Apixaban for the prevention of venous thromboembolism in people ...

apixaban with the UK licensed dose of enoxaparin (40 mg od). In APROPOS and ADVANCE-1 the
dosing of enoxaparin is according to U.S. licensed dose (30 mg bd).
Outcomes
All trials reported data on mortality, incidence of VTE, and adverse events. None of the trials reported
results for length of hospital stay, joint outcomes, or health related quality of life. Pulmonary
embolism was reported by three trials as the main post-DVT complication but results for thrombotic
syndrome are not presented in any trial.
4.2.6 Where appropriate, describe and critique any meta-analysis, indirect comparisons and/
or mixed treatment analysis carried out by the manufacturer.
This section should include a summary of the manufacturer’s methods and results as described in the
MS. The ERG should critique the methods used and interpret the results in light of the methods used
by the manufacturer and generalisability to patients in England and Wales.
The NICE scope mentions several comparators: LMWHs, fondaparinux, rivaroxaban and dabigatran
etexilate. Apixaban has only been compared directly with enoxaparin, a LWMH. All other
comparators have also been compared directly with enoxaparin. Therefore, the relative effectiveness
of apixaban compared with all comparators can be assessed using indirect comparisons.
The MS does not seem to make any attempt to assess the relative effectiveness of apixaban compared
with other LMWHs. And is not clear how enoxaparin compares to other LMWHs. According to the
MS (MS, page 25): “Enoxaparin is the most widely used LMWH in the UK (13), and is the most
widely studied. Enoxaparin was used as the comparator in the apixaban registrational trials.” And in
chapter 5.6 describing the meta-analysis (MS, page 70): “Enoxaparin was the only LMWH considered
for inclusion, as it is the most widely used LMWH VTE prophylaxis option in the UK (13) for the
THR and TKR populations.” Unfortunately, reference 13 is an internal company document, which
was not part of the manufacturer submission. Therefore the source could not be checked by the ERG.
Regarding the comparators, “only dabigatran 220mg od (standard UK dose) was included in the
submission analyses, since it is inappropriate to compare the 150mg od dabigatran dose indicated for
elderly patients with the apixaban 2.5mg bd, rivaroxaban 10mg od, and fondaparinux 2.5mg od doses
indicated for general population use.” (MS, page 70). Therefore, the following doses were used in the
main MS analyses: apixaban 2.5mg bd, rivaroxaban 10mg od, fondaparinux 2.5mg od, dabigatran
220mg od, and enoxaparin 40 mg od.
The MS describes two strategies for the indirect comparisons:
1. An indirect comparison using Bucher’s method.
2. A full mixed treatment comparison.
The main indirect comparison, using the UK dose of enoxaparin, is reported in the main report. In
appendix 15 two additional sets of indirect comparisons are reported: 1) using the US dose of
enoxaparin, and 2) using the pooled UK and US doses for enoxaparin. In appendix 16 two different
types of MTC are reported: 1) using only the UK dose of enoxaparin, and 2) using the pooled UK and
US doses for enoxaparin.
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