Fresenius Kabi: It’s Time to Pull the Plug on Voluven (hydroxyethyl starch 130/0.4)

Voluven (hydroxyethyl starch 130/0.4) was heralded to the hospital community as a cheaper alternative to albumin, but safer than previous hydroxyethyl starch (HES) products that were shown to cause bleeding and renal failure.

Although Voluven is likely “safer” than older HES products, it still is NOT safer than traditional volume repletion with normal saline or albumin.  It was a good run, Voluven, but it’s time to pull the plug.

Comparison to Older HES Products

Voluven is safer than older HES products.  Specifically, Voluven’s lower molecular weight and degree of substitution seems to confer a lower risk of coagulopathy and renal impairment.1  Because all HES products are NOT created equal, the medical community has been forced to wait for Voluven-specific trials to determine its role in volume repletion.

Comparison to Albumin

In theory, Voluven and other HES products are attractive compared to albumin because they are fully synthetic (not derived from human plasma) — thus, they can be manufactured at lower costs and do not have the theoretical risk of disease transmission.

Despite high-quality comparative data between albumin and Voluven, we do know that Voluven causes an apparent coagulopathy (eg, increased PTT or TEG findings) compared to albumin, but it isn’t clear whether this translates into hard clinical endpoints.2

A History of Fraudulent Data

Nothing can destroy a drug’s reputation quicker than fraudulent trial data.  One major author of numerous Voluven (and other HES product) trials, Joachim Boldt, has had many of his articles retracted due to data falsification and lack of IRB approval.  You can read the full story in all of its glory here.

Joachim Boldt’s disgusting actions have had dramatic effects — not only did it change public opinion regarding the “favorable” safety of Voluven, but many of his fraudulent trials were even included in a large meta-analysis.  The take-home point?  When examining the Voluven data, be very careful with the source of the data.

The 6S Trial with Tetraspan (Perner 2012)

The 6S trial was one of the first high-quality, large trials examining the use of a low molecular weight, low substitution HES product.3  Although 6S used Tetraspan (6% HES 130/0.42) and not Voluven (6% HES 130/0.4), the products are extremely similar.

In this trial, patients with severe sepsis were given either lactated ringer’s or Tetraspan (max 33 mL/kg/day).  At 90-days, Tetraspan patients had higher mortality (51% vs. 43%, p=0.03) and required more renal replacement therapy (22% vs. 16%, p=0.04).  The conclusion was clear: Tetraspan (a product that is very similar to Voluven) increased mortality and renal failure.

The CHEST Trial with Voluven (Myburgh 2012)

There was a big to-do when the 6S trial was published because of the confusion between HES 130/0.4 (Voluven) and 130/0.42 (Tetraspan).  Unfortunately for Voluven, its time in the spotlight was only months away in the same journal.

The CHEST trial was a large, 7000-patient study modeled after the SAFE study.  CHEST was designed to compare normal saline to Voluven (130/0.4) in a heterogeneous ICU patient population.  Although 90-day mortality was not different between normal saline and Voluven (17% vs. 18%, p=0.26), Voluven was associated with a greater risk of renal replacement therapy (5.8% vs. 7%, p=0.04) and renal injury (34.6% vs. 38%, p=0.005).

Is Voluven Really Cheaper than Albumin?

The CHEST trial was modeled after the SAFE trial, which compared albumin to normal saline.  In both trials, the investigator was blinded to the treatment — thus, it is possible to compare the clinical “potency” between the two agents based on how frequently patients needed additional doses.

In the SAFE trial, albumin was about 40% more “potent” than normal saline, meaning that patients receiving albumin could receive 40% less volume but still obtain the same net hemodynamic benefit.  In the CHEST trial, Voluven was a paltry 15% more “potent” than normal saline.

The biggest theoretical benefit of Voluven (cost) quickly comes into question when you consider that it may not be as potent as albumin on an mL-per-mL basis and the fact that hemodialysis is required more often with Voluven.

Fresenius Kabi: It’s Time to Pull The Plug

At this point, is there any reason to consider using Voluven at all?  It definitely causes more renal injury (including a need for hemodialysis), is unlikely to be as potent as albumin, may cause coagulopathy, and is unlikely to have a true cost benefit.  Potentially most concerning, a very similar product (Tetraspan) was shown to INCREASE mortality among patients with septic shock.

With all of that said: Fresenius Kabi — it’s time to pull the plug and voluntarily withdraw Voluven from the market.

References

  1. Langeron O, Doelberg M, Ang ET, et al. Voluven, a lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Anesth Analg. 2001;92(4):855-62. PMID 11273914.
  2. Green RS, Hall RI. Con: starches are not preferable to albumin during cardiac surgery: a contrary opinion. J Cardiothorac Vasc Anesth. 2008;22(3):485-91. PMID 18503946.
  3. Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367(2):124-34. PMID 22738085.
  4. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367(20):1901-11. PMID 23075127.

Photo by stefanx80

2 thoughts on “Fresenius Kabi: It’s Time to Pull the Plug on Voluven (hydroxyethyl starch 130/0.4)

  1. Ryan Padayachee

    It is distressingly shocking that one would write an article such as the one above. Misappropriate use of any drug/starch etc would generally yield bad results. Voluven is meant for initial resuscitation of patients-something none of these trials has shown to be used for. These trials that you quote has shown starches to be used as maintenance fluid. How does this make sense when it is not indicated to be used as such? Furthermore, the trials of which you speak of-only 1 is based on voluven whereas the others are on starches manufactured or marketed by B Braun. The CHEST trial in my opinion as well as the opinion of colleagues is highly flawed. Except for the fact that the goal of the trial was to assess mortality and the author very "smartly/conveniently" decided comment on things such as RRT etc?? Of course if patients were highly overloaded, they would require RRT!!!! Why were patients only enrolled 11 hours after admission into the trial? What fluids were they given in initial resus or did they even need to be resuscitated at all? A very valid question.. Why is it also that when RIFLE criteria was discussed, the number of patients kept changing. Surely if 7000 patients are enrolled in a trial, that number of patients should add up throughout. Where did those additional patients come from? One has to remember as it has been proven many times that starches have different properties and effects. We cannot see them as equal due to differences in Mw, molar substitution and so on. It's important to note that voluven apart from the CHEST has a wealth of information which is shown in their other trials which is more than 100.

    Reply
    1. Sean P. Kane Post author

      Thank you for the comment — certainly a controversial topic!

      Actually, both the 6S and CHEST trials used HES as part of a resuscitation strategy in patients requiring additional fluid. The CHEST trial specifically spells out that the Voluven is for resuscitation “over and above that required for maintenance or replacement fluids”.

      In what way was CHEST highly flawed? Renal replacement therapy was a very reasonable safety outcome given the toxicity seen with other HES products. In CHEST, those receiving saline actually received more fluid than the HES group — so I’m not sure that fluid overload had anything to do with the need for RRT.

      I do agree that not all starches are created equal, but the two starches used in 6S and CHEST are incredibly similar. I also acknowledge that Voluven has plenty of other trials examining its use, but I would challenge you to find an article as robust in study design and patient population as CHEST.

      As I mentioned in the article, I can think of absolutely no setting in which I would recommend a hetastarch product. Their cost benefit versus albumin is lost due to lower potency, and their safety profile is suspect at best and dangerous at worst.

      Reply

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