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

PDF printable version of Hydroxyethyl starch 130/0.4, I.V. infusion, 60 g per L, 500 mL, Voluven® 6 % (PDF 35 KB)

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


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.

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.