evidence based medicine 0705

8/2/2019 Evidence Based Medicine 0705

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Evidence-Based MedicineChapter 6: Harm

Emergency Department E-Da Hospital / I-Shou University

Chi-Wei Lee M.D.


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How do we practice EBM?Step 1: Formulating the management question to be

answered

Step 2: Searching the literature and on-line databases forevidence to answer the question

Step 3: Appraising the evidence

Step 4: Integrating this appraisal with knowledge about theunique aspects of the patient (including preferences)

Step 5: Evaluating our effectiveness and efficiency inexecuting steps 1 - 4 and seek ways to improve

them


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Harm

Clinically, we often have to judge whether a medical

intervention is harming our patients.

For example: Do statins increase the risk of cancer?

After we found an evidence about the harm from

medical literature, we have to evaluate the evidence:

1. Is this evidence about the harm valid? Validity2. Is this valid evidence about the harm important? Importance

3. Is this valid and important evidence about the harm

applicable to our patients? Applicability


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Validity

False-positiveFalse-negative


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Is this evidence about the harm valid?

1. Were groups of patients similar in all ways exceptexposure to the medical intervention?

2. Was the assessment of outcomes objective?

3. Was the follow-up of patients complete &sufficientlylong for the outcome to occur?

4. Logical diagnostic tests for causation? Exposure preceded the onset of the outcome?

Dose-response gradient?

Evidence from a dechallenge-rechallenge study?

Association consistent from study to study?

Association makes biological sense?


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Studies of whether statins cause cancer

Adverse outcome

(cancer)Totals

Present

(case)

Absent

(control)

Exposed to the

treatment (statins)

Yes

(RCT or cohort)a b a+b

No

(RCT or cohort)

c d c+d

a+c b+d a+b+c+d


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Were groups of patients similar in all ways except

exposure to the medical intervention?

Ideally, systematic review /RCT, but RCT are ill-suited (in size, duration, ethics) for evaluating mostuncommon harmful exposure.

First alternative: cohort study (prospective)

Second alternative: case-control study (retrospective)

Third alternative: case report (lack comparisongroups, only sufficient for hypothesis generation)


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Cohort studies


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Case-Control Studies


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Confounders

Because the decision to prescribe and accept treatment is purposive,not randomized, in a cohort studyexposed patients may differ from

non-exposed patients for determinants of the outcome.

For example: if people with hyperlipidemia were more likely todevelop cancer than those with normo-lipidemia, hyperlipidemiawould be a confounder when comparing the risk of cancer in people

using and not using statins.

More potential for confounding with case-control studies(retrospective) because confounders that are transient or lead to earlydeath wont even be able to be measured.

Three properties of confounders:

1. Extraneous to the questions posed

2. Determinants of the outcomes

3. Unequally distributed between exposed & non-exposed groups


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Exposed factor Outcome

Confounder

A Known CauseRelated

?


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Was the assessment of outcomes objective?

Not objective, if:

The investigator searched more aggressively for cancer in

the patients who were known to use statins.

Patients with cancer may be more likely to recall possibleexposure subjectively.

Therefore, it is better for the patients and their

investigator to be blinded to the study hypothesis.


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Was the follow-up of patients complete &

sufficiently long for the outcome to occur?

If the study lost lots of its patients to follow-up, wedalso be skeptical of its conclusions, because lostpatients may have very different outcomes from thosewho remain in the study.

If we found a study of the association between statinsand cancer that followed patients for only a few

weeks, we couldnt distinguish a true- from a false-negative association.


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Logical diagnostic tests for causation?

Exposure preceded the onset of the outcome?






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Exposure preceded the onset of the outcome?

For example: in this study of statins, all

patients known to have cancer at the beginningof the study were excluded.


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For example: An increasing severity of cancer

with increasing exposure (increased dose

and/or duration) to statins might strengthens

the association.


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Adverse outcome decreases or disappears

when the medical intervention is withdrawn.

Adverse outcome worsens or reappears when

the medical intervention is reintroduced.


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If we were able to find multiple studies or,

better yet, a systematic review of the question,we could determine whether the association

between exposure and the adverse event is

consistent from study to study.


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If the association between exposure and harm

makes biological sense (e.g. in terms ofpathophysiology), a causal interpretation

becomes morereasonable.


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Importance


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Is this valid evidence about the harm important?

Association between the exposure and outcome:

Magnitude: Relative Risk(RR) or Odd Ratio (OR)

Precision: 95% Confidence Interval (the narrower,the higher is the precision)

Translate RR and OR into a measure

comprehensible to our patients: Number Needed

to Harm (NNH)


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Relative Risk (RR) For RCTs and cohort studies

Incidence of the adverse event (risk) in the treated patients relativeto the risk in the untreated patients.

If 1000 patients receive a treatment and 20 of them have an

adverse outcome, a = 20 and a / (a + b) = 2%.

If just 2 of 1000 patients who do notreceive this treatment for thesame target disorder experienced this adverse event, c = 2 and c /(c + d) = 2 / 1000 = 0.2%.

Relative Risk= 2% / 0.2% = 10

Patients receiving the suspect treatment are 10 times as likely tosuffer the adverse event as patients treated the other way.


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Odd Ratio (OR) For case-control studies ( sample outcomes rather than exposures,

we cant calculate incidences.

If 100 cases of the adverse outcome are identified.

If 90 of them had received the putative causal agent, a = 90 and c =

10.

If in 100 control patients (free of adverse outcome), 45 of themreceived the suspect treatment, b = 45 and d = 55.

Odd Ratio = ad / bc = (90 x 55) / (45 x 10) = 11

The odds of experiencing the adverse event for patients exposed tothe putative causal agent is 11 times that of those patients notreceiving it.


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How big should RR, OR be to be important?

When RR or OR > 1, an increased riskof the adverseoutcome associated with the exposure.

When RR or OR = 1, the adverse outcome is no morelikely to occur with than without exposure to thesuspected agent.

RR > 3 (in cohort studies with less bias)

OR > 4 (in case-control studies with less bias)


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EBM online calculator Enter: OR (odd ratio) and PEER (Patient

Expected Event Rate)

Answer: NNH (Number Needed to Harm)

Online calculator
http://www.cebm.utoronto.ca/practise/ca/statscal/orToNnt.htmhttp://www.cebm.utoronto.ca/practise/ca/statscal/orToNnt.htm


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Applicability


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Is this valid and important evidence about the

harm applicable to our patients?

Is our patient so different from those included in thestudy we found?

What is our patients riskof the adverse event? Whatis our patients benefit from the therapy?

What are our patients preferences, concerns and

expectations from this treatment?

What alternative treatments are available?


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Cookbook?

Evidence based medicine is not "cookbook" medicine.

Because it requires a bottom up approach that integrates thebest external evidence with individual clinical expertise andpatients' choice.

External clinical evidence can inform, but can never replace,individual clinical expertise, and it is this expertise thatdecides whether the external evidence applies to the individualpatient at all and, if so, how it should be integrated into aclinical decision.

http://www.bmj.com/cgi/content/full/312/7023/71 (David L Sackett)
http://www.bmj.com/cgi/content/full/312/7023/71http://www.bmj.com/cgi/content/full/312/7023/71


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Good doctors

.......use both individual clinical expertise and thebest available external evidence, and neither alone isenough.

Withoutclinical expertise, practice risks becomingtyrannised by evidence, for even excellent externalevidence may be inapplicable to or inappropriate foran individual patient.

Withoutcurrent best evidence, practice risksbecoming rapidly out of date, to the detriment ofpatients.


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BestBET

http://www.bestbets.org/news/site.html

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The greatest obstacle to knowledge is not

ignorance, it is the illusion of knowledge.

Daniel Boorstein - Historian

evidence based medicine 0705

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