Trandolapril with Verapamil Hydrochloride, tablet, 2 mg-180 mg, 4 mg-240 mg, Tarka®, November 2005
Public Summary Document for Trandolapril with Verapamil Hydrochloride, tablet, 2 mg-180 mg, 4 mg-240 mg, Tarka®, November 2005
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Public Summary Document
Product: Trandolapril with Verapamil Hydrochloride, tablet, 2 mg-180 mg, 4 mg-240 mg, Tarka®
Sponsor: Abbott Australasia Pty Ltd
Date of PBAC Consideration: November 2005
1. Purpose of Application
The submission sought listing for a combination tablet of trandolapril with verapamil
as a restricted benefit for “the treatment of hypertension. Treatment should not be
initiated with this fixed dose combination.”
2. Background
This combination formulation has not previously been considered by the PBAC.
3. Registration Status
Trandolapril with verapamil hydrochloride was registered by the TGA on 24 October
2005 and is indicated for the treatment of hypertension. Treatment should not be initiated
with this fixed dose combination.
4. Listing Requested and PBAC’s View
Restricted benefit
The treatment of hypertension. Treatment should not be initiated with this fixed dose
combination.
See Recommendations and Reasons for the PBAC’s view.
5. Clinical Place for the Proposed Therapy
The use of Tarka would require the administration of a single tablet daily as opposed
to one tablet of each monotherapy agent daily.
6. Comparator
The submission nominated trandolapril and verapamil Slow Release (SR) used concomitantly;
and also used individually in order to demonstrate an additional effect as the comparators.
See Recommendations and Reasons for the PBAC’s view.
7. Clinical Trials
The submission presented five key trials that compared the short-term efficacy and
safety of Tarka with either trandolapril and/or verapamil SR monotherapy in the treatment
of hypertension. Four of 5 trials (MPF/H9507, MPF/H9510, VT067 and MPF/H9508) were
randomised, double-blind, parallel-group trials. Of those four, one (MPF/H9508) was
inappropriately included as a key trial due to the use of non-comparable doses. One
of 5 trials (Karlberg et al, 2000) was a randomised, double-blind, cross-over trial.
A meta-analysis was presented pooling the results of 3 trials (MPF/H9507, MPF/H9510
and VT067).
In addition, 6 studies were included as supporting evidence. Five of the 6 studies
were randomised, double-blind, parallel-group trials comparing the short-term efficacy
and safety of Tarka with either trandolapril or/and verapamil SR monotherapy in the
treatment of hypertension. Four of those evaluate doses that were different from the
requested strengths for listing, and one (Ruilope et al, 1999) was conducted in a
diabetic population.
The full list of trials forming the basis of the submission is tabulated below.
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
| Karlberg BE 2000 | Efficacy and safety of a new long-acting drug combination, trandolapril/verapamil as compared to monotherapy in primary hypertension. Swedish TARKA Trialists. | Blood Press 2000;9:140-5. |
| MPF/H9507 Viskoper RJ 1997 |
Verapamil and trandolapril alone and in fixed combination in moderate essential hypertension:
a multicenter, double-masked study. Verapamil and trandolapril alone and in fixed combination on 24-hour ambulatory blood pressure profiles of patients with moderate essential hypertension. |
Current Therapeutic Research 1997;58(6):331-42. Current Therapeutic Research 1997;58(6):343-51. |
| MPF/H9510 | A double-blind, randomised, parallel group study comparing the efficacy and safety of two trandolapril/verapamil SR dose combination with trandolapril monotherapy in essential hypertensive patients who have not responded sufficiently to trandolapril monotherapy. | |
| VT 067 | Antihypertensive efficacy and safety of verapamil SR 180mg/trandolapril 2mg in patients insufficiently pre-treated with single-blind trandolapril 2mg monotherapy. A double-blind randomised parallel-group comparison to trandolapril 2mg. | |
| MPF/H9508* | Double-blind, placebo-controlled clinical study to determine the influence of trandolapril, VeraTran, and a beta blocker-diuretic combination on the physical performance and pulmonary function in patients with mild to moderate hypertension. |
8. Results of Trials
The results of 4 key trials are summarised in the tables below.
Summary of the primary efficacy result in key trials
|
Trial |
ITT |
Mean change of sitting diastolic BP in mmHg from baseline to last visit (95% CI) |
Difference of change in sitting diastolic BP (mmHg) of combination over monotherapy |
|---|---|---|---|
| Karlberg 2000 - VT180/2 - V240 or T2 |
Total= |
-15.1 |
VT180/2 versus (V240 or T2) |
| MPF/H9507 - VT180/2 - V180 - T2 |
103 |
-13.4 (-14.9, -11.9) |
VT180/2 versus V180 = -3.6 (p=0.0005) |
| MPF/H9510 - VT180/1 - VT180/2 - T2 |
69 |
-7.15 |
V180/2 versus T2 = -1.8 (p=0.076) |
| VT067 - VT180/2 - T2 |
184 |
-7.0 (-8.2, -5.8) |
V180/2 versus T2 = -3.7 (p<0.001) |
VT180/2 = verapamil SR 180mg/trandolapril 2mg; VT180/1 = verapamil SR 180mg/trandolapril
1mg; V240 = verapamil SR 240mg; V180 = verapamil SR 180mg; T2 = trandolapril 2mg;
ITT = intention-to-treat; BP = blood pressure
Summary of response rates * (VT180/2 versus T2) of 3 key trials included in the meta-analysis
|
ITT population |
Point estimate |
95% CI |
p-value |
Heterogeneity |
|---|---|---|---|---|
| Relative risk (combined) Fixed effect model Random effects model |
1.44 |
1.22 to 1.69 |
<0.0001 |
Chi2=9.74 |
| Risk difference (combined) Fixed effect model Random effects model |
0.16 |
0.09 to 0.23 |
<0.0001 |
Chi2=4.21 |
* defined as a reduction in diastolic blood pressure of >10mmHg or diastolic blood
pressure <90mmHg
VT180/2 = verapamil SR 180mg/trandolapril 2mg; T2 = trandolapril 2mg; ITT = intention-to-treat;
The primary outcome of 4 key trials was change in sitting diastolic BP from baseline
to the last visit.
Three of five trials (MPF/H9570, MPF/H9510 and VT067) compared the reduction in diastolic
BP of Ziaxel® 180/2mg with trandolapril 2mg monotherapy. The results showed the contribution
of verapamil SR 180mg to diastolic BP reduction ranged from -1.8 to -3.7mmHg.
The results of the meta-analysis for risk difference showed a response rate of 0.16
(95% CI: 0.09 to 0.23; p<0.0001) that was significantly higher for the combination
therapy. However, based on the relative risk, the result failed to reach statistical
significance: RR=1.41(95% CI: 0.98 to 2.02; p=0.0635).
Tarka had a similar adverse effect profile to that of trandolapril and verapamil SR,
with the most common adverse effects being cough, headache and constipation. The rate
of adverse events seemed to be similar between the fixed-dose combination and either
trandolapril or verapamil SR monotherapy in all trials. An exception was the Ruilope
et al, 2004 supporting trial, in which, the rate of adverse events was about twice
as likely in the verapamil SR/trandolapril 180/2mg arm compared with the trandolapril
2mg arm (RR=0.46; 95% CI: 0.25-0.84; p=0.010).
See Recommendations and Reasons for the PBAC’s view.Top of page
9. Clinical Claim
The submission described Tarka (2/180mg and 4/240mg) as having significant advantages
in effectiveness over verapamil SR or trandolapril given as individual therapy.
The PBAC agreed the claim of superiority of the combinations of trandolapril and verapamil
over either individual agenda as monotherapy was weakly supported by the data.
10. Economic Analysis
The submission presented a preliminary (trial-based) economic evaluation adopting
a cost-minimisation approach. The resources included were drug costs only.
11. Estimated PBS Usage and Financial Implications
The submission estimated that in Year 3 of listing the financial cost would be less
than $10 million per year .
The PBAC considered that this was an overestimate.
12. Recommendation and Reasons
The PBAC considered that verapamil is not a drug of choice in the treatment of hypertension
and treatment of angina would constitute the majority of its use. Further, it was
the view of the PBAC that it is possible that the combination could be used in patients
with both hypertension and angina, which is beyond the requested restriction and no
evidence is provided to demonstrate an additive effect across these two indications.
There is also the potential that the proposed combination drug product could replace
ACE inhibitor with thiazide combinations, which are less costly than the proposed
combination presentations and there is no evidence of comparative effectiveness against
these combinations. Further, in either of the above situations, the financial implications
would have been underestimated. The PBAC considered that it was doubtful whether this
combination meets the criteria for listing combination products in terms encouraging
inappropriate increase in utilisation of the components.
Data presented in the submission indicate that approximately 400 patients in Australia
are on concomitant trandolapril and verapamil therapy and it is not known how many
of these are being treated for hypertension in the absence of angina. Thus, the PBAC
was of the view that the clinical need for this combination product was not clearly
demonstrated.
The PBAC agreed the claim of superiority of the combination of trandolapril and verapamil
SR over either individual component as monotherapy in lowering blood pressure was
weakly supported by the data. One of five trials (MPF/H9507) compared the reduction
in diastolic blood pressure (BP) of Ziaxel® 180/2 mg with verapamil 180 mg monotherapy
and reported a statistically significant further reduction of -3.6 mmHg. Three of
five trials (MPF/H9507, MPF/H9510 and VT067) compared the reduction in diastolic BP
of Ziaxel® 180/2 mg with trandolapril 2 mg monotherapy. These results show the addition
of verapamil SR 180 mg to trandolapril in terms of diastolic BP reduction is less
convincing, varying from -1.8 mmHg to -3.7 mmHg, which when pooled (random effects)
is -2.80 mmHg (95% CI: -3.99 mmHg to -1.60 mmHg). An excluded fourth randomised trial
also comparing the 180/2 combination with trandolapril 2 mg monotherapy reported a
non-statistically significant difference of -1.3 mmHg, but this small trial is unlikely
to have a substantial impact when included in the meta-analysis. According to the
Committee for Proprietary Medicinal Products (CPMP) guidelines, a 2 mmHg margin is
considered the minimum clinically acceptable difference in diastolic BP (DBP). The
PBAC also noted that only data corresponding to the lower dose combination was provided.
The PBAC was thus not entirely convinced that this combination meets its criteria
for listing combination products in terms of demonstrating superiority of the combination
over both of its individual components.
Further, the PBAC also noted that a review (Prospective Studies Collaboration) has
suggested that systolic blood pressure (SBP) is a more useful predictor of subsequent
clinical outcomes than DBP. The PBAC noted that inspection of the SBP results suggested
greater numerical differences would likely be generated if these results were similarly
pooled to the results for DBP and this was confirmed by the sponsor’s pre-PBAC Response.
The PBAC therefore rejected the submission because of a lack of clinical need in patients
with hypertension for the combination, concerns about inappropriate substitution for
ACE inhibitor with thiazide combinations and unconvincing evidence of superiority
over the individual components in the requested doses.Top of page
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 believes that there is a clear clinical need for a combination of trandolapril
and verapamil. Although the submission provided data that there are currently over
23,000 Australians receiving an ACE inhibitor/ calcium channel blocker combination,
the PBAC focused on the smaller number currently on the verapamil/ trandolapril combination
when assessing clinical need.
In addition, arguments that at a population level there is a limited need for the
product do not appear to take into account the fact that for individual patients the
combination of trandolapril and verapamil may provide substantial benefit in controlling
hypertension. The National Heart Foundation guidelines “Hypertension Management Guide
for Doctors 2004” indicates that a combination ACE inhibitor and Calcium channel Blocker
is useful and has a “particular role in the presence of diabetes and lipid abnormalities”
(see Page 21). The sponsor would like to work with the PBAC to examine future listing
options.
