Dabigatran etexilate mesilate, capsules, 75 mg, 110 mg (base), Pradaxa®, March 2009
Public summary document for Dabigatran etexilate mesilate, capsules, 75 mg, 110 mg (base), Pradaxa® , March 2009
Page last updated: 03 July 2009
Public Summary Document
Product:Dabigatran etexilate mesilate, capsules,
75 mg, 110 mg (base), Pradaxa®
Sponsor: Boehringer Ingelheim Pty Limited
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought a restricted benefit listing for dabigatran
for prevention of venous thromboembolic events (VTE) in adult
patients undergoing total hip replacement (THR) surgery.
2. Background
This was the first time dabigatran had been considered by the
PBAC.
3. Registration Status
Dabigatran was registered by the TGA on 24 November 2008 for
prevention of venous thromboembolic events in adult patients who
have undergone major orthopaedic surgery of the lower limb
(elective total hip or knee replacement).
4. Listing Requested and PBAC’s View
Restricted Benefit
Prevention of venous thromboembolic events in adult patients
undergoing total hip replacement surgery.
In the Pre-Subcommittee Response the sponsor had no objection to an
Authority Required listing.
For PBAC’s view see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Dabigatran would provide an alternative treatment for VTE
prevention in patients undergoing total hip replacement.
6. Comparator
Enoxaparin 40 mg given 12 hours preoperatively and then once daily
for 30 days post surgery.
Although the PBAC accepted that subcutaneous enoxaparin injection
was an appropriate main comparator at the time the submission was
lodged, the PBAC considered that oral rivaroxaban tablet was a more
appropriate comparator given that it is also a new oral therapy for
the prevention of VTE in patients undergoing elective total
replacement of the hip (or knee).
7. Clinical Trials
The submission presented one three-arm randomised trial (RE-NOVATE)
comparing dabigatran 220 mg for 28-35 days and dabigatran 150 mg
for 28-35 days with enoxaparin 40 mg 28-35 days in patients
undergoing elective total hip replacement surgery.
The trial had been published at the time of the submission, as
follows:
| Trial/First author | Protocol title | Publication Citation |
| Direct randomised trials | ||
| Eriksson et al | Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. | Lancet 2007; 370: 949-56. |
| Eriksson et al | Dabigatran etexilate is effective and safe for the extended prevention of venous thromboembolism following total hip replacement. | J Thromb Haemost, 2007; 5(S2): Abstr O-W-049. |
8. Results of Trials
The submission presented results of the primary composite outcome, total VTE and all
cause mortality, the disaggregated components of this outcome and the main secondary
outcome, major VTE and VTE related mortality for both dabigatran 200 mg and 150 mg
versus enoxaparin.
The RE-NOVATE trial was designed as a non-inferiority trial, with a pre-specified
non-inferiority margin of an absolute risk difference of 7.7% for the primary outcome
of total VTE and all cause mortality based on preserving two-thirds of the 95% CI
difference between enoxaparin and placebo. Non-inferiority was inferred if the upper
margin of the 95% confidence interval for the absolute risk difference did not exceed
this margin.
The PBAC noted a number of published trials assessing new antithrombotic drugs compared
to enoxaparin for the prevention of VTE in patients undergoing THR surgery have considered
absolute risk differences in total VTE of 4-5% as being clinically important.
(1). Dabigatran 220 mg versus enoxaparin 40 mg.
In the comparison of dabigatran 220 mg and enoxaparin 40 mg, the result for the primary
outcome, total VTE and all cause mortality, met both the predefined non-inferiority
criterion of an absolute risk difference of no more than 7.7%, and the more stringent
criterion on the basis of previous literature (a difference of no more than 4%).
The results were heavily weighted by the large proportion of asymptomatic DVT, the
clinical significance of which is still debated, especially distal asymptomatic DVT,
which account for > 75% of the observed events in the dabigatran treatment arm and
93% in the enoxaparin arm.
The rates of symptomatic DVT, non-fatal PE and death (VTE not ruled out), were all
higher in the dabigatran 220 mg treatment arm than in the enoxaparin arm, although
the trial was not sufficiently powered for testing for statistically significant differences
in these uncommon events.
(2). Dabigatran 150 mg versus enoxaparin 40 mg.
In the comparison of dabigatran 150 mg and enoxaparin 40 mg, the result for the primary
outcome, total VTE and all cause mortality (RD 1.9%, 95%CI -0.6%, 4.4%), met the predefined
non-inferiority criterion of an absolute risk difference of no more than 7.7%. However,
it failed to meet the more stringent non-inferiority criterion of a difference of
no more than 4.0% but was within the 4-5% range, noted by the PBAC to be clinically
important in a number of published trials.
The results were also heavily weighted by the large proportion of asymptomatic DVT
cases. The interpretation of the results for the main secondary outcome, major VTE
and VTE-related death (RD 0.4%, 95%CI -1.5%, 2.2%) was difficult as no non-inferiority
margin was specified for this outcome. However, the narrow confidence interval was
suggestive of non-inferiority.
The PBAC noted the trial subjects for this comparison were not representative of those
for whom this dose of dabigatran is recommended. A reduced dose of dabigatran, 150
mg daily, is recommended in patients with moderate renal impairment (creatinine clearance
30-50 mL/min). Patients with moderate renal impairment only represented 4.7% of the
full analysis set (FAS) and 5.2% of the safety population in the dabigatran 150 mg
treatment group.
The PBAC noted in terms of being an alternative in patients with moderate renal impairment,
there were insufficient numbers of patients in this subgroup across the trials presented
in the pre-PBAC response to assess the comparative benefits and harms of the 150 mg
and 220 mg daily doses.
Between 23-26% of randomised participants were excluded from the analysis of the primary
outcome in each of the treatment arms. The main reason for exclusion was lack of confirmed
VTE data. The PBAC was advised the submission did not adequately address the potential
for bias due to such high exclusion rates and the possible effects on the validity
of the results. Baseline characteristics for the primary efficacy analysis set were
not provided. Due to this, it was difficult to compare the characteristics of patients
with and without missing data to assess whether missing data were randomly distributed.
Excluded participants were fairly evenly distributed between the three treatment groups
and the reasons for exclusion were similar.
The primary safety outcome in the RE-NOVATE trial was incidence of bleeding events,
comprising of major bleeding events (MBE), clinically relevant bleeding events (CRBE),
and any bleeding events. The results are presented in the following table. The submission
also provided a summary of other adverse events.
Summary of bleeding events during the treatment perioda (safety population)
| Trial ID | Dabigatran n (%) | Enoxaparin n (%) | Risk Difference RD % (95%CI) | Relative Risk (95% CI) |
| Dabigatran 220 mg vs enoxaparin 40 mg | ||||
| N=1146 | N=1154 | |||
| Major bleeding b | 23 (2.0) | 18 (1.6) | 0.45 (-0.63, 1.53) | 1.29 (0.70, 2.37) |
| Clinically relevant bleeding | 48 (4.2) | 40 (3.5) | 0.72 (-0.85, 2.29) | 1.21 (0.80, 1.82) |
| Minor bleeding | 70 (6.1) | 74 (6.4) | -0.30 (-2.28, 1.68) | 0.95 (0.69, 1.31) |
| Bleeding requiring discontinuation | 1 (<0.1) | 1 (<0.1) | 0.00 (-0.24, 0.24) | 1.01 (0.06, 16.1) |
| Dabigatran 150 mg vs enoxaparin 40 mg | ||||
| N=1163 | N=1154 | |||
| Major bleeding b | 15 (1.3) | 18 (1.6) | -0.27 (-1.24, 0.70) | 0.83 (0.42, 1.63) |
| Clinically relevant bleeding | 55 (4.7) | 40 (3.5) | 1.26 (-0.35, 2.88) | 1.36 (0.92, 2.03) |
| Minor bleeding | 72 (6.2) | 74 (6.4) | -0.22 (-2.20, 1.76) | 0.97 (0.71, 1.32) |
| Bleeding requiring discontinuation | 1 (<0.1) | 1 (<0.1) | 0.00 (-0.24, 0.24) | 0.99 (0.06, 15.8) |
CI=confidence interval; CRBE=clinically relevant bleeding events; MBE=major bleeding
events; RD=risk difference.
a The treatment period was defined as the time from the first administration of study
drug until 3 days after the last administration of study drug.
b Primary safety outcome.
The rates of treatment-emergent bleeding events in the dabigatran treatment groups
were fairly similar to those in the enoxaparin group, although the incidence of more
severe bleeding events (MBE and clinically relevant bleeding events) tended to be
higher with both doses of dabigatran. There was insufficient statistical power to
draw any firm conclusions regarding the incidence of major bleeding events with dabigatran
compared to enoxaparin.
The rates of any adverse event (AE) resulting in prophylaxis discontinuation or hospitalisation,
and any serious AE, were similar for all three treatment groups.
There was also insufficient data to accurately determine the comparative incidence
of AEs of special interest, such as hepatic and cardiac events for the two drugs,
although the incidence of cardiac events tended to be higher in both the dabigatran
groups compared to enoxaparin. Little information was available regarding the potential
for other rare or delayed adverse events.
There was minimal information on the safety of dabigatran 150 mg in patients with
moderate renal impairment, the population for which this dose is recommended. Analyses
of the incidence of adverse events in different subgroups of patients, such as different
ages, patients with specific co-morbidities, or patients with risk factors for VTE
or bleeding, was not provided in the submission.
For further PBAC comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission claimed that both dabigatran 220 mg and dabigatran
150 mg is non-inferior in terms of comparative effectiveness and
non-inferior in terms of comparative safety to enoxaparin 40 mg for
short term prophylaxis of VTE in patients undergoing elective total
hip replacement.
For PBAC comments on these results, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis on the basis
that dabigatran 220 mg and dabigatran 150 mg were equi-effective to
enoxaparin 40 mg.
The PBAC concluded that oral dabigatran 110 mg twice daily was no
more effective, but possibly less safe, than subcutaneous
enoxaparin 40 mg once daily.
The submission claimed a cost saving for dabigatran 220 mg/day over
enoxaparin 40 mg/day taking account of drug, home visits,
preoperative administration and heparin-induced thrombocytopenia
(HIT) costs, as appropriate, over a 30-day therapy duration.
The result of the cost analysis presented in the submission relied
on the acceptance of the estimated cost-offsets related to the
provision of other healthcare resources.
The result suggested that use of dabigatran 220 mg/day produced a
cost saving when compared to enoxaparin 40 mg/day when both the
costs of medication and other healthcare resources were considered,
however this was reliant on cost-offsets and assumptions with
respect to their value, which were considered uncertain.
11. Estimated PBS Usage and Financial Implications
The submission estimated a financial cost/year to the PBS of <
$10 million in up to Year 5 of listing.
The validity of these estimates was unclear due to uncertainty
regarding the uptake rate of dabigatran, and the current level of
use of enoxaparin for this indication was unknown.
12. Recommendation and Reasons
The PBAC deferred its consideration of dabigatran as Authority
Required for the prevention of venous thromboembolic events in an
adult patient undergoing elective total hip replacement in order to
give the applicant an opportunity to compare dabigatran with
rivaroxaban, another new oral therapy available for the same
patient population.
Although the PBAC accepted that subcutaneous enoxaparin injection
was an appropriate main comparator at the time the submission was
lodged, the PBAC considered that oral rivaroxaban tablet was a more
appropriate comparator given that it is also a new oral therapy for
the prevention of venous thromboembolic events in patients
undergoing elective total replacement of the hip (or knee).
Although the sponsor of dabigatran comments briefly on this new
alternative in its pre-PBAC response, it argues that an indirect
comparison involving enoxaparin as the common reference would be
inappropriate because of methodological differences in the
trials.
As a separate issue, the PBAC did not accept that the 150 mg daily
dose was adequately justified. In terms of being a dosing
alternative, noninferiority was not clearly established compared
with enoxaparin 40 mg daily if using the more stringent
noninferiority margin of 4% absolute risk difference in the primary
outcome of total VTE and all cause mortality. In terms of being an
alternative in patients with moderate renal impairment, there were
insufficient numbers of patients in this subgroup across the trials
presented in the pre-PBAC response to assess the comparative
benefits and harms of the 150 mg and 220 mg daily doses.
The primary outcome analysed in the enoxaparin-controlled
randomised trial was a composite measure, which was dominated by a
relatively large number of asymptomatic events detected by
venography that had no direct patient relevance (especially
asymptomatic distal deep vein thromboses). Across the trial, there
were about 25% of patients who were not assessed for this primary
outcome mainly due to problems with venography, but loss to
follow-up was similar across the arms of the trial. Thus the
conclusion for non-inferiority rested on an interpolation that the
composite outcome results reflected the results for each of the
rarer and directly patient-relevant types of events included in the
composite outcome.
The PBAC was concerned that the point estimates for
treatment-emergent bleeding, although not statistically
significant, tended to favour enoxaparin over dabigatran. This is
of concern because of the small therapeutic window between reducing
clinically important thrombotic events and increasing clinically
important bleeding; the paucity of evidence available in the
extended assessment of harms and the likelihood that these trials
were underpowered to detect this outcome.
The PBAC concluded that oral dabigatran 220 mg once daily was no
more effective, but possibly less safe, than subcutaneous
enoxaparin 40 mg once daily in the restriction requested for PBS
listing.
The PBAC considered that a comparison with rivaroxaban was
relevant, given the concurrent PBAC consideration of rivaroxaban.
The PBAC therefore deferred its consideration of dabigatran to give
the applicant an opportunity to compare the two new oral therapies
for the prevention of venous thromboembolic events.
Recommendation:
Defer
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Boehringer Ingelheim has sought the advice of the PBAC on a new
submission to enable dabigatran to be listed on the PBS.
