复旦大学：《循证医学》课程教学资源（教材教案）循证医学各章教案及相关文献.pdf_大学文库

】Comment Evidence-based medicine in China Inrecent decades,evidence-based medicine has been Medical associations in every discipline have built clinical guidelines for common diseases according to Evid inf making an Joumal of Evidence-Based Pediatrics were launched in traditional chinese medicine have been established and 2001-06.Several organisations developed programmes the rigour of traditional medicine has been gradually to strengthen a national culture of evidence-based raised.The Chinese clinical trial registry was established ng th in 2007 and the number of clinical trials registered in of the a isincreasing (figure). of the in China First access to scientific evidence is not equal in all regions. Cochrane Centre (which became the 14th centre of Doctors from developed areas and large cities.such as the Internationa Cochrane Collaboration in 1999), Shanghai and Beijing,can search the literature for free Ministry of Ed cation's virtual research centre o t their university via databa es such as Me dline.Bu 4,and e areas might no be ar h nanised in 2003 mited kn nt use of the The board members of these organisations are located best evidence in their practice all around China,and have sought to disseminate Second.most of the world's dinical evidence does knowledge of evidence-based medicine throughout the ot come from China.Few results from China hav Usually 1-3 mont been indu uing educati epidemi in The New England oumal of Medicine The lance medicine have become compulsory curricula fot medical and lAMA How ever,only 0-21%of these were from students and dinical postgraduates in all universities. mainland China. Wu and colleaques'analysec randomised trials on 20 common diseases p n China's natural know ure 450 19 that only eview criteria)fre ical analy are also found in Chinese medical journals,which reduces the credibility of the evidence Third,becaus of a lack of fu nding for ir estigator-lec mo good ese clinic are ph y to ha 100- outcomes that favour the nonsor's product which could result in publication bias.>Finally.although the 2000 200 2005 2006 3007 2008 Chinese Government has made research into traditiona medicine a prionty area and randomised trals hav e 第10页第2页

Comment 532 www.thelancet.com Vol 375 February 13, 2010 Evidence-based medicine in China In recent decades, evidence-based medicine has been propagated rapidly in China, not only to doctors but also to nurses and other health-care professionals. The Chinese Journal of Evidence-Based Medicine, the Journal of Evidence-Based Medicine, and the Chinese Journal of Evidence-Based Pediatrics were launched in 2001–06. Several organisations developed programmes to strengthen a national culture of evidence-based medicine, including the clinical epidemiology committee of the Chinese Medical Association (established in 1993) working with the Chinese Clinical Epidemiology Network (ChinaCLEN; registered as part of the International Clinical Epidemiology Network in 1989),1 the Chinese Cochrane Centre (which became the 14th centre of the International Cochrane Collaboration in 1999),2 the Ministry of Education’s virtual research centre of evidence-based medicine founded in 2004, and the China Medical Doctor Association’s evidence-based medicine committee organised in 2003.3 The board members of these organisations are located all around China, and have sought to disseminate knowledge of evidence-based medicine throughout the country. Programmes (usually 1–3 months) organised by the Ministry of Education, continuing education programmes, and online education programmes are available. Clinical epidemiology and evidence-based medicine have become compulsory curricula for medical students and clinical postgraduates in all universities. Medical associations in every discipline have built clinical guidelines for common diseases according to the evidence to inform clinical decision making and teaching. Evidence-based medicine has also engaged with traditional Chinese medicine. Research teams in traditional Chinese medicine have been established and the rigour of traditional medicine has been gradually raised. The Chinese clinical trial registry4 was established in 2007 and the number of clinical trials registered in China is increasing (fi gure).5 There are, however, several concerns about the develop ment of evidence-based medicine in China. First, access to scientifi c evidence is not equal in all regions. Doctors from developed areas and large cities, such as Shanghai and Beijing, can search the literature for free at their university via databases such as Medline. But doctors in remote areas might not be able to access the best information resources, which, together with a limited knowledge of English, could prevent use of the best evidence in their practice. Second, most of the world’s clinical evidence does not come from China. Few results from China have been included in systematic reviews6 or clinical practice guidelines. I calculated that from 1999 to 2008, 1880 clinical research articles were published in The New England Journal of Medicine, The Lancet, and JAMA. However, only 0·21% of these were from mainland China.7 Wu and colleagues8 analysed randomised trials on 20 common diseases published in China’s natural knowledge infrastructure database from 1994 to 2005, and found that only 7% of them met methodological criteria (according to Cochrane review criteria). Frequent errors in statistical analyses are also found in Chinese medical journals,9 which reduces the credibility of the evidence. Third, because of a lack of funding for investigator-led randomised trials, most good-quality Chinese clinical trials are pharmaceutical premarketing trials sponsored by drug companies. Such research is more likely to have outcomes that favour the sponsor’s product, which could result in publication bias.10 Finally, although the Chinese Government has made research into traditional medicine a priority area and randomised trials have shown effi cacy for some traditional therapies, because of the low methodological quality of trials and selective 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year 50 100 150 200 250 Numbers 300 350 400 450 500 Phase 1/2 Phase 3 Phase 4 Randomised trials Observational studies Total Figure: Growth in clinical trials in China We searched ClinicalTrials.gov5 on June 15, 2009, with the term “lead principal investigator/sponsor=China”. ㄀义第 2 页

Comment www.thelancet.com Vol 375 February 13, 2010 533 Fomenting a prevention revolution for HIV 2010 heralds the year set by the UN to achieve universal access to HIV prevention, treatment, care, and support.1 Despite major achievements and heroic eff orts over the past decades by people living with HIV to assert their rights for treatment equity, to end stigma and discrimination, and to ensure more inclusive approaches to governing the response, much remains to be done. 80 countries still criminalise homosexuality.2 People living with HIV face restrictions on entry, stay, and residence in some 57 countries.3,4 About 10 million people are currently denied access to lifesaving treatment. Despite, or perhaps because of, its success, the AIDS response has itself come under attack.5,6 Coalitions of social conservatives have orchestrated a global campaign against condom promotion and supported legislation criminalising same-sex relations.7 Such actions increase stigma and isolate people most at risk of HIV at a publication of positive results, the effi cacy of most traditional therapies is uncertain.11 Several factors might contribute to this situation. Most active clinical researchers and physicians have little formal training in research methods.12 Even the editors and peer reviewers of Chinese medical journals do not know or ignore reporting criteria, such as CONSORT, STROBE, STARD, and PRISMA.13 Preclinical trial registration has not been essential for publication, even though registration results in trials that are more rigorous, effi ciently conducted, and ethically sound.14 To counter these problems, I have several suggestions. Clinical researchers in China should be formally trained and accredited in clinical trial methodology. Reporting guidelines have been translated into Chinese and published partly in Chinese,15 and are now available online.1,7 Researchers need to improve study design by adopting the advice in relevant reporting guidelines to reduce bias. National level platforms need to be established for consultation and administration of multicentre clinical trials. Journal editors must require documentation of ethics approval and clinical trial registration before manuscript acceptance. Journals in China that are members of the ICMJE16 should obey international criteria for publication. Finally, the Chinese Government should increase its support of clinical research, in the form of clinical research grants for physicians, the creation of national repositories of clinical cases and samples of serum and tissues, and fi nancial support for universities in remote areas to buy literature databases. There is a long way to go before the words of a Lancet Editorial—“China has the opportunity to lead the world not only in research quantity, but also in quality”17—are fulfi lled. Jiyao Wang Department of Internal Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China wang.jiyao@zs-hospital.sh.cn I am: president of ChinaCLEN; chair of the Clinical Epidemiology Committee of the Chinese Medical Association; vice chair of the Society of Evidence-Based Medicine, Chinese Medical Doctor Association; a board member of the Ministry of Education’s virtual research centre of evidence-based medicine; and a member of the Board of Trustees, INCLEN. I thank Xue-juan Jin for collecting information to make the fi gure. 1 China Clinical Epidemiology Network. http://www.chinaclen.org.cn (accessed Dec 13, 2009). 2 Chinese Cochrane Centre. http://www.hxyx.com/cochrane_new (accessed Oct 12, 2009) (in Chinese). 3 Chinese Medical Doctor Association. http://www.cmda.gov.cn (accessed Oct 12, 2009) (in Chinese). 4 The Chinese Clinical Trial Register. http://www.chictr.org (accessed Dec 14, 2009). 5 ClinicalTrials.gov. http://www.clinicalTrials.gov (accessed June 15, 2009). 6 Straus SE, Richardson WS, Glasziou P, Haynes RB. Evidence-based medicine: therapy, 3rd edn. London, UK: Elsevier, 2005. 7 Wang JY. Follow international reporting guidelines to raise the quality of articles about clinical research in China (Commentary). Chung Hua Hsiao Hua Tsa Chih 2010; 30: 1 (in Chinese). 8 Wu T, Li Y, Bian Z, Liu G, Moher D. Randomized trials published in some Chinese journals: how many are randomized? Trials 2009; 10: 46. 9 He J, Jin Z, Yu D. Statistical reporting in Chinese biomedical journals. Lancet 2009; 373: 2091–93. 10 Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167–70. 11 Tang J-L, Liu B-Y, Ma K-W. Traditional Chinese medicine. Lancet 2008; 372: 1938–40. 12 Schulz KF, Grimes DA. The Lancet handbook of essential concepts in clinical research. Philadelphia, PA, USA: Elsevier, 2006. 13 EQUATOR Network. Enhancing the quality and transparency of health research. http://www.equator-network.org (accessed Dec 13, 2009). 14 Yu H, Liu JP. A review of international clinical trial registration. Zhong Xi Yi Jie He Xue Bao 2007; 5: 234–42 (in Chinese). 15 Wang J, Gluud C, eds. Evidence based medicine and clinical practice, 2nd edn. Appendix 3 and 5. Beijing, China: Science Publisher, 2006: 383–87. 16 International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. http://www.icmje.org (accessed Dec 13, 2009). 17 The Lancet. Reforming research in China. Lancet 2007; 369: 880. ㄀义第 3 页

JAMA CLASSICS CELEBRATING 125 YEARS Progress in Evidence-Based Medicine SUMMARY OF THE ORIGINAL ARTICLE Evidence-Based Medicine: A New Approach to Teaching the Practice of Medicine Evidence-Based Medicine Working Group JAMA. 1992;268(17):2420-2425. A new paradigm for medical practice is emerging. Evidencebased medicine de-emphasizes intuition, unsystematic clinical experience, and pathophysiologic rationale as sufficient grounds for clinical decision making and stresses the examination of evidence from clinical research. Evidencebased medicine requires new skills of the physician, including efficient literature searching and the application of formal rules of evidence evaluating the clinical literature. See www.jama.com for full text of the original JAMA article. Commentary by Victor M. Montori, MD, MSc, and Gordon H. Guyatt, MD, MSc I N 1992 JAMA PUBLISHED AN ARTICLE BY THE EVIDENCEBased Medicine Working Group focusing on the role of evidence-based medicine (EBM) in medical education.1 Although the term evidence-based medicine first appeared in the published literature the prior year,2 the JAMA publication brought both the label and the underlying philosophy to the attention of a wider medical community. The article was audacious in suggesting that EBM represented a new paradigm in the teaching and practice of medicine by deemphasizing unsystematic clinical observations, pathophysiological inference, and authority. The article honored traditional skills (eg, understanding biology, demonstrating empathy), but emphasized new skills thatlearnersmust acquire and use: question formulation, search and retrieval of the best available evidence, and critical appraisal of the study methods to ascertain the validity of results. The article aggressively presented EBM as a fundamentally new approach. The Rapid Development and Uptake of EBM The Users’ Guides to the Medical Literature series in JAMA3 that quickly followed the article1 provided tools for learners and teachers to hone their skills in appraising and applying results of studies focused on questions of therapy, diagnosis, prognosis, and harm. Subsequent articles in this series, which eventually addressed 25 separate topics, helped readers understand the value of systematic reviews, decision and economic analyses, and practice guidelines. Courses on how to teach EBM, popular books on the subject (including one based on the Users’ Guides series4 ); related series in medical and surgical specialties; and enthusiastic uptake by junior faculty (mostly in general medicine), students, and trainees followed. The term EBM proved extraordinarily popular and is now widely used in related health fields (eg, evidence-based health policy, evidence-based nursing). The influence of EBM has been widely recognized both in lay publications (eg, the New York Times listed EBM as one of its ideas of the year in 2001) and in the academic press (eg, BMJ listed EBM as one of the 15 greatest medical milestones since 1840). Key developments since the recognition of EBM have included enormous advances in ease of accessing and understanding information, the development of preprocessed evidence-based information, and the increasing emphasis on patients’ values and preferences in clinical decision making. Evolution of EBM: Knowledge Access and Dissemination The development of the Internet has made finding and retrieving original articles much easier. Emblematic of this effort is the pioneering work of the National Library of Medicine in developing and maintaining the MEDLINE database. Users often access this database from its own interface, Author Affiliations: Knowledge and Encounter Research Unit, Department of Medicine and Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota (Dr Montori); and Clinical Advances Through Research and Information Translation (CLARITY) Research Group, Department of Clinical Epidemiology and Biostatistics, and Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada (Dr Guyatt). Corresponding Author: Gordon H. Guyatt, MD, MSc, Department of Clinical Epidemiology and Biostatistics, Health Sciences Centre, Room 2C12, McMaster University, Hamilton, ON, Canada L8N 3Z5 (guyatt@mcmaster.ca). 1814 JAMA, October 15, 2008—Vol 300, No. 15 (Reprinted) ©2008 American Medical Association. All rights reserved. Downloaded from www.jama.com by guest on August 17, 2010 第 4 页

PubMed, but also from Internet search engines (eg, Google), and from commercial MEDLINE interfaces (eg, OVID). These search and retrieval interfaces have improved with the development of “hedges,” search strategies that retrieve articles with optimal sensitivity and precision,5 and by linking the title and abstract to the full-text publications and related documents. Clinicians and other learners benefit not only from these “pull” services, but alsofrom services that electronically “push” selected evidence screened for quality, newsworthiness, and relevance to the user (eg, services produced by the McMaster Premium Literature Service [PLUS] such as the ACP Journal Club Plus). A key benefit of some of these push services is the rigorous preappraisal of evidence. For instance, the ACP Journal Club not only highlights selected articles with high methodological quality and potential relevance but also offers structured abstracts that document methodological quality criteria, which allows readers to evaluate the validity of the results. In addition, these services present pertinent results transparently and offer independent commentary. The dissemination of systematic reviews of primary studies, which was gaining credibility at the time of the EBM publication1 has also helped clinicians integrate all of the best available evidence addressing a particular clinical problem.6 Systematic reviews have demonstrated the limitations of basing practice on the most salient, most recent, or most popular study. The Cochrane database now includes more than 3000 systematic reviews and the Cochrane Collaboration has played a crucial role in advancing the science of knowledge synthesis. Relative to traditional medical texts, a number of electronic textbooks represent a revolutionary change in gathering and summarizing evidence and making recommendations—a change driven largely by EBM. These resources (eg, PIER, BMJClinical Evidence, UpToDate), which make use of the preappraised resources detailed in the previous paragraphs, increasingly bring evidence explicitly and practically to the point of care. Decision support systems that embed such summaries in the medical record and the clinical workflow are still evolving. Evolution of EBM: Values and Preferences Identifying, critically appraising, and summarizing the evidence were initial areas of focus for EBM. As the 1992 article1 had hinted, however, evidence alone is not sufficient to make clinical decisions. In 2000, the Evidence-Based MedicineWorking Group presented the second fundamental principle of EBM (the hierarchy of evidence being the first): whatever the evidence, value and preference judgments are implicit in every clinical decision.7 A key implication of this second principle is that clinical decisions, recommendations, and practice guidelines must not only attend to the best available evidence, but also to the values and preferences of the informed patient. Values and preferences refer not only the patients’ perspectives, beliefs, expectations, and goals for life and health, but also the processes individuals use to consider the available options and their relative benefits, harms, costs, and inconveniences. Since 1992, much work in the fields of shared decision making and of patient decision support technologies (ie, decision aids), the evolution of the patient rights movement, and the Internet-enabled democratization of technical information have changed the landscape substantially. Recently, the first National Health Service Constitution in Great Britain suggests that patient participation in decision making is a patient’s right8 ; in the United States, the Institute of Medicine designated evidence-based patientcentered health care delivery as a key feature of highquality medical care.9 Evolution of EBM: GRADE The pioneering work of Eddy10 in strengthening the evidence base of clinical practice guidelines preceded the EBM article.1 The Evidence-Based Medicine Working Group initially focused on the relationship between individual clinicians and the application of the original literature to clinical care. Recognition of the importance of preappraised resources and guidelines has led the EBM movement to a greater focus on the methodology of applying EBM principles to management recommendations. The Grades of Recommendation Assessment, Development and Evaluation Working Group (GRADE) has developed a framework for the formulation of treatment recommendations that is based on the contemporary principles of EBM.11 The GRADE process highlights the importance of clear specification of the question with identification of all patient-important outcomes and the necessity for systematic summaries of all the best evidence to guide recommendations. The GRADE process includes an important evolution in EBM: the definition of quality of evidence and the components that determine quality (including study design and study limitations, consistency, precision, and the extent to which the evidence directly applies to the patients, interventions, and outcomes of interest). The GRADE framework requires the specification of values and preferences in making recommendations and demands attention to circumstances (and resources for competing priorities) in deciding how confident one is that following a recommendation will do more good than harm. This system produces either strong recommendations (ideal targets for quality improvement efforts) or weak ones (ideal targets for careful incorporation of patient preferences [eg, using decision aids in practice]). EBM and the Current Health Care Context: Misuses of EBM An analogy can be made between EBM and nuclear fission: it can be very powerful when used appropriately and dangerous when used inappropriately. The term evidencebased precedes many recommendations, guidelines, and alJAMA CLASSICS ©2008 American Medical Association. All rights reserved. (Reprinted) JAMA, October 15, 2008—Vol 300, No. 15 1815 Downloaded from www.jama.com by guest on August 17, 2010 第 5 页

gorithms that are not transparently linked to the underlying evidence base and do not represent the results of a systematic and critical appraisal of that evidence. It sometimes appears as if using the term obviates the need to describe the quality of underlying evidence, the magnitude of effects, or the applicability of any of the results in the context, values, and preferences of the patients. This is particularly problematic because the EBM era has coincided with a dramatic increase in the for-profit funding of research. Researchers funded by industry interpret their results differently and in favor of the industry product relative to not-for-profit funding.12 Problems associated with industry funding include use of inappropriate control interventions, surrogate outcomes, publication and reporting bias, and misleading descriptions and presentations of research findings—all forms of corrupting the evidence base.13 Unsophisticated users of the medical literature, assuming that medical editors, peer reviewers, and topic experts have now become familiar with the tenets of EBM, may trust these corrupted research reports and advocate for their application in practice. Many medical schools and training programs, in a form of premature closure, are moving away from teaching the fundamentals of careful evidence appraisal to emphasize the implementation of evidence. The intent of this new focus is to produce high-quality, safe, and low-cost care (ie, Accreditation Council for Graduate Medical Education competencies of systems-based practice and improvement and practice-based learning14). However, abandoning appropriate skepticism regarding the effectiveness of these interventions may lead to large investments in qualityimprovement, safety, and efficiency activities that fail to yield the expected benefits. EBM in the Current Health Care Environment: Appropriate Application EBM continues to hold substantial promise for the increasing conduct of high-quality studies that address important questions using optimal study designs and large sample sizes, and the unbiased, meticulous summarization of the best evidence. Achieving this goal is crucial in a world moving hurriedly toward molecular medicine. Clinicians and researchers who understand the EBM approach and tenets will look beyond the novelty and deal with the special challenges that arise from the use of information from molecular diagnostic and prognostic tests and from treatments linked to these technologies. EBM remains the fundamental framework for investigators intent on conducting translational research from clinical research to clinical practice. When based on EBM principles, quality improvement science can realize the reliable application of evidence and make health care a high-value proposition. With the emergence of the electronic medical record, many see opportunities in the use of practice-based information to make inferences regarding treatment effectiveness and recommendations based on these inferences. However, it is essential to remember the perils of ignoring the hierarchy of evidence and abandoning awareness of the biases associated with observational studies. The medical community must resist the temptation to use information accrued in practice based on choice rather than chance to assess treatment efficacy among patient subgroups. At the same time, these information sources will likely prove valuable in detecting rare harms and unintended consequences of clinical actions.15 Reliance on easily obtained but potentially misleading evidence and the increase in commercial interests to produce and interpret evidence for physicians will remain potent. The appropriate application of EBM will continue to provide safeguards against these dangers. Clinicians will enjoy a set of increasingly accessible sources of evidence, evidence summaries, and guidelines that acknowledge the most current EBM thinking—perhaps best captured in the GRADE system—and in particular the role of values and preferences in decision making.Medical and health policy trainingmust continue to evolve, allowing clinicians and policy makers to successfully differentiate truly evidence-based sources of information and interpretation of information, from those that are not. Financial Disclosures: Dr Guyatt has acted as a consultant to UpToDate for the last 5 years; Drs Montori and Guyatt are associate editors of ACP Journal Club, and are active members of the GRADE Working Group. Both authors accept no royalties for books and honoraria for speaking on EBM as personal income, but as contributions to their respective research endeavors. REFERENCES 1. Evidence-Based Medicine Working Group. Evidence-based medicine: a new approach to teaching the practice of medicine. JAMA. 1992;268(17):2420-2425. 2. Guyatt G. Evidence-based Medicine. ACP J Club. 1991;114(suppl 2):A16. 3. Guyatt GH, Rennie D. Users’ guides to the medical literature. JAMA. 1993; 270(17):2096-2097. 4. Guyatt G, Rennie D, Meade M, Cook D. JAMA Evidence Users’ Guides to the Medical Literature. A Manual for Evidence-Based Clinical Practice. 2nd ed. Chicago, IL: McGraw Hill Co; 2008. 5. Wilczynski NL, Morgan D, Haynes RB. An overview of the design and methods for retrieving high-quality studies for clinical care. BMC Med Inform Decis Mak. 2005;5:20. 6. Montori VM, Saha S, Clarke M. A call for systematic reviews. J Gen Intern Med. 2004;19(12):1240-1241. 7. Guyatt GH, Haynes RB, Jaeschke RZ, et al. Users’ Guides to the Medical Literature: XXV: evidence-based medicine: principles for applying the Users’ Guides to patient care: Evidence-Based Medicine Working Group. JAMA. 2000;284 (10):1290-1296. 8. UK Department of Health. National Health Services Constitution. http://www .dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance /DH_085814. Accessed August 21, 2008. 9. Committee on Quality of Health Care in America, Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academic Press; 2001. 10. Eddy DM. Evidence-based medicine: a unified approach. Health Aff (Millwood). 2005;24(1):9-17. 11. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336 (7650):924-926. 12. Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA. 2003;290(7):921-928. 13. Montori V, Guyatt GH. Corruption of the evidence as threat and opportunity for evidence-based medicine. Harvard Health Policy Rev. 2007;2007(8):145- 155. 14. Accreditation Council for Graduate Medical Education. Common Program Requirements. http://www.acgme.org. Accessed April 23, 2007. 15. Avorn J. In defense of pharmacoepidemiology–embracing the yin and yang of drug research. N Engl J Med. 2007;357(22):2219-2221. JAMA CLASSICS 1816 JAMA, October 15, 2008—Vol 300, No. 15 (Reprinted) ©2008 American Medical Association. All rights reserved. Downloaded from www.jama.com by guest on August 17, 2010 第 6 页

924 BMJ | 26 APRIL 2008 | VOLUME 336 ANALYSIS advantages and disadvantages but also by their confidence in these estimates. The cartoon depicting the weather forecaster’s uncertainty captures the difference between an assessment of the likelihood of an outcome and the confidence in that assessment (figure). The usefulness of an estimate of the magnitude of intervention effects depends on our confidence in that estimate. Expert clinicians and organisations offering recommendations to the clinical community have often erred as a result of not taking sufficient account of the quality of evidence.2 For a decade, organisations recommended that clinicians encourage postmenopausal women to use hormone replacement therapy.3 Many primary care physicians dutifully applied this advice in their practices. A belief that such therapy substantially decreased women’s cardiovascular risk drove this recommendation. Had a rigorous system of rating the quality of evidence been applied at the time, it would have shown that because the data came from observational studies with inconsistent results, the evidence for a reduction in cardiovascular risk was of very low quality.4 Recognition of the limitations of the evidence would have tempered the recommendations. Ultimately, randomised controlled trials have shown that hormone replacement therapy fails to reduce cardiovascular risk and may even increase it.5 6 The US Food and Drug Administration licensed the antiarrhythmic agents encainide and flecainide for use in patients on the basis of the drugs’ ability to reduce asymptomatic ventricular arrhythmias associated with sudden death. This decision failed to acknowledge that because arrhythmia reduction reflected only indirectly on the outcome of sudden death the quality of the evidence for the drugs’ benefit was of low quality. Subsequently, a randomised controlled trial showed that the two drugs increase the risk of sudden death.7 Appropriate attention to the low quality of the evidence would have saved thousands of lives. Failure to recognise high quality evidence can cause similar problems. For instance, expert recommendations lagged a decade behind the evidence from well conducted randomised controlled trials that thrombolytic therapy achieved a reduction in mortality in myocardial infarction.8 Insufficient attention to quality of evidence risks inappropriate guidelines and recommendations that may lead clinicians to act to the detriment of their Guideline developers around the world are inconsistent in how they rate quality of evidence and grade strength of recommendations. As a result, guideline users face challenges in understanding the messages that grading systems try to communicate. Since 2006 the BMJ has requested in its “Instructions to Authors” on bmj.com that authors should preferably use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for grading evidence when submitting a clinical guidelines article. What was behind this decision? In this first in a series of five articles we will explain why many organisations use formal systems to grade evidence and recommendations and why this is important for clinicians; we will focus on the GRADE approach to recommendations. In the next two articles we will examine how the GRADE system categorises quality of evidence and strength of recommendations. The final two articles will focus on recommendations for diagnostic tests and GRADE’s framework for tackling the impact of interventions on use of resources. GRADE has advantages over previous rating systems (box 1). Other systems share some of these advantages, but none, other than GRADE, combines them all.1 What is “quality of evidence” and why is it important? In making healthcare management decisions, patients and clinicians must weigh up the benefits and downsides of alternative strategies. Decision makers will be influenced not only by the best estimates of the expected Gordon H Guyatt professor, Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada L8N 3Z5 Andrew D Oxman researcher, Norwegian Knowledge Centre for the Health Services, PO Box 7004, St Olavs Plass, 0130 Oslo, Norway Gunn E Vist researcher, Norwegian Knowledge Centre for the Health Services, PO Box 7004, St Olavs Plass, 0130 Oslo, Norway Regina Kunz associate professor, Basel Institute of Clinical Epidemiology, University Hospital Basel, Hebelstrasse 10, 4031 Basel, Switzerland Yngve Falck-Ytter assistant professor, Division of Gastroenterology, Case Medical Center, Case Western Reserve University, Cleveland, OH 44106, USA Pablo Alonso-Coello researcher, Iberoamerican Cochrane Center, Servicio de Epidemiología Clínica y Salud Pública (Universidad Autónoma de Barcelona), Hospital de Sant Pau, Barcelona 08041, Spain Holger J Schünemann professor, Department of Epidemiology, Italian National Cancer Institute Regina Elena, Rome, Italy for the GRADE Working Group Correspondence to: G H Guyatt, CLARITY Research Group, Department of Clinical Epidemiology and Biostatistics, Room 2C12, 1200 Main Street, West Hamilton, ON, Canada L8N 3Z5 guyatt@mcmaster.ca Guidelines are inconsistent in how they rate the quality of evidence and the strength of recommendations. This article explores the advantages of the GRADE system, which is increasingly being adopted by organisations worldwide GRADE: an emerging consensus on rating quality of evidence and strength of recommendations RATING QUALITY OF EVIDENCE AND STRENGTH OF RECOMMENDATIONS This is the first in a series of five articles that explain the GRADE system for rating the quality of evidence and strength of recommendations. Box 1 | Advantages of GRADE over other systems tDeveloped by a widely representative group of international guideline developers tClear separation between quality of evidence and strength of recommendations tExplicit evaluation of the importance of outcomes of alternative management strategies tExplicit, comprehensive criteria for downgrading and upgrading quality of evidence ratings tTransparent process of moving from evidence to recommendations tExplicit acknowledgment of values and preferences tClear, pragmatic interpretation of strong versus weak recommendations for clinicians, patients, and policy makers tUseful for systematic reviews and health technology assessments, as well as guidelines 第 7 页

BMJ | 26 APRIL 2008 | VOLUME 336 925 ANALYSIS indicate whether (a) the evidence is high quality and the desirable effects clearly outweigh the undesirable effects, or (b) there is a close or uncertain balance. A simple, transparent grading of the recommendation can effectively convey this key information. There are limitations to formal grading of recommendations. Like the quality of evidence, the balance between desirable and undesirable effects reflects a continuum. Some arbitrariness will therefore be associated with placing particular recommendations in categories such as “strong” and “weak.” Most organisations producing guidelines have decided that the merits of an explicit grade of recommendation outweigh the disadvantages. What makes a good grading system? Not all grading systems separate decisions regarding the quality of evidence from strength of recommendations. Those that fail to do so create confusion. High quality evidence doesn’t necessarily imply strong recommendations, and strong recommendations can arise from low quality evidence. For example, patients who experience a first deep venous thrombosis with no obvious provoking factor must, after the first months of anticoagulation, decide whether to continue taking warfarin long term. High quality randomised controlled trials show that continuing warfarin will decrease the risk of recurrent thrombosis but at the cost of increased risk of bleeding and inconvenience. Because patients with varying values and preferences will make different choices, guideline panels addressing whether patients should continue or terminate warfarin should—despite the high quality evidence—offer a weak recommendation. Consider the decision to administer aspirin or paracetamol (acetaminophen) to children with chicken pox. Observational studies have observed an association between aspirin administration and Reye’s syndrome.9 Because aspirin and paracetamol are similar in their analgesic and antipyretic effects, the low quality evidence regarding the association between aspirin and Reye’s syndrome does not preclude a strong recommendation for paracetamol. Systems that classify “expert opinion” as a category of evidence also create confusion. Judgment is necessary for interpretation of all evidence, whether that evidence is high or low quality. Expert reports of their clinical experience should be explicitly labelled as very low quality evidence, along with case reports and other uncontrolled clinical observations. Grading systems that are simple with respect to judgments both about the quality of the evidence and the strength of recommendations facilitate use by patients, clinicians, and policy makers.1 Detailed and explicit criteria for ratings of quality and grading of strength will make judgments more transparent to those using guidelines and recommendations. Although many grading systems to some extent meet these criteria,1 a plethora of systems makes their use difficult for frontline clinicians. Understanding a variety of systems is neither an efficient nor a realistic use of clinicians’ time. The GRADE system is used patients. Recognising the quality of evidence will help to prevent these errors. How should guideline developers alert clinicians to quality of evidence? A formal system that categorises quality of evidence— for example, from high to very low—represents an obvious strategy for conveying quality of evidence to clinicians. Some limitations, however, do exist. Quality of evidence is a continuum; any discrete categorisation involves some degree of arbitrariness. Nevertheless, advantages of simplicity, transparency, and vividness outweigh these limitations. What is “strength of recommendation” and why is it important? A recommendation to offer patients a particular treatment may arise from large, rigorous randomised controlled trials that show consistent impressive benefits with few side effects and minimal inconvenience and cost. Such is the case with using a short course of oral steroids in patients with exacerbations of asthma. Clinicians can offer such treatments to almost all their patients with little or no hesitation. Alternatively, treatment recommendations may arise from observational studies and may involve appreciable harms, burdens, or costs. Deciding whether to use antithrombotic therapy in pregnant women with prosthetic heart valves involves weighing the magnitude of reduction in valve thrombosis against inconvenience, cost, and risk of teratogenesis. Clinicians offering such treatments must help patients to weigh up the desirable and undesirable effects carefully according to their values and preferences. Guidelines and recommendations must therefore 第 8 页

926 BMJ | 26 APRIL 2008 | VOLUME 336 ANALYSIS Details of the GRADE working group, contributors, and competing interests appear in the version on bmj.com 1 Atkins D, Eccles M, Flottorp S, Guyatt GH, Henry D, Hill S, et al. Systems for grading the quality of evidence and the strength of recommendations I: critical appraisal of existing approaches. The GRADE Working Group. BMC Health Serv Res 2004;4(1):38. 2 Lacchetti C, Guyatt G. Surprising results of randomized trials. In: Guyatt G, Drummond R, eds. Users’ guides to the medical literature: a manual of evidence-based clinical practice. Chicago, IL: AMA Press, 2002. 3 American College of Physicians. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med 1992;117:1038-41. 4 Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002;137:273-84. 5 Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-13. 6 Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-33. 7 Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The cardiac arrhythmia suppression trial. N Engl J Med 1991;324:781-8. 8 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;268:240-8. 9 Committee on Infectious Diseases. Aspirin and Reye syndrome. Pediatrics 1982;69:810-2. widely: the World Health Organization, the American College of Physicians, the American Thoracic Society, UpToDate (an electronic resource widely used in North America, www.uptodate.com), and the Cochrane Collaboration are among the more than 25 organisations that have adopted GRADE. This widespread adoption of GRADE reflects GRADE’s success as a methodologically rigorous, user friendly grading system. How does the GRADE system classify quality of evidence? To achieve transparency and simplicity, the GRADE system classifies the quality of evidence in one of four levels—high, moderate, low, and very low (box 2). Some of the organisations using the GRADE system have chosen to combine the low and very low categories. Evidence based on randomised controlled trials begins as high quality evidence, but our confidence in the evidence may be decreased for several reasons, including: tStudy limitations tInconsistency of results tIndirectness of evidence tImprecision tReporting bias. Although observational studies (for example, cohort and case-control studies) start with a “low quality” rating, grading upwards may be warranted if the magnitude of the treatment effect is very large (such as severe hip osteoarthritis and hip replacement), if there is evidence of a dose-response relation or if all plausible biases would decrease the magnitude of an apparent treatment effect. How does the GRADE system consider strength of recommendation? The GRADE system offers two grades of recommendations: “strong” and “weak” (though guidelines panels may prefer terms such as “conditional” or “discretionary” instead of weak). When the desirable effects of an intervention clearly outweigh the undesirable effects, or clearly do not, guideline panels offer strong recommendations. On the other hand, when the trade-offs are less certain—either because of low quality evidence or because evidence suggests that desirable and undesirable effects are closely balanced—weak recommendations become mandatory. In addition to the quality of the evidence, several other factors affect whether recommendations are strong or weak (table 1). SUMMARY POINTS Failure to consider the quality of evidence can lead to misguided recommendations; hormone replacement therapy for post-menopausal women provides an instructive example High quality evidence that an intervention’s desirable effects are clearly greater than its undesirable effects, or are clearly not, warrants a strong recommendation Uncertainty about the trade-offs (because of low quality evidence or because the desirable and undesirable effects are closely balanced) warrants a weak recommendation Guidelines should inform clinicians what the quality of the underlying evidence is and whether recommendations are strong or weak The Grading of Recommendations Assessment, Development and Evaluation (GRADE ) approach provides a system for rating quality of evidence and strength of recommendations that is explicit, comprehensive, transparent, and pragmatic and is increasingly being adopted by organisations worldwide Box 2 | Quality of evidence and definitions High quality— Further research is very unlikely to change our confidence in the estimate of effect Moderate quality— Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Low quality— Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Very low quality— Any estimate of effect is very uncertain Factors that affect the strength of a recommendation Factor Examples of strong recommendations Examples of weak recommendations Quality of evidence Many high quality randomised trials have shown the benefit of inhaled steroids in asthma Only case series have examined the utility of pleurodesis in pneumothorax Uncertainty about the balance between desirable and undesirable effects Aspirin in myocardial infarction reduces mortality with minimal toxicity, inconvenience, and cost Warfarin in low risk patients with atrial fibrillation results in small stroke reduction but increased bleeding risk and substantial inconvenience Uncertainty or variability in values and preferences Young patients with lymphoma will invariably place a higher value on the life prolonging effects of chemotherapy than on treatment toxicity Older patients with lymphoma may not place a higher value on the life prolonging effects of chemotherapy than on treatment toxicity Uncertainty about whether the intervention represents a wise use of resources The low cost of aspirin as prophylaxis against stroke in patients with transient ischemic attacks The high cost of clopidogrel and of combination dipyridamole and aspirin as prophylaxis against stroke in patients with transient ischaemic attacks 第 9 页