Therapeutics
Edoxaban was noninferior to warfarin for preventing recurrent venous thromboembolism, with less bleeding
Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-15.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★★✩ H ★★★★★★✩ Patient follow-up: 95% (modified intention-to-treat analysis excluding patients who did not receive ≥ 1 dose of study drug).
Question Is edoxaban noninferior to warfarin for preventing recurrent venous thromboembolism (VTE)?
Main results
Methods Design: Randomized controlled noninferiority trial (Hokusai-VTE study). ClinicalTrials.gov NCT00986154. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, data collectors, and outcome assessors).
Edoxaban and warfarin did not differ for the composite of first recurrent VTE or VTE-related death during the overall study period or the on-treatment period (Table). Risk for clinically relevant bleeding was lower in the edoxaban group than in the warfarin group (Table).
Conclusion Edoxaban was noninferior to warfarin for preventing recurrent venous thromboembolism and resulted in less clinically relevant bleeding.
Follow-up period: ≤ 12 months. Setting: 439 clinical centers in 37 countries. Patients: 8292 adults ≥ 18 years of age (mean age 56 y, 57% men) who had objectively diagnosed acute symptomatic deep venous thrombosis (DVT) and/or acute symptomatic pulmonary embolism (PE). Exclusion criteria included contraindications to heparin or warfarin, treatment with therapeutic doses of heparin for > 48 hours, > 1 dose of a vitamin K antagonist, cancer that required long-term treatment with low-molecular-weight heparin, another indication for warfarin therapy, continuation of an aspirin dose > 100 mg/d or dual-antiplatelet therapy, or creatinine clearance < 30 mL/min. Intervention: All patients received open-label enoxaparin or unfractionated heparin for ≥ 5 days. Oral edoxaban, 60 mg/d, beginning after discontinuation of initial heparin, plus warfarin placebo (n = 4143); or warfarin, adjusted to maintain an international normalized ratio between 2.0 and 3.0, beginning with the study regimen of heparin, plus edoxaban placebo (n = 4149). Patients in the edoxaban group received 30 mg/d if they had creatinine clearance 30 to 50 mL/min, weighed ≤ 60 kg, or received concomitant treatment with potent P-glycoprotein inhibitors. Continuation of anticoagulation beyond 3 months, and up to 12 months, was determined by treating physicians. Outcomes: Primary outcome was confirmed symptomatic recurrent VTE (DVT or PE, including death due to PE). Safety outcome was confirmed clinically relevant bleeding (major or clinically relevant nonmajor bleeding). 220 primary outcome events were needed to show noninferiority of edoxaban compared with warfarin, with an upper limit of the 95% CI for the hazard ratio of 1.5 (α = 0.05, 85% power, estimated baseline event rate 3%).
*See Glossary.
Source of funding: Daiichi-Sankyo. For correspondence: Dr. H.R. Büller, Academic Medical Center, Amsterdam, The Netherlands. E-mail [email protected]. ■
Commentary In the Hokusai-VTE study, patients with popliteal, femoral, or iliac DVT or primary PE did at least as well with edoxaban as with warfarin for recurrent VTE or VTE-related mortality. Safety endpoints, including nonmajor clinically relevant bleeding, occurred less with edoxaban. A prespecified subgroup analysis found that edoxaban decreased recurrent VTE compared with warfarin in patients with evidence of right ventricular dysfunction. This finding needs to be confirmed in future studies before edoxaban can be considered superior in this population. Emerging data indicate that the novel oral anticoagulants (NOACs) should not be conceptualized as all having similar uses or properties, and use of NOACs instead of warfarin requires attention to the approved indications and contraindications. For example, patients with mechanical heart valves should not use dabigatran due to increased risk for stroke and major bleeding events (1). In addition, rivaroxaban and apixaban do not require initial treatment with parenteral heparin when used for acute VTE (2, 3).
The rapid onset of action of NOACs (hours) is in contrast to the ≥ 5 days for warfarin to take full effect, and the pharmacokinetics of NOACs provide potential for immediate use without overlapping with parenteral heparin. All patients in the Hokusai-VTE trial received a minimum of 5 days of parenteral heparin before receiving edoxaban, so that if approved, edoxaban Edoxaban vs warfarin in patients with acute symptomatic deep venous will probably require an initial 5-day heparin treatment thrombosis and/or symptomatic pulmonary embolism† period. Although the individual agents show advantages Outcomes Assessment Edoxaban Warfarin RRR (95% CI) NNT (CI) and disadvantages compared with warfarin and with each period other, NOACs clearly have a place in the treatment of VTE. Recurrent VTE or VTE-related death Clinically relevant bleeding
12 mo study
3.2%
On-treatment
1.6%
On-treatment
8.5%
3.5%
11% (−13 to 30)‡
Not significant
1.9%
18% (−14 to 40)
Not significant
18% (6 to 28)
54 (35 to 171)
10%
†VTE = venous thromboembolism; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from control event rates and hazard ratios in article. ‡Criterion for noninferiority was met because upper CI of the hazard ratio was < 1.5 (hazard ratio 0.89, CI 0.70 to 1.13).
JC4
© 2014 American College of Physicians
Downloaded From: https://annals.org/ by a Universite Laval Biblioteque User on 08/05/2017
Stephan Thomé, MD Mayo Clinic College of Medicine Rochester, Minnesota, USA References 1. Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. N Engl J Med. 2013;369:1206-14. 2. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. N Eng J Med. 2010;363;2499-510. 3. Agnelli G, Buller HR, Cohen A; AMPLIFY Investigators. N Eng J Med. 2013;369;799-808. 21 January 2014 | ACP Journal Club | Volume 160 • Number 2
Edoxaban was noninferior to warfarin for preventing recurrent venous thromboembolism, with less bleeding
Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-15.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★★✩ H ★★★★★★✩ Patient follow-up: 95% (modified intention-to-treat analysis excluding patients who did not receive ≥ 1 dose of study drug).
Question Is edoxaban noninferior to warfarin for preventing recurrent venous thromboembolism (VTE)?
Main results
Methods Design: Randomized controlled noninferiority trial (Hokusai-VTE study). ClinicalTrials.gov NCT00986154. Allocation: Concealed.* Blinding: Blinded* (patients, clinicians, data collectors, and outcome assessors).
Edoxaban and warfarin did not differ for the composite of first recurrent VTE or VTE-related death during the overall study period or the on-treatment period (Table). Risk for clinically relevant bleeding was lower in the edoxaban group than in the warfarin group (Table).
Conclusion Edoxaban was noninferior to warfarin for preventing recurrent venous thromboembolism and resulted in less clinically relevant bleeding.
Follow-up period: ≤ 12 months. Setting: 439 clinical centers in 37 countries. Patients: 8292 adults ≥ 18 years of age (mean age 56 y, 57% men) who had objectively diagnosed acute symptomatic deep venous thrombosis (DVT) and/or acute symptomatic pulmonary embolism (PE). Exclusion criteria included contraindications to heparin or warfarin, treatment with therapeutic doses of heparin for > 48 hours, > 1 dose of a vitamin K antagonist, cancer that required long-term treatment with low-molecular-weight heparin, another indication for warfarin therapy, continuation of an aspirin dose > 100 mg/d or dual-antiplatelet therapy, or creatinine clearance < 30 mL/min. Intervention: All patients received open-label enoxaparin or unfractionated heparin for ≥ 5 days. Oral edoxaban, 60 mg/d, beginning after discontinuation of initial heparin, plus warfarin placebo (n = 4143); or warfarin, adjusted to maintain an international normalized ratio between 2.0 and 3.0, beginning with the study regimen of heparin, plus edoxaban placebo (n = 4149). Patients in the edoxaban group received 30 mg/d if they had creatinine clearance 30 to 50 mL/min, weighed ≤ 60 kg, or received concomitant treatment with potent P-glycoprotein inhibitors. Continuation of anticoagulation beyond 3 months, and up to 12 months, was determined by treating physicians. Outcomes: Primary outcome was confirmed symptomatic recurrent VTE (DVT or PE, including death due to PE). Safety outcome was confirmed clinically relevant bleeding (major or clinically relevant nonmajor bleeding). 220 primary outcome events were needed to show noninferiority of edoxaban compared with warfarin, with an upper limit of the 95% CI for the hazard ratio of 1.5 (α = 0.05, 85% power, estimated baseline event rate 3%).
*See Glossary.
Source of funding: Daiichi-Sankyo. For correspondence: Dr. H.R. Büller, Academic Medical Center, Amsterdam, The Netherlands. E-mail [email protected]. ■
Commentary In the Hokusai-VTE study, patients with popliteal, femoral, or iliac DVT or primary PE did at least as well with edoxaban as with warfarin for recurrent VTE or VTE-related mortality. Safety endpoints, including nonmajor clinically relevant bleeding, occurred less with edoxaban. A prespecified subgroup analysis found that edoxaban decreased recurrent VTE compared with warfarin in patients with evidence of right ventricular dysfunction. This finding needs to be confirmed in future studies before edoxaban can be considered superior in this population. Emerging data indicate that the novel oral anticoagulants (NOACs) should not be conceptualized as all having similar uses or properties, and use of NOACs instead of warfarin requires attention to the approved indications and contraindications. For example, patients with mechanical heart valves should not use dabigatran due to increased risk for stroke and major bleeding events (1). In addition, rivaroxaban and apixaban do not require initial treatment with parenteral heparin when used for acute VTE (2, 3).
The rapid onset of action of NOACs (hours) is in contrast to the ≥ 5 days for warfarin to take full effect, and the pharmacokinetics of NOACs provide potential for immediate use without overlapping with parenteral heparin. All patients in the Hokusai-VTE trial received a minimum of 5 days of parenteral heparin before receiving edoxaban, so that if approved, edoxaban Edoxaban vs warfarin in patients with acute symptomatic deep venous will probably require an initial 5-day heparin treatment thrombosis and/or symptomatic pulmonary embolism† period. Although the individual agents show advantages Outcomes Assessment Edoxaban Warfarin RRR (95% CI) NNT (CI) and disadvantages compared with warfarin and with each period other, NOACs clearly have a place in the treatment of VTE. Recurrent VTE or VTE-related death Clinically relevant bleeding
12 mo study
3.2%
On-treatment
1.6%
On-treatment
8.5%
3.5%
11% (−13 to 30)‡
Not significant
1.9%
18% (−14 to 40)
Not significant
18% (6 to 28)
54 (35 to 171)
10%
†VTE = venous thromboembolism; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from control event rates and hazard ratios in article. ‡Criterion for noninferiority was met because upper CI of the hazard ratio was < 1.5 (hazard ratio 0.89, CI 0.70 to 1.13).
JC4
© 2014 American College of Physicians
Downloaded From: https://annals.org/ by a Universite Laval Biblioteque User on 08/05/2017
Stephan Thomé, MD Mayo Clinic College of Medicine Rochester, Minnesota, USA References 1. Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. N Engl J Med. 2013;369:1206-14. 2. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. N Eng J Med. 2010;363;2499-510. 3. Agnelli G, Buller HR, Cohen A; AMPLIFY Investigators. N Eng J Med. 2013;369;799-808. 21 January 2014 | ACP Journal Club | Volume 160 • Number 2
