ALISKIREN, tablets, 150 mg and 300 mg (as hemifumarate), Rasilez®, July 2010
Page last updated: 03 November 2010
Public Summary Document
Product: ALISKIREN, tablets, 150 mg and 300 mg (as
hemifumarate), Rasilez®
Sponsor: Novartis Pharmaceuticals Australia Pty
Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
To request an Unrestricted Benefit listing intended for the
treatment of hypertension.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Aliskiren was TGA registered on 3 June 2008 for the treatment of
hypertension.
4. Listing Requested and PBAC’s View
Unrestricted benefit
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
In a patient treated for hypertension where an agent acting on the
renin-angiotensin system (RAS) is considered to be clinically
indicated by the prescriber, the drugs currently prescribed would
be either an angiotensin II receptor antagonist (AIIRA) or an
angiotensin converting enzyme (ACE) inhibitor.
Aliskiren is a direct renin inhibitor acting on the RAS and would
be an alternative to the AIIRAs and ACE inhibitors which are
currently listed on the PBS for the treatment of
hypertension.
6. Comparator
The submission nominated irbesartan as the main comparator.
Valsartan, ramipril and lisinopril were nominated as secondary
comparators.
The PBAC did not consider this was appropriate, see
Recommendation and Reasons.
7. Clinical Trials
The submission presented thirteen randomised trials in patients with hypertension
comparing aliskiren 150 mg or 300 mg daily with irbesartan 150 mg or 300 mg daily
(3 trials), with valsartan 160 mg or 320 mg daily (3 trials), ramipril 5 mg or 10
mg daily (6 trials, including one of the irbesartan trials), and lisinopril 10 mg
or 20 mg daily (2 trials). One trial (2303) was in severe hypertension, two trials
(2324 and 2344) were in systolic hypertension in the elderly (age >65), and one trial (2307) was in diabetes.
The key trials published at the time of submission are shown in the table below:
| Trial ID/First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Direct randomised trials: aliskiren versus irbesartan | ||
| Trial 2201 | Gradman A et al. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. | Circulation 2005;111: 1012–1018 |
| Trial 2309 | Jordan J et al. Direct renin inhibition with aliskiren in obese patients with arterial hypertension. | Hypertension 2007;49:1047-1055 |
| Trial 2351 | Palatini P et al. Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study. | J Hum Hypertens. Published online on 21 May 2009; doi:1038/jhh.2009.38 |
| Direct randomised trials: aliskiren versus valsartan | ||
| Trial 2203 | Pool J et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. | Am J Hypertens 2007; 20:11–20 |
| Trial 2327 | Oparil S et al. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomized, double-blind trial. | Lancet 2007;370:221–229 |
| Trial 2331 | Geiger H et al. Combination therapy with various combinations of aliskiren, valsartan and hydrochlorothiazide in hypertensive patients not adequately responsive to hydrochlorothiazide alone. | J Clin Hypertens 2009; 11:1-9. |
| Direct randomised trials: aliskiren versus ramipril | ||
| Trial 2306 | Andersen K et al. Comparative efficacy and safety of aliskiren, an oral direct rennin inhibitor, and ramipril in hypertension: A 6-month, randomised, double-blind trial. | J Hypertens 2008;26:589–599 |
| Trial 2307 | Uresin Y et al. Efficacy and safety of the direct rennin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. | J Renin Angiotensin Aldosterone Syst 2007; 8:190–198. |
| Trial 2344 | Duprez A et al. Aliskiren for geriatric lowering of systolic hypertension: a randomized controlled trial. | J Hum Hypertens 24 December 2009. Advance online publication doi:10.1038//jhh.2009.107 |
| Direct randomised trials: aliskiren versus lisinopril | ||
| Trial 2303 | Strasser R et al. A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension. | J Hum Hypertens 2007;21:780-787 |
| Trial 2324 | Verdechhia P et al. Safety and efficacy of the oral direct renin inhibitor aliskiren in elderly patients with hypertension. | Blood Pressure 2007;16:381 – 391 |
Trials in populations other than isolated essential hypertension were located by the
sponsor but excluded from the submission. Because these trials and ASPIRE (2010) and
Ferdinand 2010, both found during the evaluation, were relevant to the submission’s
requested unrestricted listing, the results of six of these trials were presented
in the evaluation. Two of these trials (1301 and 2316-ALLAY) compared aliskiren with
losartan, one trial (Ferdinand 2010) compared aliskiren with amlodipine in combination
with hydrochlorothiazide (HCTZ), and three trials were in populations other than isolated
essential hypertension (2313-ALOFT, a safety study in heart failure; C2201-AVOID,
a study of renal protection in patients with hypertension and diabetes; and ASPIRE
(2010), a study of myocardial protection in patients with a recent myocardial infarction
with left ventricular dysfunction).
The trials published at the time of submission are shown in the table below:
| Trial ID/First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Direct randomised trials: aliskiren versus losartan | ||
| Trial 2316 - ALLAY | Solomon S et al. Effect of the direct renin inhibitor aliskiren, the angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. | Circulation 2009; 119:530-537. |
| Direct randomised trials: aliskiren versus amlodipine in combination with HCTZ | ||
| Ferdinand et al 2010 | Responses to aliskiren/hctz versus amlodipine on peripheral and central blood pressure in African American patients with stage 2 hypertension | J Am Coll Cardiol 55 (10A): A61.E586. |
| Trials in other populations | ||
| C2201 - AVOID | Parving H et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. | N Engl J Med 2008; 358:2433-2446. |
| 2313 - ALOFT | McMurray J et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. | Circ Heart Fail 2008; 1:17-24. |
| ASPIRE 2010 | Effect of the direct rennin inhibitor aliskiren on LV remodelling following MI with LV dysfunction. | American College of Cardiology website: http://www.cardiosource.com/rapidnewssummaries/acc10.asp |
8. Results of Trials
The results of change from baseline in sitting diastolic blood
pressure (DBP) are presented below:
Comparison with irbesartan
: There were no statistically significant differences in reduction
in DBP between aliskiren 150 mg and irbesartan 150 mg monotherapy,
aliskiren 300 mg and irbesartan 300 mg monotherapy, or the same
drugs combined with hydrochlorothiazide. Aliskiren 300 mg produced
statistically significantly larger reductions in DBP than
irbesartan 150 mg (Trial 2201).
Comparison with valsartan:
There were statistically significant differences in favour of
valsartan for the comparison of aliskiren 150 mg and valsartan 160
mg in Trial 2327 and for both valsartan 160 mg and 320 mg
combination treatments with HCTZ in Trial 2331. The submission
argued that as the lower bound of the 95% confidence limits for
these comparisons was less than 2 mmHg, there are no clinically
important differences between aliskiren and valsartan.
Comparison with ramipril:
There were no statistically significant differences between
monotherapy with aliskiren 150 mg and ramipril 5 mg, and aliskiren
300 mg and ramipril 10 mg in reducing DBP. Aliskiren 300 mg was
more effective than ramipril 5 mg (Trial 2339). Aliskiren in
combination with HCTZ was statistically significantly more
effective than ramipril in combination with HCTZ.
Comparison with lisinopril:
There were no statistically significant differences between
aliskiren 150 mg or 300 mg and lisinopril 10 mg.
Comparisons with losartan and amlodipine:
There were no statistically significant or clinically important
differences between aliskiren and losartan or amlodipine.
Overall, the DBP reductions reported in the trials for aliskiren
were similar to those reported with the comparator drugs. Where the
margin of < 2 mmHg difference in blood pressure changes was
applied, there were no clinically important differences in blood
pressure reduction between aliskiren and comparator drugs.
The results of change from baseline in sitting systolic blood
pressure (SBP) are presented below:
Comparison with irbesartan:
There were no statistically significant differences in reduction in
SBP between aliskiren 150 mg and irbesartan 150 mg monotherapy,
aliskiren 300 mg and irbesartan 300 mg monotherapy, or the same
drugs combined with hydrochlorothiazide.
Comparison with valsartan:
There were no statistically significant differences in reduction in
SBP between aliskiren 150 mg and valsartan 160 mg monotherapy and
aliskiren 300 mg and valsartan 320 mg monotherapy (Trials 2203,
2327). When combined with HCTZ, there was a statistically
significant difference in favour of valsartan for the comparison of
aliskiren 300 mg and valsartan 320 mg, but not for the aliskiren
150 mg versus valsartan 160 mg comparison (Trial 2331).
Comparison with ramipril:
There were statistically significant differences favouring
aliskiren between aliskiren 300 mg and ramipril 10 mg in
monotherapy (Trials 2307 and 2351) and in combination with HCTZ
(Trial 2306). There was no statistically significant difference
between monotherapy with aliskiren 150 mg and ramipril 5 mg (Trials
2339 and 2307). Aliskiren 300 mg was more effective than ramipril 5
mg (Trial 2339).
Comparison with lisinopril:
There were no statistically significant differences between
aliskiren 150 mg or 300 mg and lisinopril 10 mg.
Comparisons with losartan and amlodipine:
There were no statistically significant or clinically important
differences between aliskiren and losartan or amlodipine.
Overall, neither aliskiren nor the comparator drugs were
consistently found to be superior by demonstration of statistically
significant differences in blood pressure reduction. Aliskiren was
generally similar to comparator drugs regarding blood pressure
reduction.
Effectiveness in populations other than isolated hypertension
Trial C2201-AVOID, conducted in hypertensive patients with type 2
diabetes, found that aliskiren plus losartan resulted in greater
renal protection compared to the use of losartan alone in urinary
albumin to creatinine ratio but not in change from baseline in
estimated glomerular filtration rate (GFR).
Trial 2316-ALLAY, conducted in obese patients with hypertension and
left ventricular hypertrophy, found aliskiren plus losartan
provided no further myocardial protection (as measured by left
ventricular mass) beyond that associated with losartan alone.
Aliskiren was non-inferior to losartan alone.
The ASPIRE trial demonstrated that aliskiren adds no myocardial
protection, as measured by left ventricular end-systolic volume, in
a population with reduced left ventricular (LV) function in the
context of a recent myocardial infarction (MI). For the secondary
outcome, a composite of cardiovascular deaths, heart failure
hospitalisations, myocardial infarction, stroke, and resuscitated
sudden death, there were 39 (9%) events in aliskiren compared with
34 (9%) in placebo (HR=1.01, 95% CI 0.62, 1.63), and for all-cause
mortality there were 17 (4%) deaths in aliskiren compared with 8
(2%) in placebo (HR=1.83, 95% CI 0.79, 4.3). While the results were
not statistically significant, these results suggest the
possibility of worse outcomes in aliskiren treatment patients. No
other cardiovascular morbidity or mortality data were provided in
the submission.
A fourth trial, ALOFT, was primarily a safety study in patients
with stable heart failure.
None of these trials were designed to address clinical events and
there is currently no marker that reliably predicts benefit in
cardiovascular morbidity and mortality in heart failure or post-MI
with left ventricular dysfunction (Arend 2002). Nonetheless, the
finding of more deaths on aliskiren in ASPIRE may suggest the
possibility of worse outcomes in aliskiren treatment patients. The
submission noted three ongoing randomised outcome trials, ALTITUDE
in 8,600 patients with type 2 diabetics at high renal and
cardiovascular risk, ATMOSPHERE in 7,000 patients with patients
with heart failure and elevated BNP, and ASTRONAUT in 1,800
hospitalised heart failure patients.
For PBAC’s view, see Recommendation and
Reasons.
Comparative toxicity
Cough:
The submission presented a meta-analyses of the incidence of cough
comparing aliskiren and AIIRAs (4 trials from the submission) and
comparing aliskiren and ACEIs (8 trials from the submission). There
was no difference in the aliskiren/AIIRA comparison (17/1302 vs.
10/947, risk difference = 0.00, 95% CI -0.01, 0.02, p=0.88).
Aliskiren patients showed less cough in the aliskiren/ACEI
comparison (64/3126 vs. 176/2230, risk difference = -0.04, 95% CI
-0.06, -0.03, p<0.0001).
Diarrhoea:
Although only one trial (Trial 2351) individually showed a more
than 2-fold increase in diarrhoea with aliskiren compared to
irbesartan, 1.4% versus 0.5%, the TGA evaluation indicated
diarrhoea rates of 1.2%, 1.3%, 1.2%, 2.3%, and 9.5% for placebo, 75
mg, 150 mg, 300 mg, and 600 mg aliskiren, respectively.
Peripheral oedema:
Although an excess of peripheral oedema adverse events was not seen
in the clinical trials, cases reported since marketing often showed
a positive rechallenge increasing the likelihood of
causation.
Aliskiren is associated with an increased risk of diarrhoea and
appears to be associated with an increased risk of peripheral
oedema. It also has a risk of hyperkalemia in certain settings,
although the analysis presented was unable to detect a difference
in this risk compared to the risk of hyperkalemia with ACEIs or
AIIRAs. There are limited comparative data (four short-term trials)
on the co-use of aliskiren with either an ACEI or an AIIRA. There
are few long-term comparative safety data of aliskiren with only
three of the trials having a duration of more than 6 months and
none beyond one year.
Risks identified by the TGA, to be included in the regulatory Risk
Management Plan for aliskiren, include diarrhoea, rash, angioedema
and anaphylaxis, hyperkalemia, decreased haemoglobin and
hematocrit, and renal dysfunction. Potential risks in the Risk
Management Plan are colorectal hyperplasia, peripheral oedema, and
hypotension.
9. Clinical Claim
The submission described aliskiren as similar in terms of
comparative effectiveness and similar in terms of comparative
safety over irbesartan.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as aliskiren 150 mg daily and
irbesartan 150 mg daily and valsartan 160 mg daily, plus aliskiren
300 mg daily and irbesartan 300 mg daily and valsartan 320 mg
daily.
11. Estimated PBS Usage and Financial Implications
The financial savings/year to the PBS was estimated by the submission to be less than
$10 million per year in Year 5. The estimate is based on the assumption that aliskiren
replaces AIIRA use only. A sensitivity analysis assuming 35.5% of substitution is
from ACEI results in a cost to the PBS of less than $10 million per year in Year 5.
For PBAC’s view, see Recommendation and Reasons.
12. Recommendation and Reasons
The PBAC acknowledged that aliskiren was the first drug in a new
class of antihypertensives and it lowers blood pressure
effectively. Similar reductions in blood pressure were seen
compared with irbesartan, other AIIRAs and ACEIs. However, the PBAC
noted that unlike the ACE inhibitors and AIIRAs, no reduction in
cardiovascular mortality and morbidity has been demonstrated, and
there are currently no additional indications such as use in heart
failure, post MI, vascular disease and renal disease.
Therefore, the Committee considered, on the evidence presented in
the submission, that aliskiren was similar in efficacy to
irbesartan in blood pressure reduction only. The PBAC also
considered that the claim of similar comparative safety to
irbesartan may not be reasonable as there are no long-term safety
data and a number of safety issues to be addressed by Risk
Management Plans.
The PBAC did not agree that the comparator should be restricted to
irbesartan as the main comparator, and valsartan, ramipril and
lisinopril as secondary comparators. The PBAC considered that the
comparator should include a mix of all PBS-subsidised
antihypertensive agents including AIIRAs, ACEIs, calcium channel
blockers, beta-blockers and thiazide diuretics. The PBAC agreed
with the ESC that the relative market share of AIIRAs and ACEIs did
not inform the choice of comparator adequately, particularly as
aliskiren may be used in combination with conventional therapy,
rather than as a substitute and that clinicians were unlikely to
replace current antihypertensive therapies with a newer agent
without long term outcome and safety data.
The PBAC noted that the base case estimates of extent of use and
financial implications were based on the assumption that aliskiren
would replace AIIRAs only. The PBAC considered that in clinical
practice it was more likely that a proportion of substitution would
be from ACEIs, calcium channel blockers and other antihypertensive
agents and also from use as an add-on therapy rather than as a
direct substitute. Therefore the uptake rates are likely
underestimated as they are lower than for recently listed AIIRAs
and it is likely that uptake of a drug in a new class will be
greater than for another AIIRA.
The PBAC therefore rejected the submission for aliskiren on the
basis of uncertain clinical need for an anti-hypertensive as it
does not provide evidence of long-term clinical benefits compared
with other agents in similar therapeutic classes and uncertain cost
effectiveness.
The PBAC noted that the submission meets the criteria for an
independent review.
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 has no further comment.
