Using high quality clinical databases to complement the results of randomised controlled trials: the case of recombinant human activated protein C
BMJ 2001; 323 doi: https://doi.org/10.1136/bmj.323.7318.923 (Published 20 October 2001) Cite this as: BMJ 2001;323:923
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We were interested to read the article by Padkin et al(1) on the
serendipitous use of the ICNARC database to complement the results of
clinical trials. At least one other such high quality database exists in
the Britain.
Since 1995 the Scottish Intensive Care Society Audit Group, with
national funding from Clinical Resource and Audit Group, has collected a
very similar data set. We receive data from 100% of Scottish Adult
Intensive Care beds (in 26 units) and so can be certain that our findings
are generalisable. Because of our defined geographical area we can provide
a denominator for incidence figures.
We fully support the use of the data in the manner described by
Padkin. We had also queried our data to obtain an approximation of the
incidence of sepsis in Scotland with similar results. We have found this
type of information useful not only at a national level but also in giving
a very approximate indication of the effects on local budgets.
We are acutely aware of the limitations of such an analysis. Data
collected during the first 24 hours of intensive care and structured for
another purpose can only estimate the number of patients with sepsis and
as, Padkin at al say, cannot identify the proportion who would meet the
full entry criteria for the PROWESS trial. Because of this we believe
prospective data collection is still necessary.
One of the strengths of our organisation is our ability to collect
additional information for short periods to address specific questions.
Such an exercise is due to start soon to collect data on the incidence and
outcomes of sepsis. We have used a similar approach in the past to
identify the incidence of combined respiratory and renal failure (2) and
ARDS (3).
We believe that undue reliability cannot be given to information
gleaned from data gathered for another purpose and that such data, while
useful, should be used as a starting point for more detailed studies.
References
(1) Padkin A, Rowan K, Black N. Using high quality databases to
complement the results of randomised controlled trials:the case of
recombinant activated protein C. BMJ 2001;323:933-926(20 October)
(2)Noble JS, MacKirdy, Donaldson SI, Howie. Renal and respiratory
failure in Scottish ICUs. Anaesthesia 2001; 56:124-129
(3)MacKirdy FN, Hughes M, Ross J, Grant I. A prospective,
observational study of ARDS in a cohort of patients in Scottish ICUs,
American Journal of Respiratory and Critical Care Medicine 2000;161:A382
Competing interests: No competing interests
Having read the Prowess trial publication (Gordon et
alii,NEJM, March 8, 2001 ) I wonder about the possible
significance of seemingly small differences between the
study groups as given in table 1 of this paper - under
the headings of "preexisting conditions" and "recent
surgical history" all but one of the listed conditions are
found slightly more frequently in the control group.
Might these differences collectively be significant while
individually remaining insignificant ?
Competing interests: No competing interests
Option 5 reject on basis of lack of cost effectiveness data
The publication of the PROWESS trial 1, which involved the
therapeutic use of activated protein C (APC) in sepsis, has sparked
considerable debate here in the United States. Initial excitement
regarding this agent centred around this being the first, of a multitude
of agents tested, to demonstrate a definitive reduction in the risk of
death - 24.7% v 30.8% (an absolute risk reduction of 6.1%, with numbers
needed to treat (NNT) of 16). Excitement, however, was tempered by the
cost of the drug: $6,800 per patient treatment. The cost of saving one
additional life is thus $108,800. The frequent use of this drug will thus
require either additional resources to be injected into critical care, or
redirection of existing resources. Modern medicine requires both the
demonstration of clinical effectiveness and cost effectiveness 2;3.
Costing in critical care is notoriously difficult – there are direct,
indirect and downstream costs. However, in this circumstance, the most
important is the opportunity cost – an estimation of alternatives forgone.
The industry sponsored PROWESS trial used 28 day mortality as its
primary endpoint. This is controversial. It is possible that this agent
prolonged death rather than saving lives: longitudinal data at 3, 6 and 12
months have not been released. Equal mortality at 3 months, for example
would indicate, aside from lack of clinical efficacy, huge increases in
costs (in addition to longer durations of intensive care / hospital stay
prior to death), with little benefit.
It is surprising that the investigators did not look at the study
design of the National Institute of Health’s (NIH) ARDSNET studies into
therapeutic options in acute lung injury. In a landmark study, patients,
ventilated with tidal volumes of 4 to 6ml/kg, had an absolute reduction in
the risk of death of 8.8% (31.0 % vs. 39.8 %) – NNT of 11.3. The primary
endpoint of this study was death or discharge from hospital breathing
without support. This is clearly the outcome required by intensive care
professionals and the general public alike.
A number of other recent publications demonstrate similar outcomes
with simple, cost-effective therapies. Early aggressive goal directed
resuscitation in early sepsis resulted in an absolute reduction in the
risk of death of 15.0% (30.5% versus 40.5% NNT = 6), in a cohort of 263
patients 4. Simple control over blood glucose reduced the risk of death by
3.4% (8.0% versus 4.6%, NNT = 30) 5 in surgical intensive care patients.
Tight control of heart rate, using beta blockers, in high risk patients
undergoing major vascular surgery, resulted in an absolute reduction in
the risk of death by 13.6% (3.4% versus 17.0%, NNT = 7.3). Similar therapy
resulted in net protein gain as compared to controls 6 in children with
extensive burns. This study is important in that it demonstrated one
mechanism for preservation of physiologic reserve (growth hormone therapy
has previously failed), and thus earlier discharge from intensive care.
The critical care research fraternity needs to move away from blunt
outcome measures such as mortality and look at morbidity, length of stay,
cost effectiveness and reliable predictors of futility.
The introduction of activated protein C into our armory should not be
seen as a magic bullet. The Federal Drug Administration (FDA), having
delayed the licensing of this agent due to concerns about bleeding
complications, has applied more strict limitations to the use of the drug
than was used in the study. Indeed the use of modified SIRS criteria 7
for study entry has caused some controversy. Nobody is quite sure how to
define “sepsis”, but few are happy with current definitions 8. New
definitions will be available in the summer of 2002.
In summary, a fifth policy response to the publication of the PROWESS
trial might be – rejection on the basis of lack of cost effectiveness
data. There are many potential interventions for the treatment of sepsis,
simple cost effective therapies should be considered first.
References
1.Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-
Rodriguez A et al. Efficacy and safety of recombinant human activated
protein C for severe sepsis. N.Engl.J.Med. 2001;344:699-709.
2.Chalfin DB. Evidence-based medicine and cost-effectiveness
analysis. Crit Care Clin 1998;14:525-37.
3.Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB.
Recommendations of the Panel on Cost-effectiveness in Health and Medicine.
JAMA 1996;276:1253-8.
4.Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B et
al. Early goal-directed therapy in the treatment of severe sepsis and
septic shock. N.Engl.J.Med. 2001;345:1368-77.
5. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F,
Schetz M et al. Intensive insulin therapy in the surgical intensive care
unit. N.Engl.J.Med. 2001;345:1359-67.
6. Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal of
catabolism by beta-blockade after severe burns. N.Engl.J.Med.
2001;345:1223-9.
7. American College of Chest Physicians/Society of Critical Care
Medicine Consensus Conference: definitions for sepsis and organ failure
and guidelines for the use of innovative therapies in sepsis. Crit Care
Med. 1992;20:864-74.
8. Dellinger RP,.Bone RC. To SIRS with love. Crit Care Med.
1998;26:178-9.
Competing interests: No competing interests