Rivaroxaban for the treatment of deep vein thrombosis and ...

Appendix 4 Reproduction of Section D of the manufacturer’s clarifications – textual
and additional clarifications.
D1. Please clarify whether the references to sections 2.9 and 2.10 in section 2.12 are
correct, as these sections do not seem to reference appropriate sources of data to
answer the question posed by section 2.12 (page 25).
Section 2.12 asks for references to support the advantages for rivaroxaban described
in previous sections.
The draft SmPCs for rivaroxaban (references 2-3) are key references, which describe
the circumstances in which rivaroxaban should be delivered to patients to
whom it is prescribed.
Also relevant are the SmPCs for the LMWHs (37, 39, 40, 41), warfarin (87) and
fondaparinux (89), and the PILs (88, 90, 91), which describe the
administration requirements and extensive contraindications associated with
the current standard of care.
Safety issues in relation to LMWH and warfarin have been discussed in references 7,
10 and 13.
Increased treatment satisfaction with rivaroxaban in comparison to LMWH/VKA is
supported by an analysis described in reference 18.
D2. Please confirm that the sentence ‘from these 687 were excluded...’ should read ‘from
these, 683 were excluded..’ to match Figure 2 (page 30, section 5.2.2)
We confirm that the sentence should read `from these, 683 were excluded’.
D3. Please clarify the asterisk attached to the statement ‘treatment period 3, 6, or 12
months’ on page 37, Figure 3.
In the internal diagram from which Figure 3 was taken, the asterisk refers to a
footnote which describes the selection of treatment duration by investigators, as
described elsewhere in the submission (for example in Table 9, page 39).
D4. Page 42, states that 53% of patients in EINSTEIN-EXT had participated in
EINSTEIN-DVT. However, the figure on Page 38 suggests this figure is 34%. Note
that the numbers quoted in Figure 6 (page 51) suggest 53% is the correct value.
Please clarify.
The study identification numbers within Bayer of EINSTEIN-DVT and EINSTEIN-
PE studies are both 11702, and this appears to be associated with some confusion.
Figure 4 on page 38 of the submission correctly states the source of patients in
EINSTEIN-Ext. This Figure corresponds with the NEJM article, 16 which states:
From February 2007 through March 2009, a total of 1197 patients were enrolled in
the Continued Treatment Study. Of these patients, 34.1% had completed the Acute
DVT Study and 19.1% had completed the Acute PE (Pulmonary Embolism) Study of
the EINSTEIN program; the remaining 560 patients (47.5%) were referred from
outside both these studies (Fig. 1B).
177
Copyright 2012 Queen's Printer and Controller of HMSO. All rights reserved.