REVIEW
Heart, Lung and Circulation (2014) 23, 2–9 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.09.007
The Current and Future Role of the Novel Oral Anticoagulants—Indications Beyond Atrial Fibrillation Adam Lee, MBBS (Clin Epi)a,b, Rohan Rajaratnam, FRACPa,b,c,d* a
Liverpool Hospital, Sydney, Australia Campbelltown Hospital, Sydney, Australia The University of Western Sydney, Sydney, Australia d The University of New South Wales, Sydney, Australia b c
Received 12 September 2013; accepted 26 September 2013; online published-ahead-of-print 9 October 2013
Abstract The direct thrombin inhibitors and Factor-Xa inhibitors are novel oral anticoagulants which are gaining rapid acceptance not only as alternatives to warfarin, but also as recommended first line agents for use as stroke prophylaxis in patients with non-valvular atrial fibrillation. There are, however, other patient settings in which anticoagulation is either indicated or has a potential role. Warfarin is still the predominant anticoagulant used for the treatment and prevention of venous thromboembolic events including deep vein thrombosis and pulmonary embolism as well as in patients with mechanical prosthetic heart valves. In this article, we review the current evidence for the use of dabigatran, rivaroxaban, apixaban and edoxaban in these settings. A summary of suggested regimens utilising these agents is provided. Importantly, in addition, attention is also drawn to clinical scenarios in which use of such agents is considered inappropriate. Keywords
Anticoagulation Dabigatran Rivaroxaban Apixaban Edoxaban Warfarin
Introduction Recently, there has been much attention paid to the role of the novel oral anticoagulants, particularly in the setting of stroke prophylaxis for patients with non-valvular atrial fibrillation (AF) [1,2]. Dabigatran (a direct thrombin inhibitor), rivaroxaban and apixaban (both Factor Xa inhibitors) are all approved by the Therapeutic Goods Association (TGA) and have listings on the Pharmaceutical Benefits Scheme (PBS) for the above indication in Australia [3–8]. All three agents have regulatory approval in the USA and Europe for stroke prophylaxis in patients with non-valvular AF [9–14]. A fourth agent, edoxaban (another Factor Xa inhibitor), is currently undergoing a clinical trial in patients with AF [15]. These new anticoagulants overcome many of the longstanding limitations of warfarin including the need for frequent blood test monitoring, the marked dose variability
between individual patients, the extensive interactions with food and other medications as well as the slow onset and offset of therapeutic effect often requiring heparin or low molecular weight heparin (LMWH) cover during the initiation phase of warfarin. However, anticoagulation is also indicated in settings other than atrial fibrillation [16]; these include the prevention and treatment of venous thromboembolism (including deep vein thrombosis [DVT] and pulmonary embolism [PE]), the prevention of systemic embolism and valve thrombosis in patients with metallic prosthetic cardiac valves, and the treatment of intracardiac thrombus. There is also evidence that warfarin is effective in the treatment of ischaemic heart disease (IHD) [17,18], although it is less often used nowadays in the era of dual antiplatelet therapy. The data for the novel oral anticoagulants in these settings are less comprehensive compared to that of the atrial fibrillation population. We will review the current literature
* Corresponding author at: Department of Cardiology, Liverpool Hospital, Sydney, NSW, Australia. Tel.: +61 2 9828 3000., Email: [email protected] Crown Copyright © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.
3
Novel Anticoagulants: VTE, ACS, Valves
examining the role of these novel agents in the settings of venous thromboembolism, acute coronary syndromes and metallic prosthetic cardiac valves.
Venous Thromboembolism (VTE) Dabigatran The role of dabigatran in the treatment of venous thromboembolism was tested in the RE-COVER and RE-COVER II studies. The RE-COVER study [19] was a randomised, double-blind, non-inferiority trial testing dabigatran against warfarin in 2539 patients presenting with acute VTE; 69% with a DVT, 21% with a PE and 10% with both. Dabigatran was prescribed at a dose of 150 mg twice daily, the same as the higher dose used in the RE-LY trial in patients with AF. Patients with severe renal impairment (CrCl < 30 mL/min), haemodynamically unstable PEs and those with a concomitant need for long-term antiplatelet therapy (other than aspirin 100 mg daily) were excluded. The intended treatment duration was six months. Dabigatran was found to be non-inferior to warfarin with recurrent VTE or related death occurring in 2.4% of the dabigatran group compared to 2.1% in the warfarin group (HR 1.10, p < 0.001 for non-inferiority). There was no statistical difference in major bleeding between the two therapies, occurring in 1.6% of patients on dabigatran compared to 1.9% of patients on warfarin (HR 0.82, p = 0.38). However, there was 29% less total bleeding in patients on dabigatran compared to those on warfarin (16.9% vs. 21.9%, HR 0.71, p < 0.001). The RE-COVER II study tested the same hypothesis as RECOVER in an additional 2568 patients; its study design was similar to that of RE-COVER. Again, dabigatran was noninferior to warfarin in regards to recurrent thromboembolism (2.4% vs. 2.2%, HR 1.09, p < 0.0001 for non-inferiority) with no statistically significant differences in the rates of major bleeding between the two groups. RECOVER II has been presented in abstract form but is yet to be published [20]. It should be noted that the RE-COVER trials did not test dabigatran monotherapy versus warfarin. Both arms received a period of parenteral anticoagulation with either intravenous heparin or subcutaneous LMWH during treatment initiation until the INRs (or sham INRs in the case of patients allocated to dabigatran) were therapeutic. Patients on dabigatran received heparin or LMWH for minimum and median periods of six and nine days respectively. There has not been a published trial of dabigatran monotherapy against warfarin to date. The role of dabigatran as extended therapy for prevention of recurrent VTE events in patients who have completed a standard course of anticoagulation following an index event was tested in the RE-MEDY and RE-SONATE studies. Both studies utilised the same 150 mg twice daily dose of dabigatran as the RE-COVER trials. The RE-MEDY study [21] was a randomised, double-blind, non-inferiority trial testing extended therapy with dabigatran versus warfarin in 2866 patients with VTE whom had already received three to
12 months of anticoagulation with warfarin or dabigatran as part of the RE-COVER trials. The duration of extended therapy varied from six to 36 months. Dabigatran was found to be statistically non-inferior to warfarin in regards to the primary endpoint of recurrent or fatal VTE which occurred in 1.8% of patients treated with dabigatran compared to 1.3% of those on warfarin (HR 1.44, p = 0.01 for non-inferiority). However, 95% confidence interval (0.78–2.64) was wide with an upper limit nearing the pre-specified boundary of noninferiority (2.85); it may be questionable as to whether an upper limit of this magnitude is clinically acceptable as ‘noninferior’. There was numerically less major bleeding in patients treated with dabigatran (0.9%) compared to those on warfarin (1.8%); however, this result did not quite reach statistical significance (p = 0.06). There was, however, 29% less overall bleeding in patients on dabigatran (19.4% vs. 26.2%, HR 0.71, p < 0.001), a result consistent with the RECOVER trials. The RE-SONATE study [21] was a double blind, randomised, multi-centre trial in which extended treatment with dabigatran was compared to placebo for six months in 1353 patients whom had already completed six to 18 months of anticoagulation therapy with warfarin or dabigatran. A further six months of dabigatran resulted in 92% less recurrent or fatal VTE events compared to placebo (0.4% vs. 5.6%, HR 0.08, p < 0.001) at the cost of increased bleeding which occurred in 10.5% of patients on dabigatran compared to 5.9% of those on placebo (HR 1.82, p = 0.003). Major bleeding occurred in two patients on dabigatran compared to none on placebo.
Rivaroxaban The role of rivaroxaban in the acute treatment of VTE was tested in the EINSTEIN Acute DVT and EINSTEIN-PE studies. These trials studied patients with DVT and PE separately unlike the trials of the other agents which considered them as a single group. Extended therapy with rivaroxaban beyond the standard duration of anticoagulation was tested in EINSTEIN-Extension. The Einstein Acute DVT study [22] was an open label, randomised, non-inferiority trial testing rivaroxaban against warfarin in 3449 patients presenting with a proximal DVT but not pulmonary embolism. The dosing regimen of rivaroxaban differed from that used for AF patients in ROCKETAF; a three week ‘loading regimen’ of 15 mg twice daily was prescribed prior to ongoing therapy with 20 mg daily which is the same maintenance dose as that used in ROCKET-AF. The treatment duration varied from three to 12 months with most patients (63%) being treated for six months. Patients assigned to warfarin required LMWH cover for at least five days or until the INR was therapeutic for five days. Patients assigned to rivaroxaban did not require a period of parenteral anticoagulation although up to 48 h was allowed for pre-randomisation. Recurrent VTE occurred in 2.1% of patients on rivaroxaban compared to 3.0% of those on warfarin; this met criteria for non-inferiority, but not superiority (HR 0.68, p < 0.001 for non-inferiority, p = 0.08 for
4
superiority). Clinically relevant bleeding occurred in 8.1% of both groups (HR 0.97, p = 0.77). A pre-specified analysis of net clinical benefit accounting for both recurrent VTE and major bleeding favoured rivaroxaban over warfarin (HR 0.67, p = 0.03). The EINSTEIN-PE study [23] was an open label, randomised, non-inferiority trial testing rivaroxaban against warfarin in 4832 patients presenting with an acute PE with or without DVT. High risk patients requiring fibrinolytics or an inferior vena cava filter were excluded. The rivaroxaban treatment regimen was the same as that in the Acute DVT study with treatment duration ranging from three to 12 months; most patients (58%) were treated for six months. Rivaroxaban was found to be non-inferior to warfarin in regards to symptomatic or fatal recurrent VTE (2.1% vs. 1.8% respectively, HR 1.12, p = 0.003 for non-inferiority). There was no statistical difference in rates of clinically relevant bleeding which occurred in 10.3% of those on rivaroxaban compared to 11.4% of those on warfarin (HR 0.90, p = 0.23). Whilst not the primary safety outcome, there appeared to be less major bleeding in those treated with rivaroxaban (1.1% vs. 2.2% respectively, HR 0.49, p = 0.003). The pre-specified net clinical benefit of recurrent VTE and major bleeding was not statistically different between those treated with rivaroxaban compared to warfarin (HR 0.85, p = 0.28). The EINSTEIN-Extension study [22,24] was a randomised, double-blind, multi-centre study in which extended therapy with rivaroxaban was compared to placebo in 1197 patients whom had already completed six to 12 months of anticoagulation with either warfarin or rivaroxaban as part of the Acute DVT study. The treatment regime tested was rivaroxaban 20 mg daily for an additional six to 12 months. There was 82% less recurrent VTE in patients on rivaroxaban compared to placebo (1.3% vs. 7.1% respectively, HR 0.18, p < 0.001). Major bleeding was rare in both groups occurring in 0.7% of patients on rivaroxaban and none were on placebo. There was, however, over five times more clinically relevant bleeding in patients on rivaroxaban (6.0%) compared to placebo (1.2%) (HR 5.19, p < 0.001). Nonetheless, a pre-specified analysis of net-clinical benefit including recurrent VTE and major bleeding demonstrated superiority of rivaroxaban over placebo (HR 0.28, p < 0.001).
Apixaban Apixaban has been tested against warfarin therapy in the setting of acute VTE in the AMPLIFY trial as well as in the setting of extended therapy following a standard course of anticoagulation in the AMPLIFY-EXT trial. The AMPLIFY study [25] was a double blinded, randomised non-inferiority trial which tested apixaban against warfarin therapy in 5395 patients who presented with an acute VTE event, either a proximal DVT, a PE or both. Of this cohort, 66% presented with a DVT, 25% with a PE and 9% with both conditions. Patients were allowed to have no more than two doses of LMWH or warfarin therapy or 36 h of IV heparin prior to randomisation. Other exclusion factors
A. Lee, R. Rajaratnam
included a contraindication to enoxaparin or warfarin, moderate renal impairment, anaemia or thrombocytopaenia. Patients in the study group were assigned an apixaban ‘loading’ regime of 10 mg twice daily for the first seven days, followed by a maintenance dose of 5 mg twice daily for six months. The control group was assigned warfarin under enoxaparin cover with the latter being prescribed for at least five days or until the INR was >2.0. Matching placebo therapies were assigned to both groups; hence patients assigned to apixaban did receive subcutaneous injections for at least five days, but these were placebo; hence unlike the RE-COVER trial with dabigatran, this was a test of apixaban monotherapy. Apixaban was found to be non-inferior to warfarin in regards to the primary outcome of first recurrent VTE or VTE-related death (2.3% vs. 2.7% respectively, HR 0.84, p < 0.001 for non-inferiority). The primary safety outcome of major bleeding occurred less in those assigned to apixaban compared to those on warfarin (0.6% vs. 1.8% respectively, HR 0.31, p < 0.001 for superiority). The AMPLIFY-EXT study [26] was a randomised, doubleblind, superiority trial testing extended therapy with two doses of apixaban compared to placebo in 2486 patients whom had already completed six to 12 months of standard anticoagulation therapy with either warfarin or apixaban as part of the ongoing AMPLIFY trial. Patients were randomised equally to one of the two apixaban regimens (2.5 mg twice daily or 5 mg twice daily) or placebo for a total duration of 12 months. Recurrent VTE or all-cause mortality occurred less often in both apixaban groups (3.8% and 4.2% respectively) compared to those on placebo (11.6%). The respective hazard ratios were 0.33 and 0.36 (p < 0.001 for both groups). Major bleeding was rare in all groups (0.2%, 0.1% and 0.5% respectively). Major or clinically relevant non-major bleeding occurred in 3.2% of patients on lower dose apixaban, 4.3% of patients on higher dose apixaban and 2.7% of patients on placebo; the numerically higher rates in the apixaban groups were not statistically significant compared to placebo.
Edoxaban The Hokusai-VTE study was a randomised, double-blind, non-inferiority study in which edoxaban was compared to warfarin in 8240 patients who presented with acute venous thromboembolism [27]. Forty percent of patients in this study had suffered a PE, whilst the remainder suffered only from DVTs affecting the popliteal, femoral or iliac veins. Patients were excluded if they had more than 48 h of preceding heparin therapy or more than one dose of preceding warfarin therapy. Other exclusion criteria included contraindications to warfarin therapy, cancer requiring long-term LMWH therapy, severe renal impairment, requirement for dual antiplatelet therapy or aspirin at a dose >100 mg. Similar to the dabigatran regimen in the RE-COVER trials, all patients received a run-in period of at least five days of enoxaparin or unfractionated heparin. However, unlike in RE-COVER, edoxaban was commenced only after discontinuation of the parenteral anticoagulant. Warfarin was commenced concurrently with heparin/enoxaparin therapy. Edoxaban/
5
Novel Anticoagulants: VTE, ACS, Valves
warfarin placebos were utilised to preserve blinding. Edoxaban was prescribed at a dose of 60 mg daily to most patients but those with moderate renal impairment (creatinine clearance 30–50 mL/h) or with low body weight (
Heart, Lung and Circulation (2014) 23, 2–9 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.09.007
The Current and Future Role of the Novel Oral Anticoagulants—Indications Beyond Atrial Fibrillation Adam Lee, MBBS (Clin Epi)a,b, Rohan Rajaratnam, FRACPa,b,c,d* a
Liverpool Hospital, Sydney, Australia Campbelltown Hospital, Sydney, Australia The University of Western Sydney, Sydney, Australia d The University of New South Wales, Sydney, Australia b c
Received 12 September 2013; accepted 26 September 2013; online published-ahead-of-print 9 October 2013
Abstract The direct thrombin inhibitors and Factor-Xa inhibitors are novel oral anticoagulants which are gaining rapid acceptance not only as alternatives to warfarin, but also as recommended first line agents for use as stroke prophylaxis in patients with non-valvular atrial fibrillation. There are, however, other patient settings in which anticoagulation is either indicated or has a potential role. Warfarin is still the predominant anticoagulant used for the treatment and prevention of venous thromboembolic events including deep vein thrombosis and pulmonary embolism as well as in patients with mechanical prosthetic heart valves. In this article, we review the current evidence for the use of dabigatran, rivaroxaban, apixaban and edoxaban in these settings. A summary of suggested regimens utilising these agents is provided. Importantly, in addition, attention is also drawn to clinical scenarios in which use of such agents is considered inappropriate. Keywords
Anticoagulation Dabigatran Rivaroxaban Apixaban Edoxaban Warfarin
Introduction Recently, there has been much attention paid to the role of the novel oral anticoagulants, particularly in the setting of stroke prophylaxis for patients with non-valvular atrial fibrillation (AF) [1,2]. Dabigatran (a direct thrombin inhibitor), rivaroxaban and apixaban (both Factor Xa inhibitors) are all approved by the Therapeutic Goods Association (TGA) and have listings on the Pharmaceutical Benefits Scheme (PBS) for the above indication in Australia [3–8]. All three agents have regulatory approval in the USA and Europe for stroke prophylaxis in patients with non-valvular AF [9–14]. A fourth agent, edoxaban (another Factor Xa inhibitor), is currently undergoing a clinical trial in patients with AF [15]. These new anticoagulants overcome many of the longstanding limitations of warfarin including the need for frequent blood test monitoring, the marked dose variability
between individual patients, the extensive interactions with food and other medications as well as the slow onset and offset of therapeutic effect often requiring heparin or low molecular weight heparin (LMWH) cover during the initiation phase of warfarin. However, anticoagulation is also indicated in settings other than atrial fibrillation [16]; these include the prevention and treatment of venous thromboembolism (including deep vein thrombosis [DVT] and pulmonary embolism [PE]), the prevention of systemic embolism and valve thrombosis in patients with metallic prosthetic cardiac valves, and the treatment of intracardiac thrombus. There is also evidence that warfarin is effective in the treatment of ischaemic heart disease (IHD) [17,18], although it is less often used nowadays in the era of dual antiplatelet therapy. The data for the novel oral anticoagulants in these settings are less comprehensive compared to that of the atrial fibrillation population. We will review the current literature
* Corresponding author at: Department of Cardiology, Liverpool Hospital, Sydney, NSW, Australia. Tel.: +61 2 9828 3000., Email: [email protected] Crown Copyright © 2013 Published by Elsevier Inc on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.
3
Novel Anticoagulants: VTE, ACS, Valves
examining the role of these novel agents in the settings of venous thromboembolism, acute coronary syndromes and metallic prosthetic cardiac valves.
Venous Thromboembolism (VTE) Dabigatran The role of dabigatran in the treatment of venous thromboembolism was tested in the RE-COVER and RE-COVER II studies. The RE-COVER study [19] was a randomised, double-blind, non-inferiority trial testing dabigatran against warfarin in 2539 patients presenting with acute VTE; 69% with a DVT, 21% with a PE and 10% with both. Dabigatran was prescribed at a dose of 150 mg twice daily, the same as the higher dose used in the RE-LY trial in patients with AF. Patients with severe renal impairment (CrCl < 30 mL/min), haemodynamically unstable PEs and those with a concomitant need for long-term antiplatelet therapy (other than aspirin 100 mg daily) were excluded. The intended treatment duration was six months. Dabigatran was found to be non-inferior to warfarin with recurrent VTE or related death occurring in 2.4% of the dabigatran group compared to 2.1% in the warfarin group (HR 1.10, p < 0.001 for non-inferiority). There was no statistical difference in major bleeding between the two therapies, occurring in 1.6% of patients on dabigatran compared to 1.9% of patients on warfarin (HR 0.82, p = 0.38). However, there was 29% less total bleeding in patients on dabigatran compared to those on warfarin (16.9% vs. 21.9%, HR 0.71, p < 0.001). The RE-COVER II study tested the same hypothesis as RECOVER in an additional 2568 patients; its study design was similar to that of RE-COVER. Again, dabigatran was noninferior to warfarin in regards to recurrent thromboembolism (2.4% vs. 2.2%, HR 1.09, p < 0.0001 for non-inferiority) with no statistically significant differences in the rates of major bleeding between the two groups. RECOVER II has been presented in abstract form but is yet to be published [20]. It should be noted that the RE-COVER trials did not test dabigatran monotherapy versus warfarin. Both arms received a period of parenteral anticoagulation with either intravenous heparin or subcutaneous LMWH during treatment initiation until the INRs (or sham INRs in the case of patients allocated to dabigatran) were therapeutic. Patients on dabigatran received heparin or LMWH for minimum and median periods of six and nine days respectively. There has not been a published trial of dabigatran monotherapy against warfarin to date. The role of dabigatran as extended therapy for prevention of recurrent VTE events in patients who have completed a standard course of anticoagulation following an index event was tested in the RE-MEDY and RE-SONATE studies. Both studies utilised the same 150 mg twice daily dose of dabigatran as the RE-COVER trials. The RE-MEDY study [21] was a randomised, double-blind, non-inferiority trial testing extended therapy with dabigatran versus warfarin in 2866 patients with VTE whom had already received three to
12 months of anticoagulation with warfarin or dabigatran as part of the RE-COVER trials. The duration of extended therapy varied from six to 36 months. Dabigatran was found to be statistically non-inferior to warfarin in regards to the primary endpoint of recurrent or fatal VTE which occurred in 1.8% of patients treated with dabigatran compared to 1.3% of those on warfarin (HR 1.44, p = 0.01 for non-inferiority). However, 95% confidence interval (0.78–2.64) was wide with an upper limit nearing the pre-specified boundary of noninferiority (2.85); it may be questionable as to whether an upper limit of this magnitude is clinically acceptable as ‘noninferior’. There was numerically less major bleeding in patients treated with dabigatran (0.9%) compared to those on warfarin (1.8%); however, this result did not quite reach statistical significance (p = 0.06). There was, however, 29% less overall bleeding in patients on dabigatran (19.4% vs. 26.2%, HR 0.71, p < 0.001), a result consistent with the RECOVER trials. The RE-SONATE study [21] was a double blind, randomised, multi-centre trial in which extended treatment with dabigatran was compared to placebo for six months in 1353 patients whom had already completed six to 18 months of anticoagulation therapy with warfarin or dabigatran. A further six months of dabigatran resulted in 92% less recurrent or fatal VTE events compared to placebo (0.4% vs. 5.6%, HR 0.08, p < 0.001) at the cost of increased bleeding which occurred in 10.5% of patients on dabigatran compared to 5.9% of those on placebo (HR 1.82, p = 0.003). Major bleeding occurred in two patients on dabigatran compared to none on placebo.
Rivaroxaban The role of rivaroxaban in the acute treatment of VTE was tested in the EINSTEIN Acute DVT and EINSTEIN-PE studies. These trials studied patients with DVT and PE separately unlike the trials of the other agents which considered them as a single group. Extended therapy with rivaroxaban beyond the standard duration of anticoagulation was tested in EINSTEIN-Extension. The Einstein Acute DVT study [22] was an open label, randomised, non-inferiority trial testing rivaroxaban against warfarin in 3449 patients presenting with a proximal DVT but not pulmonary embolism. The dosing regimen of rivaroxaban differed from that used for AF patients in ROCKETAF; a three week ‘loading regimen’ of 15 mg twice daily was prescribed prior to ongoing therapy with 20 mg daily which is the same maintenance dose as that used in ROCKET-AF. The treatment duration varied from three to 12 months with most patients (63%) being treated for six months. Patients assigned to warfarin required LMWH cover for at least five days or until the INR was therapeutic for five days. Patients assigned to rivaroxaban did not require a period of parenteral anticoagulation although up to 48 h was allowed for pre-randomisation. Recurrent VTE occurred in 2.1% of patients on rivaroxaban compared to 3.0% of those on warfarin; this met criteria for non-inferiority, but not superiority (HR 0.68, p < 0.001 for non-inferiority, p = 0.08 for
4
superiority). Clinically relevant bleeding occurred in 8.1% of both groups (HR 0.97, p = 0.77). A pre-specified analysis of net clinical benefit accounting for both recurrent VTE and major bleeding favoured rivaroxaban over warfarin (HR 0.67, p = 0.03). The EINSTEIN-PE study [23] was an open label, randomised, non-inferiority trial testing rivaroxaban against warfarin in 4832 patients presenting with an acute PE with or without DVT. High risk patients requiring fibrinolytics or an inferior vena cava filter were excluded. The rivaroxaban treatment regimen was the same as that in the Acute DVT study with treatment duration ranging from three to 12 months; most patients (58%) were treated for six months. Rivaroxaban was found to be non-inferior to warfarin in regards to symptomatic or fatal recurrent VTE (2.1% vs. 1.8% respectively, HR 1.12, p = 0.003 for non-inferiority). There was no statistical difference in rates of clinically relevant bleeding which occurred in 10.3% of those on rivaroxaban compared to 11.4% of those on warfarin (HR 0.90, p = 0.23). Whilst not the primary safety outcome, there appeared to be less major bleeding in those treated with rivaroxaban (1.1% vs. 2.2% respectively, HR 0.49, p = 0.003). The pre-specified net clinical benefit of recurrent VTE and major bleeding was not statistically different between those treated with rivaroxaban compared to warfarin (HR 0.85, p = 0.28). The EINSTEIN-Extension study [22,24] was a randomised, double-blind, multi-centre study in which extended therapy with rivaroxaban was compared to placebo in 1197 patients whom had already completed six to 12 months of anticoagulation with either warfarin or rivaroxaban as part of the Acute DVT study. The treatment regime tested was rivaroxaban 20 mg daily for an additional six to 12 months. There was 82% less recurrent VTE in patients on rivaroxaban compared to placebo (1.3% vs. 7.1% respectively, HR 0.18, p < 0.001). Major bleeding was rare in both groups occurring in 0.7% of patients on rivaroxaban and none were on placebo. There was, however, over five times more clinically relevant bleeding in patients on rivaroxaban (6.0%) compared to placebo (1.2%) (HR 5.19, p < 0.001). Nonetheless, a pre-specified analysis of net-clinical benefit including recurrent VTE and major bleeding demonstrated superiority of rivaroxaban over placebo (HR 0.28, p < 0.001).
Apixaban Apixaban has been tested against warfarin therapy in the setting of acute VTE in the AMPLIFY trial as well as in the setting of extended therapy following a standard course of anticoagulation in the AMPLIFY-EXT trial. The AMPLIFY study [25] was a double blinded, randomised non-inferiority trial which tested apixaban against warfarin therapy in 5395 patients who presented with an acute VTE event, either a proximal DVT, a PE or both. Of this cohort, 66% presented with a DVT, 25% with a PE and 9% with both conditions. Patients were allowed to have no more than two doses of LMWH or warfarin therapy or 36 h of IV heparin prior to randomisation. Other exclusion factors
A. Lee, R. Rajaratnam
included a contraindication to enoxaparin or warfarin, moderate renal impairment, anaemia or thrombocytopaenia. Patients in the study group were assigned an apixaban ‘loading’ regime of 10 mg twice daily for the first seven days, followed by a maintenance dose of 5 mg twice daily for six months. The control group was assigned warfarin under enoxaparin cover with the latter being prescribed for at least five days or until the INR was >2.0. Matching placebo therapies were assigned to both groups; hence patients assigned to apixaban did receive subcutaneous injections for at least five days, but these were placebo; hence unlike the RE-COVER trial with dabigatran, this was a test of apixaban monotherapy. Apixaban was found to be non-inferior to warfarin in regards to the primary outcome of first recurrent VTE or VTE-related death (2.3% vs. 2.7% respectively, HR 0.84, p < 0.001 for non-inferiority). The primary safety outcome of major bleeding occurred less in those assigned to apixaban compared to those on warfarin (0.6% vs. 1.8% respectively, HR 0.31, p < 0.001 for superiority). The AMPLIFY-EXT study [26] was a randomised, doubleblind, superiority trial testing extended therapy with two doses of apixaban compared to placebo in 2486 patients whom had already completed six to 12 months of standard anticoagulation therapy with either warfarin or apixaban as part of the ongoing AMPLIFY trial. Patients were randomised equally to one of the two apixaban regimens (2.5 mg twice daily or 5 mg twice daily) or placebo for a total duration of 12 months. Recurrent VTE or all-cause mortality occurred less often in both apixaban groups (3.8% and 4.2% respectively) compared to those on placebo (11.6%). The respective hazard ratios were 0.33 and 0.36 (p < 0.001 for both groups). Major bleeding was rare in all groups (0.2%, 0.1% and 0.5% respectively). Major or clinically relevant non-major bleeding occurred in 3.2% of patients on lower dose apixaban, 4.3% of patients on higher dose apixaban and 2.7% of patients on placebo; the numerically higher rates in the apixaban groups were not statistically significant compared to placebo.
Edoxaban The Hokusai-VTE study was a randomised, double-blind, non-inferiority study in which edoxaban was compared to warfarin in 8240 patients who presented with acute venous thromboembolism [27]. Forty percent of patients in this study had suffered a PE, whilst the remainder suffered only from DVTs affecting the popliteal, femoral or iliac veins. Patients were excluded if they had more than 48 h of preceding heparin therapy or more than one dose of preceding warfarin therapy. Other exclusion criteria included contraindications to warfarin therapy, cancer requiring long-term LMWH therapy, severe renal impairment, requirement for dual antiplatelet therapy or aspirin at a dose >100 mg. Similar to the dabigatran regimen in the RE-COVER trials, all patients received a run-in period of at least five days of enoxaparin or unfractionated heparin. However, unlike in RE-COVER, edoxaban was commenced only after discontinuation of the parenteral anticoagulant. Warfarin was commenced concurrently with heparin/enoxaparin therapy. Edoxaban/
5
Novel Anticoagulants: VTE, ACS, Valves
warfarin placebos were utilised to preserve blinding. Edoxaban was prescribed at a dose of 60 mg daily to most patients but those with moderate renal impairment (creatinine clearance 30–50 mL/h) or with low body weight (
