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Venous thromboembolism


Table 2: Overview of Phase III trials of NOACs in the acute treatment of VTE


Dabigatran Trial Comparator


Single drug regimen


RE-COVER RE-COVER II


VKA


No, initial treatment with LMWH


Number of patients 5132 Dose


150mg BID Treatment duration Six months


Initial UFH/LMWH pretreatment


Dose adjustment


Results Efficacy


Recurrent VTE NOAC/comparator


Safety


Major bleeding NOAC/comparator


Mandatory (≥five days)


None


2.4% 2.2%


1.4% 2.0%


Rivaroxaban


EINSTEIN DVT EINSTEIN PE


Apixaban AMPLIFY


Edoxaban HOKUSAI-VTE


Enoxaparin/VKA Enoxaparin/VKA VKA Yes


Yes 8282


15mg BID (three weeks)/20mg bid


5395


10mg BID (one week)/5mg bid


3, 6 or 12 months Six months


Mandatory (48 hours) for comparator group


None


2.1% 3.0%


0.8% 1.2%


Not recorded None


2.3% 2.7%


0.6% 1.8%


initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004;140(11):867–73.


12. Yeh CH, Gross PL, Weitz JI. Evolving use of new oral anticoagulants for treatment of venous thromboembolism. Blood 2014;124(7):1020–8.


No, initial treatment with LMWH


8240 60mg OD


Flexible, up to 12 months


Mandatory (at least 5 days


30mg OD (*)


1.6% 1.9%


1.4% 1.6%


VKA: vitamin K antagonist, LMWH: low-molecular weight heparin, UFH: unfractionated heparin, eGFR: estimated glomerular filtration rate, NOAC: new oral anticoagulant drug, P-gp: P-glycoprotein, CYP3A4: cytochrome p450 3A4 (*) Dose reduction for low body weight ≤60 kg; concomitant use of P-glycoprotein (P-gp) inhibitors (ciclosporin, dronedarone, erythromycin, or ketoconazole); or moderate to severe renal impairment (CrCl 15– 50ml/min)


coagulation can prevent VTE and reduce morbidity and mortality in established VTE, but potentially increase the risk of bleeding. The balance between optimal efficacy and maximal safety has fuelled the search for new anticoagulant drugs. While LMWHs provide predictable pharmacokinetics and a rapid and reliable anticoagulant effect, their use is limited by the need for injection. On the other hand, oral VKAs have a slow onset of action. Due to their narrow therapeutic index and their unpredictable and highly variable anticoagulant effect, continuous monitoring of VKAs is mandatory. This routine testing adds cost to the health care system but, more importantly, is inconvenient for patients and physicians. To overcome the inconveniences of VKA therapy, a new generation of non-VKA oral anticoagulants has been developed. Efficacy and safety of NOACs for the prevention (edoxaban is not indicated for primary prevention) and treatment of VTE have been established and they are likely to become the treatment of choice for the majority of patients. l


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14. Ageno W. Rivaroxaban for the prevention of venous thromboembolism following major orthopedic surgery: the RECORD trials. Expert Rev Cardiovasc Ther 2009;7(6):569–76.


15. Lassen MR et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010;375(9717):807–15.


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17. Fuji T et al. Safety and efficacy of edoxaban, an oral factor Xa inhibitor, versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. Thromb Res 2014;134(6):1198–204.


18. Wolowacz SE et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis. Thromb Haemost 2009;101(1):77–85.


19. van Es N et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014;124(12):1968–75.


20. Geldhof V et al. Venous thromboembolism in the elderly: efficacy and safety of non-VKA oral anticoagulants. Thrombosis J 2014;12:21.


21. Hokusai VTE Investigators et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369(15): 1406–15.


22. EINSTEIN Investigators et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363(26):2499–510.


23. EINSTEIN-PE Investigators et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366(14):1287–97.


24. Agnelli G et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369(9):799–808.


25. Schulman S et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361(24):2342–52.


26. Agnelli G et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368(8):699–708.


27. Schulman S et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. New Engl J Med 2013;368(8): 709–18.


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