinite Indefinite
Clinical Study Reverse-AD Annexa-A and AnnexA-R Ansell et al 37.
Development phase III/approved III II
Adverse effects Cutaneous reaction, bruises at the site of application and epistaxis Urticaria, disgeusia, headaches and flushing Disgeusia, headaches and flushing

LMWH: Low Molecular Weight Heparin

Idarucizumabe, specific reserve agent of dabigatrana, was approved for clinical use in October and November 2015, in the United States and Europe, respectively and in Brazil, its liberation occurred in April 2017. Alpha andexanet, reverse of Xa factor inhibitors, was approved by the Food and Drug Administration (FDA) in an accelerated scheme, however in Brazil its usage has not been cleared yet. The most recent DOACs reverse agent, ciraparantag, is in initial phase of studies and it proposes the reverse of all types of DOACs.

Clinical Measurements

In case of greater bleeding, which occurs in critical location in association with hemodynamic instability or fall of ± 2 g/dL of hemoglobine, DOACs must be suspended, being their specific reverse agents indicated, as well as volume replacement and local hemostasis22.

In case of external bleeding, local control measurements must be performed, preferentially with criastalloides (0.9% saline, Ringer or Lactate), aiming the volemic restauration and hemodynamic stability. Hypothermia as well as acidosis must be corrected and, in case of symptomatic anemia and/or active bleeding, red blood cells must be transfused, in order to maintain hemoglobin at ± 7 g/dL in general patients and at ± 8 g/dL in coronary patients23.

Plaquets transfusion must be performed if there is less than 50.00024 and if fibronogenius crioprecipitate is less than 100 mg/dL. Care must be taken when indication DOACs in patients with morbidity that enhances the risks of bleeding, mainly dabigatran, since liver dysfunction may lead to coagulopathy and reduce the metabolism of the anticoagulant, enhancing the risk of hemorrhages. When DOACs specific reserve actions or agents are unavailable, non-specific reverse measurements should be performed.

Prothrombic complex is a complex of factors derived from human plasma capable of reversing the anticoagulating action of VKA. In animal studies, prothrombic complex was also efficient in reversing the effects of dabigatran25, with recommended dose of 50 U/kg (maximum of 4.000 U)26. There are no randomized studies evaluating the use of prothrombic complex in patients with higher bleeding due to the use of Xa factor inhibitors, therefore the dose is based on cases, series of cases and studies in pre-clinical phase, being the initial suggested dose of 50 U/kg27. AC may be used to remove the non-absorbed drug by the gastrointestinal tract and should be performed in up to 2 to 4 hours after the ingestion28.

Hemodyalisis is useful for bleeding related to dabigatran, due to low affinity to this molecule by plasmatic proteins, due to the excretion mostly by the kidneys29. On the other hand, Xa inhibitors cannot be dyalised, since present strong bonding to plasmatic proteins21.

Antifibronilitc agents may be indicated to patients with greater bleeding caused by either Xa inibitors or dabigatran. Activated VII factor, fresh frozen plasma or cryoprecipitate must be avoided due to the lack of studies showing benefits and the associated high risks (for ex., transfusional reaction, volume overload)21.

DOACs reverse agents are indicated in case of urgent reversion of the anticoagulant effect, such as in massive bleeding, in the presence of hemodynamic instability or when patient needs urgent/emergency surgery in the presence of the usage of such pharmaceuticals.

Idarucizumabe may be used to reverse the action of dabiatran. A fragment of the human monoclonal antibody produced in ovarium cels of hamsters from China connects to dabigatran with high afinity and specificity. The recognition and the bonding to dabigatran are due to the structural similarity to thrombin mediated by hydrophobic and hydrogen interactions and saline bridges. The dose adjustment is not necessary according to kidney and liver function, weight or age. The peak of idarucizumabe concentration is reached in a few minutes, followed by quick elimination30.

When 5 g of idarucizumabe is administrated, 32.1% will be recovered in urine in the period of 6 hours and less than 1% in the next 18 hours. The remaining will be eliminated through protein catabolism, mainly through the kidneys. Transitory proteteinuria has been observed, which normally reaches its peak after 4 hours of administration and disappears between 12 to 24 hours. In the absence of dabiatran in the organism, idarucizumabe has no effect in the formation of thrombin or in the coagulation parameters (dTT, ECT, TT, PATP). In phase 1 studies, no statistically significant differences were demonstrated between the side effects found in patients that received placebo or idarucizumabe, neither relevant clinical findings or altered laboratory parameters, vital signs, eletrocardiogram or physical exams alterations were found3. Idarucizumabe dose selection for the use in clinical tests was based on targets to neutralize the dose of dabigatran used in patients with AF on RE-LY study (150 mg of dabigatran twice a day). The 5 mg dose was chosen to reverse the dose of the anticoagulant in patients with moderate kydney function. In the studies that involved patients of masculine and feminine gender of different agents and kidney functions, the administration of idarucizumabe, in the dose of 2.5 g every 12 hours, resulted in the satisfactory reversion of anticoagulation by dabigatran, being this dose selected for further studies. Idarucizumabe has shown to be effective and safe in the reversion of the anticoagulant effect of the dabigatran, in bleeding situations. The safety observed in the study gives support to the use in emergency situations, and the medication has already indications for the treatment of severe hemorrhages31.

Alpha andexanet is a specific reserve agent of the Xa inhibitors criated by bioengenheering. It is a recombinant molecule with structure similar to the endogenous Xa factor, with high afinity to the Xa factor inhibitors, as well as the direct and indirect ones (rivaroxaban, edoxaban, apixaban, low molecular weight heparin and fondaparinux), but it does not have catalytic effect, so it does not performs the cleavage of the prothrombin to thrombin. The bonding site of Xa factor was substituted by alanine, which allows the bonding and removal of Xa factor inhibitors in the intravascular, restoring the activity of the endogenous Xa factor, with consequently reduction of the anticoagulant activity32.

Andexanet alpha has instravenous administration, being the first dose in bolus, followed by a maintanance dose in the next 2 hours33. The start of the action is in 2 to 5 minutes after the drug infusion and its half-life is in 30 to 60 minutes. The Xa inhibitors anticoagulant levels rise after a few hours of andexanet administration, and the drug is not removed with the reverse agent, as it happens with dabigatran, when the antibody idarucizumabe is used 34,35. Dose adjustment is not necessary. In 2 minutes after the administration, alpha andexanet showed reversion of the anticoagulant effects of all Xa factor inhibitors, including the reduction of its activity and the restoration of thrombin generation and coagulation time. Endovenous administration in bolus, followed by continuous infusion of andexanet resulted in sustained reduction of the anti-Xa factor, which returned to the levels of the placebo group 2 hours after the stop of the infusion34.

Ciaraparantag (PER977) is a small cathionic synthetic molecule, which bonds to the Xa inhibitor factor, thrombin direct inhibitors, non-fractioned heparin and low molecular weight heparin through non-covalent hydrogen bridges. Phase 2 studies investigating reversion of edoxaban and evaluating the doses of ciraparantag are in progress and plans for phase 3 studies have already been announced36.

 

CONCLUSION

DOACs constitute a great advance in prophylaxis and treatment of thrombolytic disease, which presents elevated morbiditymortality. These drugs are of easy use, present high efficiency and safety and do not need of therapeutic dose adjustment by the coagulogram, which have been elevating their use. An important obstacle regarding DOACs use was the impossibility of reversion of their action in case of severe bleeding or emergency surgeries.

Although rarely necessary, in case of immediate reversion, the existence of reverse agents enhances the security of patients, which may lead to the enhancement of their usage. For this reason, it is very important the availability of DOACs specific reverse agents, even knowing that most cases regarding bleeding related to their use do not need any drastic intervention.

 

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