The paths from research to improved health outcomes Evidence-based medicine aims to provide clinicians and patients Getting the evidence used
with choices about the most effective care based on the best
Clinicians frequently have questions about the medical care of
available research evidence. To patients, this is a natural expec-
their patients, but most go unanswered (15). Even if an “answer”
tation. To clinicians, it’s a nearly impossible dream. The U.S.
is provided, it usually comes from an out-of-date textbook within
Institute of Medicine report “Crossing the Quality Chasm” has
the immediate clinical setting. The main predictors of the attempt
documented and drawn attention to the gap between what we
to answer a question are the belief that an answer exists and the
know and what we do (1). The report identified 3 types of quality
urgency of the patient’s problem (16).
problems—overuse, underuse, and misuse. It suggested that “The
This lack of bedside use of evidence inspired the 4-step model
burden of harm conveyed by the collective impact of all of our
of bedside evidence-based medicine (8, 17): Ask an answerable
health care quality problems is staggering.” While attention has
question; track down the best evidence; critically appraise the evi-
focused on misuse (or error), a larger portion of the preventable
dence for validity, impact, and applicability; and integrate the
burden is likely to be the evidence-practice gaps of underuse and
results with the patient’s unique biology, circumstances, and values.
In teaching evidence-based medicine, integration of the steps into
Research that should change practice is often ignored for years.
the clinical setting and for real patient problems is crucial for
For example, crystalloid (rather than colloid) for shock (2), supine
changing attitudes and behavior (18). Following these steps in
position after lumbar puncture (3), bed rest for any medical con-
clinical practice is challenging, especially given the time constraints
dition (3), and appropriate use of anticoagulants and aspirin
among patients with atrial fibrillation (4). Antman and colleagues(5) documented the substantial delays between cardiovascular trial
results and textbook recommendations. However, even when best
What underlies substantial gaps between the best evidence and
practices are well-known they are often poorly implemented:
the management patients receive? Pathman and colleagues (19)
National surveys show that most cases of hypertension are unde-
described 4 stages from evidence to action: The clinician needs to
tected, untreated, or inadequately controlled (6). This has led to
be aware, then agree, then adopt, and then adhere. Their survey of
the current interest in knowledge translation (7).
physicians’ use of vaccine guidelines showed a steady decline ateach stage. For example, the rates with respect to vaccination foracellular pertussis were 90% aware, 67% agree, 46% adopt, and
P r a c t i c e f a m i n e a m i d s t t h e e v i d e n c e g l u t
What role does evidence-based medicine (8) have in bridging the
35% adhere. This is consistent with findings from research on the
research-practice gap? Surveys of clinicians suggest that a major
diffusion of innovations (20), which generally suggests a 5-stage
barrier to using current research evidence is the time, effort, and
model of knowing, accepting, deciding, implementing, and con-
skills needed to access the right information among the massive
tinuing. A subsequent systematic review of barriers to the use of
volumes of research (9). Even for a (mythical) up-to-date clinician,
evidence (9) suggested that several further stages might be added.
the problem of maintaining currency is immense. Each year,
The Figure extends the awareness-to-adherence model to include
MEDLINE indexes over 560 000 new articles and Cochrane
these newer elements—in particular, patient involvement.
Central adds about 20 000 new randomized trials. This is about1500 new articles and 55 new trials per day! Clinicians need clearand efficient strategies to sift, digest, and act on new research like-ly to benefit their patients. 2 stages can be considered: getting the
evidence straight, and getting the straight evidence used (10, 11).
G e t t i n g t h e e v i d e n c e s t r a i g h t
While individual new research articles are peer-reviewed and pub-
lished, there is little effort to set their results systematically in thecontext of other, similar studies (12). Ideally, clinicians could accessan updated, well-conducted systematic review for all questions, orat least for all clinical research. However, only about 10% of ran-
domized trials have currently been incorporated into Cochrane
systematic reviews (13). For nontherapy questions, the situation is
worse. Guidelines are not a panacea here, as they usually rely on
existing reviews or, more often, ignore evidence (14) and are rarely
presented in clinician-friendly formats. Hence, the Institute of
Medicine report recommended that we “establish and maintain a
comprehensive program aimed at making scientific evidence more
(primary research studies: sound & unsound)
useful and accessible to clinicians and patients” (1).
March/April 2005 | Volume 142 • Number 2
The model illustrates that even with high rates of transfer
between stages, there may be little effect on patient outcomes.
To carry out an intervention requires both access and know-how.
Thus, even 80% transfer at each of 7 stages would result in only a
For medications, this is challenging enough—becoming familiar
with dosing, contraindications, initiation, adverse effects, and
Using this model, we shall look, first, at the initial problem of
monitoring. For more complex interventions, such as brief coun-
getting the valid and relevant evidence into the clinical “pipelines”
seling or spinal manipulation, the learning curve is even steeper
and how this can be improved and, second, at methods for reduc-
and hence is a greater barrier to changing practice. For many such
complex interventions as smoking cessation, external cephalic ver-sion, or problem-solving therapy for depression, clinicians mayrequire additional training before carrying these out as compe-
1 . A w a r eGiven the information glut, it is not surprising that individual cli-
tently as in the trials that documented their benefits.
nicians find it difficult to be aware of all relevant, valid evidence. Profitable new interventions are likely to have a substantial mar-
5 . A c t e d o nEven when we know and accept what to do, we often forget or
keting campaign. However, for many important practice changes,
neglect to do it. Habits do not change easily, despite our best
such as low-cost pharmaceuticals or nonpharmaceuticals, aware-
intentions. Omissions are particularly easy for preventive proce-
ness is more problematic. To ease the burden, several scanning
dures, as they are often not the pressing focus of a consultation.
and alert services have arisen that help clinicians become aware of
Not surprisingly, rates of appropriate preventive procedures are
important changes. For example, each issue of the ACP Journal
frequently low. A simple reminder is often sufficient for such sim-
Club and the Evidence-Based journals results from the scanning of
ple omissions of interventions that we believe in and can do. A
more than 100 journals to identify new evidence that is valid and
review of 16 randomized trials of reminders for preventive proce-
important. This process has been augmented to build a new serv-
dures showed substantial increase in adherence for most but not all
ice, bmjupdates+ (http://bmjupdates.mcmaster.ca), which allows
areas (27). Similar but less dramatic results have been shown for
practitioners to tap into just those articles that their peers rate as
reminders in some areas of medication management (28).
highly relevant and interesting for clinical practice.
When we have remembered to suggest an applicable treatment, the
While practitioners may have heard of the benefits of a new inter-
above steps may begin all over again for the patient. For the patient
vention or the harms of an old one, they may not be persuaded to
to agree, they must be aware of the options, accept that the man-
change management based on this evidence. A central problem is
agement recommended is appropriate, and be able to undertake it.
that clinicians may be persuaded by many means other than unbi-
This may involve a complex mixture of the patient’s values and
ased evidence, such as marketing techniques, reciprocity (the obli-
beliefs, which thus need to be explored. To assist communication
gation arising from “gifts”), authority, social validation (acceptance
and understanding, patient decision aids have been developed.
by peers), and friendship/personal relationships (21, 22).
While such aids can reduce patients’ decisional conflict with their
Pharmaceutical companies and others invest considerable resources
final choice, it is less clear whether aided decisions result in better
in such methods. Hence, more work is needed to identify methods
that can best “vaccinate” clinicians against poor evidence.
Patients must also contend with competing claims and advice, adverse
Even if evidence is accepted, clinicians and guidelines may not target
effects or fear thereof, and sometimes lack of ability to pay for tests
the correct groups. For example, a review of 20 guidelines for atrial
and treatments. If resources to inform prescribers of current best evi-
fibrillation (most of which were not evidence-based) showed that the
dence are inadequate, they are woefully more so for patients, despite
proportion of patients recommended for warfarin varied between
such pioneering efforts as DipEx (www.dipex.org). Even when
13% and 100% (23). Whether there are net benefits of anticoagula-
patients accept the benefits of therapy and wish to comply, they may
tion depends on balancing the risk for stroke against the risk for
not. We may all agree to exercise more, eat less, or stop smoking, but
hemorrhage. A survey of physicians in Australia suggested good
too few do. Even for medications, dosing frequency, pill size, and
knowledge of factors that increased the hemorrhage risk, but only half
simple forgetfulness can all cause problems. Typical adherence rates
correctly identified a patient with a previous stroke as being at high
for medications are < 50%. Improving adherence to short courses of
risk for stroke recurrence (24). Similarly, a Dutch study showed that
treatment is relatively easy, but enhancing adherence with long-term
risk factors that should predict a higher prescription rate of warfarin
regimens is more difficult. Helpful elements include information
did not (25). Unfortunately, the relation between diagnosis and treat-
about the regimen, counseling about the importance of adherence
ment is rarely 1 to 1. Clinicians must usually learn about and under-
and how to organize medication taking, reminders, rewards and
stand the multiple factors that go into making a good decision that
recognition for the patient’s efforts in following the regimen, and
enlisting social support from family and friends (30).
March/April 2005 | Volume 142 • Number 2
13. Mallett S, Clarke M. How many Cochrane reviews are needed to cover exist-
Even when most clinicians are aware of evidence, there may be little
ing evidence on the effects of health care interventions? ACP J Club. 2003
effect on quality of care without further attention to the other stages.
14. Shaneyfelt TM, Mayo-Smith MF, Rothwangl J. Are guidelines following
However, we would see the initial awareness (and discrimination) of
guidelines? The methodological quality of clinical practice guidelines in the
high-quality research as the first large hurdle. While bedside evi-
peer-reviewed medical literature. JAMA. 1999;281:1900-5.
dence-based medicine has focused on clinicians becoming aware of
15. Dawes M, Sampson U. Knowledge management in clinical practice: a sys-
and accepting the best-quality research, it is clearly important but
tematic review of information seeking behavior in physicians. Int J MedInform. 2003;71:9-15.
insufficient. Not all clinicians will have or use the skills of bedside
16. Gorman PN, Helfand M. Information seeking in primary care: how physi-
evidence-based medicine (31), and even the well skilled will not
cians choose which clinical questions to pursue and which to leave unan-
implement intended changes fully. Hence, evidence-based medi-
swered. Med Decis Making. 1995;15:113-9.
cine should not just be concerned with clinical content but also
17. Sackett DL, Straus SE. Finding and applying evidence during clinical rounds:
the “evidence cart”. JAMA. 1998;280:1336-8.
with the processes of changing care and systems of care.
18. Coomarasamy A, Khan KS. What is the evidence that postgraduate teaching
in evidence based medicine changes anything? A systematic review. BMJ. 2004;329:1017.
19. Pathman DE, Konrad TR, Freed GL, Freeman VA, Koch GG. The aware-
ness-to-adherence model of the steps to clinical guideline compliance. The
case of pediatric vaccine recommendations. Med Care. 1996;34:873-89.
20. Rogers EM. Diffusion of Innovations, 5th ed. New York: Free Press; 2003.
21. Cialdini RB. Influence: The Psychology of Persuasion. New York: Quill; 1998.
22. Roughead EE, Harvey KJ, Gilbert AL. Commercial detailing techniques
used by pharmaceutical representatives to influence prescribing. Aust N Z J
1. Institute of Medicine Committee on Quality of Health Care in America.
23. Thomson R, McElroy H, Sudlow M. Guidelines on anticoagulant treatment
Crossing the Quality Chasm: A New Health System for the 21st Century.
in atrial fibrillation in Great Britain: variation in content and implications for
Washington, DC: National Academy Press; 2001.
2. Cook DJ, Guyatt GH. Review: albumin administration is not associated
24. Peterson GM, Boom K, Jackson SL, Vial JH. Doctors’ beliefs on the use of
with excess mortality in acutely ill patients. ACP J Club. 2002 Jan-Feb;136:2.
antithrombotic therapy in atrial fibrillation: identifying barriers to stroke pre-
3. Allen C, Glasziou P, Del Mar C. Bed rest: a potentially harmful treatment
vention. Intern Med J. 2002;32:15-23.
needing more careful evaluation. Lancet. 1999;354:1229-33.
25. Rutten FH, Hak E, Stalman WA, Verheij TJ, Hoes AW. Is treatment of
4. Brass LM, Krumholz HM, Scinto JD, Mathur D, Radford M. Warfarin use
atrial fibrillation in primary care based on thromboembolic risk assessment?
following ischemic stroke among Medicare patients with atrial fibrillation.
26. Hunink M, Glasziou P, Siegel J, et al. Decision Making in Health and
5. Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC. A comparison
Medicine: Integrating Evidence and Values. Cambridge: Cambridge Uni-
of results of meta-analyses of randomized control trials and recommendations
of clinical experts. Treatments for myocardial infarction. JAMA.
27. Shea S, DuMouchel W, Bahamonde L. A meta-analysis of 16 randomized
controlled trials to evaluate computer-based clinical reminder systems for
6. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and
preventive care in the ambulatory setting. J Am Med Inform Assoc.
control of hypertension in the United States, 1988-2000. JAMA. 2003;290:
28. Bennett JW, Glasziou PP. Computerised reminders and feedback in med-
7. Davis D, Evans M, Jadad A, et al. The case for knowledge translation: short-
ication management: a systematic review of randomised controlled trials.
ening the journey from evidence to effect. BMJ. 2003;327:33-5.
8. Sackett DL, Straus SE, Richardson WS, Rosenberg W, Haynes RB.
29. O’Connor AM, Stacey D, Entwistle V, et al. Decision aids for people facing
Evidence-Based Medicine: How to Practise and Teach EBM, 2d ed.
health treatment or screening decisions. Cochrane Database Syst Rev.
Edinburgh: Churchill Livingstone; 2000.
9. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clini-
30. Haynes RB, McDonald H, Garg AX, Montague P. Interventions for helping
cal practice guidelines? A framework for improvement. JAMA. 1999;282:
patients to follow prescriptions for medications. Cochrane Database Syst
10. Haynes RB, Sackett DL, Gray JA, Cook DL, Guyatt GH. Transferring evi-
31. Straus SE, Green ML, Bell DS, et al. Evaluating the teaching of evidence
dence from research into practice: 2. Getting the evidence straight. ACP J
based medicine: conceptual framework. BMJ. 2004;329:1029-32.
11. Muir Gray JA, Haynes RB, Sackett DL, Cook DJ, Guyatt GH. Transferring Acknowledgments: The authors thank Iain Chalmers and Sharon
evidence from research into practice: 3. Developing evidence-based clinical
policy. ACP J Club. 1997 Mar-Apr;126:A14-6.
12. Clarke M, Alderson P, Chalmers I. Discussion sections in reports of
controlled trials published in general medical journals. JAMA. 2002;287:2799-801.
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Eur Arch Psychiatry Clin Neurosci (1999) 249 : 238–246 I. Leykin · B. Spivak · A. Weizman · I. R. Cohen · M. Shinitzky Elevated Cellular Immune Response to Human Heat-Shock Protein-60 in Schizophrenic PatientsReceived: 26 November 1998 / Accepted: 10 July 1999 Abstract Heat shock protein-60 (HSP60) is implicated patients and in controls. Titers of IgA against HSP60 werein several aut
Nagoya University Graduate School of Medicine Education: Bachelor of Engineering, Dept. of Transportation Engineering, Tokyo Univ. of Sci., Master of Engineering, Dept. of Civil Engineering, Tokyo Univ. of Sci., 1993 Degree: Doctor of Engineering, Tokyo Univ. of Sci., 1999, Title of the Thesis: Design and analysis of randomized clinical trials with recurrent events. Employment: 1993.4-1995.