Hydroxyethyl starch 130/0.4, I.V. infusion, 60 g per L, 500 mL, Voluven® 6 %, July 2009
Public summary document for Hydroxyethyl starch 130/0.4, I.V. infusion, 60 g per L, 500 mL, Voluven® 6 %, July 2009
Page last updated: 30 October 2009
Public Summary Document
Product:Hydroxyethyl starch 130/0.4, I.V.
infusion, 60 g per L, 500 mL, Voluven® 6 %
Sponsor: Pharmatel Fresenius Kabi Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Submission
The submission sought an unrestricted benefit listing.
2. Background
This product had not previously been considered by the PBAC.
3. Registration Status
Hydroxyethyl starch 6 % 130/0.4 solution for intravenous infusion
was TGA registered on 13 November 2006 for the therapy and
prophylaxis of hypovolaemia.
4. Listing Requested and PBAC’s View
Unrestricted
The PBAC agreed with the requested listing.
5. Clinical place for the proposed therapy:
Plasma volume expanders are used alone or in combination with blood
products in the treatment of hypovolaemia. They also provide an
alternative treatment option to blood products for patients.
Hydroxyethyl starch would provide an alternative colloid
preparation to succinylated gelatin (i.e. Gelofusine®, as known
in Australia).
6. Comparator
The submission nominated gelatin succinylated 4 % (Gelofusine) I.V.
infusion as the main comparator. The submission also presented a
supplementary analysis comparing hydroxyethyl starch with a 3 %
gelatin, which is not marketed in Australia.
7. Clinical trials
The submission presented eight pivotal randomised trials directly
comparing Voluven with Gelofusine for fluid replacement in patients
undergoing cardiac (three trials), abdominal (three trials), major
orthopaedic (one trial) or paediatric (one trial) surgery. The
submission also presented five supplementary direct randomised
trials (three cardiac surgery, one abdominal surgery, one
paediatric surgery).
Publication details of the presented trials are shown in the
following table:
| Trial ID/First Author | Protocol title/ Publication title | Publication citation |
| Pivotal randomised trials | ||
| Boldt et al 2003 | Boldt J, Brenner T, et al. Influence of two different volume replacement regimens on renal function in elderly patients undergoing cardiac surgery: comparison of a new starch preparation with gelatin. | Intensive Care Med 2003; 29(5):763-9 |
| Boldt et al 2008 | Boldt J, Brosch C, et al. Comparison of the effects of gelatin and a modern hydroxyethyl starch solution on renal function and inflammatory response in elderly cardiac surgery patients. | British Journal of Anaesthesia 2008; 100(4):457-64 |
| Boldt et al 2001 | Boldt J, Suttner S, et al. Are cost of a crystalloid based volume replacement regimen lower than of a colloid based volume replacement strategy? | Infusion therapy and transfusion therapy 2001; 28:144-149 |
| Haas et al 2007 | Haas, T., et al. Effects of albumin 5% and artificial colloids on clot formation in small infants. | Anaesthesia 2007; 62(10):1000-7 |
| Haisch et al 2001a | Haisch, G., et al. Influence of a new hydroxyethyl starch preparation (HES 130/0.4) on Coagulation in cardiac surgical patients. | Journal of Cardiothoracic and Vascular Anesthesia 2001; 15(3):316-321 |
| Haisch et al 2001b | Haisch, G., et al. The influence of intravascular volume therapy with a new hydroxyethyl starch preparation (6% HES 130/0.4) on coagulation in patients undergoing major abdominal surgery. | Anesthesia and Analgesia 2001; 92(3):565-71 |
| Mahmood et al 2007 | Mahmood, A., P. Gosling, and R.K. Vohra, Randomized clinical trial comparing the effects on renal function of hydroxyethyl starch or gelatin during aortic aneurysm surgery. | British Journal of Surgery 2007; 94(4):427-433 |
| Mittermayr et al 2008 * | Mittermayr, M., et al., Effects of colloid and crystalloid solutions on endogenous activation of fibrinolysis and resistance of polymerized fibrin to recombinant tissue plasminogen activator added ex vivo. | British Journal of Anaesthesia 2008; 100(3):307-314 |
| Mittermayr et al 2007 * | Mittermayr, M., et al., Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration. | Anesthesia and Analgesia 2007; 105(4):905-17 |
| Supplementary randomised trials | ||
| Boks et al 2007 | Boks, R.H., et al., Low molecular starch versus gelatin plasma expander during CPB: does it make a difference? | Perfusion 2007; 22(5):333-7 |
| Godet et al 2008 | Godet, G., et al. Safety of HES 130/0.4 (Voluven®) in patients with preoperative renal dysfunction undergoing abdominal aortic surgery: a prospective, randomized, controlled, parallel-group. | European Journal of Anaesthesiology 2008; 25:986-994 |
| Van der Linden et al 2005 | Van der Linden, P.J., et al. Hydroxyethyl starch 130/0.4 versus modified fluid gelatin for volume expansion in cardiac surgery patients: the effects on perioperative bleeding and transfusion needs. | Anesthesia and Analgesia 2005; 101(3):629-34 |
| Witt et al 2008 | Witt, L., et al. Alteration of anion gap and strong ion difference caused by hydroxyethyl starch 6% (130/0.42) and gelatin 4% in children. | Paediatric Anaesthesia 2008; 18(10):934-939. |
| Yap et al 2007 | Yap, W.W., D. Young, and V. Pathi, Effects of gelatin and medium molecular weight starch as priming fluid in cardiopulmonary bypass--a randomised controlled trial. | Perfusion 2007;22(1):57-61 |
* These trials report the same patient population; however, the
2008 trial presents additional secondary outcomes.
8. Results of trials
Overall, the pivotal trials suggested:
- No difference between Voluven and Gelofusine for hemodynamic outcomes (three cardiac and one abdominal trial),
- No difference (one cardiac trial) or a difference favouring Voluven (one cardiac and one abdominal trial) in renal outcomes; and,
- No difference (one cardiac and one abdominal trial) or a difference favouring Gelofusine (one major orthopaedic and one paediatric trial) in coagulation outcomes.
Four of the pivotal trials found a statistically significant
difference in the volume of colloids infused, with Voluven
consistently requiring a lower volume than Gelofusine.
A meta-analysis of surrogate efficacy and safety outcomes from the
8 pivotal trials was presented. The meta-analysis suggested a
statistically significant lower blood loss and lower volume of
colloid used with Voluven, and a lower serum creatinine and higher
creatinine clearance after surgery with Voluven compared with
Gelofusine.
With respect to adverse events, coagulation parameters presented in
some trials could be considered adverse events. These were however,
not outcome based and the submission did not provide a concise
summary of trial-based adverse effects separate to primary and
secondary outcomes.
The PBAC considered the evidence indicated that the safety profile
of HES is different to succinylated gelatin however, overall
non-inferior to succinylated gelatin.
9. Clinical Claim
The submission described Voluven as equivalent in terms of
comparative effectiveness and equivalent in terms of comparative
safety to Gelofusine.
For PBAC’s views see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. Voluven 0.84
x 500mL bag and Gelofusine 1 x 500mL bag were claimed to be
equi-effective. This was based on the total colloid volumes infused
in three of the pivotal trials. In selecting the trials on which to
base the dose equivalence estimation, the submission excluded three
trials which found no significant difference between colloid
volumes (Haisch et al., 2001a,b and Mahmood et al., 2007). The
Sponsor argued that those studies excluded were done so on the
basis that Haisch 2001 (Cardiac surgery) and Haisch 2001 (Abdominal
surgery) as well Mahmood 2007 produced inconclusive differences
because they were inadequately powered to elicit a difference in
the volume of colloid used.
11. Estimated PBS Usage and Financial Implications:
The submission estimated the likely number of patients/year to be
less than 10,000 per year. The PBAC considered this to be likely an
overestimate as the sponsor derived figures Medicare Australia
script data for Gelofusine on the assumption that one prescription
represents one patient and the mean volume of colloids used per
patient in the trials cited by the sponsor exceeded one script
(1,500 mL).
The financial cost/year to the PBS/RPBS was estimated to be less
than $10 million per year.
12. Recommendation and Reasons:
The PBAC recommended the listing of hydroxyethyl starch 130/0.4
I.V. infusion on the PBS as an Unrestricted Benefit on a cost
minimisation basis to succinylated gelatin I.V. infusion
(Gelofusine) where one 500 mL bag of hydroxyethyl starch 130/0.4
(HES) is equi-effective to one 500 mL bag of succinylated
gelatin.
The PBAC did not agree with ESC that the appropriate comparator
would be intravenous normal saline. The Committee accepted there is
a clinical place for colloids even though this has diminished and
that colloids have a different role from crystalloids. That being
the case, the PBAC agreed with the Pre-PBAC Response that gelatin
succinylated 4 %, as the product that would be replaced most on the
PBS would be the appropriate comparator.
The PBAC noted that the trial evidence presented surrogate outcomes
such as haemodynamic variables, that the trial patient populations
were diverse and small and that no final outcome data such as
survival were presented. However, the PBAC considered that overall
the evidence supported non-inferiority of HES to the comparator
succinylated gelatin. The PBAC considered the evidence indicated
that the safety profile of HES is different to succinylated
gelatin, with potentially fewer adverse renal function effects,
possibly poorer coagulation outcomes and an increased incidence of
pruritus, however overall non-inferior to succinylated gelatin. The
Committee considered that it was difficult to determine the
comparative incidence of anaphylaxis, considering that anaphylaxis
is a rare event and hence that it may take many years for the
incidence of this adverse event with HES to be determined.
The PBAC did not accept higher price for HES requested over
succinylated gelatin based on a mean volume per patient of 0.84 of
a 500 mL bag compared to one 500 mL bag of succinylated gelatin.
The PBAC noted that this dose equivalence calculation
inappropriately excluded three clinical trials which found no
significant difference between the volume of HES and succinylated
gelatin used (Haisch et. al., 2001a,b and Mahmood et. al., 2007).
In addition, the PBAC considered that in clinical practice any
remaining volume in a 500 mL I.V. infusion bag would not be
utilised for another patient. The PBAC hence recommended that one
500 mL bag of HES is considered equi-effective to one 500 mL bag of
succinylated gelatin.
Recommendation
HYDROXYETHYL STARCH 130/0.4, I.V. infusion, 60 g per 1 L, 500
mL
Restriction: Unrestricted benefit
Max qty: 3
Repeats: Nil
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 thanks the PBAC for its deliberations and commentary, and has accepted the recommendations made to list Voluven on the PBS at the PBAC’s proposed listing and suggested price.
