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Oral Anticoagulation Reversal

Disease Management

Read time: 40 mins
Last updated:12th Mar 2020
Published:29th Jan 2020

There will be details of blood coagulation factors II, VII, IX and more; the coagulation cascade; haemorrhagic risk assessment, using the international normalised ratio; the factor Xa inhibitors rivaroxaban, edoxaban or apixaban; the factor IIa (thrombin) inhibitor dabigatran; the risks of warfarin treatment; current national and international guidelines; the use of fresh frozen plasma to reverse vitamin K antagonist (VKA) anticoagulation; plasma and rVIIA; and details of the anticoagulation reversal agents idarucizumab, andexanet alpha and ciraparantag are all included in this section.

Blood Coagulation

Blood coagulation involves the complex interaction of multiple factors resulting in the generation of an insoluble fibrin clot. Classically blood coagulation was considered to be a cascade involving two convergent pathways: the intrinsic (contact activation) pathway and the extrinsic (tissue factor) pathway. [Monroe and Hoffman 2006; Adams and Bird 2009; Alquwaizani et al., 2013] 

More recently, blood coagulation is considered to consist of phases, involving initiation, amplification, propagation and finally, clot stabilisation. [Monroe and Hoffman 2006; Adams and Bird 2009] {Figure 1}

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Anticoagulation

Coagulation is a rapid and tightly controlled process giving a response to tissue injury and allowing for repair to begin. However, in some acquired or inherited clinical disorders, the coagulation process is aberrantly activated, causing thrombosis. Patients needing anticoagulation therapy for the prevention or treatment of thrombosis have commonly been treated with the oral vitamin K antagonist warfarin, or parenterally with a heparin formulation [Harter et al., 2015]. Coumarin-based oral anticoagulants, which include warfarin, phenprocoumon and acenocoumarol, are used prophylactically for venous thromboembolism, systemic embolism in patients with atrial fibrillation or prosthetic heart valves, acute myocardial infarction in patients with peripheral arterial disease, and stroke or recurrent infarction in patients with acute myocardial infarction. [Ansell et al., 2004; Ansell et al., 2008 Levy et al., 2008]

As a result of warfarin’s narrow therapeutic index and a need for frequent laboratory monitoring during warfarin therapy, novel anticoagulants have been developed in recent years. [Harter et al., 2015] The targets of anticoagulant drugs are variable and are summarised in figure 2 below. Warfarin inhibits the synthesis of functional vitamin K dependent clotting factors II (prothrombin), VII, IX and X (and protein S and protein C which have an anticoagulant regulatory function); rivaroxaban, apixaban and edoxaban are direct inhibitors of factor Xa; and thrombin (factor IIa) inhibitors include the orally administered dabigatran, and the parenteral inhibitors argatroban and bivalirudin. In contrast, unfractionated heparin (UFH) and low molecular weight heparins (LMWH) enhance the activity of antithrombin 3 (AT3), an inhibitor of thrombin and other procoagulant factors. [Hirsh et al., 2003; Alquwaizani et al., 2013; Harter et al., 2015]

OACR_DM_Fig2__8239D5A6-27C9-4724-8C673851C02A6C28.png

Figure 2. The coagulation cascade outlining the interaction with anticoagulants. (Alquwaizani et al., 2013).
LMWH, low-molecular-weight heparins; UFH, unfractionated heparin.

Haemorrhage is an adverse event common to all anticoagulants. [Harter et al., 2015], with acute gastrointestinal (GI) bleeding being the most common adverse event associated with oral anticoagulant therapy. [Radaelli et al., 2015] In clinical practice, major bleeding can be associated with a significant risk of death resulting from intracerebral bleeding or significant GI bleeding; long-term morbidity such as intraocular bleeding or a less severe intracerebral haemorrhage; or bleeding requiring transfusion to maintain an adequate haemoglobin value. [Crowther & Warkentin 2008]

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Diagnostic Tests

In patients taking oral vitamin K antagonist (VKA) anticoagulants, haemorrhagic risk is assessed by the international normalised ratio (INR) which standardises the prothrombin time (PT), with risk of bleeding increasing exponentially at INR values >5.0. {Figure 3} [Landefeld and Beyth 1993; Cannegieter 1995; Palareti 1996; Makris and Watson 2001]

OACR_DM_Fig3__9D173C1E-E383-4515-A06B01B80B5007EC.png

Figure 3. Bleeding risk in relation to international normalised ratio (INR) (Adapted from: Palareti, 1996; Makris and Watson, 2001).

UK and USA guidelines for the optimal use of oral VKA anticoagulation for a range of indications have been published and recommend a target INR within the range of 2.0–3.0, although this can be adjusted based on individual patient circumstances. [Keeling et al., 2011; Holbrook et al., 2012]

In contrast, no routine monitoring of the factor Xa inhibitors rivaroxaban, edoxaban or apixaban or the factor IIa (thrombin) inhibitor dabigatran is required, since they are given at fixed doses and have predictable pharmacokinetic and pharmacodynamic responses (in patients with adequate renal function who are not taking other interacting drugs). [Steffel et al., 2018] However, monitoring of these anticoagulants is necessary in a range of circumstances including bleeding, perioperative management, reversal of anticoagulation, and suspicion of overdose. [Baglin et al., 2013]

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Bleeding Risks of Anticoagulants

As with all therapies, there are sometimes serious side effects. When treating with anticoagulation therapy, monitoring is essential to ensure that the anticoagulant effects are not detrimental to patients' health. Risk of haemorrhage is likely if there is a high level of anticoagulant within the blood stream. It is all about creating a fine pharmacokinetic balance, however if the patient is in danger of haemorrhage there are oral anticoagulation reversal treatments that should be administered urgently.

Vitamin K Antagonists

The main determinants of bleeding induced by VKA therapy are the intensity of the anticoagulant effect, duration of therapy, underlying patient characteristics including age, and the concomitant use of interfering drugs. [van der Meer et al., 1993; Levine et al., 2004]

Clinical trials have reported that warfarin treatment is associated with a significant risk of haemorrhage, with the risk of fatal or life-threatening bleeding as high as 1–3% per year. [Lankiewicz et al. 2006] In randomised trials of VKA therapy following an acute episode of ischaemic cerebrovascular disease, the risk of major bleeding, assessed from multiple studies, ranged from 2–13% with a mean duration of follow-up ranging from 6 to 30 months. [Levine et al., 2004] The risk per year of major bleeding following VKA therapy in these randomised trials ranged from 1–8.3% in patients with prosthetic heart valves; 0–6.6% in patients with atrial fibrillation (AF); 0–19.3% in patients with ischaemic heart disease; and 0–16.7% in patients with venous thromboembolism (VTE) [Levine et al., 2004]

Improved rates of major haemorrhage are achieved when patients are treated by specialist anticoagulation management service (AMS) teams rather than by a personal physician. Rates of major haemorrhage were 2.8–8.1% per patient-year of therapy for care by personal physicians (usual care) and 1.4–3.3% per patient-year of therapy for care provided by AMS. [Ansell et al., 2008]

In recent years, the use of oral anticoagulants, especially vitamin K antagonists, has increased the incidence of coagulopathy-associated intracranial haemorrhage, and accounts for up to 15% of all cases [de Oliveira Manoel et al., 2016]. A meta-analysis review of data from 20 randomised clinical trials (RCTs) of 91,671 atrial fibrillation patients reported a greater risk of intracranial haemorrhage in patients treated with warfarin compared to those treated with the NOACs edoxaban (30 mg, OR 3.42, 95% CI 1.22-7.22) and dabigatran (110 mg, OR 3.56, 95% CI 1.10-8.45). [Xu et al., 2017]

A recent multicentre study of 2,192 patients taking oral anticoagulants, including warfarin, who developed major bleeding requiring hospitalisation reported high rates of mortality in these patients, with 21% likely to die within 30 days of admission, rising to 33% for patients with intracranial haemorrhage. [Green et al., 2018]

The incidence of bleeding defined as "major" or "minor" has varied considerably between studies. [Hanley 2004] This may be due, in part at least, to the inconsistency of definitions between classification schemes in clinical research studies. [Ansell et al., 2004]

Non-Vitamin K Oral Anticoagulants

The majority of studies report that the risk of gastrointestinal (GI) bleeding with non-vitamin K oral anticoagulants (NOACs) is similar to that with warfarin [Abraham et al., 2015; Chang et al., 2015; Caldeira et al., 2015; Burr et al., 2017]; although one study comparing dabigatran with warfarin reported an increase in GI bleeding and major bleeding with dabigatran [Hernandez et al., 2015], and another reported that dabigatran reduced rates of morbidity and mortality in elderly patients compared with warfarin. [Graham et al., 2015]

The overall risk of GI bleeding associated with the novel oral anticoagulants, dabigatran and rivaroxaban was found to be similar to that for warfarin in new users of these anticoagulants. However, there was an increased risk of GI bleeding in older patients aged over 75 years, in patients taking dabigatran or rivaroxaban. [Abraham et al., 2015] A recent literature review by Cheung and Leung reported an increased risk of GI bleeding with high-dose dabigatran (150 mg bid), rivaroxaban and high-dose edoxaban (60 mg daily). [Cheung & Leung, 2017]

In patients with AF the incidence of GI bleeding events associated with dabigatran was calculated as 2.29 per 100 patient years (95% CI, 1.88–2.79); and with warfarin as 2.87 per 100 patient years (95% CI, 2.41–3.41). The incidence of GI bleeding in AF patients treated with rivaroxaban was 2.84 per 100 patient years (95% CI, 2.30–3.52); and with warfarin was 3.06 per 100 patient years (95% CI, 2.49–3.77). In non-atrial fibrillation patients, the incidence of GI bleeding with dabigatran was 4.10 per 100 patient years (95% CI, 2.47–6.80); in comparison with 3.71 per 100 patient years (95% CI, 2.16–6.40) with warfarin. The incidence of GI bleeding in non-atrial fibrillation patients was 1.66 (95% CI, 1.23–2.24) per 100 patient years with rivaroxaban; and 1.57 per 100 patient years (95% CI, 1.25–1.99) with warfarin. [Abraham et al., 2015]

The risk of GI bleeding in AF patients aged ≥76 years was higher in patients taking dabigatran than warfarin: with a calculated hazard ratio (HR) of 2.49 (95% CI, 1.61 to 3.83). In ≥76 years old patients taking rivaroxaban there was a higher risk of GI bleeding compared to warfarin in both patients with AF (HR = 2.91; 95% CI, 1.65 to 4.81) and in non-atrial fibrillation patients (HR = 4.58; 95% CI, 2.40 to 8.72). [Abraham et al., 2015]

A large retrospective cohort study of over 46,000 patients treated with dabigatran, rivaroxaban or warfarin found that the rate of Gl bleeding was highest in dabigatran users (9.01/100 person years), and lowest in rivaroxaban users (3.41/100 person years), with the rate being 7.02 per 100 person years with warfarin. However, following adjustment for potentially confounding factors there was no significant difference between dabigatran or rivaroxaban when compared to warfarin. [Chang et al., 2015]

Recent meta-analyses of the risk of major GI bleeding with NOACs which evaluated studies of apixaban, dabigatran, edoxaban and rivaroxaban concluded that these drugs are not associated with an increased risk of GI bleeding when compared to other anticoagulants (VKAs or LMW heparin). [Caldeira et al., 2015]

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Disease Burden and Treatment

Disease burden

A retrospective analysis of data from patients with AF treated from 2003 to 2007 in the USA showed that the mean costs of warfarin-associated bleeding were $41,903 for intracranial haemorrhage, and $40,586 and $24,347 for major and minor GI bleeding respectively. [Ghate et al., 2011]

Treatment

Clear strategies to swiftly and completely reverse oral anticoagulation, especially in patients experiencing a serious bleed are imperative. [Hirsh 2003; Hanley 2004] In addition, anticoagulated patients who require emergency surgery or invasive diagnostic procedures, or those with very high INRs, are also candidates for urgent anticoagulation reversal. [Hirsh et al., 2003; Hanley 2004] 

For patients anticoagulated with VKAs with a high INR three options exist to lower the INR. The first is to cease warfarin therapy; the second is to administer vitamin K; and the third, for an effective rapid response, is to infuse fresh plasma or prothrombin complex concentrate. Normalisation of high INRs following cessation of warfarin therapy commonly takes several days to achieve, with INRs being normalised within 24 hours following addition of vitamin K. More rapid reversal with fresh frozen plasma or prothrombin complex concentrates will typically normalise INR within an hour. [Hirsh 2003; Hanley 2004; Imberti et al., 2011]

Vitamin K Antagonist Associated Bleeding

Bleeding is the most significant adverse effect with warfarin therapy, being directly related to the level of INR. Warfarin has a narrow therapeutic index and is influenced by drug interactions, notably anti-platelet drugs, and environmental factors. Treatment with VKAs increases the risk of major bleeding by 0.3–0.5 % per year and the risk of intracranial haemorrhage by around 0.2 % per year in comparison to controls. [Alquwaizani et al., 2013; Harter et al., 2015]

Risk factors for warfarin-related haemorrhage include intensity of anticoagulant effect, time within the therapeutic range, advanced age, and serious comorbid conditions including cancer, prior stroke, chronic kidney disease (CKD), liver dysfunction, arterial hypertension and alcohol abuse. [Alquwaizani et al., 2013; Harter et al., 2015]

Current Guidelines

Guidelines have been published by the American College of Chest Physicians (ACCP) for the perioperative management of antithrombotic therapy, which addresses the management of patients who are receiving VKA anticoagulant therapy and require an elective surgery or procedure. Assessment of perioperative bleeding risk is considered but no guidance on reversal of bleeding associated with VKAs is provided. [Douketis et al., 2012]

European Society of Cardiology (ESC) guidelines for the management of AF which were updated in 2016, include antithrombotic management of patients using VKA anticoagulant therapy. These guidelines include the use of NOACs for antithrombotic therapy (See Bleeding associated with NOACs; guidelines). Although bleeding risk is assessed, no guidance on reversal of bleeding with anticoagulants is provided. [Kirchhof et al., 2016]

American College of Chest Physicians (ACCP) guidelines for the evidence-based management of anticoagulant therapy include recommendations for the prevention and management of bleeding complications with VKAs. These include the use of four-factor (4F) PCCs (Prothrombin complex concentrates), rather than plasma for major bleeding associated with VKAs. [Holbrook et al., 2012]

European Society of Anaesthesiology guidelines for the management of severe perioperative bleeding recommends that patients on oral anticoagulant therapy should be given prothrombin complex concentrate (PCC) and vitamin K before any other coagulation management steps for treating severe perioperative bleeding. [Kozek-Langenecker et al., 2017]

European guidelines for the management of bleeding and coagulopathy following major trauma recommend the early use of PCC for the emergency reversal of VKAs. [Roussaint et al., 2016]

Guidelines for the reversal of antithrombotics in intracranial haemorrhage have recently been published by the Neurocritical Care Society and Society of Critical Care Medicine. [Frontera et al., 2016]

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