EVIDENCE BASED MEDICINE

Self-Instructional Manual

Noel L. Espallardo, MD, MSc
 

Department of Clinical Epidemiology  UP College of Medicine and Philippine General Hospital                                     

                                                                                      Copyright, 2008 

TABLE OF CONTENTS
    CONTRIBUTORS      ACKNOWLEDGEMENT      EVIDENCE BASED MEDICINE        Introduction      SEARCHING THE MEDLINE        Session Briefing        Searching the MEDLINE Database      DIFFERENTIAL DIAGNOSIS        Session Briefing        Clinical Decision on Differential Diagnosis        Workshop Briefing        Appraisal Sheet      DIAGNOSTIC TEST        Session Briefing        Clinical Decision on a Diagnostic Test        Workshop Briefing        Appraisal Sheet       THERAPY OR PREVENTION        Session Briefing        Clinical Decision on Therapy or Prevention        Workshop Briefing        Appraisal Sheet      i    i    1      6 

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TABLE OF CONTENTS (CONT’D)     HARMFUL EFFECT        Session Briefing        Clinical Decision on Harm        Workshop Briefing        Appraisal Sheet      PROGNOSIS        Session Briefing        Clinical Decision on Prognosis        Workshop Briefing        Appraisal Sheet      HEALTH ECONOMIC ANALYSIS        Session Briefing        Clinical Decision on Health Economic Analysis        Workshop Briefing        Appraisal Sheet      SYSTEMATIC REVIEW OR META‐ANALYSIS        Session Briefing        Clinical Decision on Systematic Review or Meta‐analysis        Workshop Briefing        Appraisal Sheet      CLINICAL PRACTICE GUIDELINES        Session Briefing        How to Use a Clinical Practice Guideline        Workshop Briefing        Appraisal Sheet            48    58    69    80    90  .

 UP College of Medicine and  Philippine General Hospital.   UP College of Medicine    The department is considered as the center of evidence‐based medicine in the  Philippines.Evidence-based Medicine: Self-instructional Manual CONTRIBUTORS   Dr.      Page i . UP College of Medicine and Philippine General Hospital    They were dedicated students in the Master of Science program of the  Department of Family and Community Medicine. Leilani Apostol and Dr. The staff provided essential advice and feedback in the application of  evidence‐based.      ACKNOWLEDGEMENT   Dr. Ma Elinore Alba of the Department of Family and  Community Medicine. Noel Juban and the Faculty of the Department of Clinical Epidemiology. Their knowledge and experience in conducting  evidence‐based medicine training in Family Medicine have been very helpful in  designing this package.

  appraising. new  modalities of treatment are promoted. 1992):   Page 1 . Will  you prescribe it or not? These are common problems that may escape our  attention and diminish the quality of care we give if we make inappropriate  decisions. appraise the article then makes a decision.    In the old practice faced with this question. Before he  makes a decision. a physician will just ask a colleague  or an expert for the answer or rely on his/her prior knowledge of the disease. and using contemporaneous research findings as the basis for clinical  decisions (NLM. the physician will first try to retrieve his latest article about the  topic that he kept from his file. Everyday challenging problems arise. 2008). disease management done under  minimal or far from ideal conditions.  he evaluates the effectiveness of his decision. Later. Evidence‐based medicine follows four steps:     • formulate a clear clinical question from a patient's problem  • search the literature for relevant clinical articles  • evaluate (critically appraise) the evidence for its validity and usefulness  • implement useful findings in clinical practice. He  may also prescribe a drug because of the promotional lecture sponsored by the  manufacturer. Suppose a patient who consulted for cough  productive of yellowish phlegm and asked for a prescription of an antibiotic.Evidence-based Medicine Self-Instructional Manual EVIDENCE BASED MEDICINE INTRODUCTION   Medicine is a dynamic endeavor.       DEFINITION OF EBM   Evidence‐based medicine is defined as the process of systematically finding. This loop ensures improvement in  the quality of care.      In evidence‐based medicine (EBM) a new paradigm is introduced.       THE PARADIGM SHIFT   The traditional method of answering clinical problems was based on the  following assumptions (User’s Guide.

 too many students in crowded rooms.   • understanding of basic mechanisms of disease are necessary but  insufficient guides for clinical practice   • understanding certain rules of evidence is necessary to correctly interpret  literature on causation. Students can gain the skills to make independent assessments of  evidence.  too little time.Evidence-based Medicine Self-Instructional Manual • • • • clinical experience is the way of building and maintaining one's  knowledge   basic mechanisms of disease is a sufficient guide for clinical practice  traditional medical training and common sense is sufficient to allow one  to evaluate new tests and treatment.  The assumptions of the new paradigm are (User’s Guide. 1992):   • clinical experience are crucial but in the absence of systematic  observation one must be cautious in the interpretation of information  derived from clinical experience for it may at times be misleading.      WHY TEACH EBM   Medical education faces a problem in a present setting: too much information. which people  at the school had been developing for over a decade (NLM. 2006). There is a need to make  students asks questions about useful information and try to seek the answer for  themselves.    The term "evidence based medicine" was coined at McMaster Medical School in  Canada in the 1980's to label an “active clinical learning” strategy. and treatment  strategy    The new paradigm makes learning new things more self‐directed and less reliant  on teachers. Randomized  controlled trials have shown that evidence‐based medicine learning is more  effective than didactic learning among medical interns in family medicine. prognosis. and thus evaluate the credibility of opinions being offered by experts.    Page 2 .   clinical experts are a sufficient to generate valid guidelines for clinical  practice    The traditional assumptions are now being questioned with the new paradigm. 2008). They  provide better care in terms of providing treatment to patients with  hypertension (Espallardo. diagnostic tests.  The purpose of this course is to introduce the concept of evidence based  medicine and the use of these concepts to improve the quality of his/her own  practice. and exams that  discouraged real life‐long learning (Rangachari. 2007).

 But among those who were  already exposed to EBM there was mismatch perceived competence and their  actual performance. helps them  develop appropriate attitudes towards their studies and future practice and  orientates medical curriculums towards society's needs (Littlewood. Conduct the group discussion  with at least 5 of your colleagues.Evidence-based Medicine Self-Instructional Manual   MEDICAL STUDENTS LEARNING EBM   Currently most physicians report a moderate amount of exposure to EBM. the participants  should be able to:    • define and describe the steps in applying evidence‐based medicine into  his/her own clinical practice  • appraise and use randomized controlled trials and other types of studies  in solving clinical problems in clinical practice  • make an efficient literature search and identify problems and solutions in  the application of evidence based medicine        METHODS   This is a series of self‐reading materials and group discussions.    The pace of learning depends on your time schedule.      OBJECTIVES   After going through the readings and workshops of this manual. But  physicians in clinical research careers were more favorable towards EBM than  those in the clinical practice careers (Luebbe. This suggests that better education in EBM is needed (Caspi. Observe the rules enumerated in the succeeding section. However. Assign a facilitator and a co‐facilitator/scribe  for each discussion. Allot a fix time for  you to read the reading assignment in the manual.  2006). 2005).  Monitor your progress by reviewing the checklist provided before each section. Early experience helps medical students learn. 2007). I suggest that  you allot one day a week for the reading time and group discussion. Starting the training in the undergraduate program (medical students) is  the logical approach. You can also  try to apply critical appraisal by yourself with other topics of interest.            Page 3 .

  • Remain neutral on content and avoid evaluation and decisions on ideas.  • Allow one person to talk at a time. Facilitate rather than lead the discussion.  • Provide balance.  • Record essential information (content) and observation (group process)  for post‐discussion processing and evaluation. He/she   Page 4 .  • Focus on the topic.  • Contribute ideas to the topic being discussed. All ideas are valued.  • Meet with the facilitator during the break to discuss the process and  ideas on how to proceed.   • Encourage participation in the discussion for all participants.  • Critique on ideas and thoughts.  • Encourage equal participation among group members. clarify  discussion and bring insight on some points. He/she is also responsible for the  content and final outcome of the discussion.      ROLES AND RESPONSIBILITIES   FACILITATOR    The facilitator serves as the process facilitator. not on the person.    CO‐FACILITATOR/SCRIBE    The co‐facilitator helps the facilitator to achieve his/her objectives. He/she may  join the group discussion.  • Listen to what others have to say.  • Pose probing but non‐threatening questions to provoke thought. His/her responsibilities are to:    • Provide the process to achieve the objectives and desired outcomes.    PARTICIPANTS    The participants are encouraged to actively participate in the discussion. but must bear in mind of his/her other functions:    • Be a timekeeper to ensure progress.Evidence-based Medicine Self-Instructional Manual RULES OF DISCUSSION   The ground rules that are encouraged to be observe during the group discussion  are as follows:    • Honor the established time limits. Avoid sideline conversation.

 Sechrest L.63(7):643‐55.    Espallardo NL. Adv  Physiol Educ. Evidence‐based medicine:  discrepancy between perceived competence and actual performance among graduating medical  students. Scherpbier A. Back to the future? Active learning of medical physiology in the 1900s. 1992. Radcliffe AM.31(4):283‐7.    National Library of Medicine.  2007 Jul. BMJ. J Clin Psychol. www. The amount of learning you will get from  this course is proportional to the degree of your participation.    Users' Guides to Evidence‐based Medicine.    Rangachari PK. Thorn BE. Cunningham V. Spencer J.28(4):318‐25.nlm. Kruse L. Effectiveness of Critical Appraisal Workshop as a Method for Disseminating a  Clinical Practice Guideline on Hypertension. Ypinazar V. Dornan T. JAMA. Margolis SA. Medical Subject Headings.nih.331(7513):387‐91. Evidence‐based practice in  psychology: perceptions of graduate students in scientist‐practitioner programs. 2005 Aug  13. Green D.    Littlewood S.                                                Page 5 . Med Teach. 44 (2): 54‐60.gov/sites/entrez  (May 27.      REFERENCES   Caspi O. 2008). 2007 Dec.    Luebbe AM. McKnight P.ncbi. Callands TA. 2006 Jun. Early practical  experience and the social responsiveness of clinical education: systematic review.268(17):2420‐5. Fil Fam Phys 2006.Evidence-based Medicine Self-Instructional Manual working agreement set by the group. Figueredo AJ.

 don’t worry you can always go  back and read the previous two topics.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT SEARCHING THE MEDLINE (SESSION BRIEFING)     CHECKLIST   Have you read the previous two topics?   Yes          No    Did I get your interest now?   Yes          No    Are you ready to work with your group or colleagues?   Yes          No    If your answer is yes to all of the questions.    If your answer is yes to only one of the questions.      ANOTHER CHECKLIST   Have you formed a group?   Yes          No    Has the group elected a facilitator?   Yes          No    Has the group elected a co‐facilitator/scribe?   Yes          No    If not yet. congratulations! You have the  potential of being a quality health care provider. what are you waiting for!         ORGANIZE NOW!       Page 6 .

                                                        Page 7 .      After reading the paper.     At the end of the reading session. Focus on the use of key  terms and how to use the operant words AND or OR. you should be able to search the MEDLINE  with skill and confidence that you were able to retrieve the right answer to the  problem.       INSTRUCTIONS   Read the assignment for an article on MEDLINE search.Evidence-based Medicine Self-Instructional Manual OBJECTIVES   The purpose of the reading assignment is to introduce to the participants how to  formulate a question and search the MEDLINE for the answer. proceed to the library or internet and try searching in  the MEDLINE.

 fellows and residents of a large  teaching tertiary care hospital. The results showed that the most important  resources were English journals.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT SEARCHING THE MEDLINE DATABASE CLINICAL SCENARIO   Supposing a patient with cough came in to your clinic and asks for an anti‐biotic  drug because he wants to be relieved of his cough right away. To state the problem  clearly. my clearly stated problem will be: “Among patients  with cough (P) will anti‐biotic (I) provide symptom relief faster?”      TRADITIONAL METHOD OF LITERATURE SEARCH   A recent survey of important knowledge sources that influence clinical practice  was conducted among faculty members. text books and experience (Yousefi‐Nooraie.  2007). you must bear in mind that there are only three important elements that  the patient want to know:    • What their diseases are  • What treatment they should be given  • What is the expected outcome of the treatment    These three important elements in clinical research are basically:    • the patient (P)  • the intervention/exposure (I)  • the outcome (O)    Sometimes the researcher can add    • method (M)    Going back to our scenario. Unfortunately these  problems are vague and sometimes not clearly stated. This dominance of the traditional information resources and experience‐ Page 8 . Will you prescribe  it?     Patients usually come in to the clinic for problems.

 the Medical Subject  Headings (MeSH).. National  Institutes of Health (NIH).      MEDLINE is the largest component of PubMed and is the freely accessible online  database of biomedical journal citations and abstracts created by the U. you can access MEDLINE through PUBMED or GRATEFULMED or  through other organizations. 2005).   • additional life science journals that submit full text to PubMed Central  and receive a qualitative review by NLM. and inappropriate combination of all search  concepts (Gruppen.S. articles on plate tectonics or astrophysics)  from certain MEDLINE journals. students had fewer search errors and correspondingly higher quality  searches. primarily general science and chemistry  journals  • citations that precede the date that a journal was selected for MEDLINE  indexing. located at the U. With this  training.g.     Page 9 . missing MeSH terms.     Entrez is the text‐based search and retrieval system used at NCBI for services  including PubMed.Evidence-based Medicine Self-Instructional Manual based medicine may be one of the barriers to the dissemination of evidence‐ based medicine. Brief (two‐hour) instructional intervention on  EBM‐based techniques for searching Medline for evidence related to a clinical  problem provided to the students have been shown to be effective.  National Library of Medicine (NLM).       PUBMED. ENTREZ AND MEDLINE   PubMed was developed by the National Center for Biotechnology Information  (NCBI) at the National Library of Medicine (NLM).200 journals published in  the United States and more than 80 other countries have been selected and are  currently indexed for MEDLINE. lack of appropriate limits.  failure to search for best evidence. PubMed provides access to bibliographic information  that includes MEDLINE.    In the internet. Approximately 5.S. as well as:     • out‐of‐scope citations (e. A distinctive feature of MEDLINE is that the  records are indexed with NLM's controlled vocabulary.     Thus educational programs to develop skills of efficiently searching the research  literature need to be developed. The most common search errors were a lack of Medical Subject  Headings (MeSH) explosion.

 study  designs. Now I can browse through these articles. study subjects.  How did this happen?        Page 10 .175 and when I typed “cough AND antibiotics  AND relief” the yield was 15 articles.751 articles  and it will be impossible for me to browse these articles. This can be done by doing the  following steps:    • Identify the key concepts (should include the PIOM discussed earlier)  • Determine alternative terms for these concepts (can be facilitated with  MESH term search)  • Refine your search (use limits like publication dates.Evidence-based Medicine Self-Instructional Manual PARTS OF PUBMED HOMEPAGE   Side bar    Page header    Entrez databases  Query box  Features tab                BASIC SEARCH STRATEGY   The first step in using PubMed is to first develop a search strategy. etc)    Our clinical question in the previous scenario was “Among patients with cough  (P) will anti‐biotic (I) provide symptom relief faster?” The key concepts in my  search terms are:  • Cough  • Antibiotics  • Relief of symptoms    When I type the key term “cough” in the search box the yield was 27. patient age. a plan that  helps you look for the information you need. When I typed “cough  AND antibiotics" the yield was 2.

 the elements that belong to  both set A AND set B are 7. 9. Some of these elements can belong to two or more sets. elements labeled such as 1. 2. B. 8. Just like the Boolean principle the main operators in the MEDLINE are  also the words AND and OR. 7. 3. 11. In the above example. can belong to set  A. 12. 6. 10. the elements in set A OR  set B are 1. As a beginner this may be enough for you. 5. 4.    In the MEDLINE. articles are indexed together as set of articles based on their  key words. 2. 3.e. i. etc.e. etc.. 13 and 14. and some  of these sets may contain no elements. If you want the elements  common to the two sets you use the word AND. 8 and 9. if you want to  combine elements in two sets you use the word OR.Evidence-based Medicine Self-Instructional Manual THE BOOLEAN PRINCIPLE Searching MEDLINE A 1 10 11 2 3 9 8 4 5 12 6 7 13 14 15 16 C A OR B A AND B A AND B AND C (A AND B) OR C A AND (B OR C) A AND (B AND C) THE BOOLEAN LOGIC B     In the Boolean principle.    Searching MEDLINE TB THE BOOLEAN LOGIC 1 10 11 2 3 9 8 4 5 12 6 7 13 14 15 16 RCTs MENINGITIS TB OR RCTs TB AND RCTs TB AND RCT AND MENINGITIS   Page 11 . i. C.

 type of studies. If I have no time to browse through 15 articles. the yield was 15  articles. I can limit this further by  checking other boxes for relevance such as date of publication. I used the advance search option and  got the results shown below.     What will you type in the search box if you want randomized controlled trials on  tuberculous meningitis?           What articles will you get if you typed “tuberculosis AND randomized controlled  trial AND meningitis”?          THE ADVANCED SEARCH STRATEGY   The advance search page can be accessed by clicking the link Advanced Search  (beta) on the right side of the query box. Reading 3 articles instead of 9 will save me a lot of  time. if I want articles about tuberculosis (TB).  175 articles and when I type cough AND antibiotic relief.          Page 12 . But if  my concern is only to read randomized controlled trials (RCT) on tuberculosis I  will type in the search window “tuberculosis AND randomized controlled trial”  and it will give me 3 articles. I will type  “tuberculosis” in the search window and the result will give me 9 articles. This can also be done in the basic search but it will take  several steps.  age of subjects etc.Evidence-based Medicine Self-Instructional Manual In the example above. the yield was 2. When I type cough AND antibiotic.

Evidence-based Medicine Self-Instructional Manual       Page 13 .

 2005 Oct.    Yousefi‐Nooraie R. J Eval Clin  Pract.ncbi.nih. A controlled comparison study of the efficacy of training medical  students in evidence‐based medicine literature searching skills. www. Sources of knowledge in clinical  practice in postgraduate medical students and faculty members: a conceptual map. Acad Med.13(4):564‐8. 2007 Aug.nlm. Arndt TS. Shakiba B. Soroush AR. Mortaz‐Hedjri S.gov/sites/entrez (May 27.    National Library of Medicine. Rana GK.  2008).Evidence-based Medicine Self-Instructional Manual REFERENCES   Gruppen LD.80(10):940‐ 4.                                                                      Page 14 . PubMed OVerview.

     At the end of the reading session. congratulations!     You are all set for an exciting learning experience!      OBJECTIVES   The purpose of the reading assignment is to introduce to the participants the  concept of medical decision making using an article about differential diagnosis. After reading the paper you can proceed to conduct the group  workshop.       Page 15 . why they are asked and how to get the answers from  the paper. Focus on the  critical appraisal questions.      INSTRUCTIONS   Read the assignment for an article about a differential diagnosis.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CRITICAL APPRAISAL OF AN ARTICLE ABOUT DIFFERENTIAL DIAGNOSIS (SESSION BRIEFING)     CHECKLIST   Have you read the topic on MEDLINE search?   Yes          No    Have you gone to library?   Yes          No    Are you ready to work with your group or colleagues?   Yes          No    If your answer is yes to all of the questions. you should be able to answer the user guides  questions for the workshop.

 Research studies focus more directly on the frequency of  diseases that cause symptoms (Kroenke.  considering the possibilities based on organs that may be affected within the  proximity of the symptom like chest pain may have differential diagnosis like  herpes zoster (skin). neoplastic/neurologic.  then the patient will have unnecessary diagnostic tests performed on them.    The disease probabilities can be taken from population prevalence statistics or  from original research. inflammatory/infectious. You read in  the papers that there was an increased incidence of dengue fever in children. 1998). pneumonia (lings) or angina (heart)..  How will you optimize (request only for what is essential) the diagnostic  laboratory tests for this patient?    Naturally you can do that if you already have an initial diagnosis in mind. or more more serious if left undiagnosed and untreated (a  ‘prognostic’ approach) or more responsive to treatment (Richardson. With these approaches however the frequency or  probability of each differential will not be known. And  they are important because the probabilities of the individual differential will  help us focus our diagnostic strategies as shown in the table below. 1999).e.e. we must considering first those that are more common (a ‘probabilistic’  approach).  Instead.   If the symptom is systemic like fever.  intoxication/idiopathic. allergic/autoimmune.  Page 16 . congenital.    If we consider all known causes equally possible (the ‘possibilistic’ approach).Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CLINICAL DECISION ON DIFFERENTIAL DIAGNOSIS CLINICAL SCENARIO   Suppose a 35‐year old female patient came in to your clinic for fever and  abdominal pain for a week. This session will help you trim  down the differential diagnosis and request only for the laboratory tests that are  essential. 1997) are preferred over population  survey because they are more associated with presenting symptoms.  Unfortunately there might be many of them. Differential diagnosis is the method of limiting the possible causes of  the patient’s symptoms before making a final diagnosis. trauma and endocrine  (VINDICATE) (Friedland. vascular.    Differential diagnosis can be arrived at by using the anatomic approach i. degenerative. costochondritis (ribs). Identifying the right  differentials will make patient management more focused and efficient. the differentials can by be pathophysiology  i. There was neither diarrhea nor dysuria.

 entitled “Differential  diagnosis of typhoid fever in the emergency room”. look at the objective of the study.        CRITICAL APPRAISAL   RELEVANCE QUESTION    • Is the objective of the article on differential diagnosis similar to your  clinical dilemma?    To answer this question.much other possibilities that  treatment  smaller than one.Evidence-based Medicine Self-Instructional Manual Probabilities of Differential Diagnosis and Recommended Diagnostic Strategies     Differential Diagnosis  Diagnostic Tests  Treatment      Choose test(s) with high Start empiric  Working diagnosis –  specificity and LR+ much treatment  most possible cause  larger than one. clinical and laboratory presentation  among patients similar to your patient or case scenario.  should be ruled‐out          Remote diagnosis   None  None          SEARCH   You found an unpublished retrospective study in the archives of your  department written by a previous resident Santos AR. For differential diagnosis it is important that  the focus is to find the cause of symptoms.          Page 17 . It is important that  your article is relevant to the question you have raised in order for you to make  maximum use of the results of the study and be able to apply it to decision  making that influences patient care.  that should be ruled in        Choose test(s) with high Alternative diagnosis –  Start supportive  sensitivity and LR.

             Page 18 .       • Were the criteria for each final diagnosis explicit and credible?     Determination of final diagnosis must be clearly described.  The total number of patients included in the study was 235. However the criteria must be  explicit enough to make sure that different clinician will arrive at the similar  diagnosis (inter‐rater reproducibility). Although the inclusion criteria were fever alone as the chief complaint.    The final diagnosis in Santos’s paper was based on clinical syndromes and  criteria. may not necessarily  be based on the ultimate reference standard. An important element with these designs  is how the subjects are recruited so they can represent other patients who may  also have the same symptoms i. representativeness.Evidence-based Medicine Self-Instructional Manual VALIDITY GUIDES    • Did the study patients represent the full spectrum of patients who  present with this clinical problem?    Study designs that answer clinical questions like differential diagnosis can be a  cross‐sectional study or cohort study. Blood cultures.  there was a subgroup analysis of patients with fever and abdominal complaint. This coincides with  your case scenario.     With the symptom already defined. ultrasound and other tests were not done to establish  the final diagnosis in only 48% of the cases. This is usually defined in the inclusion and exclusion criteria of  the study.     The definition of the clinical problem under study describes the population to  which the study will be applied. the other strategies that can assure  representativeness are any of the following:  • Random selection – not always possible in clinical setting  • Consecutive patient recruitment – most feasible  • Recruitment in defined setting – must always be done    The Article by Santos included patients consulting for fever in the emergency  room. The problem usually is a symptom or an  abnormal physical examination such as headache or abdominal mass or a  combination of symptoms and abnormal physical findings like headache and  facial asymmetry.e.

 32%. To  assure ourselves with the eventual diagnosis of undetermined cases. No confidence intervals  were reported.    OVERALL. you decided that you can use this  article because it is the only available study in your setting. In most patients antibiotics were started and the patients were sent home  without fever. records cannot guarantee a  standard diagnostic approach for everybody. Then a minimum set of diagnostic work‐up that includes a thorough  history and physical examination and a few initial laboratory tests should have  been applied consistently for all patients. 34%.    The Santos study observed the patients for 24 to 48 hours in the emergency  room.Evidence-based Medicine Self-Instructional Manual • Was the diagnostic work‐up comprehensive and consistently applied?    The set of diagnostic work‐up should be thorough to come up with an accurate  diagnosis.    The diagnostic tests done for 85% of patients in the Santos study were CBC. Temperature was measured using a mercury  type thermometer and records with “febrile” as reported documentation of  fever were excluded.      • For initially undiagnosed patients. the following top three diseases were the most common  diagnosis given to adult patients with fever: a) typhoid fever. 29%. b) urinary  tract infection. was follow‐up to come up with a  diagnosis sufficiently long and complete?    Sometimes the diagnosis at the early stage of the disease is really difficult and  the patient may be classified as not having the disease or undetermined.  urinalysis and stool examination. IS THE STUDY VALID?    Although the study was a retrospective study.  Retrospective approach is usually limited because.    In the Santos study. This can be answered when the study  described a prospective approach in identifying patients in the study. we may  have to observe them over time.    WHAT ARE THE RESULTS?    What were the diagnoses and their probabilities? How precise are the estimate  of the probabilities?    The probabilities of the differential diagnosis are reported as either incidence or  prevalence with their 95% confidence interval.  Page 19 . and c) acute gastroenteritis.

 Guyatt GH. A little knowledge on epidemiology of disease  across time may be necessary to have an accurate answer to this question.    • Do you think the disease probabilities in the study still apply today?    Disease prevalence and incidence change across time.    RESOLUTION OF THE PROBLEM IN THE SCENARIO    After appraising the study of Santos you decided that your diagnostic tests will  focus on ruling in or ruling out typhoid fever. Nishikawa J. Old disease can be  controlled because of effective treatment.     In the Santos study. Cook DJ. J Gen Intern  Med 1997. Appleton and Lange. JAMA. Unfortunately you cannot find a more recent one. Evidence‐based Medicine: A framework for clinical practice.    Richardson WS. The probability of Dengue fever may differ  in different times of the year. urinary tract infection and  gastroenteritis. 1999 Apr 7.    Kroenke K.  However if the disease in question does not vary over time then this is not a  problem.  1998. Wilson MC. Seasonal variation may have been accounted for but the study  is already 9 years old. 281(13):1214‐9.  the probability is almost zero today. Symptoms and science: the frontiers of primary care research [Editorial]. Thus a paper on differential diagnosis  may still include smallpox for patients with fever and skin lesions in the 1950’s.      REFERENCES   Friedland ed. they included patients consulting in the emergency room  but were eventually sent home.  Page 20 . The cases seen in this study seemed to be the  milder cases similar to your patient. and the Evidence Based Medicine  Working Group.    The study of Santos was a three‐year retrospective study from January 1988 to  December 1991. 12: 509 ‐ 510.Evidence-based Medicine Self-Instructional Manual   CAN THE RESULTS HELP ME IN CARING FOR MY PATIENTS?    • Are the study patients similar to my own?    For a study on differential diagnosis be applied to your patient you have to be  assured that the characteristics of your patient is similar to the study’s inclusion  criteria.

 Focus on the abstract.          Page 21 . analyze the results and determine the applicability of the results.    Ask the group to read the article retrieved to answer the problem in the  scenario. Another objective is to  introduce concepts of critical appraisal of an article regarding differential  diagnosis focusing on the following:    • validity  • interpretation of the results  • applicability of the results      INSTRUCTIONS   Divide the participants into groups of six to ten persons per group. Focus on barriers and solution to the application of the  exercise in usual clinic practice. Assign a case  scenario to each group and formulate an answerable problem from the scenario.Evidence-based Medicine Self-Instructional Manual WORKSHOP CRITICAL APPRAISAL OF AN ARTICLE ABOUT DIFFERENTIAL DIAGNOSIS (SESSION BRIEFING)     OBJECTIVES   The purpose of the workshop is to introduce to the participants the concept of  medical decision making about differential diagnosis. methods and results section. Answer validity  questions.    Critically appraise the article using the appraisal sheet provided.  Establish another group consensus and note any change in decision.    Process the exercise.  Establish initial group consensus on how to proceed with the scenario. Again establish a  group consensus on how to proceed with the scenario. Note any change in  decisions.

      Page 22 .Evidence-based Medicine Self-Instructional Manual TIME ALLOTTED   The time allotted for this workshop is two hours. The recommended break‐up is:    • 15 minutes to analyze the scenario and develop consensus  • 15 minutes to read the article  • 45 minutes to appraise the validity  • 15 minutes to analyze results  • 20 minutes to establish applicability  • 10 minutes to summarize the process      DESIRED OUTCOME   The participants should make a clinical decision on the scenario based on the  critical appraisal of the evidence.

Evidence-based Medicine Self-Instructional Manual Appraisal Sheet  CLINICAL DECISION ON DIFFERENTIAL DIAGNOSIS        CLINICAL SCENARIO OR      QUESTION            SEARCH                    CRITICAL APPRAISAL        RELEVANCE  Is the objective of the article on differential diagnosis  similar to your clinical dilemma?            PRIMARY VALIDITY  Did the study patients represent the full spectrum of  GUIDES  patients who present with this clinical problem?  Definition of the clinical problem or the patient whom the  study will be applied.              Were the criteria for each final diagnosis explicit and  credible?   Determination of final diagnosis must be clearly described.                   SECONDARY VALIDITY  Was the diagnostic work‐up comprehensive and  GUIDES  consistently applied?          Page 23 .  may not necessarily be the ultimate reference standard.

Evidence-based Medicine Self-Instructional Manual OVERALL. was follow‐up to come  up with a diagnosis sufficiently long and complete?                    What were the diagnoses and their probabilities? How  precise are the estimates of probabilities?                                Are the study patients similar to my own?  Inclusion criteria. clinical definition                Do you think the disease probabilities in the study still  apply today?  Is the study recent? Could the probabilities change since the  study publication?                       Page 24 . exclusion criteria. IS THE STUDY  VALID?    WHAT ARE THE  RESULTS?    CAN THE RESULTS HELP  ME IN CARING FOR MY  PATIENTS?    RESOLUTION OF THE  PROBLEM IN THE  SCENARIO    For initially undiagnosed patients.

 Focus on the  critical appraisal questions.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CRITICAL APPRAISAL OF AN ARTICLE ABOUT A DIAGNOSTIC TEST (SESSION BRIEFING)     CHECKLIST   Have you read the previous topic on differential diagnosis?   Yes          No    Have you undergone the workshop on differential diagnosis with your group?   Yes          No    Did you enjoy the workshop?   Yes          No    If your answer is no to the last question please state the reasons below and  share it to the group before starting the next workshop. why they are asked and how to get the answers from  the paper.     After reading the paper you can proceed to conduct the group workshop.        Page 25 . you should be able to answer the user guides  questions for the workshop. At  the end of the reading session.      INSTRUCTIONS   Read the reading assignment for an article about a diagnostic test.       OBJECTIVES   The purpose of the reading assignment is to introduce to the participants the  concept of medical decision making using an article about a diagnostic test.

   Because of this application to clinical practice is not ensured. Luckily the full text  was also available.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CLINICAL DECISION ON A DIAGNOSTIC TEST     CLINICAL SCENARIO   A 70 years old female patient came in to the clinic complaining of forgetfulness.    The next weekend you went to the library and try to learn more about the  MMSE.      CRITICAL APPRAISAL   RELEVANCE     • Was the objective of the paper relevant to your clinical question?    Most of the time we read journal articles because the topic is interesting. June 1996.      SEARCH   After searching in the MEDLINE you found the article by Mulligan et al entitled “  A comparison of alternative methods of screening for dementia in clinical  settings” published in the Archive of Neurology. but you  doubt her decision.  We can only  ensure that the results of the article are applied to practice if the objectives of  the article are relevant to the clinical problems we see in clinical practice.        Page 26 .  She’s afraid that she has dementia just like her sister. Thus  the objective of the study must determine the accuracy (outcome) of the  contemplated diagnostic test (intervention/exposure) among patients  (population) similar to your case scenario. She does not want to be  subjected to MRI or CT scan. You referred her to the psychiatric resident and she  suggested that you perform the Mini‐mental State Examination (MMSE).

 use of a reference standard  and independent comparison.           Page 27 . If all groups are equally represented the average  accuracy will be obtained. The elderly age group is the population with the  highest risk of dementia thus the results from this study may be an  overestimate. If the diagnostic test  approximated the standard. The clinical utility of a test  can be seen when used among persons who are healthy. Thus the accuracy of the  test should be compared against the standard. Patients consulting in family practice usually belong to the  healthy and in‐between groups while patients consulting in the hospitals are  those in the in‐between and more severe groups.       • Did the patient sample include an appropriate spectrum of patients to  whom the test will be used?     The accuracy of a diagnostic test among patients with low risk for the disease is  different from patients with high risk of the disease. Thus the first question you should answer is whether there was a  comparison with the reference standard and whether the reference standard  used was acceptable to your setting.    In the study by Mulligan et al the reference standard used was the diagnosis of  dementia based on the DSM‐III‐R. that means the test also approximates the “truth”.  An independent comparison means that the reader of the reference standard  did not know the result of the diagnostic test being evaluated (Jaeschke. The in‐between groups may  give an underestimate of the accuracy of the test (but it is the accuracy value to  whom the test will be used) while the healthier and more severe may give an  overestimate of the accuracy. patients who are very  sick and mostly those in‐between because these are the patients who will be  requiring the test.    The study of Mulligan et al included elderly patients consulting in a geriatric  hospital and memory clinic. A reference standard for a diagnostic test is the  test that gives the information nearest to the “truth”. 1994).Evidence-based Medicine Self-Instructional Manual VALIDITY GUIDES    • Was there an independent comparison with a reference standard?    There are two elements in this guide question i. The second is whether the reader of the  reference standard was blinded to result of the diagnostic test being evaluated.e.  Awareness of the initial test result may lead to increase confirmation with  reference standard leading to bias on the accuracy of the diagnostic test being  evaluated.

 This is called verification bias (Jaeschke. In actual practice however. IS THE STUDY VALID?    Yes. and the greater the likelihood  ratio the greater is the increase in chance.  To avoid this. when positive. drugs to avoid. A likelihood ratio of greater than  1 increase the chance that the disease is present.    WHAT ARE THE RESULTS?    • What were the likelihood ratios for the different possible test results?    Likelihood ratio indicates by how much a given test result increases the pre‐test  probability of the disease. the study must show that the reference standard was done  regardless of the result of the diagnostic test being evaluated.    • Were the methods for performing the test described in sufficient detail  to permit replication?    This is necessary so that the reader will be able to duplicate the test in his/her  own setting and get the same valid result. Description should include  preparation for the patient such as diet. physicians request  to perform the reference standard based on the initial result of the diagnostic  test.    There are a lot of papers dealing with instructions on how to administer the  MMSE and its interpretation.    Page 28 . ideal  conditions for performing the diagnostic test and a step by step description of  how the diagnostic test is done and interpreted. A likelihood ratio of 1 means that the post‐test  probability is similar to the pre‐test probability.Evidence-based Medicine Self-Instructional Manual • Was the reference standard done regardless of the result of the  diagnostic test being evaluated?    In some studies.e.    OVERALL. 1994). You accepted the validity since most of the questions were answered  adequately. The reference standard is used to verify the initial finding i.    It was mentioned in the Mulligan et al study that the comparison with the DSM‐ III‐R was blind and independent.  When this happens most of the data available will be those positive for the  diagnostic test and will likely be positive in the reference standard. precautions. This will  increase the accuracy of the test. the accuracy of a diagnostic test is examined retrospectively  (chart review of actual practice).

 decide for yourself. The paper  should report measures of agreement between interpreters or raters.      Page 29 . the reproducibility of the interpretation  is necessary for the test to be adequately applied in your setting. and   • LRs of 1‐2 and 0.    CAN THE RESULTS HELP ME IN CARING FOR MY PATIENTS?    • Will the reproducibility of the test result and its interpretation be  satisfactory in my setting?    Even if the test was described very well.46 and the LR (‐) is 0.    In the Mulligan study the LR (+) MMSE is 2.5‐1 alter probability to a small (and rarely important)  degree. The  alternative clinical test is the Antisaccadic Eye Movement Test (AEMT) but did  not do very well compared with the MMSE.5‐0. The formula for computing the likelihood ratio from sensitivity and  specificity is shown below:    Likelihood ratio of a positive test            LR (+) = Sn/1‐Sp  Likelihood ratio of a negative test           LR (‐) = 1‐Sn/Sp    A rough guide in evaluating LR values:   • LRs >10 or < 0.2 generate small (but sometimes important) changes  in probability.     If agreement is not reported. then you can apply the results to your  patient.1‐0.2 generate moderate shifts in pre‐ to post‐test  probability.14.Evidence-based Medicine Self-Instructional Manual Some papers give the sensitivity and specificity values rather than the likelihood  ratio. and the inclusion criteria  include characteristics of your patient.   • LRs of 5‐10 and 0. Sometimes your clinical judgment is required. Is the interpretation simple  enough? Is the basis of the interpretation clear and specific?    The MMSE questionnaire also contains instruction on how to administer the test  and interpret the result.   • LRs of 2‐5 and 0.1 generate large. and often conclusive changes from pre‐  to post‐test probability.      • Are the results applicable to my patient?    If your setting is somewhat similar to that in the study.

How to Use an Article About a Diagnostic Test: Results and Applicability. JAMA.    RESOLUTION OF THE PROBLEM IN THE SCENARIO    After looking at the Mulligan et al study. Guyatt G. you agreed with the psychiatry resident  and even asked her help to administer the MMSE to the patient yourself. Sackett D. How to Use an Article About a Diagnostic Test: Validity Guides. and the Evidence Based Medicine Working Group. Guyatt G. then you don’t have to perform the test. JAMA. Sackett D.Evidence-based Medicine Self-Instructional Manual • Will the results change my management?    The usefulness of a diagnostic test result is whether it will help the clinician  manage his/her patient. 1994. 271(9):703-707. then the test is helpful and may be requested. 271(5):389-391. If the diagnostic test will lead the doctor decide to give  treatment or not. However if after  applying the LR value to determine the post‐test probability and this did not help  in the decision. and the Evidence Based Medicine Working Group. Jaeschke R.      REFERENCES Jaeschke R.                                                 Page 30 . 1994.

 establish a group consensus on how to proceed with the scenario. Focus on barriers and solution to the application of the  exercise in usual clinic practice.    Ask the group to read the article retrieved to answer the problem in the  scenario.  Establish another group consensus and note any change in decision. Another  objective is to introduce concepts of critical appraisal of an article regarding a  diagnostic test focusing on the following:    • Validity  • Reference standard  • Sensitivity and specificity  • Likelihood ratios  • Applicability of the results      INSTRUCTIONS   Divide the participants into groups of six to ten persons per group. Advice them to focus on the abstract.    Critically appraise the article using the appraisal sheet provided. Answer validity  questions.    Process the exercise. Note  any change in decisions. analyze the results and determine the applicability of the results.Evidence-based Medicine Self-Instructional Manual WORKSHOP CRITICAL APPRAISAL OF AN ARTICLE ABOUT A DIAGNOSISTIC TEST (SESSION BRIEFING)     OBJECTIVES   The purpose of the workshop is to introduce to the participants the concept of  medical decision making about the usefulness of a diagnostic test.                    Page 31 . Assign a case  scenario to each group and formulate an answerable problem from the scenario. methods and results section.  Again.  Establish initial group consensus on how to proceed with the scenario.

Evidence-based Medicine Self-Instructional Manual TIME ALLOTTED   The time allotted for this workshop is two hours.                                                       Page 32 . The recommended break‐up is:    • 15 minutes to analyze the scenario and develop consensus  • 15 minutes to read the article  • 45 minutes to appraise the validity  • 15 minutes to analyze results  • 20 minutes to establish applicability  • 10 minutes to summarize the process      DESIRED OUTCOME   The participants should make a clinical decision on the scenario based on the  critical appraisal of the evidence.

Evidence-based Medicine Self-Instructional Manual Appraisal Sheet  CLINICAL DECISION ON A DIAGNOSTIC TEST        CLINICAL SCENARIO OR      QUESTION            SEARCH                    CRITICAL APPRAISAL        RELEVANCE  Is the objective of the study relevant to your clinical  question?            VALIDITY GUIDES  Was there an independent and blind comparison with a  reference standard?  What was the reference standard. Were they assessed  independently?                Did the patient sample include an appropriate spectrum of  patients to whom the test will be used?                     Was the reference standard done regardless of the result  of the diagnostic test being evaluated?              Page 33 .

 IS THE STUDY  VALID?      WHAT ARE THE  RESULTS?    Were the methods for performing the test described in  sufficient detail to permit replication?                        What were the likelihood ratios for the different possible  test results?                  Will the reproducibility of the test result and its  interpretation be satisfactory in my setting?              Are the results applicable to my patient?            Will the results change my management?                  CAN THE RESULTS HELP  ME IN CARING FOR MY  PATIENTS?  RESOLUTION OF THE  PROBLEM IN THE  SCENARIO  Page 34 .Evidence-based Medicine Self-Instructional Manual OVERALL.

 why they are asked and how to get the  answers from the paper.     After reading the paper you can proceed to conduct the group workshop.      OBJECTIVES   The purpose of the reading assignment is to introduce to the participants the  concept of medical decision making using an article about therapy or prevention. you should be able to answer the user guides  questions for the workshop.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CRITICAL APPRAISAL OF AN ARTICLE ABOUT THERAPY OR PREVENTION (SESSION BRIEFING)     CHECKLIST   Have you read the previous topic on diagnostic tests?   Yes          No    Have you undergone the workshop on diagnosis with your group?   Yes          No    Did you enjoy the workshop?   Yes          No    If your answer is no to the last question please state the reasons below and  share it to the group before starting the next workshop. Focus  on the critical appraisal questions.      INSTRUCTIONS   Read the reading assignment for an article about therapy or prevention.      Page 35 .     At the end of the reading session.

 When done properly.      SEARCH   You decided to translate this clinical dilemma to an answerable question. further work‐ups revealed  hypercholesterolemia with a level of 6. it can provide the  best evidence of effectiveness.  male bank executive came to your clinic for constricting chest pain located at  mid‐sternum precipitated by exertion and relieved by rest.      RANDOMIZED CONTROLLED TRIALS   Randomized controlled trials are the standards design to prove effectiveness of  drugs or other forms of intervention. before applying the results to your patient.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CLINICAL DECISION ON THERAPY OR PREVENTION     CLINICAL SCENARIO   You are working at the out‐patient clinic in your institution when a 55 year‐old.  you decided to appraise the article using the following guides.  However.  The drug intervention  should be compared with placebo. you wanted an  article that employed randomization.   An ECG was done revealing lateral wall ischemia.  You  also decided that the article should include a population of patients that has an  elevated cholesterol who have already undergone dietary therapy for at least 6  months to be consistent with your patient’s profile.  However. one with the  Page 36 .  You gave dietary advice but  the patient claimed that he has been on a high fiber diet with low fat intake for  the past 6 months.    The article you finally retrieved included 4444 patients randomized to either  simvastatin or placebo. such as reduction in cardiovascular deaths.5 mol/liter.  His blood pressure  was 130/80. In this type of design. individuals are randomly  assigned (randomization) to either of the two or more groups.  The article must report clinically important  outcomes.  You sent the patient home on  oral nitrates and aspirin.    He is now inquiring if he should take a drug for his elevated cholesterol. heart rate was 85/minute and the respiratory rate was 20/minute.  Finally.

 randomization was done and  was written both in the abstract and methods section.  • Intervention/comparative intervention/exposure (I) – should include the  therapeutic intervention you want to test. the reader is advised to look into the article’s  abstract or methodology section.  In the absence of  randomization. it  assures that both known and unknown determinants of outcome are evenly  distributed between the treatment and control groups.      VALIDITY GUIDES    • Was the assignment of patients to treatment randomized?    In order to answer this question.    • Outcome of the study (O) – one of the outcomes measured should be the  goal you and your patient wish to work for. 1994). first ascertain if the objective of the study addresses  the clinical problem you face.      CRITICAL APPRAISAL   RELEVANCE    • Is the objective of the article comparing therapeutic interventions  similar to your clinical dilemma?    Before going any further.  Below are a few tips  that will help you decide on relevance:    • Population of the study (P )– should be similar to the characteristic of  your patient.  Appraising an irrelevant article would not be  helpful to your clinical dilemma and will be a waste of time.    Page 37 . 2000). relief of  symptoms or improvement in quality of life (Espallardo.  For the 4S study. The outcome can be the cure of a disease. these factors might be difficult to control and might be the one  strongly influencing outcome rather than the treatment itself (Guyatt.    The strength of randomization is that if the sample size is sufficiently large.Evidence-based Medicine Self-Instructional Manual intervention the other without the intervention being tested or another  intervention. Then they are observed forward in time and their  outcome compared. Randomization tries to make the two groups similar for both  known and unknown factors that may affect the outcome other than the  intervention being tested.

 1994). will be.  If  substantial numbers are “lost to follow‐up”.  If the number lost to follow‐up is less than this the reader can  decide if this affects the conclusion by assuming a “worst case scenario”.  A drop‐out rate of 20% or more is usually declared as  substantial.    Excluding non‐compliant patients from the analysis leaves behind those who  may be destined to have a better outcome and destroys the unbiased  comparison provided by randomization.         Page 38 . randomization might not be feasible.  If this is reported one can safely assume  that follow‐up was complete.    Were all patients who entered the trial properly accounted for and attributed at  its conclusion?     • Was follow‐up complete?    This is best checked by looking at the number of patients enrolled at the outset  and comparing this with the number of patients reported in the results table.  In these cases.  This  means that the numbers lost in the treatment group are assumed to have bad  outcomes and the numbers lost in the control group are assumed to have been  cured and if the conclusions differ.    Every patient who entered the trial should be accounted for at its conclusion. and those we don't know about. a clinician must rely on  weaker studies but should be aware of its potentials for errors. and the effect we see will be just that due  to the treatment assigned (Guyatt.    Another way of deciding whether follow‐up was complete is to check whether an  intention to treat analysis was done. a substantial number was lost to follow‐up. the validity of the conclusions are  open to question.Evidence-based Medicine Self-Instructional Manual At times though because of the rarity of the disease and small patient sample  size. on average.    • Were patients analyzed in the groups to which they were randomized?    It simply means that all those belonging to the control group or treatment group  are analyzed from beginning to end in this same grouping including those who  were dropped or withdrawn or changed treatment. This strategy preserves the value of randomization: prognostic factors  that we know about.  No crossing over treatment  modalities were done as this would likely lead to biased results.  equally distributed in the two groups. This principle of attributing all patients  to the group to which they were randomized results in an "intention‐to‐treat"  analysis.

    • Aside from the experimental intervention. IS THE STUDY VALID?    If you want to be strict about it. clinicians  and data analysts are likely to have an opinion regarding the experimental  treatment. you should answer yes in all 5 questions.    Blinding is the process by which the intervention being given is concealed from  the patient. are called “co‐interventions”.  This might  distort the results since they in themselves might cause changes in reported  outcomes. baseline characteristics were similar.    • Were the groups similar at the start of the trial?    To answer this question. you as the user of the journal can make the decision.    For reassurance about the study’s validity. when differentially applied  to the treatment and control groups.      Page 39 .   However.  Patients. the more likely that the results can be attributed to the  intervention.    OVERALL.  this is labeled as table 1. hence you decided that  over‐all the study was valid. blinding is necessary.  As to avoid these “reporter and  observer” bias. rather than due to the differences in these factors.  A simple rule  might be to answer yes to at least. can systematically  distort reporting of treatment outcomes.  The  greater the similarity between known prognostic factors for the control and  experimental group.  In the 4S trial.  These opinions. whether optimistic or pessimistic.    The 4S study yielded yes to all the appraisal questions.  For most studies. were the groups treated  equally?     Interventions other than the treatment under study. readers would like to be informed  that the treatment and control groups were similar for all the factors that  determine clinical outcomes of interest save for the experimental therapy. one should look for a report of the comparison of the  baseline characteristics of the experimental and control group. one primary guide and two secondary guides. the clinicians and the one who analyzes the data. and study personnel "blind" to  treatment?    To answer this question the reader is again advised to look into the abstract or  the methodology section.Evidence-based Medicine Self-Instructional Manual • Were patients. their clinicians.  You now proceed to analyze the results.

 11.  The most useful measure to use in explaining the benefit of  treatment to patients is the relative risk reduction.     Ideally.082/0.  In this case. the more precise your estimates.  But how else could this figures be compared?  The following  simple computations could help:    Risk in Control (Rc) = Death in control/N patients in the control    Risk in Treatment (Rt) = Death in treatment/N patients in treatment    Absolute Risk Reduction (ARR) = Rc – Rt = 0.082 = 0.  Patients either do or do not suffer these events and  the article frequently reports the proportion of patients who develop such  events.5% died in the placebo group and 8.71    Relative Risk Reduction (RRR) = 1 – RR = 1‐ 0. simvastatin seems better in  reducing deaths.            Page 40 .  If this is not  reported check the p‐value.115 = 0.71 = 0. one should look at the reported 95% confidence  interval.    • How precise was the estimate of treatment effect?    To decide regarding precision.115 ‐ 0. the reported minimum and maximum values of this interval should all be  positive or all be negative for the absolute risk reduction.  Relative risk is the  risk of events in the simvastatin group or new treatment relative to the placebo  or control group.  Examples of outcomes include cure  rates.Evidence-based Medicine Self-Instructional Manual WHAT ARE THE RESULTS?    • How large was the treatment effect?    Most randomized controlled trials report outcomes either as treatment success  or treatment failures and adverse effects.033    Relative Risk (RR) = Rt/Rc = 0. anywhere from </= .29 (29%)    Absolute risk reduction is the absolute difference between the proportion who  died in the placebo group compared to the simvastatin group.  In the 4S study. all above below one for  the relative risk and relative risk reduction to be considered precise. simvastatin  treatment reduces deaths 29% more than placebo. side effects or death.10 is acceptable.  By eyeballing these figures.2% died in the  simvastatin group. The closer these values.

 use one of several search strategies to come up with  Page 41 . the  researchers have substituted these physiologic measures for important  outcomes we have just mentioned. giving this drug treatment is fairly  expensive.      • Are the likely treatment benefits worth the potential harm and costs?    Computation for cost effectiveness and checking for side effects might be done  to check if the treatment benefits are worth the potential harm and costs. we should decide if the  reason is compelling enough not to apply the results of our study to our  particular patient.Evidence-based Medicine Self-Instructional Manual CAN THE RESULTS HELP ME IN CARING FOR MY PATIENTS?    • Can the results be applied to my patient care?    If your patient meets all of the inclusion criteria and none of the exclusion  criteria.  Similar findings were noted in an anti‐arrhythmia trial hen the investigators had  to stop the trials when they discovered that mortality was substantially higher in  patients receiving antiarrhythmic treatment than in those receiving placebo. we hope that you are encouraged to adapt this new paradigm in  your medical decision making.  First.  That is.  These are outcomes that are important to  the patients and will lead directly to reducing symptoms or decreasing death. define the  problem clearly.  In these cases. the applicability of the study’s results to your patient is without  question.  The steps are relatively simple.   Some studies might report improvement in cholesterol levels.  It is rare however that we get a patient who conforms to all the  characteristics of the study subjects.  However due to the marked cardiac risks for this patient you decide  to give simvastatin since your patient could also afford drug treatment.    At this point.  For reduction in these laboratory  parameters does not always translate into decrease in morbidity and mortality.  morbidity. improvement in  PFTs but these are what might be labeled as surrogate endpoints.    RESOLUTION OF THE PROBLEM IN THE SCENARIO    The article was valid and giving simvastatin reduces all deaths by 29% compared  to placebo. improving quality of life.    A dramatic example of the danger of substitute endpoints was found in the  evaluation of the usefulness of clofibrate as anti‐cholesterol drug.    • Were all clinically important outcomes considered?                  Clinically important outcomes may range form decreasing mortality.  However when we look into costs.  Second. It shown to  decrease serum cholesterol but was shown to increase all‐cause mortality.

 How to Use an  Article About Therapy or Prevention: Validity.Evidence-based Medicine Self-Instructional Manual relevant articles.  Third. Inc. Sackett D. appraise the article. 1993. 1994.    Guyatt GH.    This may sound like a tedious process but as they say practice makes perfect. JAMA. Family Medicine  Research Group. 2000. for the Evidence Based Medicine Working Group. searching. Manila.        REFERENCES   Espallardo.270(21):2598‐2601.271(1):59‐63. for the Evidence Based Medicine Working Group.    Guyatt GH. NL.  Guided by this.   And if each of us will continue asking. Cook DJ. Sackett D. Cook DJ. How to Use an  Article About Therapy or Prevention: Results and Apllicability.                                                          Page 42 . you then decide on  the action to take. Research Protocol Development for Resident Physicians. we will continue learning and  hopefully improving our patient care. JAMA.  Assess the results and the  applicability of your article to your patient.

 Answer validity  questions.  Establish initial group consensus on how to proceed with the scenario. Another objective is to introduce  concepts of critical appraisal of an article regarding treatment focusing on the  following:    • validity  • randomization  • intention‐to‐treat  • interpretation of the results  • applicability of the results  • clinically relevant endpoints  • cost‐effectiveness      INSTRUCTIONS   Divide the participants into groups of six to ten persons per group.    Process the exercise. Focus on the abstract.    Ask the group to read the article retrieved to answer the problem in the  scenario.Evidence-based Medicine Self-Instructional Manual WORKSHOP CRITICAL APPRAISAL OF AN ARTICLE ABOUT THERAPY OR PREVENTION (SESSION BRIEFING)     OBJECTIVES   The purpose of the workshop is to introduce to the participants the concept of  medical decision making about treatment. Note any change in  decisions. Assign a case  scenario to each group and formulate an answerable problem from the scenario.    Critically appraise the article using the appraisal sheet provided. establish a  group consensus on how to proceed with the scenario.  Page 43 . Focus on barriers and solution to the application of the  exercise in usual clinic practice.  Establish another group consensus and note any change in decision. Again. methods and results section. analyze the results and determine the applicability of the results.

 The recommended break‐up is:    • 15 minutes to analyze the scenario and develop consensus  • 15 minutes to read the article  • 45 minutes to appraise the validity  • 15 minutes to analyze results  • 20 minutes to establish applicability  • 10 minutes to summarize the process      DESIRED OUTCOME   The participants should make a clinical decision on the scenario based on the  critical appraisal of the evidence.                                                        Page 44 .Evidence-based Medicine Self-Instructional Manual TIME ALLOTTED   The time allotted for this workshop is two hours.

Evidence-based Medicine Self-Instructional Manual Appraisal Sheet  CLINICAL DECISION ON THERAPY OR PREVENTION        CLINICAL SCENARIO OR      QUESTION            SEARCH                    CRITICAL APPRAISAL        RELEVANCE  Is the objective of the article comparing therapeutic    interventions similar to your clinical dilemma?            VALIDITY GUIDES  Was the assignment of patients to treatment randomized?  Randomization vs. random selection              Were all patients who entered the trial properly accounted  for and attributed at its conclusion?     Was follow‐up complete?  Dropouts. withdrawals              Were patients analyzed in the groups to which they were  randomized?  Intention‐to‐treat analysis            Page 45 .

 relative risk  reduction.Evidence-based Medicine Self-Instructional Manual     OVERALL. relative risk. results               Page 46   CAN THE RESULTS HELP  ME IN CARING FOR MY  PATIENTS?  . absolute risk reduction                            How precise was the estimate of treatment effect?  95% confidence interval. p value          Can the results be applied to my patient care?  Inclusion criteria. IS THE STUDY  VALID?      WHAT ARE THE  RESULTS?    Were patients. and study personnel "blind"  to treatment?                        How large was the treatment effect?  Risk in control. exclusion criteria                Were all clinically important outcomes considered?  Outcome. risk in treatment. their clinicians.

Evidence-based Medicine Self-Instructional Manual   RESOLUTION OF THE  PROBLEM IN THE  SCENARIO                                                                Are the likely treatment benefits worth the potential harm  and costs?  Side effects. NNT. costs                  Page 47 .

 why they are asked and how to get the answers from the  paper.       OBJECTIVES   The purpose of the reading assignment is to introduce to the participants the  concept of medical decision making using an article about harm. Focus on the critical  appraisal questions.     After reading the paper you can proceed to conduct the group workshop.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CRITICAL APPRAISAL OF AN ARTICLE ABOUT HARM (SESSION BRIEFING)     CHECKLIST   Have you read the previous topic on treatment?   Yes          No    Have you undergone the workshop on treatment with your group?   Yes          No    Did you enjoy the workshop?   Yes          No    If your answer is no to the last question please state the reasons below and  share it to the group before starting the next workshop.     At the end of the reading session. you should be able to answer the user guides  questions for the workshop.      INSTRUCTIONS   Read the reading assignment for an article about harm.          Page 48 .

      SEARCH   You found the article by Zureik et al. entitled “Serum cholesterol concentration  and death from suicide in men: Paris prospective study 1” published in the  British Medical Journal.35 mmol/L but the patient was still  prescribed with anti‐cholesterol drug from his last week visit.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CLINICAL DECISION ON HARM     CLINICAL SCENARIO   You are the resident physician covering for the consultant in his clinic.      COHORT AND CASE-CONTROL STUDIES   Harmful effects of drugs or other exposure can best be studied with cohort or  case‐control study designs.     Cohort studies can also be prospective or retrospective depending on the  manner of patient recruitment.    Still doubtful. selection of subjects starts with  identifying individuals who have the same characteristics or presence or absence  of a particular cause or exposure. A cohort is any group of individuals who share the  same characteristics. but if the cohort already existed in the past and data gathering is  being done by reviewing existing clinical records then it is retrospective  (Espallardo. you went to the library and look for the harmful effect of very low  cholesterol. those  with the characteristics or causes and those without the characteristics. it’s the high cholesterol  that we should be concerned with anyway. They are  then observed forward in time and determine who among them develop the  outcome or effect (Espallardo. You met  one of his patient. He told you its okay. You  noted that his cholesterol is now only 4. In a cohort study. September 1996. 45 year old male who is on anti‐cholesterol medication. If recruitment is being done forward in time it is  prospective. 2000). You approach the  consultant and mentioned it to him.    Page 49 . 2000). They are then divided into two groups.

  This must be clearly stated by the objective of the study.      CRITICAL APPRAISAL   RELEVANCE    • Is the objective of the article on harm similar to your clinical dilemma?    Your formulated clinical question must be addressed by the objective of the  study. 2000). Both designs has a control  group for comparison.Evidence-based Medicine Self-Instructional Manual In a case‐control study. studies of harm require that a  control group for comparison should be done. but if the cases have already developed in the  past and patient recruitment is being done by reviewing existing clinical records  then it is retrospective (Espallardo. Both the cases and the control should be taken  from within the same population.    VALIDITY GUIDES    • Were there clearly identified comparison groups?    Just like studies of effectiveness of treatment. so studies of weaker design like  cohort or case‐control studies may be relied upon. inclusion of subjects starts with defining or selecting  those who have the outcome or effect. 2000). For a decision to stop the harmful exposure the article must be designed  to determine the harmful effect (outcome) of the a drug.    In a cohort study. patients with the outcome are  gathered. Then the outcome is  observed forward in time. These  are considered as the controls. If recruitment is being done as cases develop  forward in time it is prospective. In a case‐control study. Then this  group is compared with subjects who don’t have the outcome or effect. Unfortunately. a group of patients are observed. Then a group of patient without the outcome matched to the  preceding group for certain characteristics other than the exposure is also  Page 50 . randomized  controlled trials to prove harm is not ethical. Then the two groups are investigated as to the  presence or absence of hypothesized causes or risk factors for the outcome  (Espallardo. in the former controls are chosen by absence of exposure  and in the latter by absence of the outcome or disease. chemical or  environmental substances (intervention/exposure) to the patient (population). These are considered as cases.     Case‐control study can be prospective or retrospective depending on the  manner of patient recruitment. They are divided into those  with the exposure and those without the exposure.

2 when the years of observation  was extended to 15 years and beyond.          Page 51 .728 men who had measurements of serum  cholesterol. This study design can also be a basis for  establishing harmful effect.78 to 6. In cohort study.78  mmol/L). The changes  were also categorized.21 mmol/L) and high (>6. When the relation between asbestos and lung cancer was being  investigated the relative risk was only 1. 1994).21 mmol/L). They had  95% follow‐up. 1994). They grouped and categorized cholesterol levels into low (<4.    The study by Zureik observed 6. These were the comparison groups. This bias may also occur in case‐ control studies. the chance of underestimating the effect of the exposure is  high.Evidence-based Medicine Self-Instructional Manual gathered. when the detection of exposure is more diligent in the group  with the disease or outcome. there will be a higher detection rate of the outcome leading to  increase incidence of the disease in the exposed group. normal (4.    • Was follow‐up sufficiently long and complete?     The length of follow‐up must be sufficiently long enough to detect the outcome. This must be avoided. When the patient with the exposure were observed more  diligently. The presence of the exposure in both groups is then ascertained  (Levine.4 in the early years of observation  compared to the subsequent relative risk of 18.    • Were the exposures and outcomes measured in the same way in the  groups compared?    Measurement of outcomes must be similar in both groups. patients are grouped and analyzed with respect to  their outcome and exposure. This is called surveillance  bias (Levine.  If follow‐up is short.    Suicide data were taken from the national databases and death certificates in all  groups in the Zureik study. the  investigators must show that diligent observation for the outcome was done in  the groups with the exposure (high risk) as well as the groups without the  exposure (low risk). but the temporal relationship of the exposure  occurring before the outcome cannot be established.     In a cross‐sectional study.     The Zureik study observed their patients for 4 years after enrolment.

 If the relative risk is more than 1.Evidence-based Medicine Self-Instructional Manual • Is the temporal relationship between the exposure and outcome correct  and dose response gradient present?    For an exposure to cause an effect.22. the study can be considered valid.  First the exposure must be present before the outcome and second there must  be a dose response gradient. IS THE STUDY VALID?    Since all the answers to the validity guides.e.    In a case control study.     The Zureik study showed that those with low cholesterol had increased risk of  suicide with a relative risk of 3.     OVERALL.16 with a 95% CI of 1. two important criteria may be considered. The analysis was  also adjusted for age. Relative risk is usually computed  when the design is a cohort study. Cross‐sectional studies usually cannot establish temporal  relationship but it can establish a dose response gradient and a comparison  between groups. The odds ratio approximates  the relative risk.     The values of 95% confidence interval should be greater than 1 to say that the  exposure really causes harm. the odds ratio is computed.              Page 52 .38 to 7. especially when the disease is rare. i.    WHAT ARE THE RESULTS?    • What is the magnitude of the association between exposure and  outcome? Was the estimate of the risk precise?    The relative risk is the incidence of the adverse effect in the group with the  exposure divided by the incidence of adverse effect in the group without the  exposure. then the effect of the exposure is uncertain. then the exposure is causing harm  and if less than 1 the exposure reduces harm. If one value of the 95% confidence interval is less  than 1 and the other is more than 1. the higher the dose the higher is the probability  of the outcome. smoking and mean corpuscular volume.     The Zureik study measured serum cholesterol before the event of suicide so the  temporal relationship was correct.

 for the harmful effect to be  extrapolated to your patient you have to be assured that the characteristics of  your patient is similar to the study’s inclusion criteria.    RESOLUTION OF THE PROBLEM IN THE SCENARIO    Based on the appraisal you decided to go back to your consultant and inform  him about the study that you found. NL. Walter S.    Levine M. for the Evidence Based Medicine  Working Group. Family Medicine  Research Group.Evidence-based Medicine Self-Instructional Manual CAN THE RESULTS HELP ME IN CARING FOR MY PATIENTS?    • Are the study patients similar to my own?    Just like in an article about a beneficial intervention.     The Zureik study recruited men between 43 to 52 years old with similar  demographic characteristics with our patient. He thanked you for the information and  promised to withdraw the anti‐cholesterol drug when the patient comes back. but withdrawing smoking may lead to “decrease quality of  life” for smokers.  So the decision to withdraw smoking for every patient consulting in the clinic is  warranted. Inc. Lee H. How to Use an Article about Harm. 2000.271(20):1615‐1619. Holbrook A. For example  cigarette smoking has been associated with increase incidence of lung cancer  and cardiac deaths.      REFERENCES   Espallardo. 1994. Research Protocol Development for Resident Physicians.      • Should I attempt to stop the exposure?     In answering this question you should consider the following:  • How large and precise is the risk of harm?  • What are the consequences if I withdraw the exposure?  • Do I have any alternative for the exposure?    Decision is simple when the answers to these questions are clear. Manila. Haines T. Moyer V. JAMA.          Page 53 . But recently an alternative like nicotine patch has been shown  to decrease withdrawal discomfort and eventually improve smoking cessation.

 case‐control study.            Page 54 . Focus on the abstract. Focus on barriers and solution to the application of the  exercise in usual clinic practice.    Process the exercise. case series and case report  • Interpretation of the results  • Applicability of the results      INSTRUCTIONS   Divide the participants into groups of six to ten persons per group. Another  objective is to introduce concepts of critical appraisal of an article regarding a  harmful effect of a substance or drug focusing on the following:    • Validity  • Cohort study.  Establish initial group consensus on how to proceed with the scenario. methods and results section. Answer validity  questions.    Ask the group to read the article retrieved to answer the problem in the  scenario. Again.Evidence-based Medicine Self-Instructional Manual WORKSHOP CRITICAL APPRAISAL OF AN ARTICLE ABOUT HARM (SESSION BRIEFING)     OBJECTIVES   The purpose of the workshop is to introduce to the participants the concept of  medical decision making about harmful effect of a substance or drug.    Critically appraise the article using the appraisal sheet provided. establish a  group consensus on how to proceed with the scenario. Note any change in  decisions.  Establish another group consensus and note any change in decision. analyze the results and determine the applicability of the results. Assign a case  scenario to each group and formulate an answerable problem from the scenario.

 The recommended break‐up is:    • 15 minutes to analyze the scenario and develop consensus  • 15 minutes to read the article  • 45 minutes to appraise the validity  • 15 minutes to analyze results  • 20 minutes to establish applicability  • 10 minutes to summarize the process      DESIRED OUTCOME   The participants should make a clinical decision on the scenario based on the  critical appraisal of the evidence.Evidence-based Medicine Self-Instructional Manual TIME ALLOTTED   The time allotted for this workshop is two hours.                                                        Page 55 .

Evidence-based Medicine Self-Instructional Manual Appraisal Sheet  CLINICAL DECISION ON HARM        CLINICAL SCENARIO OR      QUESTION            SEARCH                    CRITICAL APPRAISAL        RELEVANCE  Is the objective of the article on harm similar to your  clinical dilemma?            PRIMARY VALIDITY  Were there clearly identified comparison groups?  GUIDES                Were the exposures and outcomes measured in the same  way in the groups compared?                Was follow‐up sufficiently long and complete?   Is the temporal relationship between the exposure and  outcome correct and dose response gradient present?              Page 56 .

Evidence-based Medicine Self-Instructional Manual   OVERALL. IS THE STUDY  VALID?      WHAT ARE THE  RESULTS?        CAN THE RESULTS HELP  ME IN CARING FOR MY  PATIENTS?    RESOLUTION OF THE  PROBLEM IN THE  SCENARIO                  What is the magnitude of the association between  exposure and outcome? Was the estimate of the risk  precise?                    Are the study patients similar to my own?                Should I attempt to stop the exposure?                     Page 57 .

      INSTRUCTIONS   Read the reading assignment for an article about prognosis.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CRITICAL APPRAISAL OF AN ARTICLE ABOUT PROGNOSIS (SESSION BRIEFING)     CHECKLIST   Have you read the previous topic on harm?   Yes          No    Have you undergone the workshop on harm?   Yes          No    Did you enjoy the workshop?   Yes          No    If your answer is no to the last question please state the reasons below and  share it to the group before starting the next workshop.       OBJECTIVES   The purpose of the reading assignment is to introduce to the participants the  concept of medical decision making using an article about prognosis. Focus on the critical  appraisal questions. why they are asked and how to get the answers from the  paper. you should be able to answer the user guides  questions for the workshop.          Page 58 .     After reading the paper you can proceed to conduct the group workshop.     At the end of the reading session.

Evidence-based Medicine Self-Instructional Manual

READING ASSIGNMENT

CLINICAL DECISION ON PROGNOSIS
   

CLINICAL SCENARIO
  Your brother consulted you because of what happened to his wife lately. She just  had a miscarriage (after 6 months of pregnancy) last week and she had not taken  her meals lately. They are already in their five years of marriage and they don’t  have a child yet. Your brother is asking you if they should take a vacation despite  his being very busy at work and he is trying to save for the house mortgage.  What will you advice him?    If you advice him to take a vacation, they might loss their house or even his job.  If you advice to continue working and let time heal his wife’s grief, the chance of  a psychological problem worsening is great.    Since you have attended a workshop on evidence based family practice, you  formulated the question “What is the chance that my brother’s wife will go  further into grief after the miscarriage considering that they still don’t have any  child yet?” and went to the library.     

SEARCH
  You typed the combination of the terms, pregnancy loss and prognosis and grief  and you were able to get across the article of Janssen et al. study entitled “A  prospective study of risk factors predicting grief intensity following pregnancy  loss” publish in the Archive of General Psychiatry last January 1997.    Now you proceed to see if the information in this study can be used to answer  your brother’s question.     

WHAT IS PROGNOSIS
  Prognosis refers to the development of possible “outcome” of disease i.e. death  in patient with cancer. Prognostic factors are characteristics of a particular  patient can be used to predict that patient's eventual outcome i.e. patients  advanced TNM cancer stage may have more death than those with less advance 

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TNM cancer stage. Prognostic factors need not necessarily cause the outcomes  but just predict their development. Thus prognosis is a prediction of the  probable outcome of a disease based on a individual's condition and the usual  course of the disease as seen in similar situations. Risk factors on the other hand  are patient characteristics associated with the development of the disease rather  than the outcome of the disease.     The study designs for prognostic and risk factors are cohort study and case‐ control study. Cross‐sectional studies do not give valid conclusions about  prognostic or risk factors because temporal relationship between factors and  outcome is not established.     A cohort study follows one or more groups (cohorts) of individuals who have not  yet suffered an adverse event and monitor the number of outcome events over  time. An ideal cohort study consists of well defined sample of subjects  representative of the population of interest, and uses objective outcome criteria.     Investigators can also collect "cases" of individuals who have already suffered  the outcome event (death due to cancer) and compare them to "controls" who  have not (cancer patients who are alive). In these "case‐control" studies the  investigators count the number of individuals in each group with a particular  prognostic factor (advance or less advance TNM cancer stage).     To be valid studies on prognosis, these observational studies must be conducted  and reported with information that address this appraisal guide (Von Elm, 2007)     

CRITICAL APPRAISAL
  RELEVANCE    • Is the objective of the article on prognosis similar to your clinical  dilemma?    Your formulated clinical question must be addressed by the objective of the  study. The PIO can still be applied in this type of article. The objective of the  study must clearly state that it is determining the prognosis (outcome) of some  patients with the prognostic factor (intervention/exposure) among patients with  the disease being studied (population).         

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VALIDITY GUIDES    • Was there a representative sample of patients without the outcome at  the start of observation?    The authors must specify how they defined or diagnosed the patients included in  the study. The authors should also specify at what stage of the disease they  started observing their patients. If these were not done bias can distort the  result of the study. If the study included patients who are more severe, the  prognosis will naturally be poor and if they include patients who are mild, the  prognosis will be good. However if you mix these patients in one study without  subgroup analysis, the results will be mixed and biased.    If this is not explicit in the study, you can look at the inclusion criteria or examine  the setting where the study was done. The inclusion criteria may give the basis  for the diagnosis, and the setting may give the stage of the disease i.e.  outpatient setting may have included patients in the earlier stage and hospital  setting may be patients in the late stage.    In the Janssen et al study, 221 women were recruited through a magazine add.  They had a stable marriage and reported a recent pregnancy loss. So these  women may have been recruited at a relatively similar stage.    • Was follow‐up sufficiently long and complete?     Just like in the paper about harm, the length of follow‐up must be sufficiently  long enough to detect the outcome. If follow‐up is short, the chance of arriving  at a good prognosis is high because few will develop the outcome resulting to  false hopes for the patient. If it is too long, the prognosis will be poor because  everybody will eventually die in the long term. Measuring prognosis over a given  period is usually acceptable i.e. 5 year survival for chronic diseases, 6‐24 months  survival for cancer, 30 days survival after ICU admission etc.    The number of lost to follow‐up will also lead to bias results especially when the  outcome is unknown. If patients were lost to follow‐up because they felt bad  about the outcome, prognosis will be better if they are excluded in the analysis.  If they were lost to follow‐up because they felt better and the investigators  assumed the worse scenario, the prognosis will look bad.    In the Janssen et al study, follow‐up was 94%, a relatively high rate.         
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e. b) Dutch Personality Inventory.    • Was there adjustment for other prognostic factors?    Age and sex are factors that can affect prognosis but something we cannot do  about. IS THE STUDY VALID?    Since all the validity questions were fulfilled.                Page 62 . a) Symptom  Checklist‐90. In subgroup analysis. multivariate analysis was done. using existing records and  surveys. these variables are included  into the model. The outcomes were measured using the Perinatal Grief Scale  immediately after pregnancy loss and at 6. age and sex.  In this approach the basic variables included in the model are the prognostic  factor and the outcome. 12 and 18 months. morbidity can be taken from  hospitalization records. and c) information about quality of  partnership. religion.    In the Janssen et al study. Definitions can be  taken from the NLM MESH definitions or ICD 10 classification of the WHO. social support etc.    The Janssen et al study. Mortality or survival can be taken from death  certificates and other medical records.Evidence-based Medicine Self-Instructional Manual • Were the criteria for determining the prognostic factor and outcome  explicit and credible?    The criteria for determining the outcome in study about prognosis are usually  straightforward I. This is usually described in the analysis section of the  methodology. etc. Doing subgroup analysis does  this. In some cases outcomes are recurrence of disease or  disease progression in which case this must be clearly defined.    Another method is through multivariate analysis or regression model approach.    OVERALL. the results of the study are presented for each  subgroup i. To adjust for age and sex. mortality. education.e. measured the following prognostic factors. Thus the prognosis of different TNM stage for cancer  can be presented in different age group or in different sex. the study can be considered to be  valid. Thus many prognostic studies look at the effect of other modifiable  prognostic factors by adjusting for age and sex.

 then the effect of the prognostic factor is  uncertain. then the factor results into poor prognosis and if less than 1 the  factor causes good prognosis. and d) did not have any living children. b) pre‐loss neurotic personalities.11.    The Janssen et al study reported that grief intensity was higher for a) women  who had been pregnant longer.05. In a case control study. the odds ratio is computed. studies report the p value for statistical significance i.    To be statistically significant. the upper and lower values of 95% confidence  interval should be greater than 1 to say that the factor gives a bad prognosis  when the outcome is death.99 it means the chance of developing the outcome is  almost two times (2x) and if the relative risk or odds risk is 9. The setting may also be important. If one value of the 95% confidence interval is less  than 1 and the other is more than 1. it means the chance of developing the  outcome is just slightly higher if the patient has the prognostic factor.Evidence-based Medicine Self-Instructional Manual WHAT ARE THE RESULTS?    • How large is the likelihood of outcome to occur in those with the  prognostic factor in a specified period of time? Was it statistically  significant?    The relative risk is the incidence of the outcome in the group with the prognostic  factor divided by the incidence of the outcome in the group without the  prognostic factor. c) pre‐loss  psychiatric symptoms. All these factors  were significant at p <0.  Page 63 . In some cases.     If the relative risk or odds risk is 1. especially when the disease is rare.89 the chance is  almost ten times (10x). If the  relative risk or odds risk is 1. The question of “how large is the chance” involves  preferential judgment from the patient and the physician.05 as significant. Relative risk is usually computed when the design  is a cohort study.e  p <0. for the prognostic factor to be extrapolated to  your patient you have to be assured that the characteristics of your patient is  similar to the study’s inclusion criteria.  Patients being observed in setting where the facilities are advanced and  complete may have better prognosis than among patients who are being  observed in resource poor setting even though they have the same prognostic  factor. If the outcome being measured is death and the relative risk is  more than 1. The odds  ratio approximates the relative risk.    CAN THE RESULTS HELP ME IN CARING FOR MY PATIENTS?    • Are the study patients similar to my own?    Just like in an article about harm.

 JAMA.Evidence-based Medicine Self-Instructional Manual   The subjects in the Janssen et al study were women who reported recent  pregnancy loss with stable marital relationship. Pocock S. because his wife’s grief may even intensify based on the results of  Janssen et al study. For example some patients with dyspepsia may become too worried  about the chronic epigastric symptom and can be reassured and counseled  about the low prognosis of dyspepsia leading to bleeding ulcer or cancer.gov/sites/entrez  (May 27. Egger M. Knowing the  probability of the outcome based on the prognostic factors present in the  patient should influence the decision to give or withhold treatment.      REFERENCES   Andreas Laupacis. www. For example  surgical excision for cancer with the hope of improving survival should be  withheld in favor of palliation treatment if the prognosis of the patient is very  poor. Gøtzsche P.ncbi. 2008). Vandenbroucke J. 1994. STROBE Initiative. George Wells.272(3):234‐237. 335: 806‐808. The subjects were similar to the  sister‐in‐law’s case.nlm. you would rather advice your brother to take a  vacation.    National Library of Medicine. How to Use an Article about Prognosis.     Prognosis data may also be helpful in reassuring anxious patients about their  outcome. Peter Tugwell for the Evidence‐Based  Medicine Working Group. Altman D.      RESOLUTION OF THE PROBLEM IN THE SCENARIO    Based on the Janssen et al study.    • Can I use the results to decide on the intervention or reassure my  patient?    Prognostic data should be used in decisions about therapy. Medical Subject Headings. BMJ 2007.nih.              Page 64 .  Strengthening the reporting of observational studies in epidemiology (STROBE) statement:  guidelines for reporting observational studies. W. Scott Richardson.    Von Elm E.

 Again. Assign a case  scenario to each group and formulate an answerable problem from the scenario. Note any change in  decisions. Focus on the abstract.    Ask the group to read the article retrieved to answer the problem in the  scenario.  Establish another group consensus and note any change in decision. establish a  group consensus on how to proceed with the scenario. The recommended break‐up is:    Page 65 . Focus on barriers and solution to the application of the  exercise in usual clinic practice.      TIME ALLOTTED   The time allotted for this workshop is two hours. methods and results section.    Process the exercise.    Critically appraise the article using the appraisal sheet provided. Another objective is to  introduce concepts of critical appraisal of an article regarding prognosis:    • Validity  • Representative sample  • Interpretation of the results  • Applicability of the results      INSTRUCTIONS   Divide the participants into groups of six to ten persons per group.  Establish initial group consensus on how to proceed with the scenario. Answer validity  questions. analyze the results and determine the applicability of the results.Evidence-based Medicine Self-Instructional Manual WORKSHOP CRITICAL APPRAISAL OF AN ARTICLE ABOUT PROGNOSIS (SESSION BRIEFING)     OBJECTIVES   The purpose of the workshop is to introduce to the participants the concept of  medical decision making using an article about prognosis.

                                                                Page 66 .Evidence-based Medicine Self-Instructional Manual • • • • • •     15 minutes to analyze the scenario and develop consensus  15 minutes to read the article  45 minutes to appraise the validity  15 minutes to analyze results  20 minutes to establish applicability  10 minutes to summarize the process  DESIRED OUTCOME   The participants should make a clinical decision on the scenario based on the  critical appraisal of the evidence.

Evidence-based Medicine Self-Instructional Manual Appraisal Sheet  CLINICAL DECISION ON PROGNOSIS        CLINICAL SCENARIO OR      QUESTION            SEARCH                    CRITICAL APPRAISAL        RELEVANCE  Is the objective of the article on harm similar to your  clinical dilemma?            PRIMARY VALIDITY  Was there a representative sample of patients without the  GUIDES  outcome at the start of observation?              Was follow‐up sufficiently long and complete?                   Were the criteria for determining the prognostic factor and  outcome explicit and credible?          Was there adjustment for other prognostic factors?            Page 67 .

Evidence-based Medicine Self-Instructional Manual OVERALL. IS THE STUDY  VALID?      WHAT ARE THE  RESULTS?        How large is the chance of the outcome to occur in a  specified period of time? How precise were they?                    Are the study patients similar to my own?            Can I use the results to decide on the intervention or  reassure my patient?                      CAN THE RESULTS HELP  ME IN CARING FOR MY  PATIENTS?    RESOLUTION OF THE  PROBLEM IN THE  SCENARIO                      Page 68 .

       OBJECTIVES   The purpose of the reading assignment is to introduce to the participants the  concept of medical decision making using an article about a health economic  analysis.  Focus on the critical appraisal questions.     After reading the paper you can proceed to conduct the group workshop.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CRITICAL APPRAISAL OF AN ARTICLE ABOUT HEALTH ECONOMIC ANALYIS (SESSION BRIEFING)     CHECKLIST   Have you read the previous topic on prognosis?   Yes          No    Have you undergone the workshop on prognosis with your group?   Yes          No    Did you enjoy the workshop?   Yes          No    Please state the reasons below and share it to the group before starting the next  workshop.     At the end of the reading session. why they are asked and how to get the  answers from the paper. you should be able to answer the user guides  questions for the workshop.    Page 69 .      INSTRUCTIONS   Read the reading assignment for an article about a health economic analysis.

 so you proceeded in appraising the article. Although  most of the pregnancies in the area were low risk. 1996). Estimation include direct and indirect costs. There are  three types of economic analysis depending on the type of outcome. In this design the cost of a particular  intervention is estimated.      HEALTH ECONOMIC ANALYSIS   Health economic analysis is a formal. You were able to get an article by Ratcliffe  and Tucker entitled “The costs of alternative types of routine antenatal care for  low‐risk women: obstetrician‐led shared care vs care by general practitioners  and midwives” published in the Journal of Health Services and Policy. most patients still go to the  nearest obstetrician who is in the city 50 kilometers away. He is now  asking you for a recommendation. Its purpose is to inform decisions on resource allocation. 1989).     What is your recommendation?      SEARCH   Having attended an EBM workshop you thought that the best way to convince  your father is to show cost‐effectiveness of handling low risk deliveries with  different types of trained physicians. If the  Page 70 . His budget for health  care is minimal but he wants to start a program for pregnant women. quantitative methods used to compare  alternative strategies with respect to their cost and their expected outcomes  (Eisenberg. 1996. It can  potentially inform decisions in institutions like hospitals and in regional or  national health policy (Russell.    Appraising the article and conveying the information to your father seemed to  be a good strategy.Evidence-based Medicine Self-Instructional Manual READINGS CLINICAL DECISION USING AN ARTICLE ON HEALTH ECONOMIC ANALYSIS     CLINICAL SCENARIO   Your father is the mayor of one of the town in the Visayas. He is planning to set‐ up a maternity hospital with a trained obstetrician in your hometown.

     When we compare the cost of giving each of the two alternatives. the point of view of the economic analysis is stated in  the objective and this is important to determine its relevance to your case  scenario.    VALIDITY GUIDES    • Did the analysis provide a full economic comparison of health care  strategies?      Physicians usually choose between two alternatives.     A full economic analysis compares not only the cost of the two alternatives but  also integrate information about efficacy of the alternatives. When we use this to make a decision.Evidence-based Medicine Self-Instructional Manual outcome being considered is effectiveness of treatment. then the point of view must be  the societal point of view. If the outcome is savings in terms of monetary units it is  called cost‐benefit analysis. If the outcomes are equal and the cost is the only  one being compared it is called cost minimization. If you are using an economic analysis for policy decision like the  government pay for this kind of drug or facility. 1997). we only give the alternative with  the lowest cost that may not be necessarily effective. it is called cost‐ effectiveness analysis. Thus cost and  Page 71 . we  give an effective alternative that the patient may not be able to afford. this is cost  analysis. Health insurance perspective is  also a payer perspective. Another alternative is the “do nothing”  alternative but may not be realistic in some cases because of ethical issues. The perspective  or “point of view” in economic analysis usually refers to the one who will pay for  the intervention.      CRITICAL APPRAISAL   RELEVANCE    • Is the objective of the article on economic analysis similar to your  clinical dilemma?    Your scenario must be addressed by the objective of the study. When we use comparison  of effectiveness such as a randomized controlled trial in making a decision. If your scenario is to assist a patient to make a  decision on an intervention in a “pay‐for‐service” setting. then the perspective  must be from the patient or “payer” perspective. Thus it  makes sense to consider cost and effectiveness when making clinical decisions. Often. The range of alternative  strategies examined must include at least the currently accepted standard and  the new alternative (O’Brien.

Evidence-based Medicine Self-Instructional Manual

outcomes should both be analyzed for each alternative strategies being  compared. This can be achieved if the study design is a cost‐benefit or a cost  effectiveness approach.    The Ratcliffe and Tucker study was a full economic valuation of the cost of tests,  investigations, personnel, cost incurred by the patients of pregnancies delivered  by obstetricians vs family physicians. The study included patients enrolled in a  randomized controlled trial to answer the effectiveness outcome.    • Were the costs and outcomes properly measured and valued?     Cost pertains to resources used and this must be differentiated from charges or  prices of commodities. The point of view of costing refers to the one who will  pay for the cost and this may differ. For example cost to government hospital or  funder may be different from the point of view of the patient. What may be cost  saving for the funder may actually be an increased cost for the patient. The ideal  point of view is from the society’s view, but this is difficult to measure. Thus  proper measurement of cost may differ from the health care system. In a system  where the payment is a fee‐for‐service set‐up, an economic analysis on the point  of view of the paying patient may be a good basis for making decision. In a  system where health care is being paid for by the government, an economic  analysis from the point of view of society may be a good basis. Thus in measuring  cost, the point of view of the analysis must be established (O’Brien, 1997).     Outcomes in health care must be an outcome that is of value to the patient and  society. It should be something that can be appreciated by the patient. For  example in making a decision about the treatment for hypertension, outcomes  like decrease in incidence of mortality or stroke, decrease in hospitalization or  myocardial infarction instead of just the lowering of blood pressure should be  the outcome to be considered. In addition these outcomes must be measured in  the best possible designs i.e. randomized controlled trials for treatment,  controlled comparison for complex intervention etc. Systematic reviews or meta‐ analysis of these interventions are better methods for establishing outcomes.     Lastly, the cost and outcome must be expressed as a ratio i.e. cost per outcome  (cost per life‐year gained, or cost per death avoided etc.). This expression of  result will give the most relevant information for decision making.    In the Ratcliffe and Tucker study costs were extracted from clinical data that  came from a randomized controlled trial. They included cost per patient, staffing  cost, non‐health services cost and mean societal cost. Cost data was available in  about 94% of subjects included in the trial.     
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• Was appropriate allowance made for uncertainties in the analysis?    Economic analysis usually depends on analysis of secondary data and since not  all data are available for each alternative, some assumptions need to be made.  There are uncertainties to these assumptions. A good economic analysis is one  that recognizes these uncertainties and look at how it affects their findings. This  method is called sensitivity analysis (O’Brien, 1997).     In sensitivity analysis the estimates for key variables in costs are changed in  order to assess their impact they on the results. The changes can be based on  variation in price index, opportunity costs, geographical price differences etc.  In  terms of outcomes, the variation can be from confidence intervals or from  lowest and highest effect noted from the studies that were reviewed.    OVERALL, IS THE STUDY VALID?    Since the study was a full economic comparison and wide perspective of cost  was considered you decided that the study was valid.    WHAT ARE THE RESULTS?    • What were the costs and outcomes of each strategy?    Economic analysis papers should have tables that report the costs of resources  used in the alternative intervention such as drugs, personnel services, facilities,  supplies etc. It should also contain tables about the outcome of each alternative.  Lastly, this is expressed as a cost‐effectiveness ratio or cost‐benefit.     The table below is a good guide to help decide the alternative to choose. “C” will  be the best choice since it is more effective and less cost. “B” is not a good  choice because it is less effective but more expensive. “A” is more effective but  more expensive as well.      Effectiveness  High  Low  Cost  High  A  B  Low  C  D      Sometimes, an alternative may be more effective but also more expensive. To  make a decision in this scenario, an incremental analysis should be done.  Incremental cost is the amount we pay for the added effectiveness of the 

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alternative. Usually the availability of resources and personal judgment may be  needed to decide whether the incremental cost is worth it.     Ratcliffe and Tucker showed that the total societal mean cost for GP or midwife  care was lower by P 2,178 and was statistically significant.     • How much does allowance for uncertainty change the result?    Looking at how uncertainties affect the results is called sensitivity analysis. A  direct approach for doing this is by computing for the cost effectiveness ratio  using the lower and upper limit of the 95% confidence interval of the  effectiveness outcome. If the cost‐effectiveness values are reversed with  sensitivity analysis then the results are considered to be soft and its reliability is  less.     CAN THE RESULTS HELP ME IN CARING FOR MY PATIENTS?    • Could my patients expect similar outcomes?      The inclusion criteria of the cited clinical trial or other studies reviewed to  determine the outcome and the setting from which the trial was done can be  duplicated in your setting will play an important factor. If the patients in the  study are similar to your patient and setting for which the intervention was given  can be duplicated, then you can expect the same outcome (O’Brien, 1997).     • Could my patients expect similar costs?    The health care system may be different from the setting where the economic  analysis was done. This difference may lead to difference in costing once applied  for decision making in your setting. Cost data may be different for two reasons:  1) clinical practice vary in resource consumption associated with the treatment  and 2) prices for resources differ from those used in the study (O’Brien, 1997).  This can only be answered if the analysis presented the detailed cost so the  reader can decide whether the costing in the study can also be applied in his/her  own setting.    Countries may differ with respect to the value they place on health benefits. If  $50,000 per life‐year is an acceptable cost‐effectiveness threshold for the US it  may not be affordable in the Philippines. Countries vary in their willingness to  pay for health care (O’Brien, 1997).          
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 Siegel JE. JAMA. for the Evidence‐Based Medicine  Working Group. Gold MR. Richardson WS. Research Protocol Development for Resident Physicians.Evidence-based Medicine Self-Instructional Manual RESOLUTION OF THE PROBLEM IN THE SCENARIO    Since most pregnancies in your hometown were low risk.                                          Page 75 . JAMA. Drummond M. 276(1)‐1172‐7. you showed to your  father that the town will save more money if they hire family physicians or  midwives rather than an obstetrician. Inc. JAMA. Levine M. 262:2879‐86. Weinstein MC. 1997. Manila. Daniels N. How to use an Article on Economic Analysis of Clinical Practice: Validity Guides. 1997. Richardson WS.      REFERENCES   Espallardo.  1989. for the Evidence‐Based Medicine  Working Group. 277(22):1802‐1806. 1996. Heyland D.     Russell LB. 277(19):1552‐1557. A guide to the economic analysis of clinical practices. NL. Drummond M. 2000.     O'Brien B.    Eisenberg JM. Clinical economics. Heyland D. The role of the cost‐effectiveness  analysis in health and medicine. How to use an Article on Economic Analysis of Clinical Practice: Results and  Applicability. Levine M. Family Medicine  Research Group.  JAMA. You called up your father one month later  and the town council opted to hire more midwives.    O'Brien B.

    Critically appraise the article using the appraisal sheet provided.      Page 76 . Focus on the abstract. establish a  group consensus on how to proceed with the scenario.    Ask the group to read the article retrieved to answer the problem in the  scenario. Assign a case  scenario to each group and formulate an answerable problem from the scenario. Note any change in  decisions.    Process the exercise. analyze the results and determine the applicability of the results. Again.Evidence-based Medicine Self-Instructional Manual WORKSHOP CRITICAL APPRAISAL OF AN ARTICLE ON HEALTH ECONOMIC ANALYSIS (SESSION BRIEFING)     OBJECTIVES   The purpose of the workshop is to introduce to the participants the concept of  medical decision making about an economic analysis.  Establish another group consensus and note any change in decision. Another objective is to  introduce concepts of critical appraisal of an article regarding an economic  analysis focusing on the following:    • Validity  • Costs in health care  • Interpretation of the results  • Incremental costs  • Applicability of the results      INSTRUCTIONS   Divide the participants into groups of six to ten persons per group. Focus on barriers and solution to the application of the  exercise in usual clinic practice.  Establish initial group consensus on how to proceed with the scenario. Answer validity  questions. methods and results section.

                                                        Page 77 . The recommended break‐up is:    • 15 minutes to analyze the scenario and develop consensus  • 15 minutes to read the article  • 45 minutes to appraise the validity  • 15 minutes to analyze results  • 20 minutes to establish applicability  • 10 minutes to summarize the process      DESIRED OUTCOME   The participants should make a clinical decision on the scenario based on the  critical appraisal of the evidence.Evidence-based Medicine Self-Instructional Manual TIME ALLOTTED   The time allotted for this workshop is two hours.

Evidence-based Medicine Self-Instructional Manual Appraisal Sheet  CLINICAL DECISION ON ECONOMIC ANALYSIS        CLINICAL SCENARIO OR      QUESTION            SEARCH                    CRITICAL APPRAISAL        RELEVANCE  Is the objective of the article on economic analysis similar  to your clinical dilemma?            VALIDITY GUIDES  Did the analysis provide a full economic comparison of  health care strategies?                Were the costs and outcomes properly measured and  valued?                   Was appropriate allowance made for uncertainties in the  analysis?          Are estimates of costs and outcomes related to the baseline  risk in the treatment?          Page 78 .

Evidence-based Medicine Self-Instructional Manual OVERALL. IS THE STUDY  VALID?      WHAT ARE THE  RESULTS?        What were the incremental costs and outcomes of each  strategy?                          Do incremental costs and outcomes differ between  subgroups?            How much does allowance for uncertainty change the  result?               Could my patients expect similar outcomes?              Could my patients expect similar costs?                    CAN THE RESULTS HELP  ME IN CARING FOR MY  PATIENTS?  RESOLUTION OF THE  PROBLEM IN THE  SCENARIO      Page 79 .

    Page 80 . you should be able to answer the user guides  questions for the workshop.     After reading the paper you can proceed to conduct the group workshop.  Focus on the critical appraisal questions.       OBJECTIVES   The purpose of the reading assignment is to introduce to the participants the  concept of medical decision making using an article about systematic reviews or  meta‐analysis.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CRITICAL APPRAISAL OF AN ARTICLE ABOUT SYSTEMATIC REVIEWS OR META-ANALYSIS (SESSION BRIEFING)     CHECKLIST   Have you read the previous topic on economic analysis?   Yes          No    Have you undergone the workshop on economic analysis with your group?   Yes          No    Did you enjoy the workshop?   Yes          No    Please state the reasons below and share it to the group before starting the next  workshop.      INSTRUCTIONS   Read the assignment for an article about systematic reviews or meta‐analysis.     At the end of the reading session. why they are asked and how to get the  answers from the paper.

    A meta‐analysis is a procedure that integrates and combine the results of two or  more primary studies that are similar in the population enrolled the intervention  used and the outcome measured. 2000). SYSTEMATIC REVIEWS AND METAANALYSIS   A review is secondary study design that integrates findings of two or more  studies that discuss similar topic usually defined by PIO. There may be some bias  when the reviewer subjectively decides which studies to include or exclude in  the review. She was  brought to the hospital for treatment of minor bruises in her knees. Meta‐analysis is like a systematic review but  applies some statistical analysis to the results. The x‐rays  were normal. A systematic review is similar to review but has a way to  systematically search the literature searching and has systematic rules in  combining the studies to be reviewed. A well conducted meta‐analysis allows a more objective  appraisal of the existing evidence about a problem than a traditional review or  systematic review. The results of systematic reviews are  more often objective than a review.      REVIEWS.   Page 81 . The pooled result is then subjected to a  statistical analysis. Your mother asked you if she needs a walker or cane to prevent  falls and subsequent injury.       SEARCH   You ask a colleague from Rehabilitation Medicine and she gave you an article  from the NHS Center for Reviews and Dissemination she got from the internet  entitled “Preventing falls and subsequent injury in older people”. Meta‐analysis may also be biased owing to the inclusion or  exclusion of some irrelevant or relevant studies respectively (Espallardo.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CLINICAL DECISION ON SYSTEMATIC REVIEW OR META-ANALYSIS     CLINICAL SCENARIO   Your grandmother had a history of fall a week ago after taking a bath.

 This is often  used for the systematic literature search and basis for inclusion or exclusion. The objective of an appropriately done meta‐analysis is often a focused  clinical objective with PIO and the method being clearly defined.     Page 82 . It therefore  becomes difficult to determine what the review is trying to achieve.    VALIDITY GUIDES    • Did the review address a focused clinical problem?    Systematic reviews of the medical literature try to summarize publications  related to a similar topic. Because several articles are combined together.Evidence-based Medicine Self-Instructional Manual   Sample of meta‐analysis result        CRITICAL APPRAISAL   RELEVANCE    • Is the objective of the article on meta‐analysis similar to your clinical  dilemma?    Your formulated clinical question must be addressed by the objective of the  study.  sometimes the purpose of the review is not clear or very broad.

Evidence-based Medicine Self-Instructional Manual In order to know what the objective of the review is. There must be a clear description of the patient and its relation with  an exposure or an outcome.    The NHS study identified trials published in computerized databases like Social  Science Citation Index. This  assures the readers that the articles used in the study were objectively chosen  and not because they agree with the authors opinion. . The focused objective  seemed to apply to your problem. PSYCHLIT. Peer review may not be  Page 83 . AMED and UNCOVER. the clinical problem must  be focused. . EMBASE.     The NHS study specifically stated that they tried to identify strategies that  prevent falls and subsequent injury in older people. a systematic search and appraisal of the  literature should be done in order to:  • ensure that no relevant articles were missed  • studies were included because they are good studies and not because  they agree with the authors opinion  • studies were excluded because they are bad studies and not because  they disagree with the author’s opinion.  Thus a standard appraisal of each article must be done. there may be some  small differences among different trials that might affect the results of the study. This assures the readers that the findings of the study  were based on a wide range of literature source and represent the most current  and complete information about the clinical problem. RCN database.     The paper should also describe how they include or exclude retrieved articles.” somewhere in the method section. .  The citations also identified reviews and peer contribution from reviewers and  other experts in the field. from 1966 to 2000 was done” must be found somewhere in the  methodology section.    • Were the criteria for searching and selecting articles for inclusion and  exclusion explicit and credible?     In conducting systematic reviews.    • Was the validity of included studies appraised and the appraisal  reproducible?    Even if all included studies are randomized controlled trials. .  The paper must contain statements like “all retrieved abstracts were reviewed  by three independent reviewers and articles that were randomized controlled  trial on . .  Statements like “an electronic search of published articles in the MEDLINE using  the terms . . using the intervention .    Thus paper should describe the method of searching for the medical literature.

 IS THE STUDY VALID?    Overall the study is valid.  When variation in patient inclusion may influence the effect. or the difference in quality of life scores between the  two groups. you should  look for clinically relevant presentation like lower mortality rates in one group  compared to the other. the confidence interval of the overall results can also be  computed and this can provide information about the precision of the results.90 and with a 95% CI of 0.     OVERALL. Differences in peer perception and interest may  lead to differences in the result of the appraisal.81 to 0. patients with high risk and  patients with low risk.     Thirty‐six randomized controlled trials were included in the meta‐analysis. The  results showed that 10‐24 weeks of exercise including balance training showed  an effective risk reduction by as much as 37% with an adjusted fall incidence  ratio of 0.     Page 84 . to see the different effect of an exposure may also be  helpful. the patient’s characteristics are varied because they  came from different studies.99.    WHAT ARE THE RESULTS?    • What are the overall results of the systematic review?     When looking at the results of a systematic review or meta‐analysis. subgroup analysis  between different patient characteristics may also help decide what kind of  patient will benefit from the intervention or will be affected by the exposure.e. Sometimes subgroup analysis i.    CAN THE RESULTS HELP ME IN CARING FOR MY PATIENTS?    • Are the study patients similar to my own?    In a systematic review. Application to patients therefore becomes wider.Evidence-based Medicine Self-Instructional Manual a reliable method of appraisal. the review must have  at least developed a checklist of criteria that focused on the methodology of the  study being appraised.     In a meta‐analysis.     The NHS study included only randomized controlled trials that evaluated  strategies to prevent falls.    While there are no agreed standards to evaluate validity.

      REFERENCES   Espallardo. Manila. balance training rather than walker devices will help  prevent further fall and subsequent injury. JAMA. 1994.     When the outcome differs between studies.    The NHS meta‐analysis included only studies done on elderly. Family Medicine  Research Group. the answer to this question  becomes evident. In this case you can look at the results of  individual studies and choose studies that give relevant outcomes and use them  to make a decision.Evidence-based Medicine Self-Instructional Manual This information can be seen in the methodology section where the researchers  describe the type of patients in the literature search and inclusion criteria of the  studies. This is a difficult  situation because the outcomes are combined and you cannot easily decide  whether the outcome is relevant or not.272(17):1367‐71. they are combined and this is  reported in systematic reviews or meta‐analysis as effect size. Cook D. Research Protocol Development for Resident Physicians.                             Page 85 .    RESOLUTION OF THE PROBLEM IN THE SCENARIO    Based on the review. 2000. Guyatt G.    Oxman A. NL. Inc. for the Evidence Based Medicine Working Group. You only need to focus on the outcome measured and decide  whether this is relevant to your patient. How to Use an  Overview.    • Are the results of the review relevant to my patient?    When the clinical question of the review is focused.

 systematic review or overview.    Process the exercise.  Establish another group consensus and note any change in decision. Focus on the abstract. analyze the results and determine the applicability of the results. Another objective is to introduce concepts of critical appraisal of an  article regarding differential diagnosis focusing on the following:    • Validity  • Review.    Ask the group to read the article retrieved to answer the problem in the  scenario. Focus on barriers and solution to the application of the  exercise in usual clinic practice.  Establish initial group consensus on how to proceed with the scenario.    Critically appraise the article using the appraisal sheet provided. methods and results section. meta‐analysis  • Interpretation of the results  • Applicability of the results      INSTRUCTIONS   Divide the participants into groups of six to ten persons per group.        Page 86 . Assign a case  scenario to each group and formulate an answerable problem from the scenario. Again. Answer validity  questions. Note any change in  decisions. establish a  group consensus on how to proceed with the scenario.Evidence-based Medicine Self-Instructional Manual WORKSHOP CRITICAL APPRAISAL OF AN ARTICLE ABOUT A SYSTEMATIC REVIEW OR META-ANALYSIS (SESSION BRIEFING)     OBJECTIVES   The purpose of the workshop is to introduce to the participants the concept of  medical decision making using an article about a systematic review or meta‐ analysis.

 The recommended break‐up is:    • 15 minutes to analyze the scenario and develop consensus  • 15 minutes to read the article  • 45 minutes to appraise the validity  • 15 minutes to analyze results  • 20 minutes to establish applicability  • 10 minutes to summarize the process      DESIRED OUTCOME   The participants should make a clinical decision on the scenario based on the  critical appraisal of the evidence.                                                        Page 87 .Evidence-based Medicine Self-Instructional Manual TIME ALLOTTED   The time allotted for this workshop is two hours.

Evidence-based Medicine Self-Instructional Manual Appraisal Sheet  CLINICAL DECISION ON SYSTEMATIC REVIEW OR META‐ANALYSIS        CLINICAL SCENARIO OR      QUESTION            SEARCH                    CRITICAL APPRAISAL        RELEVANCE  Is the objective of the article on harm similar to your  clinical dilemma?            PRIMARY VALIDITY  Did the review address a focused clinical problem?  GUIDES                Were the criteria for searching and selecting articles for  inclusion and exclusion explicit and credible?                 Was the validity of included studies appraised and the  appraisal reproducible?                Page 88 .

 IS THE STUDY  VALID?      WHAT ARE THE  RESULTS?        CAN THE RESULTS HELP  ME IN CARING FOR MY  PATIENTS?    RESOLUTION OF THE  PROBLEM IN THE  SCENARIO              What are the overall results of the systematic review?                         Are the study patients similar to my own?                Are the results of the review relevant to my patient?                            Page 89 .Evidence-based Medicine Self-Instructional Manual   OVERALL.

      INSTRUCTIONS   Read the reading assignment for an article about a clinical practice guideline.     At the end of the reading session.       OBJECTIVES   The purpose of the reading assignment is to introduce to the participants the  concept of medical decision making using an article about a clinical practice  guideline.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT CRITICAL APPRAISAL OF AN A CLINICAL PRACTICE GUIDELINE (SESSION BRIEFING)     CHECKLIST   Have you read the previous topic on systematic reviews?   Yes          No    Have you undergone the workshop on systematic reviews with your group?   Yes          No    Did you enjoy the workshop?   Yes          No    Please state the reasons below and share it to the group before starting the next  workshop. why they are asked and how to get the  answers from the paper.             Page 90 . you should be able to answer the user guides  questions for the workshop.  Focus on the critical appraisal questions.

 Guidelines. appraise and combine evidence. go beyond most overviews in attempting to address all the issues  Page 91 . good topics for guidelines are those which:    • contribute a high workload  • poor treatment risks disastrous outcomes  • change is practical with the resources you have available  • there is variation in current management (i." represent an attempt  to distill a large body of medical knowledge into a convenient.  however.Evidence-based Medicine Self-Instructional Manual READING ASSIGNMENT HOW TO USE A CLINICAL PRACTICE GUIDELINE     CLINICAL PRACTICE GUIDELINES   "Clinical Practice Guidelines are systematically developed statements to assist  practitioner decisions about appropriate health care for specific clinical  circumstances. there is uncertainty about  the best management strategy). like so much else in  healthcare today are no longer as immutable as the Laws of the Medes. how acceptable?     Clinical practice guidelines. that they are getting to the  people who are going to use them and that they are up to date.  • Educate the patients and practitioners about current "best practice. Like overviews.e."(Field. you will  have to periodically check that they are working. Guidelines. Guidelines were developed to:    • Make evidence‐based management explicit. how preventable. but some hope of reaching a consensus  • the changes you wish to implement will be acceptable to patients  • there is good evidence to back up the protocols    It might be useful to consider the criteria used to select illnesses for screening  programs (how common. how serious.     In general. which have been defined as "systematically  developed statements to assist practitioner and patient decisions about  appropriate health care for specific clinical circumstances.  • Assess professional performance.  • Make clinical decision making more objective and scientific. they gather. they need to be developed by the people  who are actually going to have to apply them."    If guidelines are to improve practice. 1990). readily useable  format.

    You then go home.      SEARCH FOR CPG   You decide that in order to find relevant answers to a variety of clinical  questions.  You then remembered a copy of the  Philippine compendium sent to you by mail 2 years ago and taught of the  Philippine Clinical Practice Guidelines on the Detection and Management of  Hypertension. Guidelines differ from decision analyses in relying more on  qualitative reasoning and in emphasizing a particular clinical context. guidelines refine clinical questions and  balance trade‐offs.  However. your patient  began asking you the relative benefits of the alternative drugs available in the  market. you did not have sufficient time to download and print  the full text version of these guidelines.  As you were about to do just that.guidelines.  You gave him the usual advice you knew based on  your knowledge of pathophysiology and pharmacokinetics.  You  initially searched ww.      Page 92 . as you  were finally closing your clinic you decided that you were not satisfied with the  answers you gave him and decided to do a search for the best available  evidence.  Since he was not overweight he was  asking if a regular exercise program would add any additional benefit in  controlling his symptoms. Like decision analyses. sit at your desk and decide to review this article in order to  be more prepared for your next patient encounter.  He claims that his  highest blood pressure for the past month was 160/90 and his usual blood  pressure was 130/90 and he has been taking a beta‐blocker for the past year.      CASE SCENARIO   At the end of a busy day in your clinic.  However.  Thinking that this was just another run of the mill hypertensive  patient you were ready to refill his prescription and give your usual advice  regarding diet and exercise.Evidence-based Medicine Self-Instructional Manual relevant to a clinical decision and all the values that might sway a clinical  recommendation. a clinical practice guideline would be the best article to retrieve.  He was also asking if he needed to have an ECG done together with  blood chemistries. urinalysis and a 2D‐Echo since his friend who consulted  another physician was advised to do that.gov and found numerous guidelines for  hypertension. you are glad to find that your last patient  is a 45/male previously diagnosed to have hypertension.  He  was relatively symptom free save for occasional headache and nape pains during  BP spikes.

 the corresponding outcomes such as  morbidity and mortality data.e. The guideline however did not include the newer generation  anti‐hypertensives.  Guideline developers then should present most of the  reasonable options seen in practice and their corresponding outcomes.     VALIDITY GUIDES    • Were all important options and outcomes considered?     Guidelines aid us in our decision making skills and we make better judgment calls  if we know all the alternative options open to us and the relative harm and  benefits of each choice.    As important as presenting all the options.   Developers should specify a focused  Page 93 .Evidence-based Medicine Self-Instructional Manual CRITICAL APPRAISAL   RELEVANCE    • Is the objective of the article on clinical practice guideline similar to  your clinical dilemma?    Your formulated clinical question must be addressed by the objective of the  clinical practice guideline.    In the case of the Philippine Clinical practice guideline on the detection and  management of hypertension.    In this hypertension guideline. reviewed. answers  questions about the best diagnostic test. Usually guideline objectives are broad i. several treatment options were presented  ranging from beta‐blockers. mortality and morbidity data together with  prevention of hypertensive complications were the outcomes given emphasis. the recommended treatment.      • Was an explicit and sensible process used to identify.  Inasmuch as all  these will be helpful and clinically relevant to individual patients. select. ACE inhibitors.  However costs and side effects were not well mentioned. calcium channel blockers  with recommendations of the best alternative for hypertensive patients with co‐ morbid conditions. prevention of complications and other measures  that improve health related quality of life should be reported. appraised and combined in order to allow them to ascertain  the validity of the gathered evidence. and  combine evidence?    Guideline developers must allow the reader to know how the evidence has been  tracked. the  expected outcome or prognosis etc. diuretics.

   Mention of tracking.  however. or to identify key research priorities.    This guideline on hypertension was released in 1995 and the latest evidence  upon looking at the bibliography was in that same year. the evidence  should be within the last 2 years before the guideline was published." to specify dates for  expiration or review. Hence. these considerations may  be used to qualify guidelines as "temporary" or "provisional. search the literature for available evidence. retrieving and appraising was done in Phase 1 of the  introduction section.    Page 94 .  Since  medical knowledge rapidly transforms. Ideally. summary on how the articles were reviewed and graded  was provided. but the complete way on how this was done was not  mentioned. the  guideline should be due for review and revision.  As such.    • Has the guideline been subjected to peer review and testing?    People may interpret evidence differently and their values as to what important  options and outcomes are may differ.    The reader is advised to check the bibliography section of the guideline and  check the dates of the most recent articles included.    • Is the guideline likely to account for important recent developments?    You should look for two important dates: the publication date of the most recent  evidence considered and the date on which the final recommendations were  made.Evidence-based Medicine Self-Instructional Manual question. there is a need to revise  guidelines periodically. you can review the recommendations to determine how useful they  will be in your practice.  However. critically appraise this  evidence and summarize the results in an easy to understand material. a guideline that has been  subjected to scrutiny by external reviewers and tested in an actual clinical  practice setting and found acceptable might be easier to use. you must scan the bibliography to get an impression of how current a  particular guideline may be.  Ideally. Some authorities also identify important studies in progress and new  information that could change the guideline. For most guidelines.  Being at present in the  year 2000 and with the rapid developments in antihypertensive medications. this will ensure that our  recommendations will not be outdated.     Once you are confident that the clinical practice guideline addresses your clinical  question and is based on a rigorous up‐to‐date assessment of the relevant  evidence.      The Philippine Clinical Practice Guidelines for Hypertension was not very clear  regarding how they searched the literature and what database they used.

 clinically important." "grade. IS THE GUIDELINE VALID?    Once you are confident that the guideline meets at least 2 out of the 3  requirements above. non‐pharmacologic advice and preventive  measures. recommendations made?    To be useful guidelines should give practical. you can review the recommendations and its applicability  to our individual patients. the Philippine Clinical Practice Guidelines  on Detection and Management of hypertension although a little bit outdated at  the present time will do.    WHAT ARE THE RECOMMENDATIONS    • Are practical.    • How strong are the recommendations?    The "strength. laboratory  work‐ups. recommendations are divided into every aspect of  any encounter with a hypertensive patient.  At present." or "force" of a recommendation should  be informed by multiple considerations:     • the quality of the investigations which provide the evidence for the  recommendations  Page 95 .  Recommendations should be simple and specific at  the same time comprehensive enough to allow the reader a chance to assess the  benefits and costs of following the particular recommendation.Evidence-based Medicine Self-Instructional Manual   OVERALL." "confidence.    In this hypertension guideline. treatment options.  The following 6 questions are  addressed by the guideline:    • How should blood pressure be measured?  • How should hypertension be diagnosed?  • How should hypertension be worked up?  • What advice should hypertensive patients receive regarding lifestyle  modification?  • How should hypertension be treated?  • How can hypertension be prevented among normotensives?    This then allows the clinician to answer aspects regarding diagnosis. unambiguous advice addressing a  particular clinical situation.

    This hypertension guideline was made to ensure the availability of a local  guideline for the detection and management of hypertension.      WILL THE RECOMMENDATIONS HELP YOU IN CARING FOR YOUR PATIENTS?    • Is the primary objective of the guideline consistent with your  objectives?    The purpose of the guideline developers for coming up with recommendations  may vary from your own. recertification). Therapy wise.   .    It is also important to note that different guideline developers use different  standards for grading their recommendations and that this should explicitly be  placed in the guideline for ease of understanding.  Since your  questions dealt with management issues. to evaluate their practice and the standard  of care they give to their patient (quality assurance) or to set limits for physician  choices (reimbursements. burdens to the patient and the health care  system. the number of positive outcomes in  relation to negative ones and the consistency of findings across different  evidences available.      The Philippine Clinical Practice Guidelines for Hypertension used a system  adopted by the Canadian Hypertension Society. this guideline is appropriate for your  purpose. costs)  the relative value placed upon different outcomes. grading of the recommendations are based on the methodological  soundness of the available evidence.          Page 96 the magnitude and consistency of positive outcomes relative to negative  outcomes (adverse effects.  Inconsistent findings are at times the reason why different  guideline developers have different recommendations regarding certain clinical  issues.Evidence-based Medicine Self-Instructional Manual • •   Thus.  In any case. a lot of Grade A  recommendation meaning that evidence is based from well‐conducted trials was  made.  Guidelines may be disseminated to assist physicians in  decision making (clinical algorithms). the purpose of the guideline  should be in line with your intended objective. in order to find  recommendations most suited to your needs.  It is not enough to look into the fact that randomized  controlled trials were used as evidence but also if findings across different trials  were consistent.

Evidence-based Medicine Self-Instructional Manual

• Are the recommendations applicable to your patients?     You must determine if the kind of patients you have are similar to those patients  targeted by the guideline.  If your patients have a different prevalence or risk of  disease, if the diagnostic and therapeutic options recommended are not  available in your area, the guideline might not apply.    The advantage of reviewing and applying a Philippine practice guideline is that it  takes into account the characteristics of our setting and hopefully allows it to be  more responsive.     RESOLUTION OF THE PROBLEM IN THE SCENARIO    Having deemed that the aforementioned guideline is valid, you would still opt to  give this patient with uncomplicated hypertension a beta‐blocker.  In terms of  diagnostics, you would request for an FBS, Serum Creatinine, Serum potassium  and urinalysis.  You would request for these tests since they would have an  effect on the antihypertensive you would choose.  Furthermore they would  provide the following additional benefits: a)detection and early treatment of  diabetes, b)detection of asymptomatic renal disease, c)detection of possible  secondary hypertension.  You would explain to your patient that since he has no  symptoms of any cardiac disease, performing an ECG and Echo is not routinely  recommended.    In terms of non‐pharmacologic advice, you would encourage him to go with  regular aerobic exercise such as walking, jogging or cycling 30 minutes per day 3‐ 4x/week since regular physical activity reduces blood pressure and results in a  decrease in all cause mortality.      A lot of decision making, considerations of options and outcomes came into play  for a relatively simple case of hypertension.  And as medical knowledge  improves, more options will be made available.  As such the need for relevant,  well‐constructed and tested guidelines to improve our clinical decision making  will always be there.  Again, we as clinicians should be able to adapt guidelines  that are valid and whose recommendations will be most appropriate and  feasible in our respective settings.     

REFERENCES
Hayward R, Wilson M, Tunis S, Bass E, Guyatt G for the Evidence Based Medicine Working Group. How to Use a Clinical Practice Guideline: Validity. JAMA, 1995;274(7):570-4

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Hayward R, Wilson M, Tunis S, Bass E, Guyatt G for the Evidence Based Medicine Working Group. How to Use a Clinical Practice Guideline: Recommendations and Applicability. JAMA, 1995;274(20):1630-2.

                                                                             

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WORKSHOP

CRITICAL APPRAISAL OF CLINICAL PRACTICE GUIDELINE
(SESSION BRIEFING)
   

OBJECTIVES
  The purpose of the workshop is to introduce to the participants the concept of  medical decision making about multiple problems related to disease  management. Another objective is to introduce concepts of critical appraisal of a  clinical practice guideline:    • validity  • recommended options and outcomes   • up‐to‐date recommendations  • relevance and certainty of the recommendations  • applicability of the recommendations     

INSTRUCTIONS
  Divide the participants into groups of six to ten persons per group. Assign a case  scenario to each group and formulate an answerable problem from the scenario.  Establish initial group consensus on how to proceed with the scenario.    Ask the group to read the article retrieved to answer the problem in the  scenario. Focus on the abstract, methods and results section. Again, establish a  group consensus on how to proceed with the scenario. Note any change in  decisions.    Critically appraise the article using the appraisal sheet provided. Answer validity  questions, analyze the recommendations and determine the applicability of the  recommendations. Establish another group consensus and note any change in  decision.    Process the exercise. Focus on barriers and solution to the application of the  exercise in usual clinic practice.       

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 The recommended break‐up is:    • 5 minutes to analyze the scenario and develop consensus  • 10 minutes to read the clinical practice guideline  • 20 minutes to appraise the validity  • 10 minutes to analyze the recommendations  • 5 minutes to establish applicability  • 10 minutes to summarize the process      DESIRED OUTCOME   The participants should make a clinical decision on the scenario based on the  critical appraisal of the clinical practice guideline.Evidence-based Medicine Self-Instructional Manual TIME ALLOTTED   The time allotted for this workshop is one hour.                                                        Page 100 .

 expected results            Was an explicit and sensible process used to identify.Evidence-based Medicine Self-Instructional Manual Appraisal Sheet  HOW TO USE A CLINICAL PRACTICE GUIDELINE        CASE SCENARIO OR  QUESTION        SEARCH     CRITICAL APPRAISAL        RELEVANCE  Is the objective of the article on clinical practice guideline    similar to your clinical dilemma?            VALIDITY GUIDES  Were all important options and outcomes considered?    Alternatives. and combine evidence?                   Is the guideline likely to account for important recent  developments?  Last update        Has the guideline been subjected to peer review and  testing?          Page 101 .  select.

 recommendations  made?                How strong are the recommendations?  Grading                Is the primary objective of the guideline consistent with  your objectives?                      Are the recommendations applicable to your patients and  setting?                   Page 102 . clinically important.Evidence-based Medicine Self-Instructional Manual OVERALL. IS THE  GUIDELINE VALID?    WHAT ARE THE  RECOMMENDATIONS      WILL THE  RECOMMENDATIONS  HELP YOU IN CARING  FOR YOUR PATIENTS?      RESOLUTION OF THE  PROBLEM IN THE  SCENARIO             Are practical.

Box 3808. when we discussed MR imaging of the knee of an adolescent patient with the orthopedic surgeons at our institution. 100% sensitivity and 100% specificity. Presented at the annual meeting of the American Roentgen Ray Society. the radiologist’s interpretations of the menisci and cruciate ligaments were compared with the arthroscopic sur- AJR:180. The sensitivity and specificity values for MR imaging of the menisci and cruciate ligaments in adolescents were as follows: medial meniscus. AJR 2003. Fifty-nine of these patients underwent surgery. Thirty-four boys and 25 girls who ranged in age from 11 to 17 years (mean age. Of the 97 patients. lateral meniscus. anterior cruciate ligament. 2002. This assertion has not been specifically addressed in the radiology literature. 156 included patients younger than 18 years. April–May 2001. However. The purpose of our study was to determine the accuracy of MR imaging in adolescents with regard to injury of the cruciate ligaments and menisci. accepted after revision June 25. 92% sensitivity and 87% specificity. 15 years) were examined. A report in the orthopedics literature states that MR imaging for internal derangement of the knee has a lower accuracy in adolescents than in adults and may even provide spurious information that alters clinical management. Durham. RESULTS. 49 were boys and 48 were girls. MATERIALS AND METHODS. 93% sensitivity and 95% specificity. Major 1 L. January 2003 17 . and accurate. For each patient. Jr. Neal Beard. has not been specifically addressed in the radiology literature. with ages ranging from 13 to 17 years (mean age. One of five musculoskeletal radiologists from our institution had prospectively evaluated each MR imaging examination. Clyde A. Address correspondence to N. Fifty-nine of these 156 patients proceeded to surgery. Of these 2140 examinations. 15 years). CONCLUSION. to our knowledge. and the orthopedic surgeons’ operative reports were used as the gold standard with which we compared the MR imaging results. the surgeons expressed concern that MR imaging would be less useful in our adolescent patient than in an adult patient because of the purported lower accuracy of MR imaging for the detection of internal derangement of the knee in adolescents. NC 27710. The clinical notes for the remaining 97 patients were evaluated for information about management and clinical improvement. 1 All authors: Department of Radiology. Helms OBJECTIVE. Our search yielded 2140 knee examinations. Materials and Methods A retrospective search of the musculoskeletal MR imaging database for knee examinations performed from January 1998 to July 2000 was conducted. and posterior cruciate ligament.Accuracy of MR Imaging of the Knee in Adolescents Nancy M. and the orthopedic surgeons’ operative reports were used as the gold standard with which the MR imaging results were compared. Of these 2140 examinations. The study group included 34 boys and 25 girls who ranged in age from 11 to 17 years (mean age. Duke University Medical Center. Major. This assertion has been made in the orthopedics literature [4] but. MR imaging has been accepted as the imaging gold standard for detection of internal derangement of the knee [1–3]. so they sometimes forego an MR imaging examination because they believe that the information from the study would not be useful and could even be misleading. all of which had been performed with a standard knee protocol on a 1.5-T magnet. Our data suggest that MR imaging of the knee in adolescents is sensitive. 2002. The purpose of our study was to determine the accuracy of MR imaging in adolescents compared with that in adults with regard to I the detection of injuries to the cruciate ligaments and menisci. 156 included patients who were younger than 18 years. The clinical notes about the remaining 97 patients were evaluated for management and improvement. 15 years).180:17–19 0361–803X/03/1801–17 © American Roentgen Ray Society n the adult population. This notion had apparently been accepted as truth by our orthopedic surgeons. M. Seattle. 0% sensitivity and 100% specificity. A database search of our institution’s records from January 1998 to July 2000 yielded 2140 MR examinations of the knee. specific. Received January 21.

Stanitski reported 75% total disagreement between clinical and MR imaging and 78. the authors state that the accuracy for MR imaging of knee abnormalities in pediatric patients is not well established. and false-negative. magnetic resonance imaging diagnoses added little guidance to patient management and at times provided spurious information. two cases of Osgood-Schlatter disease.1 Our results indicate that the accuracy of MR imaging for the detection of internal derangement of the knee in adolescents is similar to that in adults. during which we were told that MR imaging of the knee for detection of internal derangement is less useful in adolescents than adults because of a report of decreased accuracy. Results The sensitivity and specificity values of MR imaging for the detection of internal derangement of the knee in adolescents and adults are shown in Table 1.5% of the cases. The sensitivities and specificities of MR imaging for the detection of tears in the adolescent group were essentially the same as those for the adult group.7 7. and one posterior cruciate ligament tear. 8–17 years) with knee injuries. the total number of cases that were not diagnosed with pathology was 64. The surgeons referred us to an article by Stanitski [4]. In the group of adolescents with arthroscopic correlation. which resulted in a 100% sensitivity and specificity. From these data. a field of view of 16 × 16 cm. false-positive. For the lateral meniscus. surgery was performed by various orthopedic surgeons. and identical protocols were used for each of the examinations. two cases of jumper’s knee. the MR interpretations consisted of 14 true-positives. anterior cruciate ligament. 14 lateral meniscus tears.3 78. seven patellar dislocations (contusion pattern not counted in previous group). four anterior cruciate ligament tears. these values resulted in a 92% sensitivity and 87% specificity. gical findings. two hematomas. General Electric Medical Systems. The anterior cruciate ligament was identified as torn if the fibers were disrupted and were no longer parallel to the intercondylar notch. Stanitski asserted that clinical examination and arthroscopy are superior to MR imaging of adolescents. and one bucket-handle meniscus tear. and coronal fast spin-echo T2-weighted imaging (TR/TE effective. one posterior cruciate ligament injury.—All data are from [4]. Partial 10. One patient had an anterior cruciate ligament tear and a bucket-handle meniscus tear. six false-positives. there were 58 true-negatives and one false-negative. “normal” was assigned as the diagnosis in 39 patients. [5]. and one false-negative. Twenty-five patients had a final impression in the dictated report as “signal in either the meniscus or soft tissues not felt to be significant. For the posterior cruciate ligament. In this article. Meniscus tears were identified if linear high signal abutting the articular surface or abnormal morphology was seen. The idea for this retrospective database study came from repeated discussions with various orthopedic surgeons at our institution. and a slice thickness of 4 mm/ 0. 2 excitations. All the MR imaging examinations were performed on a 1. two refused surgery and two were lost to follow-up. MR Imaging. in that article. We believe that our data refute the argument that MR imaging of the knee is less accurate in adolescents than in adults. Discussion TABLE 1 Sensitivity and Specificity of MR Imaging of the Knee in Adolescents Versus Adults Adolescents (n = 59) Adults (n = 203) Sensitivity (%) 90 78 100 83 Specificity (%) 80 93 97 98 Location Sensitivity (%) Medial meniscus Lateral meniscus Anterior cruciate ligament Posterior cruciate ligament 92 93 100 0 Specificity (%) 87 95 100 100 TABLE 2 Comparison of Findings from Clinical Examination. MR findings for the anterior cruciate ligament yielded 26 true-positives and 33 true-negatives with zero false-positives and zero false-negatives. which resulted in a 93% sensitivity and 95% specificity. Articular surface. true-negative.1 14. Of the 97 patients who did not undergo arthroscopy. The orthopedics literature includes a second article written by McDermott et al. In that study. MR imaging data were then categorized as true-positive. 3500/65) with fat suppression and sagittal proton density imaging (TR/TE. Milwaukee. Forty-six patients had no additional follow-up.5 Findings Compared Total Clinical examination vs MR imaging Clinical examination vs arthroscopy MR imaging vs arthroscopy Note. A number of differences between our study and that conducted by Stanitski [4] exist. which included a series of 203 patients (Table 1). MR evaluation of the medial meniscus revealed 11 true-positives. whereas our study included results 18 AJR:180. and arthroscopic findings in 28 children and adolescents (age range.5% total disagreement between arthroscopic findings and MR imaging results. two osteochondral lesions. 42 true-negatives. one case of abnormal signal in the Hoffa fat pad. Of the four patients with anterior cruciate ligament tears. 25 anterior cruciate ligament tears. January 2003 .5 7.Major et al.” The data in Table 2 are from Stanitski’s article. WI). The remaining parameters include a matrix of 256 × 192. sensitivity and specificity for the detection of meniscal and cruciate ligament tears in our study group of adolescents were computed and compared with the same values in adults for the same radiologists (obtained from another study) over approximately the same time period. total agreement was found between clinical examination and arthroscopy in 78. two false-positives.3 14. 41 true-negatives. Other diagnoses encountered were 10 bone contusions.” Therefore. These values yielded a 0% sensitivity and 100% specificity. Our standard knee protocol includes axial. and meniscal injuries were reviewed and the conclusions were as follows: “Overall. neither true-positives nor false-positives were recorded for the MR imaging findings. Comparison of the arthroscopic and MR imaging findings yielded the following results. one Wrisberg variant of discoid lateral meniscus. 2000/20) with fat suppression. MR imaging results. First. one medial collateral ligament sprain. and Arthroscopy of the Knee Agreement (%) Total Disagreement (%) 75 14. and one false-negative. sagittal.3 78.5-T magnet (Signa. the latter study included results from only 28 patients.4 mm. arthroscopy showed 11 medial meniscus tears. Therefore. Stanitski compared clinical examination findings.

Radiology 1988.MR Imaging of the Knee in Adolescents from 59 patients. Anterior cruciate ligament tears: MR imaging compared with arthroscopy and clinical tests. the radiology literature reports 95–100% accuracy for anterior cruciate ligament tears. None of the patella dislocations had associated cartilage loss (our surgeons’ indication for operating). Graf BK. Four anterior cruciate ligament tears were identified. Correlation of arthroscopic and clinical examinations with magnetic resonance imaging findings of injured knees in children and adolescents. However. Stanitski asserted that sensitivity and specificity of MR imaging for detecting internal derangements of the knee were inferior in adolescents compared with adults. Lee JK. we believe that MR imaging of the knee is just as useful as a clinical adjunct in adolescents as in adults. Yao L. the visit consisted of one-time physical therapy or orthopedic follow-up without any additional follow-up or intervention. Stanitski CL. In circumstances in which surgery is deemed necessary. Stanitski did not provide the imaging parameters used to evaluate the meniscus. Although our primary intention was to determine the accuracy of MR imaging of the knee compared with arthroscopy in adolescents. McDermott MJ. Levy T. and there is no reason to believe that these numbers should not hold true for general radiologists. In conclusion. although the number of patients in our study is more than double that in the other study. the accuracy of the radiologists’ interpretations of the MR images of adults is not known. we also assessed the outcomes for the 97 patients who did not undergo arthroscopy. we found that the sensitivity and specificity values for MR imaging of adolescents and adults were essentially the same (Table 1). J Bone Joint Surg Br 1991. After evaluating our data. References 1. J Pediatr Orthop 1998. The osteochondral lesions were stable by MR appearance. 90– 95% for medial meniscus tears. It is well known that grade 2 intrameniscal signal is evidence of intrasubstance degeneration rather than a tear. However.166:861–864 AJR:180. Mackenzie R. Surgery was not considered for these two patients.73:452–457 7. Proper protocols will aid the radiologist (and surgeon) in accurately assessing the integrity of the meniscus. tears could have been overlooked. A potential shortcoming in our study is that only musculoskeletal radiologists interpreted MR images rather than general radiologists. Dixon AK. AJR 1994. Magnetic resonance imaging of the knee: diagnostic performance studies. Watkinson AF. Correlation of MRI and arthroscopic diagnosis of knee pathology in children and adolescents. but the patients did not undergo surgery at our institution: two did not want surgery and the other two were lost to follow-up. Therefore. Ackroyd CE. Radiology 1988. because grade 2 intrameniscal signal does not disrupt the articular surface. January 2003 19 .167:769–774 3. Palmer CR. and 85–90% accuracy for lateral meniscus tears [1–3.26:2–6 5. Tears of the anterior cruciate ligament and menisci of the knee: MR imaging evaluation. Another difference between our study and that of Stanitski [4] is that Stanitski used grade 2 meniscal signal abnormality as evidence for meniscus tear in an unspecified number of patients. A lack of follow-up could indicate that either the symptoms resolved so clinical follow-up was not needed or the patient was seen elsewhere for additional follow-up. 7]. In the Stanitski study [4]. which benefits the orthopedic surgeon as well as the patient because the information provided by MR imaging leads to decreased procedure and tourniquet time. Of the remaining patients who did undergo follow-up. Boeree NR. therefore reducing the accuracy of MR imaging for revealing meniscal abnormalities. Crues JI. Bathgate B. Magnetic resonance imaging of meniscal and cruciate injuries of the knee. De Smet AA. No additional “surgical lesions” were identified. Gillingham BL.162:905–911 4. Lazman J. Johnson C.18:675–678 6.51: 251–257 2. Am J Sports Med 1998. Wirth CR. Hennrikus WL. a small sample is a potential shortcoming of our study. In addition. Clin Radiol 1996. Lomas DJ. Phelps CT. MR imaging of the knee in adolescents can assist in preventing unnecessary surgery such as diagnostic arthroscopy. Therefore. The patient with the bucket-handle meniscus tear was among these four patients. the total number is still small. Forty-six patients did not undergo a follow-up examination. If sequences with a long TE were chosen to evaluate the meniscus. Mink J. Possible explanations for the small number of MR imaging studies in adolescents include the reluctance of orthopedic surgeons to use MR imaging in these patients because of the report by Stanitski and the possibility that adolescents are less likely to have internal derangement of the knee than adults. Meniscal tears missed on MR imaging: relationship to meniscal tear patterns and anterior cruciate ligament tears. These cases were erroneously diagnosed as tears in that study. 6. MR imaging can aid in surgical planning. Czajka J.

This report presents our findings relating to the effects of vitamin E on the primary and secondary cardiovascular outcomes. Gilles Dagenais. 524. The secondary outcomes included death from any cause.95 to 1. The primary outcome was a composite of myocardial infarction. 0.Sc. 237 Barton St. N Engl J Med 2000.) assumes responsibility for the overall content and integrity of the manuscript. the collection of data on cardiovascular disease was stopped in April 1999 on the basis of a finding by the independent data and safety monitoring board that the trial had conclusively demonstrated the benefits of ramipril and a lack of effect of vitamin E on cardiovascular events. and cancer. vegetables.16. E.13-16 but their results are conflicting.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne VITAMIN E SUPPLEMENTATION AND CARDIOVASCULAR EVENTS IN HIGH-RISK PATIENTS THE HEART OUTCOMES PREVENTION EVALUATION STUDY INVESTIGATORS* ABSTRACT Background Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis.05.Phil. 1. or at yusufs@fhs.D. 180.33). Massachusetts Medical Society. revascularization or limb amputation. Hamilton. (N Engl J Med 2000. myocardial infarction (532 vs. Janice Pogue.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk. congestive heart failure.6-9 Observational studies have indicated that persons who conJa nu ar y 2 0 .42)..22).1. After nearly 4. perhaps because of the low doses of vitamin E used in some studies. P=0. death from any cause. Effects of an Angiotensin-Converting–Enzyme Inhibitor. The study has been continued in the majority of centers to evaluate the effects of vitamin E on the incidence of cancer. M. The writing group (Salim Yusuf. 328 of those assigned to placebo. treatment with vitamin E for a mean of 4. on Cardiovascular Events in High-Risk Patients.11 and lower rates of progression of coronary artery lesions. M. Ramipril. There have been four randomized. M. Hamilton General Hospital. D. 1. hospitalization for unstable angina or congestive heart failure. 0. and death from cardiovascular causes. Jackie Bosch.15). The primary outcome was a composite of myocardial infarction.. and cancer.13. D. METHODS Study Design The Heart Outcomes Prevention Evaluation (HOPE) Study is a double-blind. on the incidence of cardiovascular events. The secondary outcomes included unstable angina. There were no significant adverse effects of vitamin E.. and other foods containing vitamins. The trial was also designed to evaluate the effects of an angiotensin-converting–enzyme inhibitor.. stroke.02. relative risk.ca. controlled trials of the relation between vitamin E and coronary heart disease. randomized trial with a two-by-two factorial deAddress reprint requests to Dr. 95 percent confidence interval. ramipril. *The investigators are listed in the Appendix of the Heart Outcomes Prevention Evaluation Study Investigators. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting–enzyme inhibitor (ramipril) or matching placebo for a mean of 4.mcmaster. and death from cardiovascular causes. 0. particularly vitamin E. Salim Yusuf at the Canadian Cardiovascular Collaboration Project Office.15 or the limited duration of treatment.15.17.M. and Peter Sleight..3-5 An inverse relation has been observed between coronary heart disease and the consumption of fruits.342:145-53. Methods We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor.16 We evaluated a high dose (400 IU per day) of vitamin E from natural sources. 95 percent confidence interval.14 the small numbers of events.342:154-60. revascularization or amputation. prospective study of patients at high risk for cardiovascular events.5 years has no apparent effect on cardiovascular outcomes. which has high bioavailability.95 to 1. 95 percent confidence interval. 1.12 However. Canada. stroke.5 years of follow-up.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). 1. Results A total of 772 of the 4761 patients assigned to vitamin E (16. There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs.2 and antioxidants such as vitamin E have been shown to slow atherosclerosis.) ©2000. complications of diabetes.05. Conclusions In patients at high risk for cardiovascular events.90 to 1. There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause.90 to 1.Sc. O 154 · XIDATIVE modification of low-density lipoprotein is an important step in the development and progression of atherosclerosis in experimental studies. 95 percent confidence interval. five-year. ON L8L 2X2. relative risk. in a large. sume more than 100 IU of vitamin E a day for more than two years have lower rates of coronary events10. relative risk. or stroke (209 vs. complications of diabetes. 0. observational studies cannot distinguish whether the lower risk of coronary heart disease associated with higher levels of vitamin E consumption is due to the vitamin or to other associated lifestyle factors such as increased exercise and other aspects of diet. 2 0 0 0 .

6) 2222 (46.7 percent at four years. stroke. the development of overt nephropathy or the need for dialysis or laser therapy among patients with diabetes. 1. and the development of heart failure or new or worsening angina regardless of the need for hospitalization. defined as worsening angina or angina at rest requiring hospitalization. (%) 1838 (38.2) — no.8) History of coronary artery disease 3857 (81. relative risk.6) 382 (8. Primary Cardiovascular Outcomes and Deaths from Any Cause A total of 772 of the 4761 patients who were assigned to receive vitamin E (16.5) and in addition to receive either 10 mg of ramipril or an equivalent placebo daily. BASE-LINE CHARACTERISTICS OF THE PATIENTS.3) 717 (15.0) 3832 (80.0) 679 (14. 277. deaths from myocardial infarction or stroke that occurred within seven days after the myocardial infarction or stroke. A computed tomographic or magnetic resonance imaging examination was recommended to define the type of stroke.2) PTCA 851 (17. There were no significant differences between the groups in the numbers of deaths from cardiovascular causes (342 in the vitamin E group vs. and diagnostic electrocardiographic changes. or ruptured abdominal aortic aneurysm. Deaths classified as due to cardiovascular causes were unexpected deaths presumed to be due to ischemic cardiovascular disease and occurring within 24 hours after the onset of symptoms without clinical or postmortem evidence of another cause.5 percent) had a primary cardiovascular event (relative risk.3) Diuretics 728 (15.2) — no.7 percent at two years. P=0. 0.00). conducted to evaluate the effects of ramipril and vitamin E in 9541 patients at high risk for cardiovascular events.9) 863 (18.1) Aspirin or other antiplatelet agents 3665 (77.2 percent) and 739 of the 4780 who were assigned to placebo (15.90. (%) Beta-blockers 1901 (39. The percentages of patients who were taking vitamin E in the vitamin E and placebo groups. HDL high-density lipoprotein. relative risk.6) Lipid-lowering agents 1352 (28.6) 1816 (38. ‡The body-mass index is calculated as the weight in kilograms divided by the square of the height in meters. 537.8) 869 (18.5) 1282 (26. 1.4 percent at the final visit.VITAMIN E SUP P L E ME NTAT ION A ND C A R D IOVASC UL A R EV ENTS IN H IGH -RISK PATIENTS sign. The results of the comparison of ramipril with placebo are reported in a companion article. eligible patients at high risk were randomly assigned to receive either 400 IU of vitamin E from natural sources or an equivalent placebo daily for 4 to 6 years (mean. (%) Current cigarette smoking — no.8) Left ventricular hypertrophy on ECG 411 (8. and ECG electrocardiogram.33) (Table 2 and Fig. 1. respectively. deaths from coronary heart disease (287 vs. pulmonary embolism. and 89. Vitamin E had no significant effect on the primary outcome either among patients who were receiving ramipril (338 events among those who were receiving vitamin E and 313 events among those who were receiving placebo. (%) 2219 (46.3 percent and 1.* PLACEBO GROUP (N=4780) CHARACTERISTIC† VITAMIN E GROUP (N=4761) Age — yr 66±7 66±7 Blood pressure — mm Hg 139±20/79±11 139±20/79±11 Heart rate — beats/min 69±11 69±11 Body-mass index‡ 28±4 28±4 Female sex — no.02).8) 1251 (26. and deaths from congestive heart failure.7) 2668 (55. Outcomes The primary outcome was a composite of myocardial infarction. (%)§ 2109 (44. 90.17 Details of the methods are given in that article17 and in a previously published article.05).0 percent at one year.08) or among patients who were not receiving ramipril (421 and 405 events. Deaths for which the cause was uncertain were presumed to be due to cardiovascular disease. 1.3) 3171 (66.0 percent at three years.16.1) CABG 1229 (25. 180. relative risk.1) 500 (10. 1. 91. were 94. 524.0) 3616 (75.3) 2037 (42. 1. or strokes (209 vs.17) (Fig.0) — no.5) 2535 (53. (%) 1012 (21. The total numbers of deaths were similar in the two groups (535 vs.2) Medications — no.2 percent and 2.8) Unstable angina pectoris 1205 (25.3) 976 (20.2 percent and 1. †CABG denotes coronary-artery bypass grafting. 2 and 3). revascularization or limb amputation.3) 1246 (26. relative risk.18 Briefly. relative risk. relative risk. 1). (%) Myocardial infarction 2499 (52. (%) Peripheral vascular disease — no. and death from cardiovascular causes. 4.0) Calcium-channel blockers 2249 (47. or a ratio of blood pressure in the ankle to blood pressure in the arm of less than 0. TABLE 1. §Peripheral vascular disease included claudication.05). 1.4) *Plus–minus values are means ±SD.05. unstable angina.06). a history of peripheral arterial disease.0) Known elevated total cholesterol 3109 (65. Myocardial infarction was diagnosed when two of the following three criteria were met: typical symptoms. respectively. increased cardiac enzyme levels (at least twice the upper limit of normal).5) — no. Secondary Cardiovascular and Combined Outcomes There were no differences between patients assigned to vitamin E and those assigned to placebo in the number of hospitalizations for unstable angina Vol ume 342 Numb e r 3 · 155 .3 percent and 2. (%) Known low HDL cholesterol 893 (18.0) Stable angina pectoris 2653 (55. dysrhythmia. Patients were evaluated every six months for a variety of outcomes.2 percent and 3. The rate of compliance with the assigned regimen was high throughout the study. myocardial infarctions (532 vs. relative risk.2) 2236 (46.6) Hypertension — no. 95 percent confidence interval. (%) 1263 (26.4) 1401 (29. hospitalization for heart failure with clinical and radiologic signs of congestion. (%) 665 (14.3) — no.1) Stroke or transient ischemic attacks 530 (11. RESULTS Characteristics of the Patients The characteristics of the 9541 patients are shown in Table 1. PTCA percutaneous transluminal coronary angioplasty. Secondary and other outcomes were death from any cause. Stroke was defined as a neurologic deficit lasting more than 24 hours. 328 in the placebo group.5) Diabetes — no. 93.9) 1870 (39.95 to 1. 1. (%) Microalbuminuria — no.

INCIDENCE OF THE PRIMARY OUTCOME VITAMIN E GROUP (N=4761) AND OF DEATHS FROM ANY CAUSE. 8). as compared with 13 of those assigned to placebo) or among those who were also taking an antiplatelet agent (11 vs. relative risk. relative risk. vitamin E did not reduce the incidence of cardiovascular events.0) (3. it is very unlikely that vitamin E had any clinically worthwhile beneficial effect on cardiovascular disease during four or five years of treatment. Primary Outcome 0.8) (11. 1. (%) Myocardial infarction.06). 156 · Ja nu ar y 2 0 . or Death from Cardiovascular Causes. or use of other drugs with respect to the primary or secondary outcomes (data not shown).The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 2. who did not have cardiovascular disease at entry.15) (0.02). 1. 1. Similar results were observed among those who received matching placebo rather than ramipril (421 vs. The relative risk of the composite outcome in the vitamin E group as compared with the placebo group was 1.2) 739 (15. There were no significant differences in the number of patients with angina of new onset (278 vs.04). P=0.22) (0. Specifically.9) (11. OUTCOME PLACEBO GROUP (N=4780) RELATIVE RISK (95% CI)* P VALUE† no.90–1.17 1. 0.54 0.14). 1. Given the large number of events and the consistent lack of difference in all secondary cardiovascular outcomes. 1576. 0.02 1.20 Subgroup Analyses Proportion of Patients 0. relative risk.00 0 500 Days of Follow-up Figure 1. §A patient may have had more than one event.95 to 1. age. there was no significant difference in the incidence of the primary outcome among patients with diabetes (325 of those assigned to vitamin E vs. 1. Results have been reported from four randomized trials of the effects of vitamin E on cardiovascular events. stroke.04) or among smokers (135 vs. 1. as compared with the incidence among patients assigned to placebo.16.16) 1. There was no increase in hemorrhagic stroke associated with vitamin E use (17 of those assigned to vitamin E had hemorrhagic stroke.5) 328 524 180 537 (6.15) or microvascular complications of diabetes (340 vs.2) 342 532 209 535 (7.2) (11. 772 (16.2) 1. 1.13.33 0. 139.05 There was no heterogeneity of results among subgroups defined according to sex. DISCUSSION (586 vs.90–1. 95 percent confidence interval. were randomly assigned to receive daily vita- .95–1.05 (95 percent confidence interval. relative risk. ‡The number of events among those receiving ramipril did not differ significantly between those assigned to receive vitamin E and those assigned to placebo (338 vs. relative risk. 2 0 0 0 In our study. 569.99 †P values were calculated with use of the log-rank test.15 Vitamin E Placebo 0. 313 of those assigned to placebo.05.13) 0. relative risk.4) (11.98 to 1.74 0. In a Chinese study. or revascularizations or limb amputations (848 vs. There was no significant difference between groups in the incidence of adverse effects or in the number of patients who stopped taking the study medication.10 0.05 (0. P=0.33). relative risk. A combined analysis of the proportion of patients who had any primary or secondary event found a nonsignificantly higher rate among those assigned to vitamin E (1630 vs. 787. 245. 405). Stroke.2) (4. during a follow-up period of four to six years.584 adults from Linxian Province.89–1.09) (Table 3). or death from cardiovascular causes‡ Death from cardiovascular causes§ Myocardial infarction§ Stroke§ Death from any cause *CI denotes confidence interval. 1.42) (0.00 (0. previous cardiovascular disease.13 0. 144.05 1.95–1. relative risk. Kaplan–Meier Estimates of the Effect of Vitamin E on the Composite Outcome of Nonfatal Myocardial Infarction. Adverse Effects 1000 1500 0. 313). 325. 29. hospitalizations for heart failure (160 vs.12).

13. in comparison with those receiving placebo only. However. 95 percent confidence interval.14 Daily treatment with 50 mg of vitamin E for five to eight years had no effect on the risk of death from coronary heart disease. 0.41 to 0. 0.02 (95 percent confidence interval. the median level of alpha-tocopherol increased significantly.1 µmol per liter in patients receiving 400 IU of vitamin E per day and to 64.2 to 51.11 to 0.10 0.00 0 500 1000 1500 0. The dose of vitamin E in this study was small.05 0. a reduction in the risk of nonfatal myocardial infarction was documented among men assigned to vitamin E only (40 vs. beta carotene.86 to 2. 0. 95 percent confidence interval. but there was no difference in deaths due to Vol ume 342 Numb e r 3 · 157 .5 µmol per liter in patients receiving 800 IU per day. P=0. Stroke Proportion of Patients Vitamin E Placebo 0. The third trial was the Cambridge Heart Antioxidant Study.89 to 1. P= 0.4 years. P=0. a large reduction in the number of patients with nonfatal myocardial infarction was observed (14 in the vitamin E group vs. and the relative risk of stroke was 1. The majority of the patients received 400 IU per day. In the remaining patients in this study. 0.005). involving 29.02 0. relative risk. there was a nonsignificant increase in the risk of death from coronary heart disease (relative risk. Kaplan–Meier Estimates of the Effect of Vitamin E on the Incidence of Myocardial Infarction (Panel A) and Stroke (Panel B). 0.42.VITAMIN E SUP P L E ME NTAT ION A ND CA R D IOVASC UL A R EV ENTS IN H IGH -RISK PATIENTS A 0.96). but not among those receiving the combination of vitamin E and beta carotene. despite large numbers of events (1204 and 907. 95 percent confidence interval.19 In this subgroup.53.90 to 1.06 Days of Follow-up Figure 3. The relative risk of myocardial infarction in the vitamin E group as compared with the placebo group was 1.95 to 1.10 0. 0.20). 1. there was no significant effect of vitamin E on nonfatal or fatal myocardial infarction. 41 in the placebo group.62. and selenium supplements or to receive placebo.33. The second trial was the Alpha-Tocopherol. which randomly assigned 2002 patients with coronary atherosclerosis to receive either vitamin E or placebo. In a subgroup of 1862 men with a pre- vious myocardial infarction at entry. from 28. min E (30 mg).20 Thus. After a median follow-up of 1. there was a 9 percent decrease in deaths from any cause without any significant reduction in cardiovascular events. 55.74). Beta Carotene Cancer Prevention Study.99).00 0 500 1000 1500 Days of Follow-up Figure 2.17 (95 percent confidence interval.5 µmol per liter at base line to 42. and the beneficial effects on overall mortality cannot be attributed only to vitamin E.15 The mean alpha-tocopherol levels increased from 34. Although the trial used a low dose of synthetic vitamin E (50 mg per day).05. the nutritional status and cardiovascular risk of this population were very different from those of Western populations. P=0.13).13 During the 5. vitamin E had no effect on coronary heart disease.5 µmol per liter at three months. respectively). Kaplan–Meier Estimates of the Effect of Vitamin E on the Incidence of Death from Any Cause.00 (95 percent confidence interval. 0.47.00 0 500 1000 1500 Days of Follow-up B 0. the number of events was small. The relative risk in the vitamin E group as compared with the placebo group was 1.04 0.05 0.15.2 years of follow-up.133 male smokers who were 50 to 69 years of age.15 Myocardial Infarction 0. P=0. 0. relative risk. in this wellconducted trial.15 Death from Any Cause Proportion of Patients Proportion of Patients Vitamin E Placebo Vitamin E Placebo 0.

980 (12.10) (0.96 0.8) 1.03) (0. such as lipid-lowering agents or antihypertensive medications.47 †P values were calculated with use of the log-rank test. revascularization or limb amputation. 2 0 0 0 placebo group (295 vs.87–1. 848 586 278 1215 762 160 530 340 (17.5) 1186 (24. In this trial.91–1. OR DEATH FROM CARDIOVASCULAR CAUSES IN LARGE TRIALS.52 0. relative risk.5) 3357/25.90–1. INCIDENCE OF SECONDARY AND OTHER OUTCOMES. unstable angina.569 (13. had high rates of compliance. †Relative risks and confidence intervals were derived by the method of Yusuf et al.020 (12. and involved high-risk patients. with events/total no. Beta Carotene Cancer Prevention Study Group.11 0.02 0. Neither difference was statistically significant. dialysis.9) (5.5 4.20) (0.07 0.6) 584/5664 (10. 284.16) (0.87 to 1.5) 64/967 (6.98 1. Such data are not available from most trials.21).37) (0.17 1.8) 787 (16.27. (%) Revascularization or limb amputation Hospitalization for unstable angina New-onset angina Worsening angina Claudication Hospitalization for heart failure Heart failure Complications of diabetes‡ *CI denotes confidence interval.02 1.04 1. P=0.1) 772/4761 (16.03–1.63 0.89) (0.2) 3273/26. 0.60 0. 0. ATBC Alpha-Tocopherol.61).32) (0.11) (0. 249.0) 571/5660 (10. worsening angina. that reduce cardiovascular events.90–1.564 (13. (%) ATBC14 50 »400 CHAOS15 300 GISSI16 Current study 400 Total 5.3) 569 (11.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 3. 1.97–1.8) 245 (5.0 1. P=0. This possibility is supported by the results of a recent Italian trial. TABLE 4.1) 325 (6. 0.8) (3. the number of events was small and there were imbalances in several base-line characteristics that call into question whether randomization resulted in truly comparable groups.95–1. the very large reduction in nonfatal myocardial infarction within a relatively short time (median.02.41) (1.0) 41/1035 (4.18.99–1.4 years) is inconsistent with the results of other interventions.12 1. 1.23) 0.13) (0.8) (16.02 1.3 3.11).9) 0. .000 patients who had had myocardial infarctions were randomly assigned to receive 300 IU of vitamin E per day or placebo for a median of 3.92–1. and laser therapy.0) 457 (9. at least over a four-to-six-year period.4) 144 (3. Furthermore. and the number of deaths from coronary heart disease was slightly smaller (227 vs.16 in which 11.02)† *CI denotes confidence interval.62 to 2.40–0. 1. Combining the data from all trials of vitamin E indicates that such treatment has little effect on the risk of death or cardiovascular events (Table 4). relative risk.. STROKE.27. and heart failure) were examined.93–1.97 (0.0) 753 (15. Furthermore.6) 1970/14.3) 739/4780 (15. relative risk.17) (0. and GISSI Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. a large number of secondary outcomes (e.* STUDY DAILY DOSE mg DURATION OF STUDY VITAMIN E PLACEBO RELATIVE RISK (95% CI) yr no.70 0. META-ANALYSIS OF THE EFFECTS OF VITAMIN E ON MYOCARDIAL INFARCTION.0) (11.92. The number of patients with nonfatal myocardial infarction was slightly higher in the vitamin E group than the 158 · Ja nu ar y 2 0 . ‡Complications included nephropathy.15 1. CHAOS Cambridge Heart Antioxidant Study.06 (0.94–1.g.21. It is therefore likely that the results of the Cambridge Heart Antioxidant Study may have been due to chance. 95 percent confidence interval.16 Our study used a high dose of vitamin E (400 IU per day).09 1.32 0.92–1. OUTCOME VITAMIN E GROUP (N=4761) PLACEBO GROUP (N=4780) RELATIVE RISK (95% CI)* P VALUE† no.6) (7. 0. 95 percent confidence interval.05 0. The study had a large number of primary outcomes and therefore had high statistical power (more than 90 percent power to detect a 13 percent relative reduction in the risk of the primary outcome). cardiovascular causes (27 vs.1) (25. 23.5 1889/14.5) (12. 95 percent confidence interval.5 years.77 to 1.

139:1180-9.328:1450-6. Peto R. Heliovaara M.22 Therefore. AstraZeneca.334:1156-62. J. Rios-Nogales. Parthasarathy S.6. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Carew TE. Natural Source Vitamin E Association. Colditz GA. 19. Hennekens CH. Hodis HN.69:261-6.328:1444-9. Reunanen A. Dietary antioxidants and risk of myocardial infarction in the elderly: the Rotterdam Study. Effects of an angiotensin-converting–enzyme inhibitor. N. Lancet 1999. Steinberg D. and C. Ripatti S. Bender. Schutze. The HOPE Study Investigators.V ITAMIN E SUP P L E ME NTAT ION A ND C A R D IOVASC UL A R EV ENTS IN H IGH -RISK PATIENTS Steinberg has hypothesized that unlike agents that lower cholesterol or blood pressure. 18.347: 781-6. Ljunggren. on cardiovascular events in high-risk patients. Am J Epidemiol 1994.349:1715-20. Cheeseman K. Vitamin E was well tolerated. Schofield PM. Gaziano JM. 11. N Engl J Med 2000. 16. we are examining whether the thickness of the carotid intima and media (an indication of the risk of early atherosclerosis) can be favorably altered by vitamin E. Manson JE. J Am Coll Nutr 1992. et al. Vitamin E consumption and the risk of coronary heart disease in men. King Pharmaceuticals. Parsons A. Dr. China: supplementation with specific vitamin/mineral combinations. Mink PJ. G. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. Geleijnse JM. Wu Y.85:1483-92. Knekt P.11 In a nested substudy. Can J Cardiol 1996. Ghadiali. Lancet 1996. Li JY. This finding provides some reassurance for the conduct of large. B. Dietary vitamin E and the attenuation of early lesion development in modified Watanabe rabbits. such as its possible effects in preventing cancer.320:915-24. Bush MJ. Willett WC. N Engl J Med 1993.26-28 In conclusion.23 Similar data are not available for vitamin E. Rangoonwala. higher vitamin E consumption was also associated with higher intake of a number of other antioxidants and micronutrients. St. Sharp CH. 5. Witztum JL. 344:793-5. 14. Mack WJ. Arch Intern Med 1998. 20. Ascherio A. Stampfer MJ. Willett WC. 8.94:153-9. den Breeijen JH. Willett WC. F. B. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women.24 If so. Carew TE. another reason may be our use of vitamin E alone. Verlangieri AJ. M. antioxidants may have to be used for more than five years to have a demonstrable benefit.10. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study.C. Seppanen R.158:668-75. Lancet 1994. Virtamo J. but observational studies that demonstrated a lower rate of coronary heart disease with vitamin E supplementation suggested that a lower risk should be evident after two years. J. et al. Aromaa A. The oxidation hypothesis of atherosclerosis. N Engl J Med 1994.6-9 It is possible that vitamin E supplementation requires these cofactors to have a beneficial effect. Proc Natl Acad Sci U S A 1987. Funded by the Medical Research Council of Canada. Rosner B. L. Whitehill. Rimm EB. Effects of d-a-tocopherol supplementation on experimentally induced primate atherosclerosis. Beta Carotene Cancer Prevention Study Group. LaBree L. Atherosclerosis 1992.11: 131-8. and the Heart and Stroke Foundation of Ontario. 15. Randomised trial of a-tocopherol and b-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. 17. the Physicians’ Health Study did not find a benefit of beta carotene (another antioxidant with a different action) after 12 years. Williams RJ. We are indebted to W. Vol ume 342 Numb e r 3 · 159 . Manson JE. A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly.P. Colditz GA. et al. Taylor PR. since the primary mechanism of these agents may be the prevention of new lesions.84:7725-9.14 or selenium13 is not supported by the findings of prospective observational studies or randomized trials. N Engl J Med 1989. it may take longer than five years to detect an effect on clinical outcomes. 10. Nutrition intervention trials in Linxian. this hypothesis can be tested only in trials in which combinations of vitamins are given. Sleight P. Khoo JC. N Engl J Med 1993.10 beta carotene. 7.342:145-53. Branch LG.5:255-60.273:1849-54. Motteram JM. Rapola JM. with no significant adverse events as compared with placebo. Bostick RM. Vitamin E consumption and the risk of coronary disease in women. Giovannucci E. Yusuf S. Steinberg D. 12. Hoechst–Marion Roussel. Although the moderate duration of vitamin E supplementation (four to six years) and the characteristics of the population may explain our finding of a lack of benefit of vitamin E. J. without other antioxidants. Negma. Schulz. JAMA 1995. longer-term trials to address unanswered questions regarding vitamin E. some such trials are now in progress. Carter.330:1029-35. Jensen. Collins R. W. Blot WJ. Ann Epidemiol 1995. GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico). The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. and disease-specific mortality in the general population. Lancet 1997.25 Although the existence of interactions between vitamin E and other vitamins. Olsson. Witztum JL. Vint-Reed for support and to Karin Dearness for secretarial help. N Engl J Med 1996. Lewis J. Dairon. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Stephens NG. The Heart Outcomes Prevention Evaluation Study Investigators. in a population like the one we studied. M. Yusuf was supported by a Senior Scientist Award of the Medical Research Council of Canada and a Heart and Stroke Foundation of Ontario Research Chair. Kushi LH. REFERENCES 1. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Virtamo J. 2. 400 IU of vitamin E administered daily for four to six years had no beneficial effects on cardiovascular outcomes in a high-risk population of patients who were 55 years of age or older. J. 4.354:447-55. 21. Schwenke DC. Prog Cardiovasc Dis 1985. 13. Klipstein-Grobusch K. et al. 9. In the epidemiologic studies that found an association between higher dietary intake of vitamin E and lower rates of coronary heart disease. Am J Clin Nutr 1999. 6. Buring JE. Steinberg’s hypothesis may be worth exploring with more prolonged follow-up or treatment to assess whether such changes in the development of atherosclerosis would translate into a benefit in terms of clinical outcomes. Pierre. ramipril. simple randomized trial of an angiotensin-converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. Stampfer MJ. A. Bourgouin. Prineas RJ. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. Gallagher PJ. Rapola JM. Bravo. 3. Mitchinson MJ. Jarvinen R. Ripatti S. Antiatherogenic effect of probucol unrelated to its hypercholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. The Alpha-Tocopherol. Folsom AR. The HOPE (Heart Outcomes Prevention Evaluation) Study: the design of a large.12:12737. However.27:335-71. cancer incidence. J Natl Cancer Inst 1993. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Colditz GA. Kelly F. et al.

68:3-20. Eur Heart J 1999.334:1145-9. et al. Buring JE. Stocker R. Galan P. Doris CI. Farkouh M.78: 914-9. Lonn EM. Background and rationale behind the SU. a prevention trial using nutritional doses of a combination of antioxidant and minerals to reduce cardiovascular diseases and cancers: SUpplementation en VItamines et Mineraux AntioXydants Study. FASEB J 1999. Upston JM. Hennekens CH. Int J Vitam Nutr Res 1998. Hercberg S.20:725-41. 24. Am J Cardiol 1996. 26. The antioxidant vitamins and cardiovascular disease: a critical review of epidemiologic and clinical trial data. Tocopherol-mediated peroxidation of lipoproteins: implications for vitamin E as a potential antiatherogenic supplement. Terentis AC.The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne 22. Clinical trials of antioxidants in atherosclerosis: are we doing the right thing? Lancet 1995. 28. 27.VI. 160 · Ja nu ar y 2 0 .346:36-8. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Ann Intern Med 1995. Study design and baseline characteristics of the Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E: SECURE. Yusuf S. Steinberg D. N Engl J Med 1996. Preziosi P.123:860-72. et al. 25. 2 0 0 0 . Flather M. Manson JE. 23. Lonn E. Yusuf S. Jha P.MAX Study.13:977-94. et al. Lack of effect of longterm supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.

Departments of Medicine (S.Z.4 to 7.8).). (J.B.D.1 years of follow-up data were available.V.D. Washington. N Engl J Med 2005. and Monica Bertagnolli. Harvard Medical School.. (W. E..P. 2005 . In light of recent reports of cardiovascular harm associated with treatment with other agents in this class.nejm. 1. M. National Cancer Institute. Western Infirmary. 2.4 percent. Boston. Solomon at the Cardiovascular Division. M. Copyright © 2005 Massachusetts Medical Society.edu.3.. Ernest Hawk.D.. methods We reviewed all potentially serious cardiovascular events among 2035 patients with a history of colorectal neoplasia who were enrolled in a trial comparing two doses of celecoxib (200 mg or 400 mg twice daily) with placebo for the prevention of colorectal adenomas.). 95 percent confidence interval. New York (A. stroke. n engl j med 352. A composite cardiovascular end point of death from cardiovascular causes. myocardial infarction. 2005.org on March 18. Ph. Peter Finn.P. McMurray. Brigham and Women’s Hospital.H.11 www. .D. 3. Statistics Collaborative. 2005 1071 Downloaded from www. 352 no. hazard ratio. conclusions Celecoxib use was associated with a dose-related increase in the composite end point of death from cardiovascular causes. and nonfatal cardiovascular events were categorized in a blinded fashion according to a prespecified scheme. Brigham and Women’s Hospital. and Memorial Sloan-Kettering Cancer Center. John J. William F. M.. All rights reserved.P. Ph. results From the Cardiovascular Division. D. Pfeffer. MA 02115.D. Boston.8 to 3. 75 Francis St. P. or heart failure was reached in 7 of 679 patients in the placebo group (1. This article was published at www.4.3 percent. Bethesda.H.F.. M. Robert Fowler. for the Adenoma Prevention with Celecoxib (APC) Study Investigators* abstract background Selective cyclooxygenase-2 (COX-2) inhibitors have come under scrutiny because of reports suggesting an increased cardiovascular risk associated with their use. as compared with 16 of 685 patients receiving 200 mg of celecoxib twice daily (2.).. 11 Cardiovascular Risk Associated with Celecoxib in a Clinical Trial for Colorectal Adenoma Prevention Scott D. M.. M.. M. *Participants in the APC study are listed in the Appendix..nejm.H. For all patients except those who died.F. Md. On the basis of these observations. org on February 15.F.harvard.. Janet Wittes.A. University of Glasgow..D. M.. or heart failure. or at ssolomon@rics..5) and with 23 of 671 patients receiving 400 mg of celecoxib twice daily (3. 95 percent confidence interval.S.D. Copyright © 2005 Massachusetts Medical Society.352:1071-80.D. stroke.S.W.J. the data and safety monitoring board recommended early discontinuation of the study drug. 2.nejm.bwh. All deaths were categorized as cardiovascular or noncardiovascular.9 to 5. Ph. 2005 vol. Scotland (J.new england journal of medicine The established in 1812 march 17 . R.) and Surgery (M. Glasgow.M.C. myocardial infarction.). Anderson. Ann Zauber. M. hazard ratio.D.org march 17... M.D.. Similar trends were observed for other composite end points.0 percent). Experimental research suggesting that these drugs may contribute to a prothrombotic state provides support for this concern. Marc A.). Solomon.V. 0. M. Address reprint requests to Dr. This article is being provided free of charge for use in Philippines. these data provide further evidence that the use of COX-2 inhibitors may increase the risk of serious cardiovascular events..D.A.

2035 patients had undergone randomization in a double-blind manner at a 1:1:1 ratio. with the results presented at their scheduled meeting on December 10.org on March 18. Participants ranged from 32 to 88 years of age and were considered to have a clinically significant risk of colorectal adenoma on the basis of a history of either multiple adenomas or a single adenoma that was at least 0.2.nejm.org). and placebo in reducing the occurrence of ad- The cardiovascular safety committee developed endpoint definitions as guidelines for adjudication. and all patients provided written informed consent before enrollment. All rights reserved.The new england journal of medicine he promise of a lower incidence of gastrointestinal side effects with the use of selective cyclooxygenase-2 (COX-2) inhibitors than with the use of nonselective nonsteroidal antiinflammatory drugs (NSAIDs) or aspirin has led to a marked increase in prescriptions for COX-2 inhibitors. t enomatous polyps in the colon and rectum one year and three years after endoscopic polypectomy. Myocardial infarction was defined on the basis of either a clinical presentation characterized by typical symptoms.nejm. was obtained for each patient. however.1-3 In addition. These guidelines were designed specifically to assess cardiovascular safety (listed in the Supplementary Appendix. All known adenomas were removed colonoscopically before drug treatment began. 2004. The trial was led by the Strang Cancer Prevention Center (New York) and cosponsored by the National Cancer Institute and Pfizer.9-11 The mechanism of this effect is suggested in part by evidence that selective inhibition of COX-2 can block the production of prostacyclin without affecting the synthesis of thromboxane A2. this class of drugs has come under scrutiny because of clinical reports that they were associated with an increased risk of serious cardiovascular harm. myocardial infarction. Copyright © 2005 Massachusetts Medical Society. .12-16 this longer-term. 2005 . Two experienced independent assessors reviewed these events using medical records and narratives supplied by site investigators. or stroke among patients receiving rofecoxib in the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial and the associated voluntary withdrawal of this drug from the market prompted the data and safety monitoring board and steering committee of a similar ongoing trial of celecoxib to request a focused reassessment of data on cardiovascular safety by an independent committee. signs. and 10 in Canada).4-8 Recently.11 www. Compliance was assessed by means of both pill counts and standard monitoring of medical records every 6 to 12 weeks. including baseline assessment of cardiovascular disease status and risk factors for cardiovascular disease. multicenter trial assessing the efficacy of celecoxib for the prevention of adenomatous polyps in patients who had undergone endoscopic polypectomy. 2005 Downloaded from www. Enrollment began in November 1999 and concluded in March 2002. despite the fact that they offer similar degrees of pain relief. This article is being provided free of charge for use in Philippines. or electrocardiographic changes associated with an elevation in the level of a cardiac marker or angiographic evi- 1072 n engl j med 352.5 cm in diameter. Patients were randomly assigned to treatment with the use of a computergenerated randomization schedule. 1 in the United Kingdom. This report describes the findings of the independent cardiovascular safety committee. The study was a prospective. The protocol was reviewed and approved by the appropriate institutional review boards.nejm. A detailed medical history. Because neither prior clinical trials nor observational studies had reported a clearly increased risk of cardiovascular events with celecoxib use. An initial review identified all deaths and potential nonfatal cardiovascular adverse events. double-blind. after stratification according to the use or nonuse of aspirin for cardiovascular prophylaxis and the enrolling center. The observation of an increased incidence of death from cardiovascular causes.5. placebo-controlled trial provided an important opportunity to evaluate the potential association.org march 17 . At the time of data review. 400 mg of celecoxib twice daily. review of cardiovascular safety methods patients The Adenoma Prevention with Celecoxib (APC) study compared the efficacy and safety of 200 mg of celecoxib twice daily. 8 in Australia. the identification of COX-2 as a promoter of intestinal tumorigenesis suggested that inhibiting this enzyme could prevent the formation of premalignant colorectal adenomas. The committee classified and adjudicated the end points by defining a hierarchy of composite end points (based on clinical importance and the prior findings with rofecoxib). available with the full text of this article at www.10 thereby potentially creating a prothrombotic state. randomized. Ninety-one sites participated (72 in the United States.

. and the group receiving 400 mg of celecoxib twice daily had a hazard ratio of 3. we constructed Cox models with terms for treatment. and one. The entire cardiovascular safety committee was unaware of the patients’ treatment assignments throughout the review process. 0. or heart failure of 2. Censoring was defined by assuming that a patient was followed for 37 months. All rights reserved. 2005 (the date defined for this analysis as the common close-out date) — whichever came first. This article is being provided free of charge for use in Philippines.4 to 28. Stroke was defined as a persistent focal neurologic event whose onset was sudden and was not due to trauma or a tumor. 7. until death. All analyses were performed according to the intention-to-treat principle.nejm. the point estimate of the number of venous thromboembolic events was also increased (though not significantly) among patients receiving celecoxib: four in the group given 400 mg of celecoxib twice daily and three in the group given 200 mg twice daily. 2005 . The Kaplan–Meier curves for the combined end point of death from cardiovascular causes. There was no apparent increase in the risk of un- Randomization codes were provided to Statistics Collaborative (Washington. as compared with one in the placebo group (hazard ratio for the two celecoxib groups combined. respectively. The results for the individual components of the composite end point are shown in Table 3.4 events per 1000 patient-years in the group given 400 mg twice daily. additional information was obtained from the investigative sites. Although the randomization was stratified according to the baseline use or nonuse of aspirin and the center. we had follow-up information for more than 97 percent of the patient-years at risk. and the need for a cardiovascular procedure. stroke. the Cox models did not include these stratifying variables. myocardial infarction. analyzed according to the time to the first event. myocardial infarction. Incidence rates were calculated for individual and composite cardiovascular events by dividing the number of patients with events by the number of patient-years at risk. Log-rank tests were used to compare the time to a cardiovascular event in the three groups for each composite end point of interest. including death from cardiovascular causes. and the associated hazard ratios are shown in Table 2.4 (95 percent confidence interval. or heart failure in the three groups are shown in Figure 1.8 years of follow-up (range. stroke. As compared with the placebo group. heart failure. and 11. Other cardiovascular events were categorized according to a preplanned schema. In addition to the increased risk of the prespecified composite end point of cardiovascular events. 2. unstable angina.C. Cox models. six in the group given 200 mg of celecoxib twice daily. myocardial infarction. For the purposes of this analysis. 3. Recommendations to the study’s data and safety monitoring board were made on the basis of data n engl j med 352. 0.8 to 3. and the interaction between subgroup and treatment and evaluated the interaction terms for statistical significance. stroke. results At the time of the analysis. were due to cardiovascular causes.8 events per 1000 patientyears in the group given 200 mg of celecoxib twice daily. three. To examine whether the effect of celecoxib varied between subgroups. with the treatment group as the only covariate.11 www.5). subgroup. D. or until January 6.1). At the time of this review. 95 percent confidence interval.8).5). The baseline characteristics were similar among the three groups (Table 1). There were six deaths in the placebo group. The annualized incidence of death from cardiovascular causes. statistical analysis available at the time of the original analysis. This analysis contains data on three additional cardiovascular events that were not included in the original report. The incidence of the prespecified composite cardiovascular end points.). the group given 200 mg of celecoxib twice daily had a hazard ratio for death from cardiovascular causes.3 (95 percent confidence interval. and six of the deaths.org on March 18. 1.org march 17.celecoxib and cardiovascular risk dence of coronary thrombosis. Copyright © 2005 Massachusetts Medical Society. stroke.4 to 7. 77 percent of the 2035 patients had completed the study.5. Important subgroups based on baseline characteristics were prespecified. with data on each patient analyzed according to the original randomized treatment assignment. and nine in the group given 400 mg twice daily. myocardial infarction. or heart failure was 3. were used to estimate hazard ratios for the two celecoxib groups as compared with the placebo group.nejm. 2005 1073 Downloaded from www. we evaluated a hierarchy of composite end points.4 events per 1000 patient-years in the placebo group. and all of the remaining surviving patients had completed at least 2.9 to 5. When this initial documentation was insufficient for adjudication.

org on March 18.4) Celecoxib. or the need for a cardiovascular procedure. which have a crucial role in vascular homeodiscussion stasis.9) 6 (0. the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial. the advice of the cardiovascular safety committee. Because the use of other selective COX-2 inhibitors.9) 66 (9.3) 188 (27. 2004.4) 201 (29. placebo-controlled.11 www.6) 13 (1.5) 96 (14.2) 20 (2. The reason for the apparent increase in cardiovascular risk associated with the use of COX-2 inhibitors is uncertain. their inclusion does not alter the overall conclusions of the report issued on December 16. The trial remained blinded. stroke. we found that twice-daily COX-2 isoenzymes on arachidonic acid.0) 122 (18. The preliminary analysis did not show an increase in risk at this dose. The cardiovascular safety committee also completed a preliminary review of cardiovascular safety in another study.6) 42 (6. 200 mg Twice Daily (N=685) 59.2) 335 (48.7±9.* Characteristic Age — yr Male sex — no. the steering committee stopped the use of study medication among the patients remaining in the trial. The hazard ratios associated with celecoxib use decreased when a broader class of cardiovascular events.19.1) 14 (2. multicenter trial. 2004. on the basis of these findings. including aspirin use at baseline (Table 4). (%) History of cardiovascular events — no.5) 277 (40. The hazard ratio associated with celecoxib was not significantly affected by any of the baseline characteristics examined.4) 184 (27. Baseline Characteristics of the Patients.7) 307 (45. which randomly assigned patients with a history of colorectal adenomas to receive either 400 mg of celecoxib once a day or placebo.1) 51 (7. including death from cardiovascular causes. valdecoxib. (%)† Current smoker — no.3) 14 (2. randomized. treatment with 200 or 400 mg of celecoxib to prevent colorectal adenomas led to a dose-related increase in the risk of serious cardiovascular events.8) 191 (28.8) 61 (9.org march 17 . arrhythmia.9±9. (%) Aspirin use — no.3) 287 (41.nejm. and parecoxib.18 our results heighten concern that this class of drug may be associated with increased cardiovascular risk. the data and safety monitoring board concluded that continued exposure to celecoxib placed patients at increased risk for serious cardiovascular events. and previous findings with drugs in the same class.7±9.9.0) 213 (31. and follow-up for the end point of adenoma continued. (%) Use of lipid-lowering drug — no. One prominent hypothesis involves the effects of COX-2 inhibitors on two key prostanoids. 2005 Downloaded from www.21 Throm- 1074 n engl j med 352.8) 31 (4. † Data were missing for one patient in the placebo group.3) 29 (4. (%) Placebo (N=679) 59.3) 200 (29.4 454 (67. prostacyclin and thromboxane A2.9) 50 (7. Copyright © 2005 Massachusetts Medical Society. All rights reserved. including unstable angina and the need for a cardiovascular procedure. There were no significant differences among the groups. On the basis of this recommendation.20 These prostanoids are generated by In a large. has also been associated with an increased rate of cardiovascular events.the action of the cyclooxygenase-1 (COX-1) and blind. (%) Myocardial infarction Cerebrovascular disease Congestive heart failure Angina Hypertension Diabetes — no.9) 22 (3.7) 64 (9.3) 260 (38. On December 16. This article is being provided free of charge for use in Philippines. stable angina.17. and heart failure. .6) 119 (17. These results were consistent among the individual components of the composite end point.1) Celecoxib.7) 321 (47.9) 11 (1. was added to the composite end point.The new england journal of medicine Table 1.nejm.4 460 (67.7 473 (69. including rofecoxib. myocardial infarction. 2005 . double. 400 mg Twice Daily (N=671) 59. Three events that were documented after the study was stopped are included in the present analysis.5) * Plus–minus values are means ±SD.

2) 5. End Point* number of patients (percent) 1 (0.3) 4.6–35. stroke.2) 20 (3. * MI denotes myocardial infarction.1–4.3) Death from cardiovascular causes.4–7. or stroke 7 (1.7) 2.3–6.8 (1. heart failure.5 (0.6) 18 (2. This article is being provided free of charge for use in Philippines.5 (0.5 1.4 2.7 12.3 9.7) 0. or angina 17 (2.4 8. 200 mg 400 mg Placebo Twice Daily Twice Daily (N=679) (N=685) (N=671) Both Celecoxib Groups (N=1356) Celecoxib.7 (1.2) 27 (2.6) 25 (3.7) 43 (3.3) 23 (3.0) celecoxib and cardiovascular risk www.0–9.5) 3. 2005 Death from cardiovascular causes.5) 3.3) 3.Table 2.8) 2.7–50. 400 mg Twice Daily (N=671) Both Celecoxib Groups (N=1356) Celecoxib. 6 1.5) 2.9 2.0–3.4 (1.8 11.4 (1.4–8. heart failure.8) 1.8–2.0 (1.9 8.4) 6 (0.0 (0.5 (1.3 (0.3 (1. 400 mg Twice Daily (N=671) Both Celecoxib Groups (N=1356) hazard ratio (95% confidence interval) 3.6) 6.4) 3.9) 9 (0.6) 2.11 Death from cardiovascular causes or nonfatal MI 6 (0. or angina or need for a cardiovascular procedure 15.2 rate/1000 patient-years Celecoxib. 2005 .2–7.4 6.6 3 (0.9) 15 (2.9) 3.6 2.0–2.5 2.nejm. nonfatal MI.8 7.8) 31 (4.4 12. Copyright © 2005 Massachusetts Medical Society. Celecoxib.9 (1.0) 1.1) 4 (0.8–3.org Death from cardiovascular causes.0 (1.7) Death from cardiovascular causes n engl j med 352. 200 mg Placebo Twice Daily (N=679) (N=685) Celecoxib.4) 39 (2.2) 8.nejm. nonfatal MI. or heart failure 11 (1. Incidence of and Hazard Ratios for the Composite End Points in the Celecoxib Groups Relative to the Placebo Group. nonfatal MI.5) 26 (3.4) 2.org on March 18.4 9.0) 16 (2.6 (0. 200 mg Twice Daily (N=685) Celecoxib.5 14. stroke.9 5.0–6.1 (0. All rights reserved.8 (1.6) 57 (4.3) 1. 1075 .8) march 17.0–3.2–9.9) Downloaded from www.6 Death from cardiovascular causes.9–5.1 1.8) 15 (2.5) 3.0) 35 (2.6) 12 (1.7 10.9 7. stroke.3–11. nonfatal MI.3–28.4 (1.9 (1.4 7.

6) 9 (1.9) 14 (2. prostacyclin.9 The selective COX-2 inhibitors may therefore suppress vascular production of prostacyclin without affecting the synthesis of platelet-derived thromboxane A2.9) 1 (0. 2005 .6) 4 (0.3) 8 (0.1) 18 (1.0) 6 (0.6) 4 (0.4) 9 (1.7) Nonfatal cardiovascular events Myocardial infarction Stroke Heart failure Thromboembolic event Resuscitation after sudden cardiac arrest Hospitalization for unstable angina Arrhythmia Cardiovascular procedure Other 3 (0.3) 9 (1.3) 11 (1.3) 6 (0.4) 11 (0.3) 5 (0. despite the fact that many patients who are taking these drugs or who are considered candidates for this therapy are at high cardiovascular risk.3) 3 (0.3) 7 (1.7) 4 (0.1) 9 (0.27 Some have attributed these findings to the potentially cardioprotective effects of naproxen.1) 6 (0.11 www.14.4) 3 (0. most of the earlier clinical trials of selective COX-2 inhibitors in patients with arthritis did not appear to show an increase in cardiovascular risk. The results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial3 and a subsequent study. which promotes platelet aggregation.The new england journal of medicine Table 3.28. APPROVe.org march 17 .5. This imbalance may promote thrombosis and increase the risk of cardiovascular events.18. They included a relatively small proportion of patients at high risk for cardiovascular events or excluded such patients. including elevated blood pressure.2.29 although this interpretation has been a source of contention.5) 1 (0. selective COX-2 inhibitors act primarily on COX-2.11 The use of active rather than placebo controls in many of these studies also made the findings difficult to interpret.4) 1 (0.4) 0 4 (0.9) 3 (0.7) 6 (0.3) 1 (0. All rights reserved. were generally short-term studies designed to assess the use of this class of drug for pain relief and to evaluate associated adverse gastrointestinal events.1) 3 (0. is the main prostanoid product of endothelial cells.8) boxane A2.10 Nonaspirin.0) 9 (1. is synthesized primarily in platelets.26 raised questions about the safety of rofecoxib.8) 15 (1.4) 3 (0.20 1076 n engl j med 352. the studies lacked adequate statistical power to confirm or refute a cardiovascular hazard related to the use of COX-2 inhibitors.10 Other potentially detrimental effects of COX-2 inhibitors have been suggested. . reported a higher risk of myocardial infarction among the patients receiving rofecoxib.nejm. 2005 Downloaded from www.1) 25 (1.23 In contrast to our findings.nejm. Copyright © 2005 Massachusetts Medical Society. nonselective NSAIDs may also not sufficiently reduce thromboxane A2 synthesis long enough to prevent platelet aggregation and atherosclerotic events. however. End Point Placebo (N=679) Celecoxib.4) 2 (0. though some reports have indicated that these drugs may have beneficial effects on vascular health.7) 9 (1. and vasodilatory actions. The VIGOR trial. Incidence of Individual Cardiovascular and Fatal Events.1) 6 (0. Conversely.4) 7 (0.9) 3 (0. which compared a nine-month course of 50 mg of rofecoxib per day (a larger dose than that usually recommended for the long-term treatment of arthritis) with naproxen in patients with rheumatoid arthritis. vasoconstriction. 200 mg Twice Daily (N=685) Celecoxib. which has antiaggregative.1) 2 (0.1) 0 5 (0.25 Consequently.org on March 18. antiproliferative. This article is being provided free of charge for use in Philippines. 400 mg Twice Daily (N=671) Both Celecoxib Groups (N=1356) number of patients (percent) Death from any cause Death from cardiovascular causes 6 (0. which express only COX-1.6) 5 (0.4) 15 (1.6) 9 (1.3) 7 (1.4) Death from noncardiovascular causes 5 (0. and smooth-muscle proliferation.22 Whereas nonselective NSAIDs inhibit both COX-1 and COX-2. synthesized as a result of the action of COX-2.6) 1 (0.24 These trials.

nejm.5 mg of rofecoxib per day. This article is being provided free of charge for use in Philippines.025 0.11 www. did not show an increased rate of cardiovascular events. The log-rank statistic of 8. the results of a randomized.040 0.73.32 The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) also showed a nonsignificant increase in the risk of cardiovascular events with lumiracoxib therapy. or Heart Failure among Patients Who Received Celecoxib (200 mg Twice Daily or 400 mg Twice Daily) or Placebo.020 0. 200 mg Placebo 6 12 18 24 30 36 Months after First Dose No.01 Celecoxib.2 CLASS differed from the VIGOR study in several important ways.015 0. which has two degrees of freedom.035 0. 400 mg Celecoxib. analysis of the data on aspirin users in this study shows that they had a higher frequency of cardiovascular risk factors at baseline than did nonusers. The cardiovascular findings with regard to celecoxib use in the APC study are consistent with those identified for rofecoxib use in the APPROVe trial. 2005 . 200 mg Placebo 671 685 679 669 681 677 665 676 675 655 675 672 651 673 668 648 670 667 576 595 585 Figure 1.005 0. report a second trial showing a significant increase in cardiovascular events when parecoxib and valdecoxib were used in the immediate postoperative period after coronaryartery bypass surgery.10. a randomized. the APPROVe trial. the use of the parenteral COX-2 inhibitor parecoxib followed by oral treatment with its active metabolite valdecoxib. In contrast. formal statistical tests of interaction showed no differential effect of celecoxib with respect to baseline cardiovascular risk.26 These results prompted voluntary withdrawal of rofecoxib from the market.org march 17.000 0 Estimated Probability of Composite End Point Celecoxib. as compared with those taking ibuprofen (but not diclofenac). or treatment with placebo followed by valdecoxib. showed no apparent increase in cardiovascular risk. at Risk Celecoxib. The failure of pharmacoepidemiologic studies to show an increased risk may be due in part to the lower doses and shorter duration of use in these studies than in clinical trials and in part to the potential for selection bias in nonrandomized studies.33 Although we found that patients with an increased cardiovascular risk at baseline appeared to have a higher absolute rate of events than those with no increase in cardiovascular risk at baseline. which involved a daily dose of 400 mg of celecoxib. 400 mg P=0.celecoxib and cardiovascular risk More recently. reported to the Food and Drug Administration.org on March 18. Topol reported that another controlled trial also showed an increased risk of cardiovascular events with treatment with 12.010 0. demonstrated an increase in cardiovascular events among patients receiving celecoxib.20 Moreover. an increased cardiac risk associated with celecoxib use in non–aspirin users. The differences in the dosing regimens between these two trials — twice daily in the APC study. controlled clinical trial of celecoxib in patients with Alzheimer’s disease.030 0. was associated with a significantly increased risk of cardiovascular thromboembolic events. was used to determine the P value.nejm. to our knowledge. Nussmeier et al. Nevertheless. CLASS enrolled relatively low-risk patients and allowed the use of aspirin for cardiovascular protection. as n engl j med 352. Although the overall absolute risk appeared to be higher among such patients. as compared with nabumetone or placebo. was terminated early because of an increased risk of cardiovascular events. preliminary analyses from the PreSAP trial. neither pharmacoepidemiologic studies nor randomized. 2005 1077 Downloaded from www.10 as compared with naproxen or ibuprofen therapy. placebo-controlled trial designed to evaluate the efficacy of rofecoxib for preventing colorectal polyps in patients with a history of colorectal adenomas. A short-term study not designed for systematic and formal assessment of cardiovascular events.30 The results of other studies have aroused concern about the safety of selective COX-2 inhibitors. In addition. controlled trials have reported clear evidence of an increased cardiovascular risk associated with celecoxib.045 0. Kaplan–Meier Estimates of the Risk of the Composite End Point of Death from Cardiovascular Causes.31 In this issue of the Journal. In a placebo-controlled trial of pain relief after coronary-artery bypass surgery. but only among patients who were not taking aspirin. FitzGerald has suggested that CLASS did not completely refute evidence of 0. Stroke.2 which used the same dose of celecoxib (400 mg twice daily) that was given to one group in the APC study and compared celecoxib with two nonselective NSAIDs. One prespecified subgroup included users of cardioprotective aspirin at baseline.050 0. the Celecoxib in Long-term Arthritis Safety Study (CLASS). In contrast. Myocardial Infarction. Copyright © 2005 Massachusetts Medical Society. . All rights reserved.

1) 3/307 (1.8) 31/914 (3.63 963 1072 4/321 (1. and differences in use of concomitant medications. If correct.25 This category may include nonselective NSAIDs (other than aspirin).7–8.11.8) 28/642 (4.4–8.0) 5/473 (1.4 (0.6) 2.2–10.86 648 1387 2/206 (1.8) 15/379 (4.6) 4. a blinded review of cardiovascular events in a large.2) 0.36.0) 5/130 (3.org on March 18.4) 3. we support the call for regulatory agencies to consider requesting a formal evaluation of long-term cardiovascular outcomes of any new drug with a mechanism of action that could augment the risk of cardiac and vascular events.37 Given the experience with COX-2 inhibitors.org march 17 .4) 11/714 (1.8) 2. Myocardial Infarction. All rights reserved.3) 0.9–6.8 (0. Subgroup No.8) 0. 2005 . including geographic differences.11 www. Our results must therefore be interpreted with caution. Other potential differences in the trials. controlled study of two doses of celecoxib for the prevention of colorectal adenomas showed a dose-related risk of such events. 1078 n engl j med 352.6) 6/617 (1.8) 34/1226 (2.34 patient education. 2005 Downloaded from www. including death from cardiovascular causes. especially if many patients who are likely to use the new agent are prone to cardiovascular disease.The new england journal of medicine Table 4.8 (0.3 (0. randomized.1) 1.2 (1.7) 3. .8) 614 1421 2/213 (0.5) 2.0 (1. In summary./total no.5) 3.0) 24/977 (2.3–19.35 and drug regulation.4) 1.8) 1.0) 25/650 (3. This article is being provided free of charge for use in Philippines. this interpretation has substantial implications for public health. these data suggest that there may be a real increase in cardiovascular risk associated with the use of celecoxib in particular and the class of selective COX-2 inhibitors in general.61 compared with once daily in the PreSAP study — support the hypothesis that sustained inhibition of prostacyclin may contribute to the increase in cardiovascular risk.9) 2.2) 3/358 (0.6–5.nejm. The increased cardiovascular risk in the APC trial was based on a small number of events in a trial that was not designed or statistically powered to evaluate cardiovascular risk.55 0.44 1078 957 4/372 (1. Incidence of Death from Cardiovascular Causes. 563 1472 3/184 (1.9 (0. Still. Although we believe we have identified all adverse cardiovascular events.5) 25/955 (2.2–13.nejm.0) 14/706 (2. we cannot rule out the possibility that some events remained unreported.79 191 1843 1/61 (1. differences in the patient population. placebo-controlled trials to assess safety as well as efficacy and the need to improve methods for assessing potential adverse cardiovascular outcomes in studies with noncardiovascular primary end points.1) 14/401 (3.4) 0. this experience underscores both the need for long-term.8 (0. Stroke.1) 8/442 (1.9) 5/466 (1. in the context of the results of the other trials reviewed involving agents in the same class.9–16. as discussed earlier.1–8.4 (0.2–6.5 (1.9 (1.6) 4/495 (0. may have contributed to the disparity in the preliminary findings. More broadly.5–6.6) 3.3–8.6) 0. or Heart Failure According to Baseline Characteristics.1 (1. Copyright © 2005 Massachusetts Medical Society. (%) Age <60 yr ≥60 yr Sex Female Male Baseline cardiovascular risk factors Yes No Diabetes Yes No Aspirin use Yes No Use of lipid-lowering drug Yes No * CI denotes confidence interval. of Patients Placebo Both Celecoxib Groups Hazard Ratio (95% CI)* P Value for Interaction no.

J. Washington.A.). Project Directors: M. Nebr. Berkeley. Kamionkowski (Gastroenterology Associates of Cleveland. Nedlands. D. Wilcox (University of Alabama at Birmingham. Pruitt (Nashville Medical Research Institute. Barish (Wake Research Associates. Foley (Regional Gastroenterology Associates of Lancaster. Ft. M. Werth (Charlotte Gastroenterology and Hepatology. Sylwestrowicz (St. Haverhill.S. Jupiter. Woloj. Tracey (Hawthorne Medical Associates. N. Bailey (Hys Medical Centre.). Statistical Team: A.).A. Gabbaizadeh (Huntington Research Group. D. Auerbach (California Professional Research. Calif. Corle. Kalgutkar AS. L. Barringer (Carolinas Medical Center. Krone (Advanced Clinical Therapeutics. DuBois (Vanderbilt University Medical Center. D. Pfeffer. A. Mollison (Freemantle Hospital.).). Meridian). C. F. Morgan (McMaster University. Ladouceur. Pa. Melbourne. C. R. Roseville. Clayton.W. Cyclooxygenase 2 inhibitors: discovery. Murphy (Southeastern Digestive and Liver Disease Institute. Calif. Doody. C. Trends Pharmacol Sci 1999.).). McMurray. Newton. N. Mass.). Goldstein JL. (Pentucket Medical Associates. Kelfer (Fallon Clinic. Fla. Torrance.the pastreports having consulting fees from Merck within two years. n engl j med 352. A.J. Oreg. et al. Tex. D. Ill. N Engl J Med 2000.). R. N. Mass. Steinbach G. Hawk. F. Crawford. Ariz. these Pfizer.). Hines. Safdi (Consultants for Clinical Research. M.F. Asheville. T.). Olympia. Queensland). North Providence.). A. Shawnee Mission. R. N. Toronto). Laine L. Krumholz (Waterside Clinical Research. Montreal). Concord. Hess.). M. F. All rights reserved. Passaic). Reicin A. Canada: G. Ga. Layton (South Puget Sound Clinical Research Center. J Biol Chem 1999. North Dartmouth. Stanton (Community Clinical Trials.org on March 18. The effect of celecoxib. Phillips. Tang. Wohlman (Northwest Gastroenterology Associates. R. M. Wyo. M. references 1. S. Hogan (Gastrointestinal Associates. Mayfield Heights.M. Lloyd (Idaho Gastroenterology. Nashville).W. Bagheri. Young (Flinders Medical Centre.). West Boylston.). Calif.A. In ib in preventing colorectal neoplasia and in relievlight of other recent reports of the adverse cardio.). Australia: H. Mass. A. Raleigh. J. C.). Riff (AGMG Clinical Research.).S. Burn (South Cleveland Hospital. Lexington). A. Man. N. Ala. Smoot (Howard University Cancer Center. Van Zantan (Queen Elizabeth II Health Sciences Centre. Puolos (Cumberland Research Associates.). Dewar (Harris Methodist Hospital Fort Worth. New York). Geenen (Wisconsin Center for Advanced Research. N Engl J Med 2000. Boston). Sask. D. J.). Baltimore). McMurray. Dallaire. E. L. M. Ee (Sir Charles Gairdner Hospital.C. Evanston. Atlanta). Minneapolis). P. Kalgutkar AS. F. G.). Halifax. Fla. D. Edmonton.). New York). Footscray.C. Portland. Namias (Gastrointestinal Physicians.C. Boston).). W. Schleinitz (Americas Doctors Research. R.). Redston.). Lincoln. Savannah. C.). Feinstat (Gastroenterology Consultants of Sacramento. 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Principal Investigators: United States: S.S. Limburg (Mayo Clinic. Huntington Station. United Kingdom: J. Phillips RKS.J. Goldberg (Regional Gastroenterology Associates of Lancaster. San Diego. Anderson. 2. S. D. Miner (Oklahoma Foundation for Digestive Research. Blitstein (Associates in Gastroenterology and Liver Disease. Bruggen (Wake Forest University Baptist Medical Center.J. Pochapin (Jay Monahan Center for Gastrointestinal Health. D. Rosen (chair). Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. This article is being provided free of charge for use in Philippines. T. San Antonio. Victoria).J. Ill.L. Klimberg (Gastroenterology Associates of Ocala. W. T.). Sorrell (Gastroenterology Specialties. Taylor. Goodwin DC. Colo. Herston. Calif. R.). Schwartz (Northwest Gastroenterologists. Rosenstein. New York). C. Worth. B. Koval (West Hills Gastroenterology Associates. in familial adenomatous polyposis. Aumais (Hospital Maisonneuve-Rosemont. Oklahoma City).11 www.). Baltimore).M.). Harlan. Bertagnolli. Hamilton. Korman (Monash Medical Centre. Kans. Bellevue. JAMA 2000. D. .R. Chicago). Winnipeg. J.). J. Carricaburu (Veterans Affairs Hospital.). et al.). Minn.C. 5. Anaheim. Cincinnati). This cardiovascular review was funded solely by data provide further evidence that long-term use of sponsored byCancer Institute.274:22903-6. Middlesbrough). Haverhill.). Lipkis (Institute for Health Care Assessment.A. Roman (South Denver Gastroenterology.342:1946-52. the National COX-2 inhibitors may increase the risk of serious Drs. J. Rubin (New Jersey Physicians.284:1247-55. Marnett LJ. Rowlinson SW. Salzberg (Atlanta Gastroenterology Associates. S.). 2005 . a cyclooxygenase2 inhibitor. Birmingham). Lake Forest. Ocala. R. Goetsch (nTouch Research. Dr. Spokane.).). G. Saltzman (Brigham and Women’s Hospital. Markowitz (Memorial Sloan-Kettering Cancer Center. Copyright © 2005 Massachusetts Medical Society. J. Macrae (Royal Melbourne Hospital. Medford. Madoff (University of Minnesota. Wilton.org march 17. Arlington Heights. W. C.). Bennetts (Northwest Gastroenterology Clinic. R. C. Milwaukee). Silpa (Gastroenterology Associates of The East Bay Medical Group. N. selectivity and the future. C. L.). V. T. Data and Safety Monitoring Board: S. and Pfeffer rehaving Wittes weighed against any potential benefits of celecox. N. Faich G. B. Bernstein (Winnipeg Health Sciences Centre.). Chicago). Colizzo (Pentucket Medical Associates.nejm. K. T. M.). S. D.). Lynch PM. Tucson. Zauber. N. R. Chung (Massachusetts General Hospital. Kerzner (Health Trends Research. Freemantle. Mass. Schietrum. These risks will need to be sulting fees from Pfizer. Englewood. Ill. D. Ohio). A. M. Cohen (Sunnybrook and Women’s Hospital. J. Makuch. Huntsville. Bombardier C. Quebec. Wash. M. Lancaster. S. Charlotte.).W. Schwartz (Jupiter Research Association. Calif. Lightdale (Columbia-Presbyterian Medical Center.C. Mass. Sheridan. Oreg. Goldstein (University of Illinois at Chicago. Eagle. Conn. N. New York). R. Alta. Sattler (Western Clinical Research. Newport Beach). Mass. Calgary. Alabaster).). Leggett (Royal Brisbane Hospital. Miss. J. Nashville). Lee (Concord Repatriation and General Hospital. M. P. Sturgeon (Americas Doctors Research. R. M. Dube (Centre Hospitalier Universitaire de Quebec.portreceivedreceived lecture fees from Pfizer. R. Medical Monitors: W.E. La. Nickl (University of Kentucky Medical Center. Solomon. Van Rosendaal (University of Calgary Health Sciences Centre.).). Oreg. M. P. R. Sontag (Veterans Affairs Medical Center.). Rochester. Marnett LJ. Maccini (Spokane Digestive Disease Center.Y. T. 3. Lanzo CA. Portland. Curtis (Newton–Wellesley Hospital. West Palm Beach. R. L. Ont. and Zauber report having received concardiovascular events. D. A. appendix The following persons participated in the APC Study: Steering Committee: M. Marks (Alabama Digestive Research Center. Calif. P. The APC was sponsored by the National Cancer Institute and covascular effects of other agents in this class. Fayetteville.nejm.). Winston-Salem. Kim.). et al. J. Yeomans (Western Hospital.ing pain. Metairie.

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