Dronedarone hydrochloride, tablet, 400 mg, Multaq®
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Product: Dronedarone hydrochloride, tablet, 400
mg, Multaq®
Sponsor: Sanofi-Aventis Australia Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought an Authority Required (Streamlined) listing
for the treatment of paroxysmal or persistent atrial fibrillation
or flutter in addition to standard therapy in patients with at
least one additional cardiovascular risk factor.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Dronedarone was TGA registered on 2 August 2010 to reduce the risk
of cardiovascular hospitalisation in patients with paroxysmal or
persistent atrial fibrillation (AF) or atrial flutter (AFL), with a
recent episode of AF/AFL and associated cardiovascular risk
factors, who are in sinus rhythm or who will be cardioverted, on
top of standard therapy.
4. Listing Requested and PBAC’s View
Authority Required (Streamlined)
Treatment of patients with paroxysmal or persistent atrial
fibrillation or flutter and at least one additional cardiovascular
risk factor (e.g. hypertension, diabetes mellitus or previous
stroke or transient ischaemic attack), in addition to standard
care. Treatment should only be initiated in consultation with a
specialist.
CAUTION:
Dronedarone is contraindicated in patients with NYHA Class IV heart
failure, or NYHA Class II-III heart failure with a recent
decompensation requiring hospitalisation.
For PBAC’s view, see Recommendations and
Reasons.
5. Clinical Place for the Proposed Therapy
Paroxysmal atrial fibrillation or flutter is a condition consisting
of intermittent and recurrent irregular heart beats that resolve
spontaneously. Persistent atrial fibrillation or flutter involves a
continued irregular heart beat – cardioversion is required to
return to sinus rhythm.
The submission proposed that the place in therapy of dronedarone is
as add-on therapy to standard therapy (anti-coagulation plus a rate
controller) and as an alternative antiarrythmic agent to amiodarone
or sotalol.
For PBAC’s view, see Recommendations and
Reasons.
6. Comparator
The submission nominated placebo on top of standard therapy,
amiodarone and sotalol as the comparators.
The Committee considered that amiodarone is the most appropriate
main comparator, with sotatol and flecainide appropriate secondary
comparators.
7. Clinical Trials
The basis of the submission was:
- Five direct randomised comparative trials comparing dronedarone and placebo (DAFNE, EURIDIS/ADONIS, ERATO, ATHENA);
- One direct randomised trial comparing dronedarone and amiodarone (DIONYSIS);
- Four direct randomised trials comparing amiodarone and placebo (Channer 2004, Galperin 2001, Kochiadakis 2000, Singh 2005 (SAFE-T));
- Ten direct randomised trials comparing sotalol and placebo (Bellandi 2001, Benditt 1999, Brodsky 1994, Fetsch 2004 (PAFAC), Kochiadakis 2000, Kochiadakis 2004 Lombardi 2006 (A-COMET II), Patten 2004 (SOPAT), Singh 1991, Singh 2005 (SAFE-T)); and
- Three meta-analyses (Hohnloser 2009, Lafuente-Lafuente 2007 and Piccini 2009).
- A mixed treatment comparison (MTC) reported by Freemantle et al and a MTC more relevant to the Australian setting, including studies of dronedarone, amiodarone and sotalol only (ie studies assessing flecainide and propafenone were excluded) referred to as the “Australian MTC”.
Publication details of the trials presented in the submission are in the following
table.
Trials and associated reports presented in the submission
| Trial ID/First author | Protocol title/ Publication title | Publication citation |
| Dronedarone versus placebo | ||
|
ATHENA Hohnoser SH, et al. Connolly SJ Hohnloser SH, et al. |
Effect of dronedarone on cardiovascular events in atrial fibrillation. Analysis of stroke in ATHENA: A placebo-controlled, double-blind, parallel-arm trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter. Rationale and design of ATHENA: A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter. |
N Engl J Med 2009; 360(7):668-678. Circulation 2009; 120(13):1174-1180. J Cardiovasc Electrophysiol 2008; 19(1):69-73. |
| DAFNE Touboul P, et al. | Dronedarone for prevention of atrial fibrillation: a dose-ranging study. | Eur Heart J 2003; 24(16):1481-1487. |
| EURIDIS/ ADONIS Singh BN, et al. | Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. | N Engl J Med 2007; 357(10):987-999 |
| ERATO Davy JM | Dronedarone for the control of ventricular rate in permanent atrial fibrillation: The Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation (ERATO) study. | Am Heart J 2008; 156(3): 527.e1-527.e9. |
| Dronedarone versus amiodarone | ||
| DIONYSOS Le-Heuzey J, et al. | A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of Dronedarone versus Amiodarone in patients with persistent atrial fibrillation: The DIONYSOS study. | J Cardiovasc Electrophysiol 2010;21(6):597-605 |
| Amiodarone versus placebo | ||
| Channer KS, et al. | A randomized placebo-controlled trial of pre-treatment and short- or long-term maintenance therapy with amiodarone supporting DC cardioversion for persistent atrial fibrillation. | Eur Heart J 2004; 25(2):144-150. |
| Galperin J, et al. | Efficacy of amiodarone for the termination of chronic atrial fibrillation and maintenance of normal sinus rhythm: a prospective, multicenter, randomized, controlled, double blind trial. | J Cardiovasc Pharmacol Therapeutics 2001; 6(4):341-350. |
| Kochiadakis GE, et al. | Low dose amiodarone and sotalol in the treatment of recurrent, symptomatic atrial fibrillation: a comparative, placebo controlled study. | Heart 2000; 84(3):251-257. |
| Singh BN, et al. (SAFE-T) | Amiodarone versus sotalol for atrial fibrillation. | N Engl J Med 2005; 352(18):1861-1872+1937. |
| Sotalol versus placebo | ||
| Bellandi F | Long-term efficacy and safety of propafenone and sotalol for the maintenance of sinus rhythm after conversion of recurrent symptomatic atrial fibrillation. | Am J Cardiol 2001; 88(6):640-645. |
| Benditt D, et al. | Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. d,l-Sotalol Atrial Fibrillation/Flutter Study Group. | Am J Cardiol 1999; 84(3):270-277. |
| Brodsky M | Comparative effects of the combination of digoxin and dl-sotalol therapy versus digoxin monotherapy for control of ventricular response in chronic atrial fibrillation. | Am Heart J 1994; 127(3):572-577. |
| Fetsch T, et al. (PAFAC) | Prevention of atrial fibrillation after cardioversion: results of the PAFAC trial. | Eur Heart J 2004; 25(16):1385-1394. |
| Kochiadakis GE, et al. | Low dose amiodarone and sotalol in the treatment of recurrent, symptomatic atrial fibrillation: a comparative, placebo controlled study. | Heart 2000; 84(3):251-257. |
| Kochiadakis GE | Sotalol versus propafenone for long-term maintenance of normal sinus rhythm in patients with recurrent symptomatic atrial fibrillation. | Am J Cardiol 2004; 94(12):1563-1566. |
| Lombardi F, et al. (A-COMET-II) | Azimilide vs. placebo and sotalol for persistent atrial fibrillation: the A-COMET-II (Azimilide-CardiOversion MaintEnance Trial-II) trial. | Eur Heart J 2006; 27(18):2224-2231. |
| Patten M (SOPAT) | Suppression of paroxysmal atrial tachyarrhythmias - Results of the SOPAT trial. | Eur Heart J 2004; 25(16):1395-1404. |
| Singh S, et al. | Efficacy and safety of sotalol in digitalized patients with chronic atrial fibrillation. | Am J Cardiol 1991; 68 (Nov.1) |
| Singh BN, et al. (SAFE-T) | Amiodarone versus sotalol for atrial fibrillation. | N Engl J Med 2005; 352(18):1861-1872+1937. |
| Meta-analyses | ||
| Hohnloser | Effect of dronedarone on cardiovascular outcomes: a meta-analysis of 5 randomized controlled trials in 6157 patients with atrial fibrillation/flutter | Presented at American College of Cardiology 58 th Annual Scientific Session 2009 |
| Lafuente –Lafuente C, et al. | Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. | Cochrane Database of Systematic Reviews 2007; (4):CD005049 |
| Piccini JP | Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. | J Am Coll Cardiol 2009 ; 54(12):1089-1095. |
8. Results of Trials
Results for the primary outcome of the ATHENA trial which was a composite endpoint
of time from randomisation to first cardiovascular hospitalisation or death from any
cause, as assessed by the Investigator, are presented in the table below.
Results of the comparison of dronedarone and placebo for the primary outcome of the
ATHENA trial
| Outcome | Dronedarone N=2,301 n (% ) | Placebo N=2,327 n (%) | HR (95% CI) |
| First CV hospitalisation or death from any cause a | 734 (31.9) | 917 (39.4) | 0.76 (0.69, 0.84) |
| First hospitalisation due to CV event | 675 (29.3) | 859 (36.9) | 0.74 (0.67, 0.82) |
| First hospitalisation | |||
| For AF | 335 (14.6) | 510 (21.9) | 0.63 (0.55, 0.72) |
| For CHF | 112 (4.9) | 132 (5.7) | 0.86 (0.67, 1.10) |
| For ACS | 62 (2.7) | 89 (3.8) | 0.70 (0.51, 0.97) |
| For syncope | 27 (1.2) | 32 (1.4) | 0.85 (0.51, 1.42) |
| For ventricular arrhythmia or non-fatal cardiac arrest | 13 (0.6) | 12 (0.5) | 1.09 (0.50, 2.39) |
| Death from any cause | 116 (5.0) | 139 (6.0) | 0.84 (0.66, 1.08) |
| From non CV causes | 53 (2.3) | 49 (2.1) | 1.10 (0.74, 1.62) |
| From CV causes | 63 (2.7) | 90 (3.8) | 0.71 (0.51, 0.98) |
| From non-arrhythmic cardiac causes | 17 (0.7) | 18 (0.8) | 0.95 (0.49, 1.85) |
| From cardiac arrhythmia | 26 (1.1) | 48 (2.1) | 0.55 (0.34, 0.88) |
| From non-cardiac CV causes b | 20 (0.9) | 24 (1.0) | 0.84 (0.47, 1.52) |
| Any hospitalisation due to any CV event or death from any cause | 1,253 (54.4) | 1,668 (71.7) | 0.76 (0.68, 0.84) |
a primary outcome b includes stroke
HR = hazard ratio, CV = cardiovascular, AF = atrial fibrillation, CHF = congestive
heart failure, ACS = acute coronary syndrome, AE = adverse event, ECV = electrical
cardioversion
Bold typography indicates statistically significant differences
The results showed that patients treated with dronedarone were statistically significantly
less likely to be hospitalised or die from any cause than placebo treated patients
(31.9% vs. 39.4%; HR 0.76 [95% CI: 0.69, 0.84]).
The overall mortality reported in the dronedarone, amiodarone and sotalol placebo
controlled trials are shown in the table below:
Overall mortality reported in the dronedarone, amiodarone and sotalol placebo controlled
trials
| Trial | Dron n/N (%) | Placebo n/N (%) | Treatment a n/N (%) | OR (95% CI) b | Peto OR (95% CI) b |
| Dronedarone versus amiodarone | |||||
| DIONYSOS | 2/249 (0.8) | - | 5/255 (2.0) | 0.40 (0.04, 2.54) | 0.43 (0.10, 1.91) |
| Dronedarone versus placebo | |||||
| ATHENA | 116/2301 (5.0) | 139/2327 (6.0) | - | 0.84 (0.64, 1.09) | 0.84 (0.65, 1.08) |
| DAFNE | 0/54 (0.0) | 0/48 (0.0) | - | NE | NE |
| EURIDIS/ADONIS | 8/828 (1.0) | 3/409 (0.7) | 1.32 (0.31, 7.77) | 1.30 (0.37, 4.60) | |
| ERATO | 1/85 (1.2) | 0/89 (0.0) | 3.18 (0.03, ) | 7.75 (0.15, 390.73) | |
| Meta-analysis (random effects) | 0.86 (0.67, 1.10) e | 0.86 (0.67, 1.10) | |||
| Amiodarone versus placebo | |||||
| Channer 2004 | - | 0/38 (0.0) # | 0/123 (0.0) # | NE | NE |
| Galperin 2001 | - | 0/47 (0.0) | 0/48 (0.0) | NE | NE |
| Kochiadakis 2000 | - | 0/60 (0.0) | 0/65 (0.0) | NE | NE |
| Singh 2005 | - | 3/137 (2.2) | 13/267 (4.9) | 2.29 (0.61, 12.70) | 2.02 (0.70, 5.80) |
| Meta-analysis (random effects) | 2.29 (0.64, 8.16) e | 2.02 (0.70, 5.80) | |||
| Indirect estimate of effect (dronedarone vs amiodarone) c | 0.38 (0.10, 1.37) | 0.43 (0.14, 1.26) | |||
| Sotalol versus placebo | |||||
| Bellandi 2001 | - | 0/92 (0.0) # | 0/106 (0.0) # | NE | NE |
| Benditt 1999 | - | 0/69 (0.0) | 0/184 (0.0) | NE | NE |
| Brodsky 1994 | - | 0/21 (0.0) | 0/39 (0.0) | NE | NE |
| Fetsch 2004 f | - | 0/88 (0.0) | 6/383 (1.6) | 3.05 (0.27, ) | 3.47 (0.44, 27.30) |
| Kochiadakis 2000 | - | 0/60 (0.0) | 0/61 (0.0) | NE | NE |
| Kochiadakis 2004 | - | 0/83 (0.0) | 0/85 (0.0) | NE | NE |
| Lombardi 2006 | - | 0/224 (0.0) | 4/223 (1.8) | 9.21 (0.67, ) | 7.52 (1.05, 53.77) |
| Patten 2004 | - | 0/251 (0.0) | 2/264 (1.0) | 4.79 (0.18, ) | 7.06 (0.44, 113.29) |
| Singh 1991 | - | 0/10 (0.0) | 0/24 (0.0) | NE | NE |
| Singh 2005 | - | 3/137 (2.2) | 15/261 (5.7) | 2.72 (0.75, 14.90) | 2.27 (0.84, 6.14) |
| Meta-analysis (random effects) | 3.40 (1.24, 9.35) e | 3.19 (1.46, 6.98) | |||
| Indirect estimate of effect (dronedarone vs sotalol) c | 0.25 (0.09, 0.72) | 0.27 (0.12, 0.61) | |||
a amiodarone or sotalol
b dronedarone or treatment (amiodarone or sotalol versus placebo), calculated during
the evaluation using StatsDirect
c dronedarone versus treatment (amiodarone or sotalol), calculated during the evaluation
d primary outcome
e random effects
f Table 3, p1390 Fetsch 2004
# not reported, assumed to be 0
Bolded typography indicates statistically significant differences
No statistically significant differences between dronedarone or amiodarone versus
placebo were observed for overall mortality. There was no clear trend for mortality
when comparing dronedarone to placebo, however there was a trend toward increased
mortality for amiodarone. Sotalol demonstrated a statistically significant increase
in the risk of mortality compared with placebo.
Mortality results from the Freemantle MTC and Australian MTC are shown in the table
below.
Comparison of MTC (Freemantle and Australian) results with the relevant direct and
indirect comparisons for mortality
| Comparison | Dronedarone | Amiodarone | Sotalol | Amiodarone | Sotalol |
| versus placebo | versus dronedarone | ||||
| Direct (Peto OR, 95% CI) | 0.86 (0.67, 1.10) | 2.02 (0.70, 5.80) | 3.19 (1.46, 6.98) | 2.32 (0.52, 10.32) | NA |
| Standard indirect (Peto OR, 95% CI) | NA | NA | NA | 2.35 (0.79, 6.96) | 3.71 (1.63, 8.43) |
| Freemantle MTC | 0.86 (0.61, 1.22) | 2.17 (0.63, 7.51) | 3.44 (1.02, 11.59) | 2.52 (0.72, 8.90) | 3.99 (1.16, 13.82) |
| Freemantle MTC using data derived during the evaluation | 0.86 (0.68, 1.10) | 2.11 (1.01, 4.40) | 3.11 (1.56, 6.21) | 1.75 (0.61, 5.07) | 2.44 (0.83, 7.20) |
| Australian MTC | 0.87 (0.69, 1.09) | 2.92 (1.17, 7.31) | 4.67 (1.89, 11.57) | 3.37 (1.34, 8.52) | 5.39 (2.15, 13.52) |
| Australian MTC using data derived during the evaluation | 0.86 (0.67, 1.10) | 2.49 (1.03, 6.01) | 3.80 (1.59, 9.07) | 1.83 (0.56, 6.04) | 2.60 (0.76, 8.99) |
| Australian MTC including ERATO and Fetsch 2004 | 0.87 (0.68, 1.11) | 2.63 (1.11, 6.22) | 3.98 (1.72, 9.21) | 1.76 (0.58, 5.37) | 2.44 (0.77, 7.70) |
NA = not applicable; NR = not reported
Bold typography indicates statistically significant differences
The MTC was an attempt to obtain a more precise estimate (i.e. narrower Confidence
Intervals) of differences in mortality (by combining trials against different comparators).
The Freemantle MTC results mirrored those derived from the direct and “standard” indirect
comparisons of dronedarone, amiodarone and sotalol versus placebo and those derived
from the comparisons of amiodarone and sotalol versus dronedarone, although the point
estimates for mortality were slightly increased.
The results of the Australian MTC which indicated a statistically significant increase
in mortality for patients treated with amiodarone compared with placebo and dronedarone,
were not supported by the results obtained from direct comparisons of these respective
treatments. As for the Freemantle MTC, the point estimates were also increased.
The PBAC noted that dronedarone is less effective than amiodarone in terms of AF recurrence,
as shown in the results from the DIONYSOS trial comparing dronedarone and amiodarone
where a statistically significantly greater proportion of patients treated with dronedarone
experienced AF recurrence (63.5% vs. 42%; OR 2.4 [95% CI: 1.65, 3.49]), and in a mixed
treatment comparison of amiodarone versus dronedarone.
There were no differences in the incidence of treatment-emergent adverse events, serious
adverse events, deaths and discontinuations due to adverse events, between dronedarone
and placebo treated patients as well as dronedarone and amiodarone treated patients.
9. Clinical Claim
The submission claimed that dronedarone is superior in terms of
comparative effectiveness over placebo, amiodarone and sotalol and
with an acceptable safety and tolerability profile.
The PBAC did not accept this claim. See Recommendation and
Reasons.
10. Economic Analysis
Three modelled economic evaluations were presented in the submission comparing:
- Dronedarone versus placebo
- Dronedarone versus amiodarone
- Dronedarone versus sotalol
The types of economic evaluations presented were cost-effectiveness
and cost-utility analyses. Each modelled economic evaluation used a
decision analysis incorporating a Markov process.
The time horizon in the modelled economic evaluations was 10 years
for the base case analyses. The models used a cycle length of 1
year duration. A 5% discount rate was applied in all models to
costs and outcomes.
In all three modelled economic evaluations, it was the probability
of having an event that was the main driver in the model, and the
relative difference in the probabilities of these events between
the two arms (i.e. treatment effect [RR]) that was the underlying
basis of the entire economic evaluation.
The 1-year event rates from the Geelong AF study (nominated in the
submission as most representative of the requested PBS population,
were applied in the economic evaluations.
For all three economic evaluations, the incremental cost per extra
quality adjusted life year (QALY) gained was less than
$15,000.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The financial costs per year to the PBS were estimated in the
submission to be in the range of $60 – $100 million in Year 5
of listing. The submission estimated net Medicare Benefits Scheme
(MBS) savings per year of between $30 - $60 million in Year 5 due
to a reduction in hospitalisations.
12. Recommendation and Reasons
The PBAC agreed with the hearing presenter, that the appropriate
clinical place of dronedarone in the management of atrial
fibrillation or flutter is in the second line setting after
anticoagulant/rate control therapy, and as an alternative to
flecainide, propafenone (not available in Australia) or sotalol. If
dronedarone were to be made available through the PBS, amiodarone
would most likely be reserved for third-line use in patients in
whom these second line medicines are ineffective or not tolerated.
The only exception to this is patients with NYHA Class III or IV
heart failure or unstable NYHA Class II heart failure, in whom
amiodarone remains the most appropriate second line treatment. The
Committee therefore considered that amiodarone is the most
appropriate main comparator, with sotatol and flecainide
appropriate secondary comparators. The Committee further noted that
flecainide is not commonly used in Australia.
The Committee noted that the restriction proposed by the sponsor,
which is consistent with the inclusion criteria for the ATHENA
trial of dronedarone versus placebo, had been extensively commented
on in the evaluation. The PBAC considered that the sponsor’s
proposed requirement for an additional cardiovascular risk factor
to AF would not be consistent with the treatment guidelines
presented in the hearing, and could not be effectively administered
by Medicare Australia. Although the PBAC noted that the
cost-effectiveness claim of the submission relied, at least in
part, upon the identification of a narrower PBS population than
that which would be eligible under a PBS restriction similar to
that for amiodarone, the Committee nonetheless agreed that a
restriction such as “prevention of recurrence of atrial
fibrillation or flutter” is to be preferred from a
clinical/treatment guidelines perspective and that any future
submission to the PBAC for dronedarone should be based upon such a
restriction.
The PBAC noted that the submission’s clinical and economic
claim for dronedarone was not based upon its effectiveness as an
anti-arrhythmic agent per se. Indeed, the only head-to-head
comparison of dronedarone and amiodarone, DIONYSOS, showed
dronedarone to be statistically significantly worse than amiodarone
in terms of the primary composite outcome of AF recurrence or
premature discontinuation due to adverse events. The submission
rather made the claim that decreased mortality is associated with
dronedarone treatment of AF, whereas increased mortality is
associated with amiodarone and sotalol treatment. The difference in
mortality between these treatments was the basis for the
submission’s claim of superior comparative effectiveness over
amiodarone and sotalol, and underpinned the economic analyses
presented.
The Committee then noted that in the ATHENA trial of dronedarone
versus placebo, dronedarone was found to reduce the rate of the
primary end point of cardiovascular hospitalisation and any cause
mortality by 24% (31.9% vs. 39.4%; HR: 0.76; 95% CI: 0.69 to 0.84),
primarily driven by the reduction in cardiovascular
hospitalisations. Death from any cause was not statistically
significantly reduced (5.0% vs. 6.0 %; HR: 0.84; 95% CI 0.66 to
1.08). Death from cardiovascular causes was reduced by 29% (2.7%
vs. 3.8%; HR: 0.71; 95% CI: 0.51 to 0.98).
However the PBAC considered that the statistical significance of
the result for cardiovascular mortality from ATHENA needed to be
interpreted with caution. This was because the statistical plan for
the ATHENA trial applied a hierarchical procedure to the secondary
endpoints to protect the global type I error of 5%. The primary
secondary endpoint in ATHENA was death from any cause. If the
difference in this endpoint was statistically significant, then
first cardiovascular hospitalisation endpoint data and,
subsequently, the cardiovascular death endpoint data were to be
analysed. Each analysis was only to be performed if the prior
analysis gave a statistically significant result. As no
statistically significant difference was found for the endpoint
death from any cause, the statistical analyses of the
cardiovascular hospitalisation and cardiovascular death outcomes
data should not have been performed.
Other clinical studies of dronedarone have yielded inconsistent
results with respect to mortality. The DIONYSOS head-to-head
comparison of dronedarone and amiodarone demonstrated no
statistical differences in mortality, however there was a trend
toward decreased mortality in patients treated with dronedarone
compared with amiodarone. On the other hand, the ANDROMEDA trial
raised the possibility that dronedarone treatment might be
associated with an increased risk of cardiovascular mortality in
some patients Although ANDROMEDA was performed in a different
population (a subpopulation of patients with severe left
ventricular dysfunction who had recently been hospitalised for
decompensated heart failure who did not necessarily have AF/AFL)
from the intended PBS population, the PBAC considered that the
clinical factors associated with an increased risk of
cardiovascular mortality for dronedarone have not yet been
satisfactorily determined, and therefore this risk cannot be
adequately excluded, even with the note proposed for inclusion in
the restriction.
The PBAC also had concerns about the relative paucity of clinical
mortality data from randomised clinical trials of amiodarone.
Additionally, the increased mortality observed for the amiodarone
and sotalol versus placebo comparisons were driven by the trial
reported by Singh et al (2005) (SAFE-T), particularly for
amiodarone. Interpreting the data from SAFE-T is made more
difficult as this study was conducted in patients with persistent
AF, a subgroup of the total AF population which probably has a
worse prognosis than other AF subgroups and as the patients in
SAFE-T received higher doses of amiodarone than used in Australian
clinical practice. Most importantly, after adjustment for the
duration of follow-up (344.08 patient-years in the amiodarone
group, 297.93 in the sotalol group, and 105.72 in the placebo
group), the mortality ratios were 1.3 in the amiodarone group as
compared with the placebo group (P=0.19) and 1.8 in the sotalol
group as compared with the placebo group (P=0.11) [Singh, B. NEJM
352:1861;2005]. Thus, the Committee considered it likely that the
submission overstated the harm associated with amiodarone.
The Committee had a number of concerns with the Australian MTC
presented in the submission and which is used to derive the
mortality difference included in the modelled economic evaluations
of dronedarone versus amiodarone and versus sotalol. Firstly, the
results of the Australian MTC indicated a statistically significant
increase in mortality for patients treated with amiodarone compared
with placebo and with dronedarone that is not supported by the
results obtained from direct comparisons of these respective
treatments, or from conventional indirect comparisons performed
during the evaluation using placebo as a common reference.
Secondly, as with the Freemantle MTC, the point estimates for
mortality are increased. Thirdly, the Australian MTC
inappropriately excluded studies assessing flecainide and
propafenone, as the strength of an MTC is argued to come from
including all available studies across the widest possible
network.
The PBAC thus considered that the submission’s assertion that
dronedarone treatment will be associated with 3.37 times less
mortality than amiodarone treatment, as derived from the Australian
MTC, was implausibly large.
Other issues with the economic models presented included that in
the model, dronedarone both extends life and improves quality of
life. However, no quality of life benefit was seen in the only
dronedarone study which showed an improvement in the composite end
point of cardiovascular morbidity and mortality, ATHENA. The trial
population of the Geelong AF study may not have been representative
of the population for whom dronedarone listing was sought and thus
the baseline risk derived from this study may not have been
reliable. The extrapolation and the method of extrapolation of the
baseline event risks from the Geelong AF study to 10 years in the
modelled economic evaluation may not be appropriate. The simpler
decision analytic model used to compare dronedarone to
amiodarone/sotalol favoured dronedarone compared to the more
complex model used for the dronedarone versus placebo
comparison.
The PBAC also noted the estimated cost to the PBS was both high and
uncertain.
Overall, the PBAC rejected the submission because of uncertainty
about the extent of clinical benefit in terms of improved survival
over the main comparator, amiodarone, and because of the resultant
uncertainty in the economic analysis.
Recommendation:
Reject
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 is currently working towards addressing the issues raised by the PBAC in order to achieve a positive PBAC recommendation for dronedarone. The Sponsor is committed to achieving a PBS listing for dronedarone, due to what the sponsor believes to be a high unmet clinical need in the treatment of patients with atrial fibrillation in Australia.
