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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

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 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 Strategies of well-built clinical questionsAND/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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • Randomized controlled trial.pt (publication type)

  • Random.tw (text word)

  • Drug Therapy.sh (subject heading)


Critically appraising the evidence
Critically Appraising the Evidence of well-built clinical questions

  • 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 of well-built clinical questions(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 of well-built clinical questions(in decreasing order of preference)

  • 4. Cohort studies

  • 5. Case-Control studies

  • 6. Case reports


General terms
General Terms of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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? of well-built clinical questions

  • 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? of well-built clinical questions

  • 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 of well-built clinical questions

  • 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? of well-built clinical questions

  • 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? of well-built clinical questions

  • 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? of well-built clinical questions

  • 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 of well-built clinical questions

  • 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? of well-built clinical questions


Terms about diagnotic tests
Terms about diagnotic tests of well-built clinical questions

  • 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 tests of well-built clinical questionsLikelihood 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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? of well-built clinical questions

  • 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 of well-built clinical questions

  • Relative Risk (RR)

  • Relative Risk Reduction (RRR)

  • Absolute Risk Reduction (ARR)

  • Number Needed to Treat (NNT)

  • Confidence Intervals


Basic statistics
Basic Statistics of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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? of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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 of well-built clinical questions

  • 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. of well-built clinical questions

  • 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 of well-built clinical questions

  • Search Articles

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

  • 2. Limit 1. To Human and English 93-00 306

  • 3. Prednisone 21048

  • 4. Limit 3. To Human and English 93-00 3572

  • 5. Combine 2. And 4. 9

  • 6. Randomized Controlled Trial.pt 263913

  • 7. Combine 5. And 6. 1


  • Trial
    Trial of well-built clinical questions

    • Annals of Internal Medicine September ‘96

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

    • Randomized

    • Blinded


    Trial1
    Trial of well-built clinical questions

    • 4 Groups

      • Acyclovir plus Prednisone

      • Acyclovir plus Prednisone placebo

      • Prednisone plus Acyclovir placebo

      • Two placebo


    Trial2
    Trial of well-built clinical questions

    • 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 of well-built clinical questions

    • 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 of well-built clinical questions

    • 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.? of well-built clinical questions

    • 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 of well-built clinical questions

    • 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 of well-built clinical questions

    • 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 of well-built clinical questions

    • 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