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Venous thromboembolism


surgery are at a very high risk of developing VTE, due to the combination of postoperative hypercoagulability, local vascular damage, and immobilisation. Guidelines recommend the routine use of prophylactic doses of an anticoagulant to prevent VTE.4,5


UFH, LMWH, or


fondaparinux reduce this risk of VTE by 40–60%, and have traditionally been the mainstay of postoperative thromboprophylaxis.4


Because of the high risk of both thrombosis and bleeding in these patients, initial clinical development programmes of NOACs focused on this population to establish whether NOACs are a safe and effective alternative for standard thromboprophylaxis with LMWH. In total, the four approved NOACs have been compared with standard


thromboprophylaxis based on subcutaneous LMWH for the prevention of VTE following major orthopaedic surgery in 13 Phase III clinical trials, including over 35,000 patients.13 Rivaroxaban in a once-daily oral dose of 10mg was asociated with a reduced risk of asymptomatic and symptomatic VTE, without significant increases in major bleeding compared to enoxaparin. A pooled analysis of the trials, however, showed a small but significant increase in major and clinically relevant non-major bleeding.14 Apixaban at a twice-daily dose of 2.5mg was more effective than enoxaparin 40mg once daily, but not as effective as enoxaparin 30mg twice daily, and without increase in bleeding.15,16 Edoxaban was studied in a Japanese population, showing a superior efficacy of the 30mg once-daily administration of edoxaban compared with edoxaban 20mg twice daily, with a similar risk of bleeding.17 Edoxaban does not have an indication for prevention of VTE in the European Union. Three Phase III trials have compared two doses of dabigatran (150 and 220mg once daily) with enoxaparan 40mg once daily or 30mg twice daily. Overall, dabigatran was as effective as 40mg enoxaparin, but not as effective as the higher enoxaparin dose. Bleeding risk was comparable between all doses.18


Treatment of acute VTE 14


The combination of rapid-acting parenteral LMWH followed by long-term therapy of regularly monitored VKA has been the standard treatment for stable patients with VTE. After the efficacy and safety of a short course of NOACs had been validated on a large scale in postoperative patients, clinical


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Table 1: Comparison of key features of anticoagulant drugs Mechanism


Affected coagulation factor(s)


Unfractionated heparin


LMWH Fondaparinux


Vitamin K antagonists


Indirect: Inhibition of vitamin K metabolism, reduction of levels of functional factors


Non-VKA oral anticoagulants


– Dabigatran


– Rivaroxaban – Apixaban – Edoxaban


trials focused on acute VTE treatment. In total, over 27,000 patients with VTE were randomised to either NOAC therapy or VKA treatment19


to evaluate whether


unmonitored use of a fixed-dose oral drug could safely replace VKA treatment, with its often cumbersome need for monitoring and dose-adjustment. Key features of the design and the results of these trials are summarised in Table 2. A comprehensive meta-analysis of the


VTE trials with NOACs has been published.19


In short, the use of NOACs in a


fixed dose was as effective as VKA titrated to achieve an international normalised ratio of 2–3, and this was consistent regardless of the initial presentation (VTE or PE), body weight, and the presence of (moderate) renal insufficiency. Interestingly, there was even a suggestion for a superior efficacy in elderly patients.20


Importantly, treatment


Once-daily regimens are more patient-friendly, and may increase compliance. By contrast, twice-daily dosing may provide more continuous anticoagulant protection.


A second important difference between the NOACs is the initial treatment phase. In the trials with dabigatran and edoxaban,


with NOACs was associated with a 39% relative risk reduction in major bleeding, and a 63% and 64% reduction in intracranial and fatal bleeding, respectively. Although the design of the trial programmes with the different NOACs share many similarities, there are some important differences that impact on clinical use (Table 2). First, while edoxaban and rivaroxaban are given in a once-daily dose,21–23 dabigatran and apixaban are dosed twice daily.24,25


Direct inhibition of active factor


IIa Xa


Rapid Rapid


No No


Yes Yes


(IX, XI) X II


Indirect: Potentiation of antithrombin


X > II X


II, VII, IX, X Onset Very rapid


Rapid Rapid


Very slow


Requires routine


monitoring Yes


No No


Yes


Orally available No


No No


Yes


treatment with a NOAC was started after an initial course of parenteral anticoagulation, typically LMWH during 5–7 days.21,25


In


contrast, treatment with rivaroxaban and apixaban was not preceded by LMWH, but required an intensified dosing for the first part of the treatment. For rivaroxaban, an initial phase of 15mg twice daily was given for three weeks, after which the maintenance dose of 20mg once daily was started.22,23


With apixaban, the initial


treatment consisted of one week of 10mg twice daily, followed by 5mg twice daily for the rest of the treatment.24


Long-term secondary prevention of VTE


Due to the need for subcutaneous administration of heparins, the practical therapeutic options for long-term secondary VTE prophylaxis are currently limited to VKAs. Recent studies have shown that extended therapy with NOACs is safe and effective, offering attractive options for secondary prevention.26,27


In summary, NOACs offer clear practical advantages over VKA therapy as well as a superior safety profile without compromising on efficacy across a wide population of VTE patients. On the other hand, the availability of different drugs with different doses may challenge the appropriate use of these drugs by physicians. Further challenges include management of under- or over-dosing and the management of bleeding.


Conclusions VTE is a frequent and serious condition caused by abnormal activation of clotting in the venous system. Drugs that suppress


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