Evidence Based Neurology

Evidence Based Neurology Maurizio A. Leone Neurologic Clinic University Hospital “Maggiore della Carità”, Novara, Italy I International Course on Neuroepidemiology in Eastern Europe, Chisinau, Moldova. September 24-28, 2012

The need for EBM • What is EBM ? • The story • How can I practice EBM ? • What are the “products” of EBM ? • Limitations of and criticisms to EBM

On the need of Evidence Based Medicine Few medical decisions are based on evidence

Why do we need RANDOMIZED CONTROLLED TRIALS ? In the early1980s newly introduced antiarrhythmics were found to behighly successful at suppressing arrhythmias. Notuntil a RCT was performed was it realized that, althoughthese drugs suppressed arrhythmias, they actually increasedmortality. The CAST trial revealedExcess mortality of 56/1000. By the time the results of this trial were published, at least100,000 such patients had been taking these drugs.

Caveat • Many medical decisions are taken on the basis of: • etiopathogenetic theories • experience • other factors (pharma industry, other interests, ideology…)

Probability of a result favouring study drug in industry-sponsored trials OR = 4.05 (2.98-5.51)

On the need of Evidence Based Medicine Few medical decisions are based on evidence Deterioration of knowledge after graduation

Performance deteriorates …. 1. Level of blood pressure. 2. Patient’s age. 3. The physician’s year of graduation from medical school. 4. The amount of target-organ damage. Determinants of the clinical decision to treat some, but not other, hypertensives:

On the need of Evidence Based Medicine Few medical decisions are based on evidence Deterioration of knowledge after graduation Delay in transferring results from research to clinical practice

Systematic review of bed rest after spinal tap 10 trials of bed rest after spinal puncture no change in headache with bed rest Increase in back pain Protocols in UK neurology units - 80% still recommend bed rest after LPSerpell M, BMJ 1998;316:1709–10 …evidence of harm available for 17 years preceding... Allen, Glasziou, Del Mar. Lancet, 1999

On the need of Evidence Based Medicine Few medical decisions are based on evidence Deterioration of knowledge after graduation Delay in transferring results from research to clinical practice Limited resources

Information epidemic: how to keep up-to-date ? MEDLINE 2010 2,000 articles / day approx 75 new trials published every day Bastian, Glasziou, Chalmers (2010) 75 Trials and 11Systematic Reviews a Day: How Will We Ever Keep Up? PLoS Med 7(9)

Median minutes/week spent reading about my patients (self report): Medical Students: 90 minutes House Officers: 0 (up to 70%=none) Senior House Officers: 20 (up to 15%=none) Registrars: 45 (up to 40%=none) Senior Registrars 30 (up to 15%=none) Consultants: Grad. Post 1975: 45 (up to 30%=none) Grad. Pre 1975: 30 (up to 40%=none)

The need for EBM What is EBM ? The story How can I practice EBM ? What are the “products” of EBM ? Limitations of and criticism to EBM

Evidence (from Latin “evidentia”) In Italian (Rumanian-Moldovan): Anything that is clear and obvious, that doesn’t need any further demonstration In English: The available body of information indicating whether a belief or a proposition is true or valid (= proof, testimony, sign).

‘Background’ Questions • About the disorder, test, treatment, etc. 2 components: a. Root*+ Verb: “What causes …” b. Condition: “… stroke?” • * Who, What, Where, When, Why, How

Background learning:basic neurosciences, neuroanatomy, neurophysiology, neuropharmacology, amd neuropathology Foreground learning:Clinical decision-making, history taking, examining, diagnosing, and therapeutic intervening.

Evidence-Based Medicine:The Practice Translation to an answerable question (patient/manoeuvre/outcome). Efficient track-down of the best evidence Critical appraisal of the evidence for its validity and clinical applicability Integration of that critical appraisal with clinical expertise and the patient’s unique biology and beliefs. Evaluation of one’s performance.

Dave Sackett Evidence-based Medicine: the story Pierre Charles Alexandre Louis (Paris, 1830): “A true science is merely a summary of facts which have no value unless they are expressed in numbers ... The statistics represent the only and fundamental basis of all the medical studies ‘. He was the promoter of “La Societé d’Observation Medicale”, a cultural movement supporting the concept that knowledge about a disease, its history, clinical presentation and treatment, could be derived from aggregated patient data rather than from individual experience. Archibald Cochrane (1972): “It is surely a great criticism of our profession that we have not organized a critical summary, by specialty or subspecialty, adapted periodically, of all relevant randomized controlled trials.” 1981: (McMaster Medical School, Canada): “How to read clinical journals", a series of articles describing the strategies of critical approach to the biomedical literature. These articles are among the top reprinted in the history of biomedical literature. 1986: The focus of Sackett and coll. gradually moves from "how to read the biomedical literature" to "how to use the biomedical literature to solve clinical problems."

1993 JAMA: first article of the movement of Evidence-Based Medicine 1993: founding of the Cochrane Collaboration, an international network to “prepare, update and disseminate systematic reviews of controlled trials on the effects of health care and, where there is no controlled trials, systematic reviews of existing evidence, however.” http://www.cochrane.org

Review Groups • Back • Consumers and communication • Dementia & cognitive improvement • Incontinence • Infectious diseases • Injuries • Movement disorders • Multiple sclerosis • Muskuloskeletal • Musculoskeletal injuries • Neuromuscular disease • Pain, palliative and supportive care • Drugs and alcohol • Epilepsy • Eyes and vision • Stroke

Evidence-Based Medicine:The Practice Translation to an answerable question (patient/manoeuvre/outcome). ????

Structure of the clinical question Courtesy of Luca Vignatelli

Structure of the clinical question

Components: PICO(T) • Population • Intervention • Control • Outcome • T (Time) Formulate a research question that can be answered Can coffee reduce daytime drowsiness? Intervention Population In healthy adults engaging in normal activity, does coffee reduce daytime drowsiness compared with de-caffeinated coffee? Outcome Control

Evidence-Based Medicine:The Practice Translation to an answerable question (patient/manoeuvre/outcome). Efficient track-down of the best evidence

Traditional information instruments • The expert (colleague):lack of obiectivity and completeness of information. • Medical books (printed):often incomplete, outdated, lack of quantitative data. Selection of scientific evidence is not systematic neither explicit; generally organized by disease and not by clinical presentations. • Journals:too many, fragmentation of topics, rarity of definitive studies to be transferred to clinical practice.Traditional (narrative) reviews:same methodological shortcomings of the medical books: selection bias, self-quotation and harmony with the opinion of the author.Randomized Clinical Trials (RCTs):difficult to adapt their results to the individual patient. Selected populations, complex patients excluded. Ideal world and peculiar competence and motivation of doctors. Often surrogate rather than clinically significant end-points, often relative and not absolute (NNT) measures are reported.

GUIDELINES / HTA SECONDARY LITERATURE PRIMARY LITERATURE CLINICAL STUDIES Pyramid of the production of medical literature Courtesy of Luca Vignatelli

DATA-BANKS OF GUIDELINES / HTA SECONDARY DATA-BANKS PRIMARY DATA-BANKS RCTs DATA-BANKS How to organize the search of evidence in the literature

Clinical research, synthesis of studies and recommendations Primary Studies Results of research Sinthesis . . . . . . Systematic Reviews Meta-analyses . . . . . . . . . . . . . . . . . . . . . . . .       HealthTechnology Assessments (HTA)Guidelines Recommendations

Evidence-Based Medicine:The Practice Translation to an answerable question (patient/manoeuvre/outcome). Efficient track-down of the best evidence Critical appraisal of the evidence for its validity and clinical applicability We needn’t always carry out all 5 steps to provide E-B Care

Guidelines are: Recommendations of clinical practice, produced through a systematic process, to assist physicians and patients in deciding which are the most appropriate method of care in specific clinical circumstances.

Aims of the guidelines To ensure the highest degree of appropriateness of the interventions, reducing the possible variability in clinical decisions (due to lack of knowledge and subjectivity in the definition of strategies of care).

Basic methodological elements Multidisciplinarity Use of systematic reviews Explicit evaluation of quality of evidence Strenght of recommendations

Requirements of a guideline Validity Reproducibility Representativeness Applicability Flexibility Clarity Documentation Update

Who produce guidelines? National and Regional Agencies Scientific Societies (EFNS,….) Research Institutions Ad hoc Associations ..

Where to find guidelines?

The quality of evidence (levels of evidence) depends on: Appropriatness of study design Quality of study conduction and analysis Effect size Appropriatness and relevance of outcomes The strength of a recommendation reflects the extent to which we can, across the range of patients for whom the recommendations are intended, be confident that desirable effects of a management strategy outweigh undesirable effects.

EFNS Guidelines: classes of evidence • Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required: • (a) randomization concealment • (b) primary outcome(s) is/are clearly defined • (c) exclusion/inclusion criteria are clearly defined • (d) adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias • (e) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences • Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e • Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment • Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion

EFNS Guidelines: rating of recommendations • Level A: (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies • Level B: (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence • Level C: (possibly effective, ineffective, or harmful) rating requires at least two convincing class III studies

Grades of Recommendation Assessment, Development and Evaluation

Evidence Based Neurology