Oral Anticoagulants
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.
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.
Aspirin
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]
Heart Failure
Recent studies have shown that warfarin can be effective in treating patients with heart failure, in the absence of atrial fibrillation. A double-blind, double-placebo randomised controlled trial (RCT) of 2305 patients in sinus rhythm who had a reduced left ventricular ejection fraction received warfarin (target INR of 2.0–3.5) or aspirin (325 mg per day). The primary outcome was the time to the first event in a composite endpoint comprising ischaemic stroke, intracerebral haemorrhage, or death from any cause. There was no significant difference between warfarin treatment and aspirin with respective values for primary outcome being 7.47 events per 100 patient-years and 7.93 events per 100 patient-years (hazard ratio (HR)=0.93; 95% confidence interval (CI), 0.79–1.10; p=0.40). Warfarin was associated with a significant reduction in the rate of ischaemic stroke in comparison with aspirin throughout the follow-up period (0.72 vs. 1.36 events per 100 patient-years; HR=0.52; 95% CI, 0.33–0.82; P=0.005). However, the rate of major haemorrhage was significantly higher in the warfarin group: 1.78 events per 100 patient-years compared with 0.87 in the aspirin group (95% CI, 1.36–3.12; p<0.001). [Homma et al., 2012]
A meta-analysis of heart failure patients in sinus rhythm compared treatment with warfarin or aspirin. Four RCTs (including Homma et al., 2012) with a total of 3663 patients were analysed. There was no significant difference in mortality (odds ratio (OR)=1.01, 95% CI, 0.86–1.19) between warfarin and aspirin treatment groups; the risk of ischemic stroke was reduced with warfarin (OR=0.49, 95% CI, 0.32–0.74), but warfarin had an increased risk of major bleeding (OR=2.01, 95% CI, 1.40–2.88). [Rengo et al., 2013]
Valvular Heart Disease
Antithrombotic therapy with VKAs is used in patients with prosthetic heart valves. The American Heart Association (AHA) and American College of Cardiology (ACC) guidelines for the management of patients with valvular heart disease include guidelines for antithrombotic therapy for prosthetic valves; and dealing with excessive anticoagulation and serious bleeding. Anticoagulation with a VKA and INR monitoring is recommended for patients with a mechanical prosthetic valve. Reversal of VKA anticoagulation using prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) in patients with mechanical valves with uncontrollable bleeding is recommended. [Nishimura et al., 2014]
Joint European guidelines on the management of valvular heart disease include guidance on management after valve replacement. The majority of complications from valve replacement arise from thromboembolism and VKA-related bleeding. Target INRs are dependent on the thrombogenicity of the prosthesis and the presence or absence of patient-related risk factors (mitral or tricuspid valve replacement; previous thromboembolism; AT; mitral stenosis of any degree; left ventricular ejection fraction <35%). The INR target range in the absence of these risk factors is 2.5–3.5 and with ≥1 risk factor is 3.0–4.0. Intravenous PCC in combination with oral vitamin K is recommended for severe bleeding. [Vahanian et al., 2012]
Venous Thromboembolism
NICE guidance on the diagnosis, management and thrombophilia testing for venous thromboembolic (VTE) diseases indicates that VKA anticoagulation should be offered to patients with confirmed proximal deep venous thrombosis (DVT) or pulmonary embolism (PE) within 24 hours of diagnosis and VKA therapy continued for 3 months. VKA anticoagulation can be extended beyond 3 months to patients with an unprovoked PE or unprovoked proximal DVT taking into account the patient’s risk of VTE recurrence and risk of major bleeding. [National Institute for Health and Care Excellence (NICE) 2012]
American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy for VTE disease include early initiation of VKA anticoagulation for patients with acute DVT of the leg or acute PE, with a recommended therapeutic INR range of 2.0–3.0 (target INR of 2.5). [Kearon et al., 2012]
European Society of Cardiology (ESC) guidelines on the diagnosis and management of acute pulmonary embolism recommend the use of a VKA with a target INR of 2.0–3.0, or NOAC as an alternative, to overlap with acute-phase parenteral anticoagulation. The standard duration of oral anticoagulation should be at least 3 months. [Konstantinides et al., 2014]
A systematic review of the duration of treatment with VKAs in symptomatic VTE found that there was a consistent and strong reduction in the risk of recurrent VTE events during prolonged treatment with VKA (risk ratio (RR) = 0.20, 95% CI, 0.11–0.38). Data was analysed from 11 studies with a total of 3,716 participants with studies which compared VKA anticoagulation duration for 1 month vs 3 months; 3 months vs 6 months; or 3 months vs 12 months. Warfarin was the most common VKA used in these studies, with acenocoumarol, fluindione and dicoumarol being used in some studies as an alternative to warfarin. [Middeldorp et al., 2014]
Transient Ischaemic Attacks
Analysis of the combined results of two RCTs of AF patients with prior transient ischaemic attacks (TIAs), prior ischaemic stroke or both, showed the benefit of warfarin in the secondary prevention of ischaemic stroke. The relative risk reduction in ischaemic stroke by warfarin in comparison to aspirin was 56% for AF patients with prior TIA (p=0.09), and 63% for those with prior stroke (p<0.001). The absolute rate reduction in stroke by warfarin compared with aspirin, averaged 4% per year for TIA patients and 7% per year for patients with prior stroke. [Hart et al., 2004]
The large RE-LY trial [Connolly et al., 2009] compared the Factor IIa (thrombin) inhibitor dabigatran with warfarin in patients with AF. A predefined subgroup analysis of the RE-LY trial compared patients with a previous TIA or stroke treated with dabigatran (110 mg or 150 mg twice daily) or with warfarin (dose adjusted to INR 2.0–3.0). There were no significant differences in the incidence of stroke or systemic embolism between the warfarin group or either dabigatran treatment group. The frequency of stroke or systemic embolism was 2.78% per year with warfarin compared with 2.32% per year for 110 mg dabigatran (RR=0.84, 95% CI, 0.58–1.20) and 2.07% per year for 150 mg dabigatran (RR=0.75, 95% CI, 0.52–1.08). Compared with warfarin, the rate of major bleeding was significantly lower in patients on 110 mg dabigatran (RR=0.66, 95% CI 0.48–0.90) and similar in those on 150 mg dabigatran (RR 1.01; 95% CI, 0.77–1.34). [Diener et al., 2010]
Paracetamol
A recent systematic review and meta-analysis assessed the safety of paracetamol (acetaminophen) when used in patients taking VKAs. Analysis of 225 patients in 7 RCTs showed that paracetamol was associated with a mean increase in the INR of 0.62 (95% CI: 0.46–0.78) compared to placebo. None of the studies reported a major bleeding episode. Regression analysis showed that paracetamol was associated with a dose-dependent increase in INR: each daily gram was associated with a significant mean increase of the INR of 0.17 (95% CI, 0.004–0.33). [Caldeira et al., 2015]
Pharmacogenetics
The pharmacokinetics and pharmacodynamics of VKAs, including warfarin, are known to be influenced by genotypes of the CYP2C9 and VKORC1 genes. The enzyme encoded by the CYP2C9 gene (cytochrome P450 2C9) is a key enzyme involve in the metabolism of warfarin, whilst VKORC1 encodes the drug target of warfarin, vitamin K epoxide reductase. [Dean, 2012; Limdi, 2012] The combination of variant genotypes in these genes is a major cause of inter-individual differences in VKA drug dosage, with the impact most marked following initiation of VKA therapy. [Beinema et al., 2008] The range of expected therapeutic warfarin doses based on CYP2C9 and VKORC1 genotypes is shown in Table 1:
Table 1. Range of expected therapeutic warfarin doses based on CYP2C9 and VKORC1 genotypes. [Dean, 2012]
Of the VKAs warfarin, acenocoumarol and phenprocoumon the effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulation are least pronounced with phenprocoumon. [Beinema et al. 2008]
Aspirin
Aspirin antiplatelet monotherapy is no longer recommended solely for stroke prevention in patients with AF. [National Institute for Health and Care Excellence (NICE), 2014]
Comparison of aspirin with warfarin for the treatment of patients in sinus rhythm [Homma et al., 2012; Rengo et al., 2013] is reviewed in the previous section.
Comparison of aspirin with warfarin for the treatment of AF patients with prior TIAs, prior ischaemic stroke, or both [Hart et al., 2004] is reviewed in the previous section.
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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.
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Factor Xa Inhibitors
Factor IIa Inhibitors
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]
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)
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)
Apixaban
Apixaban was both non-inferior and superior to warfarin in 18,201 patients with AF in the ARISTOTLE trial (NCT00412984). Rates of the primary outcome, ischaemic or haemorrhagic stroke or systemic embolism were 1.27% per year with apixaban in comparison with 1.60% per year with warfarin (HR=0.79; 95% CI, 0.66–0.95; P<0.001 for non-inferiority; P=0.01 for superiority). Rates of major bleeding were 2.13% per year with apixaban and 3.09% per year with warfarin (HR=0.69; 95% CI, 0.60–0.80; P<0.001), and death from any cause were 3.52% and 3.94% respectively (HR=0.89; 95% CI, 0.80–0.99; P=0.047). [Granger et al., 2011] (Figure 3)
Figure 3. Kaplan–Meier curves for (A) the primary efficacy (stroke or systemic embolism) and (B) safety outcomes (major bleeding) (Granger et al., 2011).
The AVERROES trial {NCT00496769} of 5599 patients with AF who had an increased risk for stroke and were unsuitable for VKA therapy reported that apixaban reduced the occurrence of stroke or systemic embolism in comparison with aspirin. The rates of these primary outcome events, were 1.6% per year with apixaban and 3.7% per year with aspirin (HR=0.45; 95% CI, 0.32–0.62; p<0.001). Rates of major bleeding were not significantly different: 1.4% per year in the apixaban group and 1.2% per year in the aspirin group (HR=1.13; 95% CI, 0.74–1.75; p = 0.57). Risk of intracranial bleeding was similar with 11 cases with apixaban and 13 with aspirin reported. [Connolly et al., 2011]
Apixaban has received approval for stroke prevention in at-risk patients with non-valvular AF [Camm et al., 2012; Heidbuchel et al., 2013], with guidelines for the management of AF with NOACs being published. [Camm et al., 2012; Heidbuchel et al., 2013]
The AMPLIFY trial {NCT00643201} for the treatment of acute VTE compared a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) of oral apixaban with placebo in 5395 patients. Rates of the primary efficacy outcome, symptomatic recurrent VTE or death from VTE were 8.8% in the placebo group, 1.7% with 2.5 mg apixaban (difference of 7.2%; 95% CI, 5.0–9.3; p<0.001) and 1.7% with 5 mg apixaban (difference of 7.0%; 95% CI, 4.9–9.1; p<0.001). Rates of major bleeding were reduced in both apixaban groups: 0.5% with placebo, compared with 0.2% with 2.5 mg apixaban, and 0.1% with 5 mg apixaban. [Agnelli et al., 2013a] (Figure 4)
Figure 4. Kaplan–Meier curves for (A) the first event of recurrent VTE or VTE-related death and (B) for the first episode of major bleeding (Agnelli et al., 2013a).
Extended treatment of VTE with apixaban (10 mg twice daily for 7 days, then 5 mg twice daily for 6 months) was compared to conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 2486 patients in the AMPLIFY-EXT trial {NCT00633893}. Apixaban was non-inferior to conventional therapy (P<0.001). Rates of recurrent symptomatic VTE or death related to VTE were 2.3% with apixaban compared with 2.7% in the conventional therapy group (RR=0.84; 95% CI, 0.60–1.18; difference in risk -0.4%; 95% CI, -1.3 to 0.4). Both major bleeding and the composite outcome of major bleeding and clinically relevant non-major bleeding were significantly reduced in the apixaban treatment group. Rates of major bleeding were 0.6% with apixaban and 1.8% with conventional therapy (RR=0.31; 95% CI, 0.17 to 0.55; P<0.001); and for the composite outcome were 4.3% with apixaban and 9.7% with conventional therapy (RR=0.44; 95% CI, 0.36–0.55; p<0.001). [Agnelli et al., 2013b]
Apixaban is recommended by the UK’s National Institute for Health and Care Excellence (NICE) for treatment and prevention of DVT and PE in adults. [National Institute for Health and Care Excellence (NICE) 2015]
Edoxaban
Comparison of two doses of edoxaban (30 or 60 mg) with warfarin in 21,105 patients with moderate to high risk AF showed non-inferiority of both dosing regimens in the ENGAGE AF-TIMI 48 trial (NCT00781391). Rates for the primary efficacy endpoint of stroke or systemic embolism were 1.50% per year with warfarin, compared with 1.18% with 60 mg edoxaban (HR=0.79; 97.5% CI, 0.63–0.99; p<0.001 for non-inferiority) and 1.61% per year with 30 mg edoxaban (HR=1.07; 97.5% CI, 0.87–1.31; p=0.005 for non-inferiority). Major bleeding rates were significantly reduced with edoxaban. The annualised rate of major bleeding was 3.43% with warfarin compared with 2.75% with high dose edoxaban (HR=0.80; 95% CI, 0.71–0.91; p<0.001) and 1.61% with low dose edoxaban (HR=0.47; 95% CI, 0.41–0.55; p<0.001). [Giugliano et al., 2013] (Figure 5)
Figure 5. Kaplan–Meier curves for (A) the primary efficacy (stroke or systemic embolic event) and (B) principal safety (major bleeding) outcomes (Giugliano et al., 2013).
Edoxaban received EMA approval for the prevention of stroke and systemic embolism in patients with AF in 2015. [European Medicines Agency 2015]
Comparison of edoxaban with warfarin in 8240 patients for the treatment of symptomatic VTE in the Hokusai-VTE trial (NCT00986154) showed non-inferiority of edoxaban for efficacy and superiority for the principal safety outcome. Rates for the primary efficacy outcome, recurrent symptomatic VTE were 3.2% with edoxaban and 3.5% with warfarin (HR=0.89; 95% CI, 0.70–1.13; p<0.001 for non-inferiority). Rates for the principal safety outcome of major or clinically relevant non-major bleeding were 8.5% with edoxaban group and 10.3% with warfarin (hazard ratio, 0.81; 95% CI, 0.71–0.94; p=0.004 for superiority) [Hokusai-VTE Investigators 2013] (Figure 6)
Figure 6. Kaplan–Meier cumulative event rates for the primary efficacy outcome, recurrent VTE (Hokusai-VTE Investigators 2013).
Factor IIa Inhibitors
Dabigatran is a direct factor IIa (thrombin) inhibitor which reversibly and competitively binds to the active site on thrombin. In addition, it has indirect anti-platelet effects by reducing the pro-activating and pro-aggregatory effects of thrombin. [Alquwaizani et al., 2013]
The active form of dabigatran by formed by hydrolysis of the oral prodrug, dabigatran etexilate due to the action of non-specific plasma and liver esterases. In common with other NOACs (Xa inhibitors) dabigatran has a rapid onset and a predictable anticoagulant response which eliminates the need for monitoring. [Alquwaizani et al., 2013].
Dabigatran
Dabigatran is one of a new generation of oral anticoagulants for stroke prevention in patients with non-valvular atrial fibrillation recently recommended in guidelines from the National Institute for Health and Care Excellence for England and Wales. [NICE 2013]
Atrial fibrillation
The RE-LY trial (NCT00262600) compared dabigatran with warfarin in 18,113 patients with AF. Rates of the primary outcome, stroke or systemic embolism were 1.53% per year with dabigatran (110 mg) and 1.69% per year with warfarin (RR=0.91; 95% CI, 0.74–1.11; p<0.001 for non-inferiority). Superiority to warfarin was demonstrated in patients receiving 150 mg of dabigatran who had a primary outcome rate of 1.11% per year (RR=0.66; 95% CI, 0.53–0.82; p<0.001 for superiority). Rates of major bleeding were 3.36% per year with warfarin, compared with 2.71% per year with 110 mg dabigatran (p=0.003), and 3.11% with 150 mg dabigatran (p=0.31). Rates of haemorrhagic stroke were 0.38% per year in the warfarin group, compared with 0.12% per year with 110 mg dabigatran (p<0.001) and 0.10% per year with 150 mg dabigatran (p<0.001). However, the higher dose of dabigatran was associated with a significantly increased risk of GI bleeding compared to warfarin (RR=1.50; 95% CI, 1.19–1.89; p<0.001). [Connolly et al., 2009] (Figure 7)
Figure 7. Cumulative hazard rates for the primary outcome of stroke or systemic embolism, for 110 mg dabigatran, 150 mg dabigatran, and warfarin groups (Connolly et al., 2009).
A subgroup analysis of the RE-LY trial compared patients with a previous transient ischaemic attack or stroke in the three treatment groups. Stroke or systemic embolism occurred at a rate of 2.78% per year on warfarin, 2.32% per year on 110 mg dabigatran (RR= 0.84, 95% CI, 0.58–1.20) and 2.07% per year on 150 mg dabigatran (RR= 0.75, 95% CI, 0.52–1.08). In comparison to warfarin, rates of major bleeding were significantly lower in patients on 110 mg dabigatran (RR=0.66, 95% CI, 0.48–0.90) and similar in patients on 150 mg dabigatran (RR=1.01; 95% CI, 0.77–1.34). [Diener et al., 2010]
Dabigatran has received approval for stroke prevention in at-risk patients with non-valvular AF, and included in guidelines for the management of AF with NOACs. [Camm et al., 2012; Heidbuchel et al., 2013]
Acute VTE
Comparison of dabigatran with warfarin in 2539 patients with acute VTE in the RE-COVER trial (NCT00291330) showed non-inferiority of dabigatran for recurrent VTE, the primary efficacy outcome. Rates of recurrent VTE were 2.4% with dabigatran and 2.1% with warfarin (difference in risk = 0.4%; 95% CI, −0.8 to 1.5; P<0.001 for non-inferiority). Rates of major bleeding episodes were similar: 1.6% with dabigatran and 1.9% with warfarin (HR=0.82; 95% CI, 0.45–1.48). Lower rates of major or clinically relevant non-major bleeding events were observed with dabigatran (5.6%) than with warfarin (8.8%; HR=0.63; 95% CI, 0.47–0.84), and lower rates of any bleeding episode were observed with dabigatran (16.1%) compared to warfarin (21.9%; HR=0.71; 95% CI, 0.59–0.85). [Schulman et al., 2009]
Extended use of dabigatran compared to warfarin or placebo in VTE was investigated in the RE-MEDY (NCT00558259) and RE-SONATE (NCT00558259) trials.
Recurrent VTE
Dabigatran was non-inferior to warfarin for recurrent VTE following 36 months of therapy. Recurrent VTE was observed in 1.8% of patients treated with dabigatran and 1.3% with warfarin (HR=1.44; 95% CI, 0.78–2.64; P=0.01 for non-inferiority). Major bleeding was non-significantly lower with dabigatran: 0.9% vs. 1.8% with warfarin (HR=0.52; 95% CI, 0.27–1.02; P=0.06); major or clinically relevant bleeding was less frequent with dabigatran (5.6%) than warfarin (10.2%; HR= 0.54; 95% CI, 0.41–0.71; P<0.001). Compared to placebo, recurrent VTE was observed significantly less with dabigatran for the 18 month duration of the trial: 0.4% of patients treated with dabigatran and 5.6% with placebo (HR=0.08; 95% CI, 0.02–0.25; P<0.001). Major bleeding occurred in 0.3% of patients in the dabigatran group and 0.0% in the placebo group; and major or clinically relevant bleeding occurred more commonly with dabigatran than placebo (5.3% vs. 1.8%; HR=2.92; 95% CI, 1.52–5.60). [Schulman et al., 2013] (Figure 8)
Figure 8. Cumulative risk of recurrent VTE or related death (or unexplained death in the placebo-control study). (A) comparison of dabigatran with warfarin, (B) comparison of dabigatran with placebo (Schulman et al., 2013).
Dabigatran is recommended by the UK’s National Institute for Health and Care Excellence (NICE) for the treatment and prevention of recurrent DVT and PE in adults. [National Institute for Health and Care Excellence (NICE) 2014]
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Oral Anticoagulants References
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al., Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013a;369:799-808.
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