Slayt 1

Introduction to Evidence-Based Medicine

Prof. Dr. R. Erol Sezer

Books:

Straus SE, Glasziou P, Richardson WS, Haynes RB. Evidence-based medicine: how to practice and teach it. Fourth Edition 2011. Churchill Livingstone Elsevier.

Glasziou P, Del Mar C, Salisbury J. Evidence-based Practice Workbook. BMJ Books, Blackwell Publishing, 2007.

Mayer D. Essential Evidence-based Medicine. Second Edition 2010. Cambridge University Press.

R. Brian Haynes, David L. Sackett, Gordon H. Guyatt, and Peter Tugwell. Clinical Epidemiology: How to do clinical practice research. Third edition, 2006. Lippincott Williams & Wilkins.

Howick J. The philosophy of evidence-based medicine. 2011, Blackwell Publishing Ltd.

Greenhalgh T. How to read a paper: the basics of evidence-based medicine. Fourth edition, 2010.BMJ Books

Turkish National Medical Education Accreditation Board (UTEAK)

NATIONAL STANDARDS FOR UNDERGRADUATE MEDICAL EDUCATION

2.4. Inclusion of courses/activities on principles of scientific methodology and evidence-based medicine in the curriculum BS.2.4.1. The curriculum must include scientific methodology courses and implementations to improve analytical and critical thinking skills of the students

DS.2.4.1. Evidence-based medicine practices should take part in undergraduate medical education curriculum.

BS: Basic standardDS: Development standardLearning Outcomes/ Competences for Undergraduate Medical Education in Europe, The Tuning Project (Medicine)

Graduates in medicine will have the ability to: apply the principles, skills and knowledge of evidence-based medicineEvidence-based medicine (EBM) has been defined as the conscientious, explicit, and judicious use of the best evidence in making decisions about the care of individual patients

http://ebm.mcmaster.ca/documents/how to teach ebcp workshop brochure 2009.pdf7EBM requires the integration of the best research evidence with ourclinical expertise and our patients unique values and circumstances.

Straus SE, Glasziou P, Richardson WS ,Haynes RB. Evidence-based medicine: how to practice and teach it. Fourth Edition 2011. Churchill Livingstone Elsevier.By best evidence we mean research findings from clinically relevant research, especially from patient-centered (or patient oriented) research.

(Not from disease oriented research) Evidence means grounds for belief .The flecainide story:Glasziou P, Del Mar C, Salisbury J. Evidence-based Practice Workbook. BMJ Books, Blackwell Publishing, 2007...In 1979 the developer of the defibrilator, Bernard Lown, pointed out in an address to the American College of Cardiology that one of the biggest causes of death was heart attack, particularly among young andMiddle-aged men (20-64 year olds). People had a heart attack, developed arrythmia, and died from arrythmia..He suggested that a safe and long acting antiarrythmic drug that protects against ventricular fibrilation would save millions of lives.

In fact in an article published in 1977 ventricular premature depolarizations were reported to be a risk factor for sudden death and nonsudden cardiac death after myocardial infarction.Ruberman et al. Ventricular premature beats and mortality after myocardial infarction. NEJM 1977;297:750-757In response to the challenge expressed by Albert Lown, a paper was published in 1981 in the NEJM introducing a new drug called flecainide.

(Anderson JL. Oral flecainide acetate for treatment of ventricular arrhythmia. NEJM 1981;305:473-477)The paper described a study in which patients who had just had heart attack were randomly assigned to groups to receive either a placebo or flecainide and were then switched from one group to the other (a cross-over trial).

..The researchers counted the number of premature ventricular contractions (PVCs) as a measure of arrythmia.

The results can be seen in the following figure:

Anderson JL. Oral flecainide acetate for treatment of ventricular arrhythmia. NEJM 1981;305:473-477PVCs/12 hours Effects of flecainide and placebo on number of premature ventricular contractions (PVCs) among nine patients who had just had heart attack (Each line represents one patient)The patients on flecainide had fewer PVCs than patients on placebo. When the flecainide patients were crossed over to the placebo treatment, the PVCs increased again.

Conclusion was straightforward: flecainide reduces arrythmias (PVCs). Therefore people who have had heart attack should be given flecainide.After the results were published flecainide was approved by the US Food and Drug Administration and became fairly standard treatment for heart attack.Several years laterThe Cardiac Arrhythmia Suppression Trial (CAST) designed to test whether the suppression of asymptomatic or mildly symptomatic ventricular arrhythmia with the drug flecainide after myocardial infarction would reduce mortality started to recruit patients in june 1987.It was a multicenter , randomized, placebo controlled clinical trial

(or briefly a randomized control trial RCT)Recruitment of study subjects (inclusion and exclusion criteria ) was described in the study protocol:

..patients were eligible for enrolment six days to two years after myocardial infarction if they had an average of six or more ventricular pramature depolarizations per hour on ambulatory electrocardiographic monitoring of at least 18 hours duration

All of the following rules for a valid RCT study were implemented

Was the assignment of patients to treatments randomised?Was the randomization concealed ?Were the groups similar at the start of the trial?Was follow-up of patiens sufficiently long and complete?

Were all patients analyzed in the groups to which they were randomized?Were patients, clinicians and study personnel kept blind to treatment?Were the groups treated equally, apart from the experimental therapy?Recruitment was planned to last three years from June 1987 to June 1990

However, in April 1989 the Data Monitoring Committee(DMC) sometimes called Data and Safety Monitoring Board(DSMB) terminated the flecainide trial.(An independent group of experts who monitor patient safety and treatment efficacy data while aclinical trialis ongoing. There are typically three reasons a DMC might recommend termination of the study: safety concerns, outstanding benefit, and futility.)

Because:

Cardiac arrhythmia suppression trial GnEcht DS et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. Cardiac Arrhythimia Supression Trial. NEJM 1991;324:781-788.% Alivethe number needed to harm (NNH), is the number of patients that one would need to expose to a risk factor before an additional patient is harmed by side effects of the treatment. To calculate NNH one must first calculate the absolute risk reduction (ARR). The ARR is the absolute difference of the event rates of the two groups being compared (|EER CER|)

Experimental event (death) rate =13/100Control event (death) rate:3/100AAR = (13/100) (3/100)= 10/100NNH = 1/ (10/100) =10

When 100 patients receive the drug 10 additional patient will die because of using it.

It means:One additional patient will die just because of receiving the drug when 10 patients use it.The NNT (Number needed to treat) is the number of patients that must be treated with the proposed therapy in order to have one additional successful result. To calculate NNT one must first calculate the absolute risk reduction (ARR).

NNT=1/ ARRThe concepts of NNT and NNH help physicians balance the benefit and risk of therapy.Over the 18 months following treatment, more than 10% of people who were given flecainide died, which was almost triple the rate of deaths among the placebo group.Despite a perfectly good mechanism for the usefulness of flecainide (it reduces arrhythmias), the drug was clearly toxic and, overall, did more harm than good.

By the time results of this trial were published, at least 100 000 such patients had been taking this drug.

We can not rely on pathophysiologic (mechanistic) reasoning and evidence.This type of evidence is also described as disease oriented evidence (DOEs).

Best evidence regarding interventions comes from randomized controlled trials focusing on patient-centered (or patient oriented) outcomes such as mortality, quality of life , survival, cure. This type of evidence is also described as patient oriented evidence that matters (POEMs)It was shown that many widely used therapies that had been adopted based on lower form of evidence (coming from expert opinion and/or pathophysiologic reasoning) proved to be useless when subjected to randomized trials.Jeremy howick states in his book (The philosophy of evidence-based medicine. 2011, Blackwell Publishing Ltd)

The EBM philosophy of evidence is best expressed in the EBM hierarchies The idea behind the many different hierarchies can be summed up quite simply with three central claims:

1. Randomized trials or systematic reviews of many randomized trials generally offer stronger evidential support than observational studies (cohort studies, case-control studies, case series, cross-sectional studies).2. Comparative clinical studies in general including both randomized clinical trials and observational studies offer stronger evidential support than mechanistic reasoning (pathophysiologic rationale) from more basic sciences.3. Comparative clinical studies in general including both randomized clinical trials and observational studies offer stronger evidential support than expert clinical judgementEvidence from animal studies can not be relied on regarding helpful effects, however it may provide very important information regarding harm. All known human carcinogens that have been studied adequately for carcinogenicity in experimental animals have produced positive results in one or more animal species (Wilbourn et al., 1986; Tomatis et al., 1989). ..By clinical expertise we mean the ability to use our clinical skills and past experience to rapidly identify each patients unique health state and diagnosis, their individual risks and benefits of potential interventions, and personal values and expectations.Straus SE, Glasziou P, Richardson WS ,Haynes RB. Evidence-based medicine: how to practice and teach it. Fourth Edition 2011. Churchill Livingstone Elsevier.

By patient values we mean the unique preferences, concerns and expectations each patient brings to a clinical encounter and which must be integrated into clinical decisions if they are to serve the patient.Straus SE, Glasziou P, Richardson WS ,Haynes RB. Evidence-based medicine: how to practice and teach it. Fourth Edition 2011. Churchill Livingstone Elsevier.By patient circumstances we mean their individual clinical state and the clinical setting.Straus SE, Glasziou P, Richardson WS ,Haynes RB. Evidence-based medicine: how to practice and teach it. Fourth Edition 2011. Churchill Livingstone Elsevier.

The complete practice of EBM comprises five steps:

Step 1-Formulating an answerable clinical question:

Converting the need for information (about prevention, diagnosis, prognosis, therapy, causation) into an answerable question.

Step 2- Searching the available evidence :

Tracking down the best evidence with which to answer that question.Step 3: Critically appraising that evidence for its validity (closeness to the truth), impact (size of the effect), and applicability (usefulness in our clinical practice)

Step 4: Integrating the critical appraisal with our clinical expertise and with our patients unique biology, values and circumstances.Step 5: Evaluating our effectiveness and efficiency in executing steps 1-4 and seeking ways to improve them both for the next time.EBM practice begins and ends with patients.

It is a new paradigm to provide the best possible care to patients

It is a new paradigm for lifelong learning in medicineEvidence-based medicine(EBM) is also calledevidence-based health care(EBHC) orevidence-based practice(EBP) to broaden its application from medicineto theallied health professions.

Evidence-based health service is the practice of evidence-based medicine at the organizational or institutional level. Emergence of EBM Early Pioneers

Archie Cochrane (UK, 1909-1988)

David Sackett: (1934- )

David Sackett: (1934- )

He founded the first department of Clinical Epidemiologyin Canada atMcMaster University, and the Oxford Centre for Evidence-Based Medicine.He is well known for his textbooksClinical Epidemiology and Evidence-Based Medicine.

In the early 1990s he and his colleagues at McMaster University coined the term Evidence-based medicineA 1955 clinical trial report that changed David Sacketts career

Archie Cochrane (UK, 1909-1988)He said in 1972 many standards of care were found to be ineffective.he suggested that because resources would always be limited, they should be used to provide equitably those forms of health care which had been shown in properly designed evaluations to be effective. In particular, he stressed the importance of using evidence from randomised controlled trials because these were likely to provide much more reliable information than other sources of evidence..

In 1979 he wrote, "It is surely a great criticism of our profession that we have not organised a critical summary, by specialty or subspecialty, adapted periodically, of all relevant randomised controlled trials. His challenge led to the establishment during the 1980s of an international collaboration to develop theOxford Database of Perinatal Trials.

In 1987, the year before Cochrane died, he referred to a systematic review of randomised controlled trials (RCT's) of care during pregnancy and childbirth as "a real milestone in the history of randomised trials and in the evaluation of care", and suggested that other specialties should copy the methods used. His encouragement, and the endorsement of his views by others, led to the opening of the first Cochrane centre (in Oxford, UK) in 1992 and the founding of The Cochrane Collaboration in 1993.

The Cochrane CollaborationMottoWorking together to provide the best evidence for health careFormation1993TypeInternational NPOPurpose/focusIndependent research into data about health careHeadquartersOxford, EnglandRegionservedWorldwideOfficiallanguagesEnglishSteering Group Co-ChairsJeremy Grimshaw,Jonathan CraigVolunteersOver 28,000 as of 2011Websitewww.cochrane.org

Claridge AC et al. History and development of Evidence-based Medicine. World J Surg. 2005:29:547-53 Number of papers on MEDLINE per year with keywords evidence-based medicine

Glasziou P et al. Evidence-based Practice Workbook. Second edition, BMJ Books/Blackwell Publishing. 2007 Number of randomized controlled clinical trials by year..Surveys conducted among clinicians from various disciplines have found that clinicians are interested in learning the necessary skills for practicing EBM. One survey of the UK GPS suggested that many clinicians already practice in the using mode, using evidence based summaries generated by others (72%), EBP.. guidelines (84%), Far fewer claimed to understand..the appraising tools of NNTs(35%), and confidence intervals (CIs) (20%).

Straus SE, Glasziou P, Richardson WS ,Haynes RB. Evidence-based medicine: how to practice and teach it. Fourth Edition 2011. Churchill Livingstone Elsevier.

Step 1

Formulating an anwerable foreground clinical question

Evidence-based medicine gives you a method to find answers to research answerable foreground questions that arise in daily clinical work.Foreground questions concern specific knowledge that could directly inform one or more clinical decisions we will make with our patients during clinical practice.Main types of foreground questions that arise in clinical practice

Therapy: How to select treatments to offer our patients, that do more good than harm and that are worth the efforts and costs of using them. Aetiology and risk factors: What causes the problem.

Prevention: How to reduce the risk of a disease and how to diagnose disease early by screening

Prognosis: How to estimate our patients likely clinical course over time and anticipate likely complications of the disorder

Diagnostic tests: how to select and interpret diagnostic testsA clinical question you have in mind during a patient encounter can be divided into four components. Dissecting the question into its component parts and restructuring it so that it is easy to find the answers is an essential first step in EBP. This restructured problem is called a PICO (pee-co) question.Population and clinical Problem: P

Intervention (or indicator or Index test): I

Comparison / Control: C

Outcome of clinical importance: O

Population and clinical problem or Pshows who the relevant people are in relation to the clinical problem that you have in mind.

Intervention (or indicator or index test) shows the management strategy or exposure or test you want to find out

Intervention: A procedure (such as drug treatment, surgery, diet)

Indicator: exposure to an harmful agent or a factor that might affect a health outcome

Index test: A diagnostic test or a screening test

Comparator: This shows an alternative or control strategy, exposure or test foe comparison with the one you are interested in.

Outcome: This shows what you are most concerned about happening (or stopping happening AND/OR what the patient is most concerned about. The 6S hierarchy of organization of pre-appraised evidence

Systems: Computerized decision supportSummaries: Evidence-based digital textbooks (eg, UpToDate, ACP Med, CE, PIER, UTD, Dynamed) Synopses of syntheses: Evidence-based journal abstracts (eg, ACPJC, EBM, EBN, DARE)Syntheses: Systematic reviews (eg, ACPJC, EvidenceUpdates, Cochrane)Synopses of studies: Evidence-based journal abstractsStudies: Original journal articles (eg, ACPJC,EvidenceUpdates)

Evidence-based digital textbooks:

ACP Med: American College Of Physicians MedicineCE: Clinical EvidencePIER: Physicians Education and Information ResourceUpToDateACP Journal ClubDatabase of Reviews of EvidenceEvidence-Based MedicineEvidence-Based Nursing

The British doctor Richard Asher noted in one of his essays for doctors:

If you can believe fervently in your treatment, even though controlled tests show that it is quite useless, then your results are much better, your patients are much better, and your income is much better, too.