Starch safety in resuscitation – when will we ever learn?
Andy Parrish has in interest in evidence-based medicine, works in the Department of Internal Medicine, Frere and Cecilia Makiwane hospitals, East London, and is affiliated to Walter Sisulu University, Rhodes University and the University of Cape Town, South Africa.
Marc Blockman has an
interest in drug policy and evidence-based medicine and works
in the Department of Internal Medicine, Division of Clinical
Pharmacology, Groote Schuur Hospital and University of Cape
Town, South Africa.
Recent trials have failed to demonstrate a survival benefit
from the use of hydroxyethyl starches (HES) as a colloid in
fluid resuscitation and have raised concerns of renal harm. In
severe sepsis, there is a concerning signal of increased
mortality. New high-quality systematic reviews consistently
demonstrate a statistically non-significant relative risk of
death of 1.08 - 1.10 and a significant 25% increased chance of
requiring renal replacement therapy. The HES literature contains
many industry-affiliated reviews of indifferent quality.
Traditional efficacy confidence limits may warrant re-evaluation
when considering these harms. Newer formulations of HES and more
focused indications for use show benefit on surrogate endpoints,
but these trials are currently underpowered to ensure safety.
S Afr Med J 2013;103(6):365-367.
The recent publication of several large well-conducted trials on hydroxyethyl starch (HES) has led to a re-examination of evidence for colloids in medicine. A Cochrane review1 showed no mortality advantage from HES, albumin, modified gelatins or dextran when compared with crystalloids. A 2011 review of HES2 raised concerns of increased harm, particularly with older HES formulations, and this concern was reiterated in a 2013 review.3 In a recent editorial4 it was suggested that the accrued evidence now allows us to declare that starches have reached the ‘end of the road’ in the care of critically ill patients with sepsis.
In such patients the baseline mortality rate can be as high as
40%. 5 Even assuming half that
(20%), a relative risk of 1.09 gives an absolute mortality
increase of 1.8%, or one extra death for every 56 high-risk
patients prescribed HES as used in the underlying trials. The
South African (SA) public sector spent R45 million on HES in
2011 (pharmaceutical directorate, personal communication). If
HES was used in a similar way to that in the sepsis trials, this
might mean several hundred excess deaths annually in this
The new trials
The CHEST study6 compared 90-day mortality in 7 000 patients admitted to intensive care units (ICUs) and resuscitated with either 6% HES 130/0.4 or saline. The two groups had similar mortality rates, but more patients in the HES group required renal replacement therapy (7.0% v. 5.8%; relative risk (RR) 1.21, 95% confidence interval (CI) 1.00 - 1.45). Patients in the 6S study5 had severe sepsis and were given 6% HES 130/0.42 or Ringer’s acetate. Mortality at 90 days in the 398 patients in the HES group was 51%, while it was 43% in the 400 assigned to Ringer’s acetate (RR 1.17, 95% CI 1.01 - 1.36). At 90 days, more patients in the HES group needed renal replacement therapy (22% v. 16%; RR 1.35, 95% CI 1.01 - 1.80).
The same pattern was seen in the 196-patient CRYSTMAS study,7 which was only powered to detect a difference in volumes infused between 6% HES 130/0.4 and saline in patients with sepsis. The product manufacturer was involved in the design, analysis and write-up of the study. The 90-day mortality was non-significantly higher in the HES group (40% v. 33% using intention to treat data; RR 1.2, 95% CI 0.83 - 1.74).
VISEP8 (2008) compared the older 10% HES 200/0.5 with Ringer’s lactate in 537 patients with severe sepsis. Total HES volumes infused were high, with a median cumulative volume of 70 ml/kg, and the dose limit of 20 ml/kg/day was exceeded by more than 10% on at least one day in more than 38% of patients. The trial was stopped early because of increased renal failure and a trend to increased mortality in the HES group. Mortality at 90 days was 41% in the HES group and 33.9% in the control group (RR 1.21, 95% CI 0.97 - 1.51). Renal replacement therapy was required in 31% of the HES group and in 18.8% of controls (RR 1.66, 95% CI 1.22 - 2.25).
Further interesting studies await publication. The blinded
240-patient Basel study for the evaluation of starch infusion
for septic patients (BaSES9 ) was completed in May 2011.
The unblinded 3 000-patient CRISTAL trial10 compared
‘any colloid’ with crystalloid. The latter trial was reported
(International Symposium on Intensive Care and Emergency
Medicine 2013) to show a statistically significant overall
survival benefit from early colloid use, but the details await
full publication and careful HES subgroup analysis.
New systematic reviews
There have been several recent high-quality systematic
reviews (Table 1). The Cochrane review on colloids was updated
The RR of death in 15 trials of HES was 1.10 (95% CI 1.02 -
1.19), and that in the Gattas review11
(third-generation HES products) was 1.08 (95% CI 0.97 - 1.21).
Most recently, Zarychanski et al.
performed a high-quality systematic review of all HES
products. 3 The mortality RR was
1.09 (1.02 - 1.17) after excluding seven early trials by Boldt
et al., whose research
corpus must be regarded with caution after multiple
retractions.12 The Haase review,13
looking only at a highly defined subset of starch trials
(high-quality trials, third-generation HES, sepsis), found a
very similar RR of 1.11 but with an expected wider CI (1.00 -
1.23). ‘Multiple-look’ meta-analyses increase the risk of
false-positive results, which was addressed in this review
using trial sequential analysis (wider 95% CI 0.95 - 1.29).
None of the other patient-relevant clinical endpoints, such as
length of ICU stay, use of mechanical ventilation or presence
of major bleeding, showed a statistically significant
advantage of HES over crystalloids.
Both the Gattas11
reviews found convincing evidence of renal harm. In Gattas et al.’s review, there was a 27%
relative increase in the need for renal replacement therapy in
patients given HES compared with crystalloid (RR 1.27, 95% CI
1.10 - 1.46). The equivalent RR in the Zarychanski review was
1.32 (95% CI 1.15 - 1.50) where the control intervention was not
Assessing the potential for harm
Formal assessment of harm is complex, and may be unfamiliar to clinicians without expertise in pharmaco-epidemiology. Convincing safety signals usually require large numbers in the numerator, and registration trials are underpowered for this. Patient numbers several times higher than those used in efficacy trials are required. Accrual of harms may not proceed at the same rate as benefits, so acute resuscitation trials with short-term endpoints will not detect harms taking weeks to accrue. An appropriate comparator is important – pooling trials where some control groups were given other colloids rather than crystalloids dilutes harm signals.
The 0.05 type I error rate used to measure the certainty of an effect is purported to have originated with Fischer14 and was adopted by the Food and Drug Administration (FDA)15 and other medicines regulators. It makes sense to minimise the probability of a false-positive statement when determining efficacy. However, do we need to be 95% sure of danger before avoiding a course of action?16 Table 2 illustrates the effect of changing type 1 error rates on statements of certainty.
Unlike the albumin controversy, where an earlier Cochrane
raised concerns about harm that were not confirmed in a
subsequent large trial (SAFE18 ), the current HES harm
signal comes from information on more than 10 000 patients
and is robust.
Scoring reviews versus keeping score of the number of reviews
Manufacturers react appropriately to safety concerns by
commissioning reviews. Guidelines on assessing the quality of a
systematic review exist.19 High-quality reviews are
reliable if the underlying trials are unbiased, and if adequate
patient numbers have accrued. A ‘review of reviews’ on HES
raises some concerns. 20 The authors identified 165
reviews published between 1976 and 2010, of which 7% contained a
meta-analysis. Of the higher-quality reviews, 83% were not
supportive of HES versus 20% of the lower-quality reviews. Of
124 positive reviews, 70 were written by only 14 experts, and 10
of these authors had identifiable potential conflicts of
interest. An unsuspecting reader is more likely to encounter
multiple low-quality positive reviews than the few high-quality
ones. Simple repetition does not imply truth.
Identifying industry influence
It is helpful to identify reviews at risk of bias. Clues include finding authors with clear affiliations to HES manufacturers, reviews listing a manufacturer as sponsor or originator of a review, and reviews looking at endpoints where the focus is on physiological variables or other short-term surrogate markers rather than patient-relevant clinical measures. Missing features often include a clearly defined trial search strategy, and a table listing inclusions and exclusions, and the reasons for these. Lack of power to detect harm even after study pooling may be underemphasised. Measure of internal validity (trial quality scores) may be absent, and control groups inappropriate. Pooling methods may be unusual or use methods that do not take account of differences in baseline prevalence and trial size.21 The introduction and discussion sections may contain non-scientific ‘emotive’ words and product trade names.
For example, a 2013 industry-associated review22 of 17
studies of HES in surgical patients found ‘no evidence of renal
dysfunction’. Only 6 of these studies (a total of 437 patients)
had a crystalloid comparator, trial quality was not formally
reported, and there was evidence of heterogeneity.
Imagine another decade of HES use following current practice.
If industry-associated opinion leaders are right, our patients
would be unscathed. However, if the systematic reviews are
correct, we would have ignored powerful signals of harm, and
continued to expose our patients to a product that may increase
mortality in sepsis, and may increase the need for dialysis in
resuscitation. With these caveats, and in the absence of
adequately powered studies to confirm safety in other
situations, it is difficult to justify ongoing use of these
Conflict of interest. The authors
have no financial or intellectual conflict of interest.
1. Perel P, Roberts I, Ker K. Colloids versus crystalloids for ﬂuid resuscitation in critically ill patients. Cochrane Database Syst Rev 2013, Issue 2. Art. No.: CD000567. [http://dx.doi.org/10.1002/14651858.CD000567.pub6]
2. Hartog CS, Kohl M, Reinhart K. A systematic review of third-generation hydroxyethyl starch (HES 130/0.4) in resuscitation: Safety not adequately addressed. Anesth Analg 2011;112(3):635-645. [http://dx.doi.org/10.1213/ANE.0b013e31820ad607]
3. Zarychanski R, Abou-Setta AM, Turgeon AF, et al. Association of hyroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation. JAMA 2013;309(7):678-688. [http://dx.doi.org/10.1001/jama.2013.430]
4. Prowle JR, Pearse RM. Is it the end of the road for synthetic starches in critical illness? BMJ 2013;346:f1805. [http://dx.doi.org/10.1136/bmj.f1805]
5. 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):124-134. [http://dx.doi.org/10.1056/NEJMoa1204242]
6. 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):1901-1911. [http://dx.doi.org/10.1056/NEJMoa1209759]
7. Guidet B, Martinet O, Boulain T, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Critical Care 2012;16(3):1-10. [http://dx.doi.org/10.1186/cc11358]
8. Brunkhorst FM, Engel C, Bloos F, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358(2):125-139. [http://dx.doi.org/10.1056/NEJMoa070716]
9. ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT00273728 (accessed 8 April 2013).
10. ClinicalTrials.gov. http:// clinicaltrials.gov/ct2/show/NCT00318942 (accessed 8 April 2013).
11. Gattas DJ, Dan A, Myburgh J, et al. Fluid resuscitation with 6% hydroxyethyl starch (13/0.4 and 130/0.42) in acutely ill patients: Systematic review of effects on mortality and treatment with renal replacement therapy. Intensive Care Med 2013;39(4):558-568. [http://dx.doi.org/10.1007/s00134-013-2840-0]
12. Myburgh J. CHEST and the impact of fraud in fluid resuscitation research. Crit Care Resusc 2011;13(2):69-70.
13. Haase N, Perner A, Hennings LI, et al. Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: Systematic review with meta-analysis and trial sequential analysis. BMJ 2013;346:f839. [http://dx.doi.org/10.1136/bmj.f839]
14. Cowles M, Davis C. On the origins of the 0.05 level of statistical significance. Am Psychol 1982;37:553-558. http://www.radford.edu/~jaspelme/611/Spring-2007/Cowles-n-Davis_Am-Psyc_orignis-of-05-level.pdf (accessed 15 April 2013).
15. Katz R. FDA: Evidentiary standards for drug development and approval. Neurotherapeutics 2004;1:307-316.
16. Berger VW, Hsieh G. Rethinking statistics: basing efficacy alpha levels on safety data in randomised trials. Israeli Journal of Emergency Medicine 2005;5(3):55-60. http://www.isrjem.org/IJEM_Aug_AlphaLevels_Proof.pdf (accessed 16 April 2013).
17. Alderson P, Bunn F, Lefebvre C, et al. Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev 2002, Issue 1. Art. No. CD001208. [http://dx.doi.org/10.1002/14651858.CD001208]
18. The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350(22):2247-2256. [http://dx.doi.org/10.1056/NEJMoa040232]
19. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med 2009;151(4):264-269. [http://dx.doi.org/10.7326/0003-4819-151-4-200908180-00135]
20. Hartog CS, Skupin H, Natanson C, et al. Systematic analysis of hydroxyethyl starch (HES) reviews: Proliferation of low-quality reviews overwhelms the results of well-performed meta-analyses. Intensive Care Med 2012;38(8):1258-1271. [http://dx.doi.org/10.1007/s00134-012-2614-0]
21. Lievre M, Cucherat M, Leizorovicz A. Pooling, meta-analysis and the evaluation of drug safety. Current Controlled Trials in Cardiovascular Medicine 2002;3(1):6. [http://dx.doi.org/10.1186/1468-6708-3-6]
22. Martin C, Jacob M, Vicaut E, et al. Effect of waxy maize-derived starch 130/0.4 on renal function in surgical patients. Anesthesiology 2013;118(2):387-394. [http://dx.doi.org/10.1097/ALN.0b013e31827e5569]
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