Evidence Based Medicine by Dr. Harmanjit Singh, GMC, Patiala


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  • Status: Recommended
    These two definitions come from two of the leaders of the current "Evidence Based Medicine" movement; The term "Evidence Based Medicine" first appeared in one of Guyatt's papers.
    Both men are from McMaster University in Hamilton, Ontario which is a center of EBM development and teaching.
  • Status: Recommended
    There is no definitive list of the benefits of EBM. These 5 bullet points were culled from a number of journal articles and the Guyatt, "Users' Guide" textbook.
    If time is an issue, not all of the bullet points need to be covered. The two most-often cited reasons are:
    delay of bench to bedside research
    Managing the primary literature
    Other bullets can be covered as time allows.
  • Status: Recommended
    This bullet point can be used to illustrate to points:
    Managed care companies often use cost-cutting measures (such as treatment algorithms) under the name of "Evidence Based Medicine."
    Even in the absence of managed care, it is important for clinicians to know when treatments are wholly ineffective so that money is not wasted.
    When cost is a barrier for a patient, decisions about the trade-offs in cost can be made in a deliberate, defensible way.
  • Status: Recommended
    Graphical representation of the typical delay between an intervention being published in the primary literature, and its widespread application in routine clinical practice.
    The next series of slides give examples to back up this "years to decades" claim.
  • Status: Detailed
    Note that this six-year delay is the time between secondary research and routine clinical practice. The delay from the earliest RCTs would be longer.
    Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC. A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. Treatments for myocardial infarction. JAMA 1992; 268(2): 240-8.
  • Status: Detailed
    Note that this six-year delay is the time between secondary research and routine clinical practice. The delay from the earliest RCTs would be longer.
    Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC. A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. Treatments for myocardial infarction. JAMA 1992; 268(2): 240-8.
  • Status: Detailed
    Diagrams from this article are covered in subsequent slides.
    Citation: Contopoulos-loannidis GD, Alexiou GA, Gouvias TC, Ionnidis JP. Medicine. Life cycle of translational research for medical interventions. Science 2008;321:1298-9.
  • Status: Recommended
    Summary slide or reasons EBM is needed to help manage the number of articles published in the primary literature.
  • Status: Recommended
    This slide says that EBM provides tools to help alert clinicians to potentially misleading marking. This includes at least three phenomena:
    Publication bias in which negative studies are less likely to be published. Equally series.
    "File drawer phenomena," in which studies run by pharmaceutical companies are selectively submitted for publication in order to present only the most favorable studies to the public.
    Deliberately under-powered studies, that show "no difference" between the drug of the funding company vs. the drug of a competing company. ("Me too" drugs.)
    One tool that is used to help detect publication bias is "registries" of clinical trials (such as clinicaltrials.gov). Trials are registered prior to completion, so studies which have gone unpublished are easier to track down. Registries also guard against "post hoc" statistical analysis, in which study data is mined for a statistically significant finding, even if it is not related to the original hypothesis of the study.
  • Status: Detailed
    A counter-intuitive result, again demonstrating our inability to make accurate predictions based on physiologic reasoning alone.
    Either cardiac compensatory mechanisms are more complicated than we know; or
    Beta-blockers do not work the way we think they do (or they have additional, unknown actions); or
  • Status: Detailed
    This slide shows an example of "Volunteer bias": The people who volunteer for clinical studies are not representative of the public in general.
    In this particular example, the volunteer bias was named "The Well Woman Effect," in which the volunteers of the initial cohort studies were sufficiently health conscious, that the genuine, increased risks of MI, stroke, and venous thromboembolism were not apparent.
  • Status: Detailed
    This slide again demonstrates the risk of physiologic reasoning, but also to consider side effects and other outcomes when studying an intervention.
  • strongest evidence for therapeutic interventions is provided by systematic review of randomized, double-blind, placebo-controlled trials involving a homogeneous patient population and medical condition. In contrast, patient testimonials, case reports, and even expert opinion have little value as proof because of the placebo effect, the biases inherent in observation and reporting of cases, difficulties in ascertaining who is an expert, and more.
  • Status: Foundational.
    This foundational slide includes definitions of Internal and External validity. Even though these terms are not used in the Critical Appraisal questions (as defined in the Users' Guide, understanding these concepts may help the student understand why the Critical Appraisal questions are chosen as they are.
  • Status: Detailed
    While the rest of this presentation describes what RBM is, the following series of slides describes what RBM is not. These slides are meant to refure many of the criticisms of EBM that can be found in the literature.
    Most of the criticisms that are found in the literature can be attributed to a lack of understanding EBM: either equating EBM with "treatment algorithms," or overly rigid interpretation of the Hierarchy of Evidence and over-reliance on Randomized Controlled Trials.
  • Status: Detailed
  • Evidence Based Medicine by Dr. Harmanjit Singh, GMC, Patiala

    3. 3. Definitions: • "The integration of best research evidence with clinical expertise and patient values” (David Sackett, et al. Evidence-based Medicine. How to Practice and Teach EBM, 2000) • "The conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients..." (Gordon Guyatt, M.D., et al. Users' Guides to the Medical Literature, 2002) What is EBM?
    4. 4.  Traces of EBM`s origin in ancient Greece & Chinese medicine  Prof. Archie Cochrane, Scottish epidemiologist, through his book Effectiveness and Efficiency: Random Reflections on Health Services (1972), advocated concepts behind EBM.  “Evidence based" was first used in 1990 by David Eddy  “Evidence-based medicine" first appeared in the medical literature in 1992 in a paper by Guyatt et al  Methodologies used to determine "best evidence“, estb. by McMaster University Research Group led by David Sackett & Gordon Guyatt  Recently broadened interest due to information explosion that increased dramatically in the last decade.
    5. 5. Any practice that applies: - Up-to-date information from relevant & valid research about usefulness of various diagnostic tests - Predictive power of prognostic factors - The beneficence of a particular treatment method
    6. 6.  There is evidence that something works, is good and benefits the patient, do it  There is evidence that something does not work, is harmful, does not benefit the patient, do not do it  There is insufficient evidence, be conservative, relying on individual clinician expertise
    7. 7. X 1) Evidence-based medicine ignores clinical experience and clinical intuition. X 2) Understanding of basic investigation and pathophysiology plays no part in evidence-based medicine. X 3) Evidence-based medicine ignores standard aspects of clinical training such as the physical examination.
    8. 8. What is the need? • Cost • Delay of "bench-to-bedside" research • Managing the primary literature • Counter misleading marketing • Dealing with conflicting results Why EBM?
    9. 9. What is the need? • Cost • Delay of "bench-to-bedside" research • Managing the primary literature • Counter misleading marketing • Dealing with conflicting results Why EBM? increasing pressure to • demonstrate effectiveness of interventions • utilize the most cost effective measures How do you know what really works or is the most cost effective?
    10. 10. Delay of "bench-to-bedside" research: Why EBM? Secondary Research Routine Clinical Practice Primary Literature Years-to-Decades
    11. 11. Delay of "bench-to-bedside" research: Why EBM? Secondary Research Routine Clinical Practice Primary Literature Thrombolytic Drugs for acute MI: 6 years from the first Systematic Reviews of RCTs until most review articles and textbooks recommended their use. (Antman, Lau, et al. JAMA 1992)
    12. 12. Delay of "bench-to-bedside" research: Why EBM? Secondary Research Routine Clinical Practice Primary Literature Aspirin after acute MI: Not recommended by expert opinion until 6 years after the first systematic review. (Antman, Lau, et al. JAMA 1992)
    13. 13. Delay of "bench-to-bedside" research: Why EBM? Secondary Research Routine Clinical Practice Primary Literature "Life Cycle of Translational Research" Median time from "initial discovery of a medical intervention" to a "highly cited article" was 24 years. (Contopoulos-loannidis, Alexiou, et al. Science 2008)
    14. 14. Managing the primary literature Why EBM? •MEDLINE adds 4500 records daily. •60,000 articles/yr from 120 journals •Just within their own fields, physicians would need to read 19 articles per day, 365 days per year, to keep up with research. (Oxford Center for EBM) •Not all (~10%) of these articles are considered high quality and clinically relevant. (Oxford) EBM helps you find the most appropriate article for a specific clinical question.
    15. 15. • Counter misleading marketing Why EBM? Pharmaceutical companies invest considerable resources to promote products based on skewed or selective evidence (or emotion appeals through direct-to-consumer advertising). EBM provides tools to help alert clinicians to potentially misleading marketing. (Glasziou, Hayes. The paths from research to improved health outcomes, Evidenced Based Nursing, 2005; 8(2):36-8.)
    16. 16. Dealing with conflicting results Why EBM? • Beta-blockers initially avoided after MI due to pathophysiologic reasoning that they would decrease compensatory sympathetic mechanisms • Later shown to decrease hospitalization & death:
    17. 17. Dealing with conflicting results Why EBM? • Based on 16 cohort studies (and some physiologic reasoning) HRT used to be recommended for postmenopausal women to reduce the risk of CHD. • Women’s Health Initiative show it actually increased the risk of MI, stroke, and venous thromboembolism:
    18. 18. Dealing with conflicting results Why EBM? • Since the 1960s, lidocaine was used for VF & VT prophylaxis in patients with acute MI. • A meta-analysis showed some reduction in VF & VT, but a probably increase in actual mortality:
    19. 19. Need of EBM for clinical pharmacologists? • Expert opinion regarding drug therapy during clinical rounds • Answering queries in drug information unit • Formulating local guidelines • Hospital medication policy • As a regulator • In pharmaceutical industry- identifying unmet medical needs and developing the drug development program • Devices/ diagnostics • Generating evidence
    20. 20. Animal Research / Lab studies Case Series/Case Reports Case Control studies Cohort studies Randomized Controlled Trial Systematic  Review Meta- Analysis
    21. 21. 1.  Construct a well-built clinical question and classify it into one category (therapy, diagnosis, etiology or prognosis) 2.  Find the evidence in health care literature 3.  Critically appraise or formally evaluate for validity and usefulness 4.  Integrate the evidence with patient factors to carry out the decision 5.  Evaluate the whole process
    22. 22. TYPES OF QUESTIONS 1. BACKGROUND QUESTIONS  Asked for general knowledge about a disorder  Has two essentials components:  a question root ( who, what, where, how, why) with a verb  a disorder  Textbooks answer background questions, they contain collected & synthesized wisdom for topics that do not change often.
    23. 23. 2. FOREGROUND QUESTIONS Asked for specific knowledge about managing patients with a disorder It has 4 components (PICO analysis): P - Patient/Population I - Intervention C - Comparison O - Outcome
    24. 24. Type of Question Suggested best type of Study Therapy RCT>cohort > case control > case series Diagnosis Prospective, blind comparison to a gold standard Etiology/Harm RCT > cohort > case control > case series Prognosis Cohort study > case control > case series Prevention RCT>cohort study > case control > case series Cost Economic analysis
    25. 25.  What is the primary problem, disease or co- existing conditions  On what groups do you want information     How would you describe a group of patients similar to the one in question     Sometimes age or sex of a patient may be relevant and should be included.
    26. 26.  What medical event do you want to study the effect of?     Which main intervention are you considering, prescribing a drug, ordering a test, ordering surgery. 27
    27. 27.  Compared to what?    Better or worse than no intervention at all or than another intervention?    What is the main alternative to compare with the intervention, are you trying to decide between two drugs, a drug and a placebo, or two diagnostic tests.   Sometimes there is no comparison 28
    28. 28.  What is the effect of the intervention?   What do you hope to accomplish, measure, improve, or affect with this intervention?    What are you trying to do for the patient, relieve or eliminate the symptoms, reduce side effects, reduce cost 29
    29. 29. 2. SEARCHING EVIDENCE My students are dismayed when I say to them, “Half of what you are taught as medical students will in 10 years have been shown to be wrong. And the trouble is , none of us knows which half” (Dr Sydney Burwell)
    30. 30. PRIMARY LITERATURE resources include articles and studies presented in peer-reviewed journals like NEJM, JAMA, Journal of Postgraduate Medicine, Lancet, BMJ, etc. SECONDARY LITERATURE is compiled by indexing and abstracting services that can be used to systematically locate various types of published literature. Different formats of secondary literature are available in the form of various databases like Medline, Cochrane Library, PubMed, National Library of Medicine Gateway, International Pharmacy Abstracts, Current Contents, and Toxline. TERTIARY LITERATURE is core knowledge established via primary literature or accepted as standard of practice within the medical community. The tertiary reference may consist of textbooks on various drugs or disease topics (e.g. Harrison's Principles of Internal Medicine), compendia (a vast array of information about many drugs such as the Physician's Desk Reference).
    31. 31. Some websites often used Evidence Based Medicines Review (www.ovid.com) Cochrane Library (update.cochrane.co.uk) MEDLINE (via www. ncbi.nlm.nih.gov/PubMed
    32. 32. 3: CRITICALLY APPRAISE THE EVIDENCE "Critically appraise" refers to determining the appropriateness of a some evidence (usually a journal article) for a particular clinical situation. Internal validity: Refers to the soundness of the research methodology • Does the study measure what it says it is measuring? • Related to efficacy: performance under ideal (or laboratory) conditions. Randomization – done or not ? Method of Randomization – Mentioned or not ? Blinding – Done or not ? Concealment of randomization – Done or not ? Were the groups similar at the start of the trial ? Follow up done or not? Were all enrolled patients included in the conclusion of the study? Intention to treat analysis (ITT)- Done or not?  Are the benefits worth the harm and cost?
    33. 33.  External validity:  Refers to generalizability of the results.  Related to effectiveness: How meaningful are the results in real life?  Will the results help your patient?  Were the study patients similar to your patient?  Three broad questions are use to critically appraise an article: 1. Are the results valid? 2. What are the results? 3. How can I apply these results to my patient? 34
    34. 34. • Compare the patient with those in the study (similar disease state and stage, similar baseline characteristics ) • Consider the patient’s baseline risk for the outcome of interest and other risks associated with therapy • Consider the patient’s values, beliefs, concerns and readiness for the intervention: 35
    35. 35.  Once the therapy is administered, evaluate the following - Did I formulate a focused question? - Did I use the most appropriate resource ? - Did the evidence work in my patient? - Reassess the strategy - Collaborate with your colleagues and professional bodies in developing practice guidelines 36
    36. 36. Assess the patient Clinical question that arises out of clinical examination Ask the patient Construct a well-built clinical question from the findings in step 1 Access information Appropriate resources need selected & searched for Appraise evidence Information gathered in step 3 critically appraised Apply findings Validated evidence integrated with clinical expertise & patient preferences Assess outcomes Performance of the evidence with the patient needs to be evaluated Add knowledge Information so gathered added to clinician’s knowledge base for future reference
    37. 37.  Minimizes the error in patient care  Reduces the cost of treatment  Optimizes the quality of patient care  Helps in advancement of knowledge and keeping pace with scientific progress 38
    38. 38.  Technology and online information resources must be available to the clinicians  Understanding of the epidemiological study designs and concepts of biostatistics is must  Attitude of the clinician. One must realize that clinical performance depends upon regular updating of knowledge and not merely on the years of clinical experience 39
    39. 39. Conclusion: What EBM is NOT These are some of the criticisms you will sometimes hear about evidenced based medicine. NOT... But it is... • "Cookbook" medicine • Rigid adherence to clinical guidelines • Managed care • Cost-cutting measures A rigorously systematic way to: • Evaluate the strength of available evidence • Evaluate the appropriateness of available evidence for a particular clinical situation • A way to avoid waste by considering both the efficacy and effectiveness of a particular intervention in a particular clinical setting.
    40. 40. Conclusion: What EBM is NOT NOT... But it is... The same thing as • clinical epidemiology • biostatistics • study design Build on these concepts so you can better understand the strength of inferences from available evidence. Limited to Randomized Controlled Trials Recognition that: • Some study designs (esp. RCTs) are less susceptible to bias than others, and therefore less likely to mislead. • RCTs are not always available (or are of poor quality) but other evidence can (and should) be used in clinical decision making as long as you understand its limitations.
    41. 41. 42
    42. 42. 1. Sackeit DL. Evidence based medicine: what it is and what it isn't. BMJ 1996. Vol 312: 71-72. 2. Sackett DL, Haynes RB. 13 steps, 100 people, 1,000,000 thanks. Evid Based Med 1997;2:101–102. 3. Rajashekhar HB, Kodkany BS, Naik VA, Kotur PF, Goudar SS. Evidence Based Medicine And Its Impact On Medical Education. Indian J. Anaesth. 2002; 46 (2) : 96-103. 4. Giacomini MK, Cook DJ. Users’ guides to the medical literature: XXIII. Qualitative research in health care. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA 2000;284:357–362. 5. Selvaraj S, Kumar y, Elakiya M, Saraswathi C, Balaji D, Nagamani P, et al. Evidence-based medicine - a new approach to teach medicine: a basic review for beginners. Biology and Medicine 2010; Vol 2 (1): 1-5.
    43. 43. You are a second year resident posted in D.I.U. You receive a call from emergency medical department of your hospital. The resident there had received a case of organophosphate poisoning a day ago. The patient was critical at the time of admission. The resident tried her best and managed the patient with atropine and supportive measures. The patient did not survive. Their case will be discussed in a statistical meet. Their Unit is worried that the people from other units will criticize this management. She wants your help and needs to know what are the chances a timely use of pralidoxime could have saved the patient. Situation
    44. 44.  What are the compounds causing organophosphorous poisoning?  What are the treatment options for OP?  Etc ……
    45. 45.  P- Any patient presenting with acute OP  I- Pralidoxime treatment  C- Placebo  O – Mortality THE QUESTION: Will pralidoxime treatment decrease the mortality in patients presenting with acute organophosphorous poisoning?
    46. 46.  Books  Internet Resources  Pubmed  Medline  Google scholar  MD Consult
    47. 47.  235 patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo
    48. 48.  Randomisation – done  Method of Randomisation - Mentioned  Concealment of randomisation – Done  Blinding – Done  Intention to treat analysis (ITT)- Done  Reasons for withdrawal - none
    49. 49.  EER= 30/121=.248  CER= 18/114= .158  RR= .248/.158=1.567  RRI= .248-.158/.158=.5696  ARI= .248-.158=.09  NNH= 1/.09=11
    50. 50.  Out of every 11 patients treated with pralidoxime, 1 will die.  Hence the resident was right in not treating the OPP patient with pralidoxime.