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Introduction to Evidence Based Medicine. Bradford S. Pontz, M.D. Assistant Professor of Medicine Georgetown University Medical Center. Patient W.R. 55 year old healthy male presents with 3 days right-sided back pain, 2 days rash Exam shows vesicular lesions

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Introduction to Evidence Based Medicine

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Introduction to evidence based medicine

Introduction to Evidence Based Medicine

Bradford S. Pontz, M.D.

Assistant Professor of Medicine

Georgetown University Medical Center


Patient w r

Patient W.R.

  • 55 year old healthy male presents with 3 days right-sided back pain, 2 days rash

  • Exam shows vesicular lesions

  • Patient says his friend was given a medication to treat the shingles and prednisone and wants to know if this will make his experience less miserable


Overview and objectives

Overview and Objectives

  • 1. Definition

  • 2. How to ask Clinical Questions you can answer

  • 3. Searching for the Best Evidence

  • 4. Critically Appraising the Evidence

  • 5. Applying Evidence


Definition

Definition

  • Evidence-based medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients


Definition1

Definition

  • Making the best decision requires sound judgment based on the following:

    • clinical expertise

    • knowledge of patient values and preferences

    • evidence from the literature


How to ask clinical questions you can answer four elements of well built clinical questions

How to Ask Clinical Questions you can Answer - Four Elements of well-built clinical questions

  • 1. Patient or problem - ask “how would I describe a group of patients similar to mine?” compromise between precision and brevity

  • 2. Intervention - ask “what main intervention am I considering?” usually a treatment or exposure


Four elements of well built clinical questions

Four Elements of well-built clinical questions

  • 3. Comparison intervention - usually vs. placebo or vs. established therapy

  • 4. Outcome - what could this treatment hope to accomplish or what could result from this exposure?


Search strategies and or

Search StrategiesAND/OR

  • AND ing searches for intersection of searches (studies that contain all search words)

  • OR ing searches for union of searches (simply adds them, but studies duplicated will appear only once in result of your OR)


Search strategies medline

Search Strategies - Medline

  • Enter topic as subject heading (check box labelled “Map Term to Subject Heading”)

  • Enter any limits (years, language, etc.)

  • “Explode” topic if necessary

  • Next enter topic as index text word (do not check box)

  • Next enter topic as “topic.af” (all fields)

  • Then, combine these three searches using OR (creates union of first three searches)


Search strategies medline1

Search Strategies - Medline

  • Do this for as many aspects (in terms of search words) as seems necessary to limit search

  • Finally AND the results of these searches for individual topics


Search strategies medline2

Search Strategies - Medline

  • Methodologic filter is a way to further refine your search

  • Searches for all studies that involve the parameter you want (often a large number)

  • In Medline, search for your parameter with a suffix


Search strategies medline3

Search Strategies - Medline

  • Randomized controlled trial.pt (publication type)

  • Random.tw (text word)

  • Drug Therapy.sh (subject heading)


Critically appraising the evidence

Critically Appraising the Evidence

  • Hierarchy of Types of Studies

  • A few general terms

  • Assessing validity and importance of three main types of studies

    • diagnosis

    • prognosis

    • treatment


Hierarchy of types of studies in decreasing order of preference

Hierarchy of Types of Studies(in decreasing order of preference)

  • 1.Systematic reviews and meta-analyses

  • 2.Randomized, controlled clinical trials with definitive, significant results

  • 3.Randomized, controlled clinical trials with less definitive results (a point estimate suggesting a clinically significant effect, but with confidence intervals that suggest the possibility of more equivocal results)


Hierarchy of types of studies in decreasing order of preference1

Hierarchy of Types of Studies(in decreasing order of preference)

  • 4. Cohort studies

  • 5. Case-Control studies

  • 6. Case reports


General terms

General Terms

  • Hypothesis: “Purpose is to examine Treatment X in lowering blood pressure compared to standard Treatment Y”

  • Null hypothesis is no difference


General terms1

General Terms

  • P value is a level of probability, deemed as statistically significant, chosen as grounds for rejecting the null hypothesis.

  • Traditionally p<.05 = less than 5% probability that difference between treatments is due to chance or unknown reason rather than true difference in treatments


General terms2

General Terms

  • Validity - external validity is the degree to which the results of a study hold true in other settings and/or apply to populations beyond those included in a study, such as your own patients. Consider possible differences:

    • gender- compliance

    • stage or severity of disease


Primary end points

Primary End Points

  • Most directly and clearly portray the actual condition of interest. Should state how possibility of end point will be assessed:

    • cancer prevalence by biopsy

    • coronary artery disease by angiogram

    • peptic ulcer evaluated by endoscopy


Is this evidence about a diagnostic test valid

Is this evidence about a diagnostic test valid?

  • Was there an independent, blind comparison with a reference “gold” standard of diagnosis?

  • Was it evaluated in an appropriate spectrum of patients?


Is this evidence about prognosis valid

Is this evidence about prognosis valid?

  • Was a defined, representative sample of patients assembled at a common (usually early) point in the course of their disease?

  • Was follow-up sufficiently long and complete?


If follow up not optimal do a worst case analysis

If Follow-up not Optimal, do a “Worst-Case” Analysis

  • 100 patient enter, 4 die, 16 lost to follow-up

  • Death rate = 4/(100-16) = 4/84 = 4.8%

  • Survival rate = 100%-4.8% = 95.2%

  • Worst case - What if all 16 lost died?

  • Death rate=(4+16)/(84+16) = 20/100 = 20%

  • Survival rate = 100%-20% = 80%


Is this evidence about treatment valid

Is this evidence about treatment valid?

  • Was the assignment of patients randomized and double-blind?

  • Were the groups similar at the start?

  • Apart from the experimental intervention, were the groups treated equally?

  • Were all accounted for at the end of the trial and analyzed in the groups to which they were randomized? (“intention to treat”)


No randomized trials found

No randomized trials found?

  • Refine your search

  • Consider whether a treatment effect is so large you can’t imagine it would be false(+)

  • Evidence from non-randomized trial showing that treatment is useless or harmful is somewhat acceptable. False (-) conclusions less likely than false (+)


Is evidence from a systematic review valid

Is evidence from a systematic review valid?

  • Are the trials randomized?

  • Were the results consistent from study to study?

  • Does it include a methods section that describes:

    • search methods

    • methods for assessing individual study validity


Critically appraising the evidence1

Critically Appraising the Evidence

  • Hierarchy of Types of Studies

  • A few general terms

  • Assessing validity and importance of three main types of studies

    • diagnosis

    • prognosis

    • treatment


Is evidence about a diagnostic test important

Is evidence about a diagnostic test important?


Terms about diagnotic tests

Terms about diagnotic tests

  • Sensitivity = a/(a+c) = 731/809 = 90%

  • Specificity = d/(b+d) = 1500/1770 = 85%

  • LR+ = sens/(1-spec) = 90%/15% = 6

  • LR- = (1-sens)/spec = 10%/85% = 0.12

  • pos. pred. Value = a/(a+b) = 731/1001 = 73%

  • neg. pred. Value = d/(c+d) = 1500/1578 = 95%


Terms about diagnostic tests likelihood ratios

Terms about diagnostic testsLikelihood Ratios

  • Definition - probability of that test result in people with the disease divided by the probability of the result in people without the disease

  • Can be calculated for a range of values of test results rather than just pos. vs. neg.

  • Can be used with pre-test odds to calculate post-test odds


Terms about diagnostic tests

Terms about diagnostic tests

  • Prevalence = (a+c)/(a+b+c+d) = 809/2579 = 32%

  • Pretest odds = prevalence/(1-prevalence) = 31%/69% = 0.45

  • Post-test odds = pretest odds X LR

  • Post-test probability = post-test odds/(post-test odds + 1)


Example ferritin for diagnosis of iron deficiency anemia

Example - Ferritin for Diagnosis of iron deficiency anemia

  • Assume a pre-test odds of 1:1 (a 50-50 chance)

  • Suppose Ferritin = 60

  • Post-test odds = 1X6 = 6

  • Post-test probability = 6/(6+1) = 6/7 = 86%


Is evidence about treatment important

Is evidence about treatment important?

  • A statistically significant result (e.g. p<.05) may not be clinically significant.

  • May show that one treatment is better than another, but does not necessarily suggest the impact that treatment might have in your own clinical practice


Bottom line clinical effects

Bottom Line Clinical Effects

  • Relative Risk (RR)

  • Relative Risk Reduction (RRR)

  • Absolute Risk Reduction (ARR)

  • Number Needed to Treat (NNT)

  • Confidence Intervals


Basic statistics

Basic Statistics

  • CER = Control Event Rate = risk of outcome event of interest in the control group = A/(A+B)

  • EER = Experimental Event Rate = risk of outcome event rate in the experimental group = C/(C+D)


Relative risk

Relative Risk

  • Aka Risk Ratio

  • is the ratio of risk of the outcome event in the experimental (intervention or treated group) to the risk in control group

  • RR = EER/CER = [C/(C+D)]/[A/(A+B)]

  • RR = [350/(350+947)]/[404/(404+921)]

  • RR = 0.865 or about 87%


Relative risk reduction

Relative Risk Reduction

  • Essentially the complement of RR

  • The percent reduction in the experimental group event rate compared with the control group event rate

  • RRR = [(CER-EER)/CER] X 100 OR

  • RRR = 1-RR

  • RRR = (1-0.865) = 13.5%


Absolute risk reduction

Absolute Risk Reduction

  • Aka Risk Difference = difference in the event rate between a control group and an experimental group

  • ARR = CER-EER

  • ARR = A/(A+B) - C/(C+D)

  • ARR = 404/(404+921) - 350/(350+947)

  • ARR = 0.041 or 4.1%


Number needed to treat

Number Needed to Treat

  • NNT = 1/ARR

  • NNT = 1/0.041 = 24

  • NNT is particularly useful to clinicians who want to know whether the probable benefits of some treatments or intervention will be worthwhile in their patients


Confidence intervals

Confidence Intervals

  • Basic research concept - experiment repeated will yield slightly different results each time

  • Approximation of the true effect is called the point estimate

  • CI = larger neighborhood in which true effect is likely to reside


Confidence intervals1

Confidence Intervals

  • Expressed with a given degree of expected certainty such as 95%

  • True result will lie outside the range only 5% of the time (2.5% of the time above and 2.5% of time below)

  • For example, an absolute risk reduction of 4.1% could have 95% CI of -1.0 to 9.2


Hypothetical treatment study

Hypothetical treatment study

  • Suppose experimental group is group 1. 15 of 125 patients have a given outcome. Proportion of outcome is p1=r1/n1=15/125=12%.

  • Suppose control group is group 2. 30 of 120 patients have a given outcome. Proportion of given outcome is p2=r2/n2=30/120=25%.


Can you apply a diagnostic test

Can you apply a diagnostic test?

  • Is it affordable, available, accurate and precise in your setting?

  • Can you estimate pretest probability?

    • Data from personal or practice experience

    • Data from the report itself- Speculation

  • Will the resulting post-test probabilities affect your management? Would you treat based on results? Would patient agree to?


Applying treatment evidence

Applying Treatment Evidence

  • Can you apply evidence about prognosis to your patient?

  • Can you apply evidence about treatment?

    • Is your patient so different from those in trial that its results cannot be applied? Usually can extrapolate at least a direction of effect

    • How great a benefit might you expect from treatment?


N of 1 trial

N of 1 Trial

  • Problems with classic trial of therapy

    • Many illnesses or lab abnormalities are self-limited

    • Placebo effect can lead to improvement in symptoms

    • Conclusions can be biased by our own expectations and those of the patient


N of 1 trial1

N of 1 Trial

  • Clinician and patient agree to trial

  • Patient undergoes pairs of treatment periods

  • Both patient and clinician are blinded

  • Treatment targets are monitored (symptom diary, etc.)

  • Pairs of treatment periods are replicated until both pt. and clinician are convinced that treatments are really different or not


Patient w r1

Patient W.R.

  • 1. Patient group/problem

  • 2. Intervention

  • 3. Comparison

  • 4. Outcome

  • Question: Does prednisone in addition to standard antiviral therapy, compared to standard antiviral therapy alone, improve pain in immunocompetent patients with acute herpes zoster?


Search strategy medline ovid

Search Strategy - Medline Ovid

  • SearchArticles

  • 1.Herpes Zoster [Drug Therapy, Therapy]1410

  • 2. Limit 1. To Human and English93-00306

  • 3. Prednisone21048

  • 4. Limit 3. To Human and English 93-003572

  • 5. Combine 2. And 4.9

  • 6. Randomized Controlled Trial.pt263913

  • 7. Combine 5. And 6.1


  • Trial

    Trial

    • Annals of Internal Medicine September ‘96

    • 200 immunocompetent patients presented with herpes zoster within 72 hours randomized to 4 groups

    • Randomized

    • Blinded


    Trial1

    Trial

    • 4 Groups

      • Acyclovir plus Prednisone

      • Acyclovir plus Prednisone placebo

      • Prednisone plus Acyclovir placebo

      • Two placebo


    Trial2

    Trial

    • 21 day trial period

    • Prednisone given in taper 60, 30, 15 mg

    • Acyclovir 800 mg 5X/day

    • Primary End Points

      • time to uninterrupted sleep

      • time to return to 100% usual activity

      • time to no use of analgesic agents


    Trial3

    Trial

    • No difference in pain at 6 months

    • Quality of life assessments improved during 6 months

    • Acyclovir plus Prednisone vs. double placebo, RR for time to cessation of acute neuritis was 3.02, time to return to 100% usual activity was 3.22


    Trial4

    Trial

    • RR not shown for Acyclovir plus Prednisone vs. Acyclovir plus Prednisone placebo for primary endpoints

    • Raw data not shown so cannot be calculated

    • Graph of time to healing (secondary endpoint) is shown yielding minorly faster with prednisone, p values but not CI shown


    What to tell w r

    What to tell W.R.?

    • Few studies that address question in rigorous way (randomized, placebo-con.)

    • One study that did, claimed a beneficial effect for adding prednisone but did not report/analyze data fully

    • No convincing evidence to support use at this time


    Resources

    Resources

    • Website http://cebm.jr2.ox.ac.uk/

    • Also try www.eboncall.co.uk

      • can be reached from link at first website

      • concise evidence-based reviews called CATs (Clinically Appraised Trials) for on-call situations

      • Be sure to review the Levels of Evidence and Grading system


    Summary how to practice ebm

    Summary - How to Practice EBM

    • Pose Clinical Questions you can Answer

    • Use search strategies to narrow search, make more efficient and fruitful

    • Critically appraise results using statistical analysis

    • Accept limitations of available literature

    • Discuss with patient reasons for your decision


    Summary how to practice ebm as a house officer or student

    Summary - How to practice EBM as a house officer or student

    • Use literature to answer specific clinical questions, rather than only routinely reading weekly journals

    • Accept time limitations on your own ability to search for evidence

    • Select cases/diagnoses where you will use EBM

    • Encourage your teachers to use EBM


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