Effectiveness and safety of novel oral anticoagulants compared with vitamin K-antagonists in the treatment of acute symptomatic venous thromboembolism- a systematic review and meta-analysis

van der Hulle T, Kooiman J, den Exter PL, et al.
J Thromb Haemost. 2013 Dec 13. doi: 10.1111/jth.12485

Background

Vitamin K antagonists (VKA) are very effective in preventing recurrent venous thromboembolism (VTE), including acute pulmonary embolism (PE) and deep vein thrombosis (DVT). In comparison to placebo VKA give a relative risk reduction of approximately 85%, resulting in a risk of recurrence of about 3% during treatment [1].
Disadvantages of treatment with VKA include the need for individual tailoring of the dose based on monitoring the international normalized ratio (INR), and the number of major bleeding complications (2.1 % during the first six months of treatment) [2].
The recently developed new direct oral anticoagulants (NOACs) have relatively stable pharmacokinetics and pharmacodynamics, making regular laboratory monitoring not needed [3]. In trials in patients with acute VTE similar effectiveness for preventing recurrent VTE and a lower risk of bleeding was seen with NOACs, compared with VKA [4-8].
This systematic review and meta-analysis was to estimate risk of recurrent VTE and bleeding complications in patients with acute VTE, on treatment with VKA or NOACs. Five studies met the selection criteria [4-8 ], which yielded data from 24455 patients. PE was seen in 10796 patients (44%) and 13607 patients had isolated proximal DVT.

Main results

• During treatment 241 of 12515 (2.0%) patients on NOACs underwent VTE, as compared with 273 of 12153 patiënten (2.2%) on VKA. There was no significant difference in combined relative risk between the treatments (0.88, 95%CI: 0.74-1.05).
  Fatal PE occurred in 0.07% of NOAC-treated and in in 0.09% of VKA-treated patients. The relative risk for all-cause mortality was 0.97 (95%CI: 0.83-1.14).
• Serious bleedings occurred in 1.1% of NOAC-treated patients and in 1.7% in the VKA-group (combined relative risd: 0.60, 95%CI: 0.41-0.88). Number needed to treat (NNT) was 149 (95%CI: 88-476) for NOACs as compared with VKA.
• Non-fatal bleedings were seen in 0.23% and 0.63% in NOAC- and VKA-treatment respectively (relative risk: 0.38, 95%CI: 0.23-0.62). NNT was 263 (95%CI: 153-1000).
• The combined relative risk for clinically relevant non-severe bleedings was 0.76 (95%CI: 0.58-0.99), with substantial heterogeneity between studies.
• Non-fatal intracranial bleedings occurred in 0.09% of patients on NOACs, as compared with 0.25% on VKA-treatment (relative risk: 0.39, 95%CI: 0.16-0.94).
• Severe gastrointestinal bleedings were reported in four studies. The combined relative risk was 0.68 (95%CI: 0.36-1.30). Only the Re-Cover study, which evaluated dabigatran, found a higher incidence in patients treated with dabigatran, as compared with VKA (risk difference: 0.31%, 95%CI: -0.26 to 0.89).
• Fatal bleedings occurred in 0.06% of patients treated with NOACs and in 0.17% of VKA-treated patients (relative risk: 0.36, 95%CI: 0.15-0.87, NNT: 1111).
• In a fixed network analysis no statistically significant difference was seen with respect to the  efficacy and safety endpoints, when dabigatran, apixaban and edoxaban were compared with rivaroxaban.

Conclusion

This meta-analysis shows that NOAcs are equally effective as VKA with regard to the efficacy outcome, namely recurrent VTE in patients with acute VTE. NOAC treatment gave a significantly lower risk of all studies bleeding complications than did VKA treatment, with gastro-intestinal bleedings as the only exception.
Because NNTs were quite high, the benefit of treatment with NOACs is limited in absolute terms, in patients with acute VTE who only need anticoagulation for a short period of time.

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