Rivaroxaban, tablet, 15 mg and 20 mg, Xarelto® - March 2012
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Public Summary Document
Product: Rivaroxaban, tablet, 15 mg and 20 mg, Xarelto®
Sponsor: Bayer Australia Limited
Date of PBAC Consideration: March 2012
1. Purpose of Application
The submission sought an Authority Required (STREAMLINED) listing for:
1) Initial treatment of confirmed acute symptomatic deep vein thrombosis (DVT) without symptomatic pulmonary embolism (PE) – 15 mg tablets; and
2) Continuing treatment of confirmed acute symptomatic DVT without symptomatic PE, and for the prevention of recurrent venous thromboembolism (VTE) with appropriate treatment duration of up to two years, dependent on the risk of VTE recurrence – 20 mg tablets.
A separate submission requesting an Authority Required (STREAMLINED) listing for rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation who meet certain criteria was also considered at the March 2012 PBAC meeting.
2. Background
Rivaroxaban had not been previously considered by the PBAC for this indication.
At its March 2009 meeting, the PBAC recommended an Authority Required 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.
3. Registration Status
Rivaroxaban 15 mg and 20 mg tablets were TGA registered on 13 April 2012 for the following indications:
- Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke;
- Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent DVT and pulmonary embolism (PE).
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Initial treatment of confirmed acute symptomatic deep vein thrombosis (DVT) without symptomatic pulmonary embolism (PE). This treatment should be followed by the recommended 20 mg once daily rivaroxaban recurrent venous thromboembolism (VTE) prophylactic regimen.
| Form & Strength | Max. Qty | No. of repeats |
| Tablet 15 mg | 42 | 0 |
Authority Required (STREAMLINED)
Continuing treatment of confirmed acute symptomatic deep vein thrombosis (DVT) without symptomatic pulmonary embolism (PE), and for the prevention of recurrent venous thromboembolism (VTE) with appropriate treatment duration of up to two years, dependent on the risk of VTE recurrence. Subsequent to completion of the recommended acute three week 15 mg twice daily rivaroxaban treatment regimen.
| Form & Strength | Max. Qty | No. of repeats |
|---|---|---|
| Tablet 20 mg | 28 | 5 |
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Therapeutic Guidelines – Cardiovascular (2008)
states that deep vein thrombosis of the legs has an incidence of about 1 in 1000 of the adult population per annum, and can be complicated by pulmonary embolism and/or the post thrombotic syndrome (PTS). Venous thromboembolism represents a spectrum of disease that includes both DVT and PE. Anticoagulation is highly effective in preventing PE and is indicated in most cases of DVT.
The submission proposed that the place in therapy of rivaroxaban is as an alternative to other PBS listed therapies for the treatment of DVT and prevention of recurrent VTE, namely low molecular weight heparin (LMWH - enoxaparin and dalteparin), unfractioned heparin, and warfarin.
6. Comparator
The submission nominated the treatment regimen of enoxaparin followed by warfarin as the main comparator. This was considered appropriate.
7. Clinical Trials
The submission presented one open-label randomised trial (EINSTEIN-DVT) investigating rivaroxaban 15 mg twice daily for three weeks, followed by 20 mg once daily compared with enoxaparin 1 mg/kg twice daily for a minimum of 5 days + vitamin K antagonist (VKA - warfarin or acenocoumarol) individually titrated dose to achieve a target international normalised ratio (INR) range of 2.0 – 3.0. Subjects included in the EINSTEIN-DVT trials were patients with symptomatic proximal DVT without symptomatic PE. An additional trial, the EINSTEIN-EXT trial, compared rivaroxaban 20 mg once daily with placebo for 6 – 12 months in patients who had completed 6 – 12 months of anticoagulant treatment for acute VTE, was also presented to provide supplementary evidence regarding the safety of rivaroxaban.
Details of the trials published at the time of
the submission are in the table below.
Trials and associated reports identified in the submission
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Phase III trials | ||
| EINSTEIN-DVT Bauersachs R et al |
Oral rivaroxaban for symptomatic venous thromboembolism. | The New England Journal of Medicine 2010; 363 (26): 2499-2510. |
| EINSTEIN-EXT Buller HR |
Once-daily oral rivaroxaban versus placebo in the long-term prevention of recurrent symptomatic venous thromboembolism. The EINSTEIN-extension study. (abstract) | Blood 2009: 114. |
No evidence was presented regarding the use of rivaroxaban for treatment of symptomatic distal DVT.
8. Results of Trials
The results for the primary composite outcome (recurrent symptomatic DVT and fatal/non-fatal PE) are presented in the following table. The primary outcome was analysed on the basis of both an intention-to-treat (ITT) principle and a per protocol (PP) population up to the end of the intended duration of treatment, using a Cox’s proportional hazard model stratified for intended treatment duration and adjusted for baseline malignancy.
Summary of results for the primary effectiveness outcome in the EINSTEIN-DVT trial
| Population | ITT (N = 3,449) |
PP (N = 3,096) |
|---|---|---|
| Cox’s proportional hazard modela | ||
|
Hazard ratio [95% CI] a,b |
0.680 [0.443,1.042] |
0.698 [0.444, 1.097] |
|
p-value for non-inferiorityb,c |
<0.0001 |
<0.0001 |
|
p-value for superiority |
0.0764 |
0.1191 |
| Incidence | ||
|
Rivaroxaban group, n/N (%) |
36/1731 (2.1%) |
32/1525 (2.1%) |
|
Enoxaparin/VKA group, n/N (%) |
51/1718 (3.0%) |
46/1571 (2.9%) |
| Absolute risk difference [95% CI] a |
-0.9% [-1.9%, 0.2%] |
-0.8% [-1.9%, 0.3%] |
| Relative risk [95% CI] a |
0.70 [0.46, 1.07] |
0.72 [0.46, 1.12] |
| Number needed to treat [95% CI] |
NNTB 113 |
NNTB 121 |
CI = confidence interval; ITT = intention-to-treat; NNTB = number needed to treat
to benefit; NNTH = number needed to treat to harm; PP = per protocol.
a Rivaroxaban vs enoxaparin/VKA
b Hazard ratio and p-value estimates based on stratified proportional hazards model,
with stratification based on intended treatment duration.
c The asymptotic one-sided p-value for non-inferiority was calculated based on the
log-hazard ratio estimated for rivaroxaban versus comparator, on its standard error
and on the log of the non-inferiority margin of 2.0.
The PBAC noted that a hazard ratio (HR) of 0.68 (95% CI: [0.44, 1.04]) (rivaroxaban vs. enoxaparin/VKA) was reported for the ITT population, for the composite outcome of recurrent symptomatic DVT and fatal/non-fatal PE. Similar results were reported in the PP population. The incidence data showed that the difference in the rate of primary composite event between the two treatment arms was mainly driven by the outcome of symptomatic DVT only.
Results of incidences of the primary composite endpoint and its components, during the intended treatment period are presented in the table below.
Incidence of the primary effectiveness endpoint and its components in the EINSTEIN-DVT trial
| Outcome/components | Incidence | RDa % [95% CI] | RRa [95% CI] | |
|---|---|---|---|---|
| Riva | Enox/VKA | |||
| ITT population | N=1,731 | N=1,718 | ||
| Components | ||||
| Primary composite outcome (recurrent symptomatic DVT and fatal/non-fatal PE) |
36 (2.1%) |
51 (3.0%) |
-0.9 [-1.9, 0.2] |
0.70 [0.46, 1.07] |
| Components | ||||
|
Death (PE cannot be excluded) |
3 (0.2%) |
6 (0.4%) |
-0.2 [-0.6, 0.2] |
0.50 [0.12, 2.00] |
|
Death (PE confirmed) |
1 (<0.1%) |
0 (0%) |
0.1 [-0.1, 0.2] |
Not calculable |
|
Symptomatic PE and DVT |
1 (<0.1%) |
0 (0%) |
0.1 [-0.1, 0.2] |
Not calculable |
|
Symptomatic PE only |
20 (1.2%) |
18 (1.1%) |
0.1 [-0.6, 0.8] |
1.03 [0.59, 2.08] |
| Symptomatic DVT only |
14 (0.8%) |
28 (1.6%) |
-0.8 [-1.6, -0.1] |
0.50 [0.26, 0.94] |
| PP population |
N=1,525 |
N=1,571 |
||
| Primary composite outcome (recurrent symptomatic DVT and fatal/non-fatal PE) |
32 (2.1%) |
46 (2.9%) |
-0.8 [-1.9, 0.3] |
0.72 [0.46, 1.12] |
|
Death (PE cannot be excluded) |
2 (0.1%) |
5 (0.3%) |
-0.2 [-0.5, 0.2] |
0.41 [0.08, 2.12] |
|
Death (PE confirmed) |
0 (0%) |
0 (0%) |
0.0 [0.0, 0.0] |
Not calculable |
|
Symptomatic PE and DVT |
1 (<0.1%) |
0 (0%) |
-0.1 [-0.1, 0.2] |
Not calculable |
|
Symptomatic PE only |
17 (1.1%) |
16 (1.0%) |
0.1 [-0.6, 0.8] |
1.10 [0.56, 2.16] |
| Symptomatic DVT only |
13 (0.9%) |
26 (1.7%) |
-0.8 [-1.6, 0.0] |
0.52 [0.27, 1.00] |
CI = confidence interval; DVT = deep vein thrombosis; Enox = enoxaparin; ITT = intention-to-treat;
PE = pulmonary embolism; PP = per protocol; RD = risk difference; Riva = rivaroxaban;
RR = relative risk; VKA = vitamin K antagonist
a Rivaroxaban vs enoxaparin/VKA.
The trial prespecified that the minimum clinically important difference (MCID) margin was the upper 95% CI for the HR of 2.0, for the primary composite outcome. The PBAC noted that the choice of this margin was not clearly justified. However, the observed upper limits of the 95% CIs from the results of the trial, i.e., upper limit for the HR of 1.04, and 0.2% for the absolute risk difference are unlikely to include clinically important differences.
For PBAC’s view, see Recommendations and Reasons
The principal safety endpoints in the EINSTEIN-DVT trial were major bleeding or clinically relevant non-major bleeding event during the period between randomisation to 2 days after cessation of medication.
The PBAC noted the risks of major bleeding or clinically relevant non-major bleeding events was higher in the rivaroxaban group during the earlier study period (0 – 4 months) and in the enoxaparin/VKA group after month 6.
About 90% of the principal safety events were clinically relevant non-major bleeding events, which occurred more in the rivaroxaban arm than in the enoxaparin/VKA arm. Higher incidences of all bleeding events and bleeding-related treatment discontinuation were observed in patients receiving rivaroxaban therapy. The risk of fatal bleeds was numerically lower in the rivaroxaban arm compared to enoxaparin/VKA. Therefore any increase in bleeds did not appear to be causing increased mortality.
9. Clinical Claim
The submission described rivaroxaban as non-inferior in terms of comparative effectiveness and non-inferior in terms of comparative safety with enoxaparin/VKA for treatment of acute symptomatic DVT without symptomatic PE. The PBAC accepted this claim.
For PBAC’s view, see Recommendations and Reasons
10. Economic Analysis
The submission presented a cost minimisation analysis. The submission claimed that the data supported that rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily for the remainder of the 6-month treatment period is equi-effective to enoxaparin 1 mg/kg twice daily for 8.7 days + warfarin 5mg for 6 months.
The Pre-Sub-Committee Response (PSCR) presented a revised cost-minimisation analysis incorporating the lower dose regimen of enoxaparin (1.5 mg/kg once daily). The proportional split between the lower and higher regimens was determined from the Intercontinental Medical Statistics (IMS) patients audit data for patients starting on LMWH going onto warfarin maintenance therapy. It was assumed all initial enoxaparin therapy daily doses listed above 100 mg would require two injections. Of note, all patients in the audit receiving twice daily enoxaparin injections had proximal DVT and those receiving once daily enoxaparin injections had distal DVT. The revised analysis also accounted for the reduced home nursing visits for the proportion of patients only requiring a single visit per day. The MBS costs per GP visit had also been corrected in the PSCR.
The PBAC considered that basing the economic analysis on a duration of 6 months ignored the differing influence of fixed and variable costs. Hospitalisation costs were incurred in the first week and thus fixed, whereas drug costs, GP visits and INR testing were variable with time. The variable cost difference in drug acquisition costs less GP visits and INR testing was offset by the fixed initial difference in hospital costs ($270.42) between the two treatment arms. The overall cost of rivaroxaban therapy was higher than that for enoxaparin/VKA for any treatment duration longer than 6 months.
For PBAC’s view, see Recommendations and Reasons
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients treated per year to be less than 10,000 patients in year 5 of listing, at an estimated net cost per year to the PBS of less than $10 million in year 5.
The PBAC considered that these estimates may be underestimates, with the main areas of uncertainty being the incidence rates used in the submission, market uptake, duration of therapy and usage outside the requested PBS restriction (such as primary prophylaxis for DVT and/or use beyond 2 years).
For PBAC’s view, see Recommendations and Reasons
12. Recommendation and Reasons
The PBAC recommended listing rivaroxaban 15 mg and 20 mg tablets on the PBS on a cost minimisation basis compared with enoxaparin and warfarin with a cost offset for the additional INR tests associated with warfarin treatment.
The PBAC noted the results of the EINSTEIN-DVT trial. The PBAC considered rivaroxaban to be non-inferior in terms of clinical effectiveness compared to enoxaparin and warfarin in the prevention of recurrent venous thromboembolism (VTE) and fatal/non fatal pulmonary embolism (PE) in patients with symptomatic proximal deep vein thrombosis (DVT) without PE. In regard to safety there were some differences in bleeding risk, but the PBAC overall agreed with the submission that it is non-inferior in terms of safety compared to warfarin and enoxaparin.
The PBAC did not accept the cost analysis presented by the submission. The PBAC considered that there was not sufficient evidence presented to justify the additional cost offsets in relation to hospitalisation, nursing time, and GP visits compared with enoxaparin and warfarin treatment that were claimed by the submission. The PBAC noted the revised cost-minimisation analysis presented in the Pre-Sub-Committee Response which took into consideration the lower dosage regimen of 1.5 mg/kg/day. Based on this the PBAC accepted that the equi effective doses for 6 months treatment are rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily for 6 months is equivalent to enoxaparin 1 mg/kg twice daily for 8.7 days or enoxaparin 1.5 mg/kg once daily for 8.7 days (taking into account the proportions of patients receiving twice daily and once daily dosing), both followed by warfarin 5 mg daily for 6 months.
The PBAC was concerned with use beyond the requested PBS restriction, such as primary prophylaxis of DVT and/or use beyond 2 years and noted that this may add substantially to the overall cost. The PBAC therefore recommended that a Risk Sharing Agreement be entered into, using financial caps based on the financial expenditure estimates presented in the submission, adjusted for the lower price of rivaroxaban resulting from lesser offsets than claimed by the submission. If estimated expenditure increased above the caps the price should revert to the cost of enoxaparin and warfarin.
The PBAC recommended the Safety Net 20 Day rule should apply.
The PBAC recommended that rivaroxaban is suitable for inclusion in the PBS medicines for prescribing by nurse practitioners within collaborative arrangements under a Shared Care Model.
Recommendation:
RIVAROXABAN, tablet, 15 mg and 20 mg
Restriction:
Authority Required (STREAMLINED)
Initial treatment of confirmed acute symptomatic deep vein thrombosis without symptomatic
pulmonary embolism.
Note
No applications for increased maximum quantities and/or repeats will be authorised.
Note
Shared Care Model:
For prescribing by nurse practitioners where care of a patient is shared between a
nurse practitioner and medical practitioner in a formalised arrangement with an agreed
management plan. Further information can be found in the Explanatory Notes for Nurse
Practitioners.
Max quantity: 42 (15 mg)
Repeats: 0
Restriction: Authority Required (STREAMLINED)
Continuing treatment of confirmed acute symptomatic deep vein thrombosis without symptomatic
pulmonary embolism.
Continuing treatment for prevention of recurrent venous thromboembolism.
Note
No applications for increased maximum quantities and/or repeats will be authorised.
Note
Shared Care Model:
For prescribing by nurse practitioners where care of a patient is shared between a
nurse practitioner and medical practitioner in a formalised arrangement with an agreed
management plan. Further information can be found in the Explanatory Notes for Nurse
Practitioners.
Max quantity: 28 (20 mg)
Repeats: 5
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 welcomes the PBAC’s positive recommendation and will work with the Pharmaceutical Evaluation Branch and the PBAC to make rivaroxaban available for patients suffering from deep vein thrombosis.
