Rivaroxaban, tablet, 10 mg, Xarelto®, March 2009
Public summary document for Rivaroxaban, tablet, 10 mg, Xarelto®, March 2009
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Public Summary Document
Product: Rivaroxaban, tablet, 10 mg,
Xarelto®
Sponsor: Bayer Australia Limited
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought a section 85 Authority required (Streamlined)
listing and a section 100 (s100) Private Hospital Authority
required listing for rivaroxaban for prevention of venous
thromboembolism (VTE) in a patient undergoing hip or knee
replacement.
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate facilities.
2. Background
This was the first time rivaroxaban had been considered by the
PBAC.
3. Registration Status
Rivaroxaban was TGA registered on 24 November 2008 for the
prevention of venous thromboembolism (VTE) in adult patients who
have undergone major orthopaedic surgery of the lower limbs
(elective total hip replacement, treatment for up to 5 weeks;
elective total knee replacement, treatment for up to 2
weeks).
4. Listing Requested and PBAC’s View
Section 85 Authority Required (STREAMLINED)
For the prevention of venous thromboembolism in an adult patient
undergoing elective total hip replacement surgery (treatment for up
to 5 weeks);
For the prevention of venous thromboembolism in an adult patient
undergoing elective total knee replacement surgery, (treatment for
up to 2 weeks).
Section100 (Highly Specialised Drug)
Private hospital authority required
For the prevention of venous thromboembolism in an adult patient
undergoing elective total hip replacement surgery (treatment for up
to 5 weeks);
For the prevention of venous thromboembolism in an adult patient
undergoing elective total knee replacement surgery, (treatment for
up to 2 weeks).For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Rivaroxaban will provide an oral alternative to the currently
available injectable anti-thrombotic drugs used to prevent venous
thromboembolism (VTE) in patients who have undergone major
orthopaedic surgery of the lower limb (total hip or knee
replacement).
6. Comparator
The submission nominated enoxaparin as the main comparator. The
PBAC accepted this as appropriate.
7. Clinical Trials
The submission presented two randomised key trials to support the
listing of rivaroxaban for total hip replacement and one randomised
trial to support the listing of rivaroxaban for total knee
replacement, as follows:
Total hip replacement:
- RECORD 1: comparing rivaroxaban 10 mg for 35 days with enoxaparin 40 mg for 35 days, consistent with current best practice; and
- RECORD 2: comparing rivaroxaban 10 mg for 35 days with enoxaparin 40 mg for 12 ± 2 days
Total knee replacement:
- RECORD 3: comparing rivaroxaban 10 mg for 12 ± 2 days with enoxaparin 40 mg for 13 ± 2 days, consistent with both current and best practice.
The PBAC agreed that the duration of enoxaparin use in the trials
submitted (medians ranged from 13 to 36 days in hip replacement and
13 days in knee replacement) reflected the range of durations in
Australian practice.
The trials published at the time of the submission, are as follows:
| Trial/First author | Protocol title | PublicationCitation |
| Direct randomised trial(s) | ||
| RECORD 1 | ||
| Eriksson, B. et al | Oral Rivaroxaban Compared with Subcutaneous Enoxaparin for Extended Thromboprophylaxis after Total Hip Arthroplasty: The RECORD1 Trial. | ASH Annual Meeting Abstracts 2007, vol. 110, no. 11, Abstract 6, 2007. |
| Eriksson, B. et al | Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. | New England Journal of Medicine, 358(26): 2765-2775, 2008. |
| RECORD 2 | ||
| Kakkar A. K. et al. 2007 | Extended Thromboprophylaxis with Rivaroxaban Compared with Short-Term Thromboprophylaxis with Enoxaparin after Total Hip Arthroplasty: The RECORD 2 Trial. | ASH Annual Meeting Abstracts 2007, vol. 110, no. 11, Abstract 307. |
| RECORD 3 | ||
| Lassen M. R, et al | Rivaroxaban - An Oral, Direct Factor Xa Inhibitor - for Thromboprophylaxis after Total Knee Arthroplasty: The RECORD3 Trial. | ASH Annual Meeting Abstracts 2007, vol. 110, no. 11, Abstract 308. |
| Lassen M. R, et al | Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. | New England Journal of Medicine, 358(26): 2776-2786, 2008. |
ASH=American Society of Hematology; DVT=deep vein thrombosis;
PE=pulmonary embolism; VTE=venous thromboembolism.
8. Results of Trials
The results of the trials and associated reports presented in the submission are described
below:
Total hip replacement
The results for the primary composite outcome, total VTE, in RECORD 1 and RECORD 2,
demonstrated that rivaroxaban was significantly superior in efficacy to enoxaparin
in the prevention of VTE in adult patients undergoing elective total hip replacement
over the duration of the trial (median time of 13 to 36 days). The disaggregated components
of this endpoint also favoured rivaroxaban. The PBAC noted the observed risk difference
in each of the trials (RECORD 1: -2.6%, 95%CI -3.7%, -1.5%; RECORD 2: -7.3%, 95%CI
-9.4%, -5.2%) was likely to be significant given the incidence of total VTE in the
comparator group of 3.7% and 9.3% for RECORD 1 and RECORD 2 respectively.
Total knee replacement
The results for the primary composite outcome, total VTE, in RECORD 3 demonstrated
that rivaroxaban was significantly superior in efficacy to enoxaparin in the prevention
of VTE in adult patients undergoing elective total knee replacement over the duration
of the trial (median time of 13 days). The observed risk difference (-9.2%, 95% CI
-12.4%, -5.9%) was likely to be regarded as clinically significant given the incidence
of total VTE in the enoxaparin treatment group was 18.9%.
The PBAC noted the results for total VTE in all three trials were heavily weighted
by the larger proportion of asymptomatic deep vein thrombosis (DVT) and distal DVT.
However, the secondary composite outcome measures, which excluded all distal DVT,
also supported the superior efficacy of rivaroxaban over enoxaparin in patients undergoing
total hip replacement (THR) and total knee replacement (TKR).
Between 30-35% of randomised participants were excluded from the analysis of the primary
outcome in each of the trials. The main reason for exclusion was inadequate assessment
(either no venography or unilateral or non-evaluable venography). Excluded participants
were evenly distributed between treatment groups in all of the trials and the reasons
for exclusion were also similar between groups. Comparison of the baseline characteristics
between the safety population and the primary efficacy analysis set for each trial
failed to detect any differential loss to follow-up between the treatment groups.
The primary outcome for all of the RECORD trials was total VTE, a composite endpoint
including any symptomatic or asymptomatic DVT (proximal and/or distal), non-fatal
pulmonary embolism (PE), and death from all causes. The PBAC noted the recommendation
in current international guidelines is to use a composite, including all proximal
DVT, symptomatic non-fatal pulmonary embolism (PE), VTE related death or death due
to any cause, ± symptomatic distal DVT. Asymptomatic distal DVT was not included in
the recommended composite endpoints in these guidelines. Although the primary composite
outcome in all three trials included asymptomatic distal DVT, both the disaggregated
components of this endpoint, and a number of secondary composite outcomes which did
not include all distal DVT, supported the superiority of rivaroxaban over enoxaparin
in all of the trials included in the submission.
The submission provided data on the incidence of treatment-emergent major bleeding
and a summary of other adverse events in each of the RECORD trials. The safety of
prolonged use of rivaroxaban has not been evaluated.
A summary of the treatment emergent bleeding events in the direct randomised trials
is shown in the table below:
| Trial ID | Rivaroxaban n with event/N (%) | Enoxaparin n with event/N (%) | Risk Difference RD % (95%CI) | RR (95% CI) |
| Total hip replacement | ||||
| RECORD 1 | ||||
| Major bleeding a | 6/2209 (0.3) | 2/2224 (<0.1) | 0.18 (-0.07,0.43) | 3.02 (0.61,15.0) |
| Any bleeding | 133/2209 (6.0) | 131/2224 (5.9) | 0.13 (-1.26,1.52) | 1.02 ( 0.81,1.29) |
| Clinically relevant bleeding | 70/2209 (3.2) | 56/2224 (2.5) | 0.65 (-0.33,1.63) | 1.26 (0.89,1.78) |
| Non major bleeding | 128/2209 (5.2) | 129/2224 (5.8) | -0.01(-1.38,1.37) | 1.00 (0.79,1.27) |
| Non major clinically relevant bleeding | 65/2209 (2.9) | 54/2224 (2.4) | 0.51(-0.44,1.47) | 1.21 (0.85,1.73) |
| Other non major bleeding | 71/2209 (3.2) | 77/2224 (3.5) | -0.25 (-1.31,0.81) | 0.93 (0.68,1.28) |
| Major bleeding including surgical site bleeding b | 40/2209 (1.8) | 33/2224 (1.5) | 0.33 (-0.42,1.08) | 1.22 (0.77,1.93) |
| RECORD 2 | ||||
| Major bleeding a | 1/1228 (<0.1) | 1/1229 (<0.1) | 0.00 (-0.00 0.00) | 1.00 (0.06,5.98) |
| Any bleeding | 81/1228 (6.6) | 68/1229 (5.5) | 1.06 (-0.82,2.95) | 1.19 (0.87,1.63) |
| Clinically relevant bleeding | 41/1228 (3.3) | 34/1229 (2.8) | 0.57 (-0.79,1.93) | 1.21 (0.77,1.89) |
| Non major bleeding | 80/1228 (6.5) | 67/1229 (5.5) | 1.06 (-0.81,2.94) | 1.20 (0.87,1.64) |
| Non major clinically relevant bleeding | 40/1228 (3.3) | 33/1229 (2.7) | 0.57 (-0.77,1.91) | 1.21 (0.77,1.91) |
| Other non major bleeding | 43/1228 (3.5) | 36/1229 (2.9) | 0.57 (-0.82,1.97) | 1.20 (0.77,1.85) |
| Major bleeding including surgical site bleeding b | 23/1228 (1.9) | 19/1229 (1.6) | 0.33 (-0.70,1.35) | 1.21 (0.66,2.21) |
| Total knee replacement | ||||
| RECORD 3 | ||||
| Major bleeding a | 7/1220 (0.6) | 6/1239 (0.5) | 0.09 (-0.48,0.66) | 1.18 (0.40,3.52) |
| Any bleeding | 60/1220 (4.9) | 60/1239 (4.8) | 0.08 (-1.63,1.78) | 1.02 (0.72,1.44) |
| Clinically relevant bleeding | 40/1220 (3.3) | 34/1239 (2.7) | 0.53 (-0.82,1.89) | 1.19 (0.76,1.87) |
| Non major bleeding | 53/1220 (4.3) | 54/1239 (4.4) | -0.01 (-1.63,1.60) | 1.00 (0.69,1.44) |
| Non major clinically relevant bleeding | 33/1220 (2.7) | 28/1239 (2.3) | 0.45 (-0.79,1.68) | 1.20 (0.73,1.97) |
| Other non major bleeding | 22/1220 (1.8) | 31/1239 (2.5) | -0.70 (-1.85,0.45) | 0.72 (0.42,1.24) |
| Major bleeding including surgical site bleeding b | 21/1220 (1.7) | 17/1239 (1.4) | 0.35 (-0.63,1.33) | 1.25 (0.67,2.37) |
RR=relative risk.
a Primary safety outcome. This outcome does not include bleeding at the surgical site.
b Incidence of treatment emergent major bleeding events after removing the restriction
to extra-surgical site for those bleeding events associated with a fall in haemoglobin
of ≥2g/dL or for those bleeding events leading to transfusions of ≥2units of whole
blood or packed cells.
The incidence of major bleeding in the trials in patients undergoing THR (RECORD 1
& 2) was low for both drugs ( <0.1 – 0.31) and there was no statistically significant
difference between the rivaroxaban and enoxaparin treatment groups in either trial.
The PBAC noted trials were underpowered for detecting any statistically significant
difference in the rate of treatment-emergent major bleeding events. The PBAC also
noted there were insufficient data to determine accurately the comparative incidence
of cardiovascular events for the two drugs. Minimal information was available regarding
the potential effect of rivaroxaban on hepatic and renal function or the potential
for other rare or delayed adverse events. There were no safety data for patient groups
other than those undergoing elective total hip replacement and elective total knee
replacement.
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The submission claimed that rivaroxaban was superior in terms of
comparative effectiveness and equivalent in terms of comparative
safety over enoxaparin for prevention of VTE in patients undergoing
elective total hip replacement and elective total knee
replacement.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
A modelled economic evaluation was presented. The type of economic
evaluation presented was a cost-utility analysis with a 5.25 years
time horizon.
The outcomes used in the economic evaluation were years of life
(YoL) gained and quality-adjusted life-years (QALYs) gained. An
individual patient level simulation was used to generate the
results.
The model based on RECORD 1 was driven by the transition
probabilities in the extrapolation period and consequent costs of
diagnosis and treatment of long-term complications, as well as
their utilities. Risks of recurrent VTE and of post-thrombotic
syndrome (PTS) after symptomatic DVT were not derived from the
population for whom PBS listing is sought. Utilities values were
derived from varied population using varied methods.
Compared with the model based on RECORD 1, the model based on
RECORD 2 was more significantly driven by age-stratified VTE rates
and the long term extrapolations.
The trial-based economic evaluation using RECORD 1 and RECORD 2
resulted in an incremental cost-effectiveness ratio (ICER) of up to
$75,000 per QALY dependent on the inclusion of symptomatic,
asymptomatic, recurrent VTE, PTS and pulmonary embolism (PE)
complications. The ICER for RECORD 1 and RECORD 2 dropped to
between $15,000 - $45,000 and less than $15,000, respectively,
following the inclusion of the risk reduction for recurrent VTE and
long-term complications in the economic evaluation.
With respect to RECORD 3, the preliminary economic evaluation
resulted in an ICER of between $105,000 – $200,000 per QALY.
However, in the stepped economic evaluation, an ICER in the range
of $15,000 - $45,000 accounting for a risk reduction in the
conversion of asymptomatic to symptomatic VTE within 90-days post
surgery in the economic evaluation was calculated. Rivaroxaban was
more effective and less costly than enoxaparin if the risk of
post-thrombotic syndrome (PTS) in the long term for asymptomatic
patients, and pulmonary embolism (PE) case fatality rate in the
long term were accounted for in the economic model.
The economic evaluation showed that the utility values and the
conversion from asymptomatic to symptomatic VTE and its long-term
complications appeared to drive the model in demonstrating the
greater effectiveness and lower cost of rivaroxaban over
enoxaparin.
In all three models, the incremental gains in years of life and
quality-adjusted life-years were minimal, which resulted in an ICER
sensitive to small changes in both costs and effectiveness.
Sensitivity analyses indicated that the model was sensitive to the
proportion of people who needed home nursing to assist with
enoxaparin injection, as well as the transition probabilities
between VTE and its long term extrapolations, all of which were
subject to uncertainty.
The time horizon played an important role in the ICER calculation.
In the model based on each of the RECORD trials, the incremental
cost/YoL and incremental cost/QALY decreased dramatically from Year
0.25 to Year 5.25, even in the absence of extrapolation of long
term events.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients/year
expected to receive rivaroxaban for total hip and knee replacement
would be between 50,000 – 100,000 in Year 5, with a financial
cost/year to the PBS of < $10 million.
The submission’s estimates however were considered an
approximation due to uncertainty regarding the expected rate of
uptake of rivaroxaban and the current level of use of enoxaparin
for this indication.
12. Recommendation and Reasons
The PBAC recommended listing of rivaroxaban tablet 10 mg for the
prevention of venous thromboembolism in adult patients undergoing
elective total replacement of the hip or knee on the basis of
uncertain but overall acceptable cost-effectiveness compared with
enoxaparin. Listing under section 100 was not recommended as
rivaroxaban does not meet all five selection criteria. The maximum
quantities should align with the pack sizes and the Therapeutic
Goods Administration (TGA)-recommended durations of use (five weeks
for hip replacement and two weeks for knee replacement) to minimise
wastage. The PBAC noted that the quantities to be subsidised by the
PBS would differ according to whether the therapy is initiated in
the public hospital setting or the private hospital setting.
The PBAC agreed that subcutaneous enoxaparin was the appropriate
main comparator, and that the duration of its use in the trials
submitted (medians ranged from 13 to 36 days in hip replacement and
13 days in knee replacement) reflected the range of durations in
Australian practice.
The primary outcome analysed in the randomised trials 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 trials, there were 30% to 35% 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 each trial. Thus the conclusion for superior
effectiveness rested on a reckoning 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 rivaroxaban. This is
of concern because of the potential of increasing clinically
important bleeding; the exclusion of surgical site bleeding from
the definition of “major bleeding” unless also
associated with haemoglobin changes and/or requiring transfusion;
the paucity of evidence available in the extended assessment of
harms; the likelihood that these trials were underpowered to detect
this outcome; and the lack of an accepted asymptomatic endpoint or
measure that is more commonly occurring and can predict these rare
events.
The PBAC noted that, despite concerns with the use of (a) utilities
from across multiple sources, and (b) transition probabilities
between events derived from non-surgical patients, the economic
evaluation was relatively robust to these sources of uncertainty.
The incremental cost-effectiveness ratio was most sensitive to the
time horizon, reflected by the large reduction in the ICER from the
0.25-year duration of follow-up in the trials to the 5.25-year
duration of the modelled economic evaluation. This reflects the
sensitivity of the economic evaluation both to small differences in
the major clinical outcomes of pulmonary emboli and deaths and also
to the justified inclusion of recurrent venous thrombotic events
and the post-thrombotic syndrome.
The PBAC concluded that oral rivaroxaban 10 mg once daily was more
effective, but possibly less safe, than subcutaneous enoxaparin 40
mg once daily in the restrictions requested for PBS listing and
across the range of durations of use of enoxaparin currently used
in Australia. The Committee recommended listing on the basis of
uncertain but overall acceptable cost-effectiveness.
The PBAC suggested that the NPS consider providing a RADAR suitable
for consumers as well as a RADAR suitable for health
professionals.
Recommendation:
RIVAROXABAN, tablet, 10 mg, 15 tablet pack, 30 tablet pack
Restriction:
Authority Required
Prevention of venous thromboembolism in a patient undergoing total
hip replacement.
Max Qty: 10, 1(15 tablet pack), 1(30 tablet pack)
Repeats: 1(10 tablets), 1(15 tablet pack), nil (30 tablet
pack)
NOTE:
No applications for increased maximum quantity and/or repeats will
be authorised for the 30 tablet packAuthority
Required
Prevention of venous thromboembolism in a patient undergoing total
knee replacement.
Max Qty: 10, 1(15 tablet pack)
Repeats: nil
NOTE:
No applications for increased maximum quantities and/or repeats
will be authorised.
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
Bayer is pleased with the positive PBAC recommendation and
encourages anyone interested in further discussing the data to
contact the company. Bayer does not agree with the PBACs conclusion
regarding safety. A published meta-analysis of the RECORD 1-3
trials is now available (post-PBAC) which (addresses this issue
and) supports the companies claim of similar safety.
