A thorough look at the pitfalls of Evidence Based Medicine to bear in mind when you read a journal publication - though respect to medical researchers for their efforts to find "the truth" systamatically

1. The Problem of Evidence
Barbara Stanley FRCA
With thanks to Dr Jan Friedrich

2. Aims
• To categorise and illustrate some of the
published arguments against EBM
• Demonstrate why published trials don’t
necessarily result in reliable evidence
• To try and examine the impact EBM
outside of everyday practice
• (almost) Everything I am going to say has
been published somewhere in a journal!

3. Definitions
• Evidence ‘ that which furnishes or tends to
furnish proof’
Merriam-Websters Dictionary of Law
• Evidence based medicine ‘The judicious use of
the best current evidence in making decisions
about the care of individual patients’
• Evidence-based practice ‘ integration of best
research evidence with clinical expertise and
patient values’

4. Strengths of EBM
• Prevent unnecessary wide variations in
clinical practice
• Reduce the use of unproven interventions
• Produce consistent practice guidelines
• Rid medicine of dogmatic practice and
concepts that are incorrect or outdated

5. Origin of EBM
• Epidemioligists of McMaster University in
1993
• Archibald Cochrane 1909-1988 –
Professor of Chest Disease and Honorary
Director of MRC’s Epidemiology Unit,
Cardiff
• Poor use of scientific method in Medicine

6. Origins of EBM
• “It is surely a great criticism of our profession
that we have not organised a critical
summary...of all relavant randomised controlled
trials”
Effectiveness and Efficiency: Random
Reflections on Health Services 1972
• 10% therapies proven – rest may even harm
• Promoted RCT as best way to prove
effectiveness
• Promoted use healthcare resources to
‘maximise the delivery of effective intervention’
A categorisation and analysis of the criticisms of
EBM. Cohen et al. Int J Med Inform 2004

7. Use of EBM
• ‘Regulatory’- rationalise practice at level of
health service delivery and control
expenditure
• ‘Bedside’- treatments with the best
evidence offered to individual patients

8. Categorisation of criticisms
1. Aplicability
2. Effects on proffession
3. Workload for clinicians
4. Interpretation

9. Common Criticisms 1: Applicability
• Medicine based on evidence, rather than
Evidence Based Medicine
• ‘Basic error’ – biological variablity hinders the
extrapolation of data obtained from basic lab or
clinical research to the treatment of individual
patients
• Applies only to that which can be objectively
measured
• ‘Orphan specialties’
• Does lack of evidence mean an intervention
doesn’t work?
• EBM itself has never been validated

10. Category 2: Effects on the Profession
• Promotes ‘doing’ rather than ‘thinking’ and
promotes ‘mindless algorithms’ and ‘protocols
which act as straightjackets to care’
Ethics and EBM. Loewy. 2007
• EBM protocols tend to be seen as ‘the right
way’ instead of the ‘current’ way – ‘insists
rather than assists’
• Skew toward pharmacological interventions
and treatments rather than preventative
measures or complex social interventions
leading to the expectation of a ‘pill for every
ill’

11. Category 3: Workload
• The sheer volume of it! Two MILLION articles
published annually in 23,000 biomedical journals
Evidence-Based Medicine for the New Millenium:Critical
Appraisal and Pragmatic Approach.Ibrahim and Stuart.
Ann Saudi Med.1999
• Trials beget more trials to confirm or refute
results
• Sorting ‘good’ and ‘robust’ from...’poor’ and
‘weak’?

12. Workload
• Increased expectation of clinicians and trainees
contribution to evidence base – increasing
numbers of poorly designed trials unlikely to
make useful contribution – yet appear in peer
reviewed journals
• ‘...busy clinicians who devote their scarce
reading time to selective, efficient, patient driven
searching,appraisal, and incorporation of the
best available evidencecan practice evidence
based medicine.’
D. Sackett. EBM:what it is and what it isn’t. BMJ 1996

13. Category 4:Interpretation
• Publication bias – ‘Studies with positive
findings are more likely to be published
than studies with negative or null results’
AMA Trustee Joseph M. Heyman 2004
• ‘Any tendency to put negative results in a
drawer ..can bias reviews of treatments
reported in the medical literature, making
them look more effective than they really
are.’ AMA Trustee Joseph M. Heyman 2004

14. Interpretation
• Metanalysis may amplify errors and bias of the trials
examined
• Similarly designed RCT’s researching same question
often disagree
Cohen et al. 2004 A categorization and analysis of criticisms EBM
• ‘Subgroup analysis... Influence conclusions much more
than is justified’
Subroup analysis and other (mis)use of baseline data in clinical trials.
Aassmann et al.Lancet 2000;355:1064-69
• "If you find that [a] study was not randomized we'd
suggest that you stop reading it and go on to the next
article
EBM turns patients into pets. L Gorman. Independence
Institute. 2004

15. Industry and EBM
• Declaration Helsinki – ‘...investigators are obliged to
preserve the accuracy of results.Negative as well as
positive results should be published... Any possible
conflict of interest should be declared in the publication..
• ‘Studies show that research funded by pharmeceutical
and food manufacturers are likely to report results
beneficial to the industry......’
‘Does Industry support bias resaerch? Chimonas.
Chen et al American Sociological Assoc 2007..
• Negative findings were found in 13% of industry-funded
trials vs 35% of non-industry funded
Yaphe, Edman et al Family Practice 2001

16. Conflict of interest in EBM: Vioxx
• VIGOR study 2000 NEJM showed 4 x increase
risk MI in Vioxx vs. Naproxen
• Merck scientists attributed this to protective
effects Naproxen (not validated)
• Scandal centres around communication between
researchers and Merck executives regarding
increased CV risk and failure of Merck to
disclose this to FDA as early as 1996 –
uncovered by The Wall Street Journal
• APPROVe study 2004 Demonstrated
unequivocal increase in risk MI – Merck
withdrew Vioxx

17. The price of Vioxx
• 27,000 law suits
• $4.85 billion Vioxx legal expenses
• Merck’s ultimate liability estimated to be $10 -$25 billion
Merck agrees to settle Vioxx suits for $4.5 billion.
Berenson. NY Times Review 2007
• Study quoted ‘ghostwriting’ (failure acknowledge as
author a contributor to a manuscript) in 13% research
articles, 10% review articles, 6% editorials and 11%
Cochrane reviews: Guest authorship (designation of
individual as author who does not meet criteria) identified
in 16% research articles, 26% review articles, 21%
editorials and 41% Cochrane reviews
Guest Authorship and Ghostwriting in
publications related to Rofecoxib. JAMA 2008

18. • "Between 1997 and 2004," the
pharmaceutical industry critic Sheldon
Krimsky noted in a 2005 open piece in the
Newark Star-Ledger, "12 major prescription
drugs, with a market value of billions of
dollars, were recalled by the FDA." Krimsky
claims such dangerous drugs have been
allowed to reach the market because
"conflicts of interest have become endemic in
the system of drug evaluation," a trend that
"has been exacerbated by the rise of for-profit
clinical trials, fast-tracking drug approvals,
government-industry partnerships, direct
consumer advertising and industry-funded
salaries for FDA regulators" since the mid-
1990S.

19. Evidence and the Media

20. A History of MMR
• Introduced in 1988
• Fall in mumps by 79% over subsequent 2
years and further – to a 92% total
reduction
Monovalent mumps vaccine or combined MMR vs.
placebo or no vaccine. Ellman et al. BMJ Feb 2007
• 1992- withdrawal of early version –
mumps component associated with
meningitis

21. MMR and Autism
• Media and public furore
• Wakefield paid by solicitor (£435,643) of parents
litigating for alleged injury as a result of MMR
• All 12 children specifically referred to
substantiate lawsuit
• Ethics committee led to believe tests were
routine and would be performed in absence of
study
• Wakefield lied about behavioural symptom onset
and vaccination timing
• One child suffered 12 bowel perforations
The MMR-autism scare – our story so far. Brian Deer

22. MMR and Autism
• Found to have constipation
• “increased vascularity and irregularities entirely
subjective”
• Ileo-lymphoid hyperplasia is common, benign
and not linked to inflammatory bowel
• Wakefields own tests did not find MMR virus in
childrens bowel
• Wakefield patented a monovalent measles
vaccine as competitor to MMR – as well as ‘cure’
for IBD and autism
The MMR-autism scare – our story so far. Brian Deer

23. MMR and Autism
• Lancet published apology and Wakefield’s co-
authors a retraction
• In my view, if we had known the conflict of
interest Dr Wakefield had in this work I think that
would have strongly affected the peer reviewers
about the credibility of this work and in my
judgement it would have been rejected."
Richard Horton, Editor The Lancet Feb 2004
• 23 subsequent studies that refute link
MMR vaccine does not cause autism. Examine the
Evidence! www.immunize.org/catg.d/p4026.pdf

24. Subsequent research
• Finland – 3 million doses, no reports autism
• UK- Autism incidence rising but no ‘step-up’ since MMR
Bandolier database: ‘No Measles in Finland’ Lancet 1997
• Denmark- no increase in autism with MMR in 537,303
children studied, 440,665 vaccinated
A population based study of MMR and autism.
Madsen et al. NEJM 2002 ,7;347 ,1477-82
• Japan – Incidence autism continued to rise after MMR
was discontinued
MMR-vaccine and regression in autism:negative results
presented from Japan. Uchiayma et al. J Aut Devel Disord.
2007.37:210-17

25. Measles resurgence
• Incidence of measles risen. 1,000 cases in UK 2007 vs.
449 in 2006 vs. 77 in 2005
• 200 cases SE London Jan-May 2008
• Including 1 fatality
• Herd immunity requires 95% uptake
BBC News: Emergency Measles steps ordered: May 2008
• Average uptake 88.6% for MMR and 5.2% for at least 1
single antigen vaccine
Millennium Cohort Study Child Health Grp Factors
associated with uptake of MMR in a contemporary UK cohort:
prospective cohort study. Pearce A et al. BMJ 2008. 336, 754-7
• Uptake rates only 71% first dose and 50% second
Health Protection Agency

26. When Evidence divides us-the
case of Activated Protein C
• PROWESS – phase III multicentre DBPCRCT of
1,690 patients with sepsis.
• Stopped early by independent board as
objectives met
• Absolute and relative risk-reduction for death
were 6.1% and 19.4%. Mortality rate 30.8%
placebo vs 24.7% APC
• Multiple subgroup analyses performed- for which
PROWESS was not powered
Recombinant APC:the key is clinical risk of death not subset
analysis. Dellinger. Crit Care 2006

27. When Evidence divides us-the
case of Activated Protein C
• Criticisms of the PROWESS trial include:
– A change in protocol during the trial – pts with
metastatic ca or pancreatitis or organ failure
>24 hrs excluded–
– The test drug was manufactured from a
different cell line
– A change in placebo drug to albumin 0.1%
from saline
Risks and benefits Activated Protein C for Severe Sepsis.
Warren et al. NEJM 2002

28. Controversy
– FDA analysis indicated an improvement of
efficacy pre protocol amendment mortality
was 28% APC vs 30% placebo, after 31%
placebo vs 22% APC
– Conflict over the change in protocol and the
different source split FDA Advisory
Committee 10 to 10 as to the safety and
efficacy of the drug
Risks and benefits Activated Protein C for Severe Sepsis.
Warren et al. NEJM 2002

29. Suspicious facts brought to light
• Adequacy of Blinding – obviously different fluids
were ‘wrapped’ in plastic and some sites couldn’t
use albumin as placebo
• Further sites added after protocol ammendment
– supposedly to incraese pt recruitmet but were
noted to;
– Show a strong effect for the drug
– Had performed well in a previous Lilley –funded drug
study
– Weren’t recruiting any more than previous sites that
had been dropped
Conflict of opinion-is PROWESS real progress? AF
Mackenzie.ICM 2006,32;610-12

30. Not as robust as we thought?
• DNR order rates were lower in APC group after
protocol change 9% vs 17% in placebo group–
end point was 28 day mortality
• A change in outcome of only 14 patients would
remove the statistical significance of PROWESS
mortality improvement
• Home discharge rates were similar in placebo
and APC groups
• Patients lost to follow-up at 3 months, making
survival stats at 1 and 2.5 yrs questionable
Conflict of opinion-is PROWESS real progress? AF
Mackenzie.ICM 2006,32;610-12

31. And....
• Calculation of APACHE II score varies
between clinicians up to 20% - PROWESS
demonstrated no benefit in patients with
scores <20 and increased risk of bleeding
Risks and benefits Activated Protein C for Severe
Sepsis. Warren et al. NEJM 2002
• PROWESS was stopped early –
Disproportional treatment effect?

32. But the supporters rallied;
• Subsequent arguments claimed that;
– APC from new cell line had no difference in
vitro
– If indeed it was more effective than the
previous batch then a better product is
available
– Protocol ammendments actually ended up
excluding subsets of patients more likely to
benefit
Assessing the use of APC in the treatment of severe
sepsis.JP Seigel. NEJM 2002

33. More Confusion
– Confirmatoy studies ‘ ‘ENHANCE’
– ENHANCE – single arm unblinded study to
gather more safety and efficacy data
– mortality reduction rates similar but bleeding
rates higher 3.6% vs 2.4% POWESS
– Showed better mortality reduction if given
<24hours of organ dysfunction
Clinical trials in severe sepsis with drotrecogen
alpha (activated). P-F Laterre: Crit Care 2007:S5

34. – ADDRESS looked at single organ failure or
APACHE<25 but was
• Stopped early in accordance with the futility
guidelines-chance of meeting the defined
objective was <5%
• Mortality rates in APACHE II scores of >25
higher in drotaa group 29.5%compared to
placebo 24.7%(subgroup analysis)
• AND mortality rates in APACHE II >25 placebo
group were 24.7% vs 43.7% in PROWESS
• Conclusion – sample size too small to detect
difference – only 2,640 enrolled
Clinical trials in severe sepsis with drotrecogen alpha
(activated). P-F Laterre: Crit Care 2007:S5

35. • Commentators argue over definition of high
risk of death. This not clearly defined in
PROWESS except via APACHE II score,
included multi and single organ failure
• ‘Seasoned clinician’s clinical assessment of
high risk of death’
Recombinant APC:the key is clinical risk of death not
subset analysis. Dellinger. Crit Care 2006
• Reviewers of evidence have financial links to
Eli Lilley (authors of above cited papers)

36. Post Marketing Surveys
• Higher mortality rates than PROWESS or
ENHANCE overall – 45%
• Attributed to a sicker poulation and later use of
APC
• Higher bleeding events 7.3%, again attributed to
sicker population
• ‘study underpowered to adequately assess the
risk-benefit ratio for DAA...’
Evaluating the use of Drotrecogen Alpha in adult severe
sepsis:a Canadian multicentre observational study. Kanji et al
Intensive Care Med 2007, 33:517-523

37. Cochrane Review ab 004388
• ‘There is insufficient evidence to support
the use of human recombinant activated
protein C for adults or children with severe
sepsis; moreover there is an increased
risk of internal bleding associated with it’s
use.’
Cochrane Reviews. November 2007

38. Other ICU Evidence controversies-
Tight Glycaemic Control
• Tight glycaemic control in cardiac surgery ICU
patients significantly reduced mortality, length
stay and infection.
• Mortality benefits may persist up to 4 years later
with tight glycaemic control for 3 days
Strict Blood glucose control during ICU after cardiac surgery:
Impact on 4 yr survival. Ingels et al.Eur Heart J 2006;27,2716-24
• Morbidity benefit seen in medical ICU poulation
with stay >3 days,but no mortality improvement.

39. Other ICU Evidence controversies-
Tight Glycaemic Control
• Outcome worse in patients in ICU <3 days
who could not be identified before therapy.
• Logistic regression analysis identified
hypoglycaemia as an independent risk
factor for death.
Intensive Insulin Therapy in the Medical
ICU. Van de Berghe et al. NEJM
2006;354;449-61

40. VISEP study
• Multicentre trial severe sepsis for intensive
insulin therapy(4.6-6.1mmol/l) vs
conventional (glucose 11.1mmol/l)
• Intensive insulin therapy stopped early for
safety as hypoglycaemia occured 12.1%
intensive insulin grp vs 2.1%
• Mortality rates no different at 28 days
Intensive Insulin Therapy and Pentastarch Resus
in Severe Sepsis. Brnkhorst et al. NEJM. 2008;
358;125-39

41. • Intensive insulin not indepedant risk factor
for death BUT hypoglycaemia was
• Intensive insulin group showed tendancy
to stay longer in ICU
• No morbidity reduction identified
• Assumption that second intervention (HES
vs Ringers) would not influence results
Intensive Insulin Therapy and Pentastarch Resus
in Severe Sepsis. Burnkhorst et al. NEJM. 2008;
358;125-39

42. Glucontrol Trial
• 1100 pts – 4.4 – 6.1mmol/l vs 7.8 – 10mmol/l.
• No survival benefit;
• Episodes hypoglycaemia more frequent
• Mortality rates higher in those with at least 1
hypoglycaemic episode
• Tight control = four – six times increase
incidence hypoglycaemia
Controversies about tight glucose control. Devos and Presier.
Expert Rev. Endocrinol. Metab;3;295-97 (2008)

43. Summary
• Control of blood sugar desirable and confers a
survival advantage- absolute mortality reduction
of 4.83%
• Severe Hypoglycaemia increases mortality risk –
even a single episode
• Tight glycaemic control associated with up to six
times increased risk severe hypoglycaemia
• What range to aim for?
Severe hypoglycaemia in critically ill patients:Risk factors
and outcomes.Krinsley. Cri Care Med.2007;35,2262-68

44. Controversies in Evidence in ICU:
Albumin
• Cochrane collaboration – albumin increases
mortality in trauma patients
• Criticised as it omitted several studies
• SAFE study – no difference in mortality overall
A comparison of Albumin and Saline for fluid resusin the
ICU. SAFE study. NEJM 2004;350,2247-56
• Subsequent subgroup analysis in traumatic brain
injury = more deaths in albumin group 25% vs
15%

45. Controversies in Evidence in ICU –
Albumin
• Once head injured excluded, overall
mortality in trauma group with albumin
was still higher (14% vs 10% p-0.06).
(Authors of SAFE conclude by chance)
• Excluded burns, hypoalbuminaemia, liver
failure and cardiac surgery.
Fluid resus among the critically ill: more water
under the bridge. M. Jaka. CJA 2006,53:1258-59
.

46. Controversies in Evidence in ICU –
Albumin
• SOAP study: observational of use albumin
accross European ICU’s. Those receiving
albumin had cancer or cirrhosis, were surgical
admissions and had higher SAPS II and SOFA
scores with a longer ICU stay
• When these factors were corrected for using
both the Cox proportional hazard model and a
propensity analysis, albumin use was still an
independent predictor of lower 30 day survival.
SOAP Study.Crit Care 2005

47. Summary
• ICU and hospital mortality rates higher in
pts who received albumin
Is albumin administration in the acutely ill associated with
increased mortality? Results of the SOAP study. Vincent et al.
Crit Care. 2005,8;R745-754
• Conclusion: not for head injured patients,
or trauma....or ICU patients

48. Trials stopped early
• Tend to show large treatment benefit – Bisoprolol trial
showed treatment effect of 0.09 (prevention of cardiac
death/non fatal MI) in patients with positive Dobutamine
echo undergoing elective vascular surgery and is
inconsistent with the effect of beta blockers in thousands
of post MI patients – 0.65 – 0.85
• Trial short vs longterm Warfarin on thromboembolic
complications post hip arthroplasty showed large
treatment benefit. Once result adjusted for full sample
size no benefit seen
Randomized Trials Stopped Early for Benefit: A systematic
Review. Montori et al. JAMA 2005;294(17)2203-09

49. Trials stopped early
• Are increasing in frequency – 0.008% in
1980 – 84 vs 0.1% in 2000-2004
• Tend to be reported in high impact factor
journals - 0.1% in 1980 – 84 vs 1.2% in
2000-2004
Randomized Trials Stopped Early for Benefit: A systematic
Review. Montori et al. JAMA 2005;294(17)2203-09

50. The Law and EBM
• Perhaps the real fear behind critcisms of EBM
• Evidence-based medicine (EBM) is the
integration of best research evidence with
clinical expertise and patient values
• Medical malpractice currently centres around the
‘Bolam’ principle – a doctor is not liable if his
practice follows a responsible body of medical
opinion
Medical Law and Ethics. SE Salako. BMJ 2003

51. A move away from Bolam
• Bolitho vs City and Hackney Health Authority
(1998) child with repeated episodes respiratory
distress eventually died after failure to be
attended by duty doctor. Issue became should
she have intubated during earlier episodes and
would the child have survived. Expert opinion
was divided but majority would have intubated
earlier than the arrest. Judge ruled in favor
minority opinion because it was reasonable – ie
against majority of expert testimony
Bye-Bye Bolam. Mbrazier. Med Law Review 2000

52. The Law and EBM
• Expert testimony under increased scrutiny
–’Where clinical guidelines have been
developed....the Judge will be enabled to
judge the individual expert testimony in
context of the professions’ considered
judgement’
Bye-Bye Bolam. Mbrazier. Med Law Review 2000
• Commentators fear that doctors, to avoid
litigation, will cease to treat the individual and
concentrate on ticking the relevent boxes

53. Guidelines and negligence
• Proportion guidelines fall short of quality markers
– courts do not call experts in guideline
methodology to assess robustness and quality
How does evidence based guidance influence
determinations of medical negligence? Hurwitz.
BMJ 2004
• GMC – doctors should “normally follow
guidelines”
• Guidelines may not protect doctors. Helling vs
Carey(1974): occular pressure not measured in
pt <40 for glaucoma as not standard practice. “
opthalmologists prosecuted
EBM and the Law. C. Williams 2004

54. Practice Outside Guidelines and
keeping up to date
• Practice outside guidelines lawful: Cranley vs Medical
Board West Australia (1990)GP gave i.v Diazepam to
heroin users against Australia’s Methodone guidelines,
but small body opinion concluded this was acceptable
practice
How does evidence based guidance influence
determinations of medical negligence? Hurwitz.
BMJ 2004
• Burton vs Brooklyn doctors hospital. Doctors found liable
for causing blindness in prem baby by liberal 02
administration when evidence suggested it was harmful
EBM and the Law. C. Williams 2004

55. Litigation for Practice within
guidelines
• Merenstein case(2003) PSA not checked
in patient <50yrs in accordance with
guidelines and agreement with patient,
subsequently found to have Gleason 8
tumour. $1 million damages from Family
Practice Residency Programme despite
informed patient consent and adherence
to guidelines
Rethinking informed consent: the case for shared
medical decision making. King, Moulton. Am J Law
Med. 2006

56. Summary
• Precedent setting cases which
– Rule in favour of minority opinion
– Rule against doctors who practice within
guidelines
– Rule against doctors who don’t keep up to
date
– Beginning to question ‘expert testimony’ and
Bolam principle

57. EBM and Public Opinion
• There is an over reliance on RCT’s that retards
innovation
• In 2002 $125 million ALLHAT trial (antihypertensive trial
sponsored by National Heart,Lung and Blood Institute)
concluded diuretics should be 1st
line despite subsequent
criticism of failure to achieve adequte control and bias of
the trial in diuretics favour , use of primitive drug
therapies and the observation that diuretics increase all-
cause mortality in Caucasian men by 11%
EBM turns patients into pets. L Gorman. Independence
Institute. 2004

58. • The problem with evidence-based medicine is that its
proponents want everyone to pretend that high-priced
literature searches can substitute for the informed
judgment that is the foundation of science-based
medicine
• Had law given evidence-based masters dominion over
specialists in treating high blood pressure, the millions of
Americans who don't fit the ALLHAT profile would have
been subjected to cheap treatments known to produce
poorer outcomes. In short, when the law finally requires
evidence-based medicine, you'll know that medicine is
going to the dogs.
EBM turns patients into pets. L Gorman. Independence
Institute. 2004

59. On prosecution despite adherence
to guidelines…..
• ..He defined EBM as a cost saving method and
stated his belief that the few lives saved were
not worth the money. He urged the jury to return
the verdict to teach residencies not to send any
more residents …believing in EBM
• The jury sent a message to the residency
programme that they didn’t believe in Evidence
Based Medicine. They also sent a message
saying they didn’t believe in national guidelines
and they didn’t trust the shared decision making
model
Winners and Losers. Merenstein. JAMA 2004

60. What can we conclude?
• Look for transparency of method and
measurements in publications
• Be aware of conflicts of interest
• Don’t change your practice immediately
• No-one can have an exhaustive
knowledge of evidence
• The law may be changing
• Therapies based on evidence and sound
scientific and physiological principles

61. And Finally...
• ‘There’s no Evidence for that!’

62. • “The art of medicine consists in amusing
the patient while nature cures the disease”
Francois Marie Arouet (Voltaire)

63. References
• ‘Adrenal Insufficiency and Steroids’: Andy Walden PhD,
MRCP: AnaesthesiaUK
• ‘SAFE,VASST,LIPOS Trial 3, CORTICUS and more;
Implications for the Surviving Sepsis Campaign
Guidelines’ Gregory S. Martin MD, MSc: Medscape
Critical Care: Highlights of the Society of Critical Care
Medicine 36th
Critical Care Congress, Feb 2007
• ‘Fluid resuscitation among the critically ill: more water
under the bridge’ M J Jacka MD MSc FRCPC, D
Alberton BSc (PHARM), R T Noel Gibney, MB FRCPC:
Can J Anesth 2006/53:12/1258-9

64. References
• ‘Conflicting clinical trial data: a lesson from albumin’
Greg Martin: Critical Care 2005, 9:649-650
• Intensive Insulin Therapy in the Medical ICU. Greet Van
den Berghe, M.D, PhD., et al NEJM 2006;354:449-61
• Severe hypoglycaemia in critically ill patients: Risk
factors and outcomes. Krinsley, J. F et al: Critical Care
Medicine, 2007
• Warning signs:E-mails suggest Merck knew Vioxx’s
Dangers at Early Stage. Nov 1 2004 The Wall Street
Journal
• The consequences and Lessons of the Vioxx Recall. M
Etzler. 2007

65. References
• Clinical trials in severe sepsis with drotrecogin alpha
(activated). Pierre-francoise laterre. Critical care 2007,
11(suppl 5):s5
• Recombinant Activated Protein C: the key is clinical
assessment of risk of death, not subset analysis. Phillip
Dellinger. Critical Care 2006, 10:114
• What do evidence based secondary journals tell us
about the publication of clinically important articles in
primary healthcare journals? K A McKibbon et al. BMC
Medicine 2004,2:33
• Guest Authorship and Ghost writing in Publications
related to Rofecoxib. Ross, Hill et al JAMA 2008;299(15)
1800-1812

66. References
• Journal reading habits of Internists Sanjay Saint et al. J
Gen Intern Med. 200 December, 15(12):881-884
• Evidence-Based Medicine in the Law Beyond Clinical
Practice Guidelines: What Effect Will EBM Have on the
Standard of Care? Carter L. Williams Washington and
Lee Law Review Winter 2004
• Ethics and Evidence-Based Medicine: Is There a
Conflict? Erich H Loewy, MD Medscape Bioethics 2007
• Ethics and Evidence-Based Medicine Simon R
Tomlinson MJA Feb 2002 vol 176:137
• Winners and Losers. D Merenstein: JAMA 2004,291;15-
16`

67. References
• Risks And Benefits of Activated Protein C Treatment for Severe
Sepsis. H. Shaw Warren, MD, Anthony F. Suffrendi MD, N Engl J
Med, vol 347, no. 13, September 2002
• Randomised Trials Stopped Early For Benefit: A Systematic Review.
Victor M. Montori et al. JAMA 2005:294(17):2203-2209
• Is Statistical Significance Always Significant? Ronald L. Koretz, MD
Nutrition in Clinical Practice 20:393-307, June 2005
• Parachute use to prevent death and major trauma related to
gravitational challenge:a systematic review of randomised controlled
trials. Gordan C. Smith and Jill Pell. BMJ 2003;327;1459-1461
• False dichotomies:EBM, clinical freedom and tha art of medicine. M.
Parker. J Med Ethics; Medical Humanities 2005;31:23-30
• A categorisation and analysis of the criticisms of Evidence-Based
Medicine. Aaron Michael Cohen et al. Intl J Medical Informatics
(2004) 73, 35-43

68. References
• Subgroup analysis and other (mis) uses of baseline data
in clinical trials. Susan F. Assamann et al.Lancet
2000:355:1064-69
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