Apixaban, tablet 2.5 mg, Eliquis® - July 2011
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Public Summary Document
Product: Apixaban, tablet 2.5 mg,
Eliquis®
Sponsor: Bristol-Myers Squibb Australia Pty
Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The submission sought an Authority required listing for the
prevention of venous thromboembolism (VTE) in patients undergoing
total knee replacement (TKR) or total hip replacement (THR).
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Apixaban was TGA registered on 21 July 2011 for the prevention of
venous thromboembolic events (VTE) in adult patients who have
undergone elective total hip or total knee replacement
surgery.
4. Listing Requested and PBAC’s View
Authority Required
Prevention of venous thromboembolism in a patient undergoing total
knee replacement.
Note:
No applications for increased maximum quantities and/or repeats
will be authorised for the 20 tablet pack.
Maximum quantity: 20
Repeats: 0
Authority Required
Prevention of venous thromboembolism in a patient undergoing total
hip replacement.
Note:
No applications for increased maximum quantities and/or repeats
will be authorised for the 60 tablet pack.
Maximum quantity: 60
Repeats: 0
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Venous thromboembolic events (VTE) represent a major cause of
morbidity and a significant cause of mortality in hospitalised
patients. Total hip replacement (THR) and total knee replacement
(TKR) are high risk factors for VTE if no thromboprophylaxis is
administered. VTE is associated with serious complications
including post-thrombotic syndrome, recurrent deep vein thrombosis
and death.
The submission proposed that the place in therapy of apixaban is as
an alternative oral therapy to rivaroxaban, and to enoxaparin for
the prevention of VTE in patients undergoing either THR or
TKR.
6. Comparator
The submission nominated rivaroxaban as the main comparator and
enoxaparin as a secondary comparator. This was accepted by the
PBAC.
7. Clinical Trials
The submission presented two randomised trials comparing apixaban
(2.5mg twice daily (BD)) with enoxaparin (40mg sub-cutaneously (SC)
once daily (QD)) in patients undergoing TKR (ADVANCE-2, length of
treatment: 11 ± 2 days) or THR (ADVANCE-3, length of
treatment 34 ± 3 days).
The submission also presented two indirect comparisons with two
randomised trials comparing rivaroxaban (10mg QD) with enoxaparin
(40mg SC QD) in patients undergoing TKR (RECORD-3, length of
treatment 10-14 days) or THR (RECORD-1, length of treatment 35
days). A sensitivity analysis of the indirect comparison for THR
was also conducted using two randomised trials (RECORD-2 and Kanan)
comparing rivaroxaban (10mg QD) with enoxaparin (40mg SC QD).
Publication details of the trials and associated reports presented
in the submission are in the table below.
| Trial ID | Protocol title/ Publication title | Publication citation |
| Common reference: enoxaparin | ||
| Apixaban vs enoxaparin trials: TKR | ||
| ADVANCE-2 (CSR 185047) (NCT00452530) Lassen MR et al . Lassen MR et al . | Late breaking clinical trial: The ADVANCE-2 study: A randomized double-blind trial comparing apixaban with enoxaparin for thromboprophylaxis after total knee replacement. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. | Journal of Thrombosis and Haemostasis , 2009; 7 (S2) (pp 1203-1204), 2009. Lancet , 2010; 375(9717):807-15. |
| Rivaroxaban vs enoxaparin trials: TKR | ||
| RECORD-3 (NCT00361894) Lassen MR et al . Lassen MR et al . Lassen, MR et al . Lassen MR et al . Lassen MR et al . | Rivaroxaban - An oral, direct, Factor Xa inhibitor - for thromboprophylaxis after total knee arthroplasty: The RECORD3 trial. Rivaroxaban: An oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in total knee replacement surgery - Results of the RECORD3 study. The oral, direct factor Xa inhibitor rivaroxaban vs enoxaparin for prevention of venous thromboembolism after total knee replacement: RECORD3. A phase III study of rivaroxaban - an oral, direct factor Xa inhibitor - versus subcutaneous enoxaparin after total knee replacement: RECORD3. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. | Blood , 2007; 110(11, Part 1):97A-98A. XXIst Congress of the International Society on Thrombosis and Haemostasis ; 2007 Jul 6-12; Geneva. Br.J.Haematol . 2008; 141 (Suppl 1): Abs177. Pathophysiology of Haemostasis and Thrombosis , 2008; 36(Suppl 1):A15. New England Journal of Medicine , 2008; 358(26):2776-86. |
| Misselwitz F et al . | Rivaroxaban, an oral, direct factor-Xa inhibitor in the prevention of venous thromboembolisms after total knee replacement - Results of the RECORD3 study. Rivaroxaban, ein oraler, direkter Faktor-Xa-Hemmer zur Pravention von venosen Thromboembolien nach totalem Kniegelenkersatz - Ergebnisse der RECORD3-Studie. | Medizinische Klinik , 2008, 103(3):15. |
| Apixaban vs enoxaparin trials: THR | ||
| ADVANCE-3 (CSR 185035) (NCT00423319) Lassen MR et al . Lassen MR et al . | Randomized double-blind comparison of apixaban and enoxaparin for thromboprophylaxis after hip replacement: The advance-3 trial. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. | 21st International Congress on Thrombosis - The Start of a New Era Antithrombotic Agents Milan Italy . Conference Publication: 37 (pp A20), 2010. New England Journal of Medicine , 2010; 363(26):2487-2498 |
| Rivaroxaban vs enoxaparin trials: THR | ||
| Kanan Kanan PS et al . | Estudo comparativo entre rivaroxaban e enoxaparina na profilaxia de tromboembolismo venoso profundo em pacientes submetidos à artroplastia total do quadril. Comparative study between rivaroxaban and enoxaparin in deep venous thromboembolism prophylaxis in patients submitted to total hip arthroplasty. | Rev Bras Ortop , 2008; 43(8):319-28. |
| RECORD-1 (NCT00329628) Eriksson BI et al . Eriksson BI et al . Eriksson BI et al . Haas S et al . Haas S et al . | Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprophylaxis after total hip arthroplasty: The RECORD1 trial. Oral rivaroxaban compared with subcutaneous enoxaparin for extended thromboprophylaxis after total hip arthroplasty: RECORD1 trial. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. Rivaroxaban, an oral, direct factor Xa inhibitor in extended prophylaxis of thromboembolism after total hip replacement: RECORD1. Oral rivaroxaban in comparison with enoxaparin in the extended thrombosis prophylaxis after hip replacement: The RECORD1 study. Orales Rivaroxaban im Vergleich zu Enoxaparin in der verlangerten Thromboseprophylaxe nach Huftgelenkersatz: Die RECORD1-Studie. | Blood , 2007; 110(11, Part 1):9A-10A. Br.J.Haematol . 2008 (Suppl. 1); 141, Abs224. New England Journal of Medicine , 2008; 358(26):2765-75. Pathophysiology of Haemostasis and Thrombosis , 2008; 36(Suppl 1):A15. Medizinische Klinik , 2008; 103(3):15. |
| RECORD-2 (NCT00332020) Kakkar AK et al . Kakkar A K et al . Kakkar AK et al . Kakkar AK et al . Mouret P et al . | Extended thromboprophylaxis with rivaroxaban compared with short-term thromboprophylaxis with enoxaparin after total hip arthroplasty: The RECORD2 trial RECORD2: extended thromboprophylaxis with rivaroxaban versus short-term thromboprophylaxis with enoxaparin after total hip replacement. A phase III study of extended thromboprophylaxis with oral rivaroxaban versus short-term subcutaneous enoxaparin after total hip replacement: RECORD2. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Extended thrombosis prophylaxis with rivaroxaban in comparison to short-term thrombosis prophylaxis with enoxaparin after total hip replacement: The RECORD2 study. Verlangerte Thromboseprophylaxe mit Rivaroxaban im Vergleich zur Kurzzeit-Thromboseprophylaxe mit Enoxaparin nach totalem Huftgelenkersatz: Die RECORD2-Studie. | Blood , 2007; 110(11, Part 1):97A. Br.J.Haematol . 2008; 141 (Suppl 1): Abs176. Pathophysiology of Haemostasis and Thrombosis , 2008; 36(Suppl 1):A15. Lancet , 2008; 372(9632):31-9. Medizinische Klinik , 2008, 103(3):15 |
8. Results of Trials
The primary efficacy outcome in all studies was a composite of all VTE / all-cause
death.
TKR
The results of the primary and secondary outcomes from the ADVANCE-2 trial are presented
in the following table. The PBAC noted that around 35% of the sample had non-evaluable
venograms and so were excluded from the analysis, and much of the efficacy is driven
by a reduction in asymptomatic DVT.
Results of primary and main secondary outcome in ADVANCE-2
| Trial ID | Apixaban 2.5mg BID n with event/N % (95% CI) | Enoxaparin 40mg QD n with event/N % (95% CI) | RD % (95% CI) | RR (95% CI) |
| Primary outcome: All VTE/All-Cause Death* | 147/976 15.06 (12.96, 17.46) | 243/997 24.37 (21.81, 27.14) | -9.27 (-12.74, -5.79) | 0.62 (0.51, 0.74) |
| Main secondary outcome: Major VTE** | 13/1195 1.09 (0.62, 1.88) | 26/1199 2.17 (1.47, 3.18) | -1.04 (-2.03, -0.05) | 0.50 (0.26, 0.97) |
NR = Not reported; RD = risk difference, RR = relative risk.
* Primary data set: All randomised patients who, during the intended treatment period,
had an adjudicated and evaluable bilateral venogram; or had an adjudicated VTE; or
died due to any cause.
event associated with the endpoint, during the Intended Treatment Period.
** Randomised subjects with either an adjudicated and evaluable bilateral proximal venogram or an adjudicated event associated with the endpoint, during the Intended
Treatment Period
In ADVANCE-2, apixaban was shown to be statistically significantly superior to enoxaparin
for the primary outcome of the composite of all VTE/all-cause death (RR=0.62 [95%
CI: 0.51, 0.74]), and the main secondary outcome of major VTE (RR=0.50 [95% CI: 0.26,
0.94]).
The results of the indirect comparison of apixaban and rivaroxaban using ADVANCE-2
and RECORD-3 are presented in the following table.
Summary of results of the indirect comparison of efficacy outcomes
| Trial ID | Apixaban | Rivaroxaban | Indirect estimate of effect c (95% CI) | ||||
| Treatment effect a (95% CI) | Apixaban n with event/ N (%) | Enoxaparin n with event/ N (%) | Enoxaparin n with event/ N (%) | Rivaroxaban n with event/ N (%) | Treatment effect b (95% CI) | ||
| Primary Efficacy Endpoint (all VTE/ all-cause death), Relative Risk | |||||||
| ADVANCE-2 | 0.62 (0.51,0.74) | 147/976 (15.06%) | 243/997 (24.37%) | – | – | – | – |
| RECORD-3 | – | – | – | 166/878 (18.91%) | 79/824 (9.59%) | 0.51 (0.39,0.65) | – |
| Pooled d | – | – | – | – | – | – | 1.219 (0.893,1.664) |
| Primary Efficacy Endpoint (all VTE/ all-cause death), Absolute Risk Difference | |||||||
| ADVANCE-2 | -0.09 (-0.13,-0.06) | 147/976 (15.06%) | 243/997 (24.37%) | – | – | – | – |
| RECORD-3 | – | – | – | 166/878 (18.91%) | 79/824 (9.59%) | -0.09 (-0.13,-0.06) | – |
| Pooled d | – | – | – | – | – | – | 0.000 (-0.048,0.048) |
| Secondary Efficacy Endpoint (Major VTE), Relative Risk | |||||||
| ADVANCE-2 | 0.50 (0.26,0.97) | 13/1195 (1.09%) | 26/1199 (2.17%) | – | – | – | – |
| RECORD-3 | – | – | – | 24/925 (2.60%) | 9/908 (1.00%) | 0.38 (0.18,0.82) | – |
| Pooled d | – | – | – | – | – | – | 1.313 (0.479,3.597) |
| Secondary Efficacy Endpoint (Major VTE),Absolute Risk Difference | |||||||
| ADVANCE-2 | -0.01 (-0.02,-0.00) | 13/1195 (1.09%) | 26/1199 (2.17%) | – | – | – | – |
| RECORD-3 | – | – | – | 24/925 (2.60%) | 9/908 (1.00%) | -0.02 (-0.03,-0.00) | – |
| Pooled d | – | – | – | – | – | – | 0.005 (-0.011,0.021) |
CI = confidence interval; n = number with event; N = number in group; RR = relative risk
a proposed drug over common reference
b main comparator over common reference
c inferred as proposed drug over main comparator
d pooled using the random effects model
From the pooled results of the indirect comparison for the primary and secondary efficacy
endpoints, apixaban was shown to be non-inferior to rivaroxaban in TKR (RR=1.219 [95%
CI: 0.893, 1.664 and RR=1.313 [95% CI: 0.479, 3.597] for the primary and secondary
outcomes respectively).
THR
The results of the primary and secondary outcomes from the ADVANCE-3 trial are presented
in the following table. The PBAC noted that approximately 30% of the sample had non-evaluable
venograms and so were excluded from the analysis, and much of the efficacy is driven
by a reduction in asymptomatic DVT.
Results of primary and main secondary outcome, in ADVANCE-3
| Trial ID | Apixaban 2.5mg BID n with event/N % (95% CI) | Enoxaparin 40mg QD n with event/N % (95% CI) | RD (95% CI) | RR % (95% CI) |
| Primary outcome: All VTE/All-Cause Death* | 27/1949 1.39 (0.95, 2.02) | 74/1917 3.86 (3.08, 4.83) | -2.47 (-3.54, -1.50) | 0.36 (0.22, 0.54) |
| Main secondary outcome: Major VTE** | 10/2199 0.45 (0.24, 0.85) | 25/2195 1.14 (0.77,1.69) | -0.68 (-1.27, -0.17) | 0.40 (0.15, 0.80) |
NR = Not reported; RD = risk difference, RR = relative risk.
* Primary data set: All randomised patients who, during the intended treatment period,
had an adjudicated and evaluable bilateral venogram; or had an adjudicated VTE; or
died due to any cause.
event associated with the endpoint, during the Intended Treatment Period.
** Randomised subjects with either an adjudicated and evaluable bilateral proximal venogram or an adjudicated event associated with the endpoint, during the Intended
Treatment Period
In ADVANCE-3, apixaban was shown to be statistically significantly superior to enoxaparin
for the primary outcome of the composite of all VTE/all-cause death (RR=0.36 [95%
CI: 0.22, 0.54]), and the main secondary outcome of major VTE (RR=0.40 [95% CI: 0.15,
0.80]).
The results of the indirect comparison of apixaban and rivaroxaban using ADVANCE-3
and RECORD-1 are presented in the following table.
Summary of results of the indirect comparison of efficacy outcomes
| Trial ID | Apixaban | Rivaroxaban | Indirect estimate of effect c (95% CI) | ||||
| Treatment effect a (95% CI) | Apixaban n with event/ N (%) | Enoxaparin n with event/ N (%) | Enoxaparin n with event/ N (%) | Rivaroxaban n with event/ N (%) | Treatment effect b (95% CI) | ||
| Primary Efficacy Endpoint (all VTE/ all-cause death), Relative Risk | |||||||
| ADVANCE-3 | 0.36 (0.23, 0.56) | 27/1949 (1.39) | 74/1914# (3.86) | – | – | – | – |
| RECORD-1 | – | – | – | 58/1558 (3.72) | 18/1595 (1.13) | 0.30 (0.18, 0.51) | |
| Pooled d | – | – | – | – | – | – | 1.18 (0.60, 2.34) |
| Primary Efficacy Endpoint (all VTE/ all-cause death), Absolute Risk Difference | |||||||
| ADVANCE-3 | -0.025 (-0.035, -0.015) | 27/1949 (1.39) | 74/1914 (3.86) | – | – | – | – |
| RECORD-1 | – | – | – | 58/1558 (3.72) | 18/1595 (1.13) | -0.026 (-0.037, -0.015) | |
| Pooled d | – | – | – | – | – | – | 0.001 (-0.014, 0.016) |
| Secondary Efficacy Endpoint (Major VTE), Relative Risk | |||||||
| ADVANCE-3 | 0.40 (0.19, 0.83) | 10/2199 (0.45) | 25/2195 (1.14) | – | – | – | – |
| RECORD-1 | – | – | – | 33/1678 (1.97) | 4/1686 (0.24) | 0.12 (0.04, 0.34) | |
| Pooled d | – | – | – | – | – | – | 3.31 (0.93, 11.76) |
| Secondary Efficacy Endpoint (Major VTE),Absolute Risk Difference | |||||||
| ADVANCE-3 | -0.007 (-0.012, -0.015) | 10/2199 (0.45) | 25/2195 (1.14) | – | – | – | – |
| RECORD-1 | – | – | – | 33/1678 (1.97) | 4/1686 (0.24) | -0.017 (-0.024, -0.010) | |
| Pooled d | – | – | – | – | – | – | 0.010 (0.002, 0.019) |
# Should be 1917
CI = confidence interval; n = number with event; N = number in group; RR = relative risk
a proposed drug over common reference
b main comparator over common reference
c inferred as proposed drug over main comparator
d pooled using the random effects model
From the pooled results of the indirect comparison for the primary and secondary efficacy
endpoints, apixaban was shown to be non-inferior to rivaroxaban in THR (RR=1.18 [95%
CI: 0.60, 2.34 and RR=3.31 [95% CI: 0.93, 11.76] for the primary and secondary outcomes
respectively).
The main safety outcome in all trials was major bleeding.
TKR
A summary of bleeding events from ADVANCE-2 is presented in the following table.
Summary of bleeding events in ADVANCE-2, during the treatment period
| Trial ID | Apixaban 2.5mg BID n with event/N % (95% CI) | Enoxaparin 40mg QD n with event/N % (95% CI) | RD (95% CI) | P Value |
| Major Bleeding* | 9/1501 0.60 (0.30,1.16) | 14/1508 0.93 (0.54,1.57) | -0.33 (-0.95, 0.29) | 0.3014 |
| CRNM Bleeding* | 44/1501 2.93 (2.19,3.93) | 58/1508 3.85 (2.98,4.95) | -0.91 (-2.20, 0.38) | 0.1668 |
| Major or CRNM Bleeding* | 53/1501 3.53 (2.71,4.60) | 72/1508 4.77 (3.81,5.98) | -1.24 (-2.66, 0.18) | 0.0881 |
| Any Bleeding* | 104/1501 6.93 (5.75,8.34) | 126/1508 8.36 (7.06,9.87) | -1.39 (-3.29, 0.51) | 0.1412 |
NR = Not reported; RD = risk difference, RR = relative risk, CRNM Bleeding = clinically
relevant non-major bleeding. *Treated subjects. Adjusted to take into account type
of surgery.
From the results of ADVANCE-2, event rates for major bleeding, clinically relevant
non-major (CRNM) bleeding, the composite of major or CRNM bleeding endpoint, and any
bleeding were lower in the apixaban group than in the enoxaparin group. The differences
were not statistically significant.
The results of the indirect comparison of safety outcomes from ADVANCE-2 and RECORD-3
are presented in the following table.
Summary of results of the indirect comparison of safety outcomes
| Trial ID | Apixaban | Rivaroxaban | Indirect estimate of effect c (95% CI) | ||||
| Treatment effect a (95% CI) | Apixaban n with event/ N (%) | Enoxaparin n with event/ N (%) | Enoxaparin n with event/ N (%) | Rivaroxaban n with event/ N (%) | Treatment effect b (95% CI) | ||
| Primary Safety Endpoint (Major Bleeding Events), Relative Risk | |||||||
| ADVANCE-2 | 0.64 (0.28,1.49) | 9/1501 (0.60%) | 14/1508 (0.93%) | – | – | – | – |
| RECORD-3 | – | – | – | 6/1239 (0.50%) | 7/1220 (0.60%) | 1.18 (0.40,3.52) | – |
| Pooled d | – | – | – | – | – | – | 0.545 (0.138,2.147) |
| Primary Safety Endpoint (Major Bleeding Events), Absolute Risk Difference | |||||||
| ADVANCE-2 | -0.00 (-0.00, 0.00) | 9/1501 (0.60%) | 14/1508 (0.93%) | – | – | – | – |
| RECORD-3 | – | – | – | 6/1239 (0.50%) | 7/1220 (0.60%) | -0.00 (-0.00, 0.01) | – |
| Pooled d | – | – | – | – | – | – | -0.004 (-0.013,0.004) |
| Secondary Safety Endpoint (CRNM Bleeding Events), Relative Risk | |||||||
| ADVANCE-2 | 0.76 (0.52,1.12) | 44/1501 (2.93%) | 58/1508 (3.85%) | – | – | – | – |
| RECORD-3 | – | – | – | 28/1239 (2.26%) | 33/1220 (2.70%) | 1.20 (0.73,1.97) | – |
| Pooled d | – | – | – | – | – | – | 0.637 (0.339,1.195) |
| Secondary Safety Endpoint (CRNM Bleeding Events),Absolute Risk Difference | |||||||
| ADVANCE-2 | -0.01 (-0.02,0.00) | 44/1501 (2.93%) | 58/1508 (3.85%) | – | – | – | – |
| RECORD-3 | – | – | – | 28/1239 (2.26%) | 33/1220 (2.70%) | 0.00 (-0.01,0.02) | – |
| Pooled d | – | – | – | – | – | – | -0.014 (-0.031,0.004) |
CI = confidence interval; n = number with event; N = number in group; RR = relative risk
a proposed drug over common reference
b main comparator over common reference
c inferred as proposed drug over main comparator
d pooled using the random effects model
There was no significant difference between the pooled results of the indirect comparison
of safety outcomes for apixaban and rivaroxaban in TKR (RR=0.545 [95% CI: 0.138, 2.147]
for major bleeding events and RR=0.637 [95% CI: 0.339, 1.195] for CRNM bleeding events).
THR
A summary of bleeding events from ADVANCE-3 are presented in the following table.
Summary of bleeding events in ADVANCE-3, during the treatment period
| Trial ID | Apixaban 2.5mg BID n with event/N % (95% CI) | Enoxaparin 40mg QD n with event/N % (95% CI) | RD (95% CI) | P Value |
| Major Bleeding* | 22/2673 0.82 (0.54,1.25) | 18/2659 0.68 (0.42,1.08) | 0.15 (-0.33, 0.64) | 0.54 |
| CRNM Bleeding* | 109/2673 4.08 (3.39,4.90) | 120/2659 4.51 (3.79,5.38) | -0.44 (-1.53, 0.66) | 0.43 |
| Major or CRNM Bleeding* | 129/2673 4.83 (4.08,5.71) | 134/2659 5.04 (4.27,5.94) | -0.21 (-1.38, 0.95) | 0.72 |
| Any Bleeding* | 313/2673 11.71 (10.55,12.99) | 334/2659 12.56 (11.36,13.88) | -0.85 (-2.61, 0.90) | 0.34 |
NR = Not reported; RD = risk difference, RR = relative risk, CRNM Bleeding = clinically
relevant non-major bleeding. *Treated subjects.
From the results of ADVANCE-3, event rates for major bleeding, CRNM bleeding, the
composite of major or CRNM bleeding endpoint, and any bleeding were similar in the
apixaban and enoxaparin groups.
The results of the indirect comparison of safety outcomes from ADVANCE-3 and RECORD-1
are presented in the following table.
| Trial ID | Apixaban | Rivaroxaban | Indirect estimate of effect c (95% CI) | ||||
| Treatment effect a (95% CI) | Apixaban n with event/ N (%) | Enoxaparin n with event/ N (%) | Enoxaparin n with event/ N (%) | Rivaroxaban n with event/ N (%) | Treatment effect b (95% CI) | ||
| Primary Safety Endpoint (Major Bleeding Events), Relative Risk | |||||||
| ADVANCE-3 | 1.22 (0.65, 2.26) | 22/2673 (0.82) | 18/2659 (0.68) | – | – | – | – |
| RECORD-1 | – | – | – | 2/2224 (0.09) | 6/2209 (0.27) | 3.02 (0.61, 14.95) | – |
| Pooled d | – | – | – | – | – | – | 0.40 (0.07, 2.24) |
| Primary Safety Endpoint (Major Bleeding Events), Absolute Risk Difference | |||||||
| ADVANCE-3 | 0.001 (-0.003, 0.006) | 22/2673 (0.82) | 18/2659 (0.68) | – | – | – | – |
| RECORD-1 | – | – | – | 2/2224 (0.09) | 6/2209 (0.27) | 0.002 (-0.001, 0.004) | – |
| Pooled d | – | – | – | – | – | – | 0.000 (-0.006, 0.005) |
| Secondary Safety Endpoint (CRNM Bleeding Events), Relative Risk | |||||||
| ADVANCE-3 | 0.90 (0.70, 1.16) | 109/2673 (4.08) | 120/2659 (4.51) | – | – | – | – |
| RECORD-1 | – | – | – | 54/2224 (2.43) | 65/2209 (2.94) | 1.21 (0.85, 1.73) | – |
| Pooled d | – | – | – | – | – | – | 0.75 (0.48, 1.15) |
| Secondary Safety Endpoint (CRNM Bleeding Events),Absolute Risk Difference | |||||||
| ADVANCE-3 | -0.004 (-0.015, 0.007) | 109/2673 (4.08) | 120/2659 (4.51) | – | – | – | – |
| RECORD-1 | – | – | – | 54/2224 (2.43) | 65/2209 (2.94) | 0.005 (-0.004, 0.015) | – |
| Pooled d | – | – | – | – | – | – | -0.009 (-0.024, 0.005) |
CI = confidence interval; n = number with event; N = number in group; RR = relative risk
a proposed drug over common reference
b main comparator over common reference
c inferred as proposed drug over main comparator
d pooled using the random effects model
There was no significant difference between the pooled results of the indirect comparison
of safety outcomes for apixaban and rivaroxaban in THR (RR=0.40 [95% CI: 0.07, 2.24]
for major bleeding events and RR=0.75 [95% CI: 0.48, 1.15] for CRNM bleeding events).
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The PBAC accepted the clinical claims of the submission that in TKR
or THR surgery, apixaban 2.5 mg twice daily is non-inferior to
rivaroxaban 10 mg daily in efficacy and safety (primary claim), and
in TKR or THR surgery, apixaban is superior to enoxaparin 40 mg
daily in efficacy and non-inferior in safety (secondary
claim).
10. Economic Analysis
Apixaban versus rivaroxaban
The submission presented a cost minimisation analysis for apixaban
versus rivaroxaban. The equi-effective doses were estimated as
apixaban 2.5mg twice daily over 10-14 days for TKR and over 30-35
days for THR and rivaroxaban 10mg daily over 10-14 days for TKR and
over 30-35 days for THR. The doses were based on clinical trial
evidence from ADVANCE-2 and RECORD-3 (for TKR) and ADVANCE-3 and
RECORD-1 (for THR).
Apixaban versus enoxaparin
A modelled evaluation was presented for apixaban versus enoxaparin.
The model had a decision tree phase populated by ADVANCE-2 (TKR)
and ADVANCE-3 (THR) event data to model events occurring in the
first 90 days post surgery and a 5-year Markov phase to capture
longer-term events such as recurring VTE and post-thromboembolic
syndrome (PTS). Utility values/decrements and administration costs
were applied and the results presented as costs per QALY
gained.
Base case results of the model showed the incremental
cost-effectiveness to be dominant (i.e. more effective and less
costly) for both THR and TKR.
11. Estimated PBS Usage and Financial Implications
The likely number of patients was estimated in the submission to be
between 10,000 and 50,000 in Year 5, with an estimated net cost to
the PBS of less than $10 million in Year 5, using the original
requested maximum quantity of 20 tablets for TKR .
In its pre-PBAC response, the Sponsor advised that a 30 tablet pack
would be available which was claimed to result in the listing being
cost neutral to the PBS.
12. Recommendation and Reasons
The PBAC recommended the listing of apixaban on a cost minimisation
basis compared with rivaroxaban. The equi-effective doses are
apixaban 2.5mg twice daily over 10-14 days for total knee
replacement (TKR) and over 30-35 days for total hip replacement and
rivaroxaban 10mg daily over 10-14 days for TKR and over 30-35 days
for THR. The PBAC considered that the proposed maximum quantity of
20 tablets for TKR to be insufficient for a course of treatment for
many patients and inconsistent with the listing for rivaroxaban.
The Committee advised that listing should proceed only on the basis
of provision of a 30 day pack.
The requested restriction was accepted as consistent with both
rivaroxaban and dabigatran, the currently listed oral
anti-thrombotic agents listed for this patient group.
The PBAC accepted rivaroxaban as the appropriate comparator in
preference to dabigatran, as rivaroxaban has the same mode of
action, as a direct, inhibitor of the coagulation factor Xa.
Further, rivaroxaban also has the greatest market share of the
orally administered anticoagulants, with dabigatran only ~1% of
total VTE-prophylaxis utilisation. Enoxaparin was accepted as a
secondary comparator.
The PBAC noted that the submission was based on an indirect
comparison via the common comparator, enoxaparin. The submission
presents two randomised trials comparing apixaban (2.5mg bd) with
enoxaparin (40mg SC daily) in patients undergoing TKR (ADVANCE-2,
length of treatment: 11 ± 2 days) or THR (ADVANCE-3, length
of treatment 34 ± 3 days).
The submission also presents two indirect comparisons with two
randomised trials comparing rivaroxaban (10mg daily) with
enoxaparin (40mg SC daily) in patients undergoing TKR (RECORD-3,
length of treatment 10-14 days) or THR (RECORD-1, length of
treatment 35 days). The primary efficacy outcome in all studies was
a composite of all VTE/ all-cause death and the main safety outcome
was major bleeding.
An indirect comparison of the primary efficacy endpoint measured in
ADVANCE-2 and RECORD-3 demonstrates that apixaban is statistically
non-inferior to rivaroxaban in TKR. The PBAC noted there may be
some limitations with regards to the exchangeability of the trials,
but this was insufficient to alter the PBAC’s acceptance of
the clinical claim of non-inferiority.
A similar conclusion was drawn with respect to the indirect
comparison of the primary efficacy endpoint measured in ADVANCE-3
and RECORD-1 with respect to non-inferiority between apixaban and
rivaroxaban in THR.
With respect to safety, the PBAC noted that the overall trend from
the ADVANCE clinical trials was that the incidence of bleeding
events numerically favoured apixaban over enoxaparin. This was not
the case with rivaroxaban. Although there are limitations with
respect to exchangeability of the trials, on the basis of the
indirect comparison the PBAC accepted that apixaban is likely to be
no worse than rivaroxaban in terms of bleeding. However, the PBAC
was concerned that CYP 3A4 inhibitors dramatically increase
apixaban levels. In view of this safety concern, the PBAC
recommended that the National Prescribing Service should be asked
to review the various (oral) anticoagulant prophylactic therapies
for TKR and THR.
The PBAC accepted the clinical claims of the submission that in TKR
or THR surgery, apixaban 2.5 mg twice daily is non-inferior to
rivaroxaban 10 mg daily in efficacy and safety (primary claim), and
in TKR or THR surgery, apixaban is superior to enoxaparin 40 mg
daily in efficacy and non-inferior in safety (secondary
claim).
The PBAC noted that with the listing of a 30 tablet pack for TKR,
the listing of apixaban on the PBS is likely to be cost
neutral.
The PBAC recommended that apixaban be included in the PBS medicines
for prescribing by nurse practitioners within a shared care
model.
Recommendation:
APIXABAN, tablet, 2.5 mg
Restriction:
Authority Required
Prevention of venous thromboembolism in a patient undergoing total
knee replacement.
Note:
No applications for increased maximum quantities and/or repeats will be authorised.
Maximum Quantity 30
No. of Repeats 0
Authority Required
Prevention of venous thromboembolism in a patient undergoing total hip replacement.
Note:
No applications for increased maximum quantities and/or repeats will be authorised.
Maximum Quantity 60
No. of Repeats 0
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
The sponsor has no comment.
