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Oral Anticoagulation Reversal

Oral Anticoagulants

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

Details of the effects that VKAs can have on patients with atrial fibrillation, heart failure, valvular heart disease, venous thromboembolism and transient ischaemic attacks; the use of paracetamol and an adjuvant therapy; how the CYP2C9 and VKORC1 genes affect blood coagulation; and details of non-vitamin K oral anticoagulants, such as factor Xa inhibitors, rivaroxaban, apixaban, edoxaban, and the factor IIa inhibitor dabigatran are all included in this section.

Oral Vitamin K Antagonists

Oral vitamin K antagonists (VKAs) and non-vitamin K oral anticoagulants (NOACs) are prescribed to prevent or treat excessive blood coagulation, however, they can also be used to treat conditions such as valvular heart disease, heart failure and atrial fibrillation. 

VKAs include warfarin, acenocoumarol and phenprocoumon; NOACs include the Factor Xa inhibitors rivaroxaban, apixaban and edoxaban, and the Factor IIa (thrombin) inhibitor dabigatran. 

Warfarin

Warfarin is commonly used as an anticoagulant in patients with ischaemic stroke, prosthetic heart valves, atrial fibrillation (AF), ischaemic heart disease, and venous thromboembolism (VTE). [Crowther & Warkentin 2008]

Guidelines for the optimal use of oral VKA anticoagulation for different indications have been published {link to Disease Management VKA Guidelines}. The target international normalised ratio (INR) is generally in the range of 2.0–3.0 (see diagnostic tests section for more information) in order to achieve adequate antithrombotic effects while minimising haemorrhagic risk.

In addition to warfarin, other VKAs are available for clinical use, including acenocoumarol, phenprocoumon and anisindione. Clinical studies using VKAs are generally dominated by the use of warfarin. On this basis, US guidelines for the perioperative management of antithrombotic therapy with VKAs refer solely to warfarin. [Douketis et al., 2012]

Atrial Fibrillation

AF is an important risk factor for stroke, and anticoagulation therapy using VKAs such as warfarin is a well established preventive therapy for AF patients. Clinical trials have demonstrated that in patients with AF, warfarin treatment reduces the risk of ischaemic stroke by 68% and ischaemic and haemorrhagic stroke by 62%. The benefit of long-term anticoagulation therapy is countered by the increased risk of bleeding with warfarin. [Rockson and Albers 2004] European guidelines for anticoagulation in AF for both VKA and NOACs have been published. 

The American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for AF recommend oral anticoagulation as the optimal choice of antithrombotic therapy for patients with AF at a high risk of stroke. Dabigatran (150 mg twice daily) rather than adjusted-dose VKA therapy, is the preferred choice of oral anticoagulation. [You et al., 2012]

The UK’s National Institute for Health and Care Excellence (NICE) guidelines for management of AF recommend the use of apixaban, dabigatran, rivaroxaban or a VKA for anticoagulation. Aspirin monotherapy solely for stroke prevention in patients with AF is not recommended. [National Institute for Health and Care Excellence (NICE), 2014]

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Non-Vitamin K Oral Anticoagulants

A focused update of the 2010 ESC guidelines for the management of AF was issued in 2012. [Camm et al., 2012] This was partly in response to positive phase III clinical trial data with the NOACs dabigatran, rivaroxaban and apixaban, [Patel et al., 2011; Granger et al., 2011; Connolly et al., 2009] and their subsequent approval for stroke prevention in at-risk patients with non-valvular AF. Comparable data for edoxaban was not available at the time of publication.

Factor Xa Inhibitors

The orally administered direct factor Xa inhibitors rivaroxaban and edoxaban inhibit factor X activity by binding to the active site of the protease [Harter et al., 2015; European Medicines Agency 2015].

In common with other NOACs (IIa inhibitors) factor Xa inhibitors have a rapid onset and a predictable anticoagulant response which eliminates the need for monitoring. [Alquwaizani et al., 2013].

Rivaroxaban

In the randomised ROCKET AF trial {NCT00403767} of 14,264 patients with non-valvular atrial fibrillation (AF), who have an increased risk for stroke, rivaroxaban (20 mg daily) was non-inferior to warfarin for the primary endpoint of the study, the prevention of stroke or systemic embolism {Figure 1 below}. Rivaroxaban significantly reduced fatal bleeding and intracranial haemorrhage in comparison to warfarin. Respective rates of fatal bleeding with rivaroxaban and warfarin were 0.2% and 0.5% (p=0.003); and of intracranial haemorrhage were 0.5% and 0.7% (P=0.02). No significant differences in clinically relevant bleeding were observed: rates were 14.9% per year in the rivaroxaban group and 14.5% per year in the warfarin group (HR=1.03; 95% CI, 0.96–1.11; p=0.44). [Patel et al., 2011]

OACR_OA_Fig1__20A98B8F-FFF1-42B6-82890119361C3BEC.png

Figure 1. Cumulative rates of the primary endpoint (stroke or systemic embolism) in the ROCKET-AF trial in the intention-to-treat population (Patel et al., 2011).

A recent review of data from the ROCKET AF trial, which used a point-of-care device subsequently withdrawn due to low INR readings, concluded use of the device did not have any significant clinical effect on the primary efficacy and safety outcomes of the trial. [Patel et al., 2016]

Evaluation of gastrointestinal (GI) bleeding in patients treated with rivaroxaban or warfarin in the ROCKET AF trial showed that there was a significantly higher rate of clinical GI bleeding in patients treated with rivaroxaban compared to warfarin. Respective rates were 3.61 and 2.60 events/100 patient-years (HR=1.42; 95% CI, 1.22–1.66). However, severe GI bleeding rates were similar between both treatment groups and fatal GI bleeding events were rare, occurring at respective rates of 0.01 and 0.04 events per 100 patient-years in the rivaroxaban and warfarin groups, respectively. [Sherwood et al., 2015]

Rivaroxaban has received approval for stroke prevention in at-risk patients with non-valvular AF, and current guidelines reflect the efficacy of rivaroxaban in treating patients with non-valvular AF. [Camm et al., 2012; Heidbuchel et al., 2013]

Comparison of oral rivaroxaban against subcutaneous enoxaparin combined with a VKA for symptomatic VTE in 3449 patients with acute DVT showed non-inferiority of the Factor Xa inhibitor for the primary outcome, recurrent VTE. Respective VTE rates for rivaroxaban and enoxaparin/VKA were 2.1% and 3.0% (HR=0.68; 95% CI, 0.44–1.04; p<0.001). Major bleeding or clinically relevant non-major bleeding was 8.1% in each treatment group. A parallel RCT showed that rivaroxaban was superior to placebo with respective recurrent VTE rates of 1.3% and 7.1% (HR=0.18; 95% CI, 0.09-0.39; p<0.001). [EINSTEIN Investigators, 2010] (NCT00440193 and NCT00439725) (Figure 2)

OACR_OA_Fig2__8930BCBE-DC23-4F99-B43C3A329B1F0AB1.png

Figure 2. Kaplan–Meier cumulative event rates for the primary efficacy outcome, recurrent VTE in the two trials. (A) rivaroxaban compared with enoxaparin/VKA; (B) rivaroxaban compared with placebo (EINSTEIN Investigators, 2010).

Rivaroxaban was also non-inferior to enoxaparin/VKA in 4832 patients with acute symptomatic PE, with or without DVT. The rate of the primary efficacy outcome, symptomatic recurrent VTE, was 2.1% in the rivaroxaban group and 1.8% in the enoxaparin/VKA group (HR=1.12; 95% CI, 0.7–1.68). There was no significant difference in rates of major or clinically relevant non-major bleeding: these were 10.3% and 11.4 % respectively. However, there was a significantly reduced rate of major bleeding with rivaroxaban compared to standard therapy (1.1% vs 2.2%; HR=0.49; 95% CI, 0.31–0.79; p=0.003). [EINSTEIN–PE Investigators, 2012] (NCT00439777)

The American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy of VTE recommend anticoagulation with rivaroxaban as one option for acute DVT or PE; the other being initial anticoagulation with parenteral (heparin) anticoagulant therapy. [Kearon et al., 2012]

In a double-blind, placebo-controlled trial (ATLAS ACS 2–TIMI 51) of 7817 patients with a recent acute coronary syndrome, rivaroxaban significantly improved the primary efficacy endpoint, a composite of death from cardiovascular causes, myocardial infarction, or stroke. Rates were 8.9% with rivaroxaban and 10.7% with placebo (HR=0.84; 95% CI, 0.74–0.96; p=0.008). Rivaroxaban, compared with placebo, significantly increased the rates of major bleeding (2.1% vs. 0.6%, p<0.001) and intracranial haemorrhage (0.6% vs. 0.2%, p=0.009), but not fatal bleeding (0.3% vs. 0.2%, p=0.66). [Mega et al., 2012] (NCT00809965)

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