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Clinical Studies and Health Services Research

B+JD Young Investigator Initiative, May 14, 2005. Clinical Studies and Health Services Research. Kurt P. Spindler, MD Professor & Vice Chairman, Orthopaedics Director, VSM & Ortho PCC Vanderbilt University Medical Center Nashville, Tennessee. Define EBM.

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Clinical Studies and Health Services Research

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  1. B+JD Young Investigator Initiative, May 14, 2005 Clinical Studies and Health Services Research Kurt P. Spindler, MD Professor & Vice Chairman, Orthopaedics Director, VSM & Ortho PCC Vanderbilt University Medical Center Nashville, Tennessee

  2. Define EBM • Application of scientific method to clinical research in medicine • Recommends clinical decision making based on highest level of evidence (study design) • Levels of evidence determined by study design and minimization of bias during completion of study

  3. WHY Controlled Trials? • Most Valid Decision Making (EBM and clinical outcomes) • Most ETHICAL when: • Introducing revolutionary technology • New biologic treatments • Fundamental shifts clinical practice • You, the investigator, would participate • Safety established clinically relevant animal model! • Patient BENEFITS worth COSTS

  4. Real Life Example Comparisons(i.e., Controlled Trials) • FASTEST HORSE: SEABISCUIT VS MAN-O-WAR? Match race! • FASTEST STREET CAR? Drag Race like Fast and Furious! • STRONGEST “MAN”? Lift off or Arm Wrestle! • BEST TEAM? Super Bowl, March Madness, World Series, NHL, etc! WHY SHOULD PHYSICIANS BELIEVE BEST TREATMENT WITHOUT FAIR COMPARISONS? HOWEVER OUR PATIENTS KNOW BETTER !

  5. Ethics of Controlled Trials • Is it ethical to apply new technologies before they have been proven in controlled trials? • Gortex ACL replacement • Thermal chondroplasty • Thermal shrinkage ACL or ACL graft • Conversely, not only ethical but our obligation to prove efficacy and value in controlled trials? a.WHY ? Best care patients Cost effective resource utilization b.CAVEAT: Safety, biologic incorporation, and biomechanical improvements documented in translational models (clinically relevant animal models)

  6. Types Research • Basic Science • Biologic: gene, protein, cell • Biomechanic: in vitro studies • Translational (Animal Models) • Evaluate primary variable in complex biologic environment • Clinical Studies (Results = Outcomes) • Objective: XR, instrumented laxity, ROM • Subjective: Outcome questionnaires

  7. CLINICAL PRACTICE Extreme CAUTION YES: EBM MAYBE • Controlled Clinical Trials • outcomes • complications • risk/benefit • cost/benefit • HUNDREDS OF THOUSANDS • In vitro • cell/matrix • gene • biomechanic • THOUSANDS • In vivo • relevant animal • models • biology • healing • biomechanic • safety • TENS OF THOUSANDS Study Design: Cost:

  8. History Practice of Medicine • Experienced Based predominated 19th century and before • Biologically Plausible began 20th century a. example in-vitro tests results and apply results to clinical practice b. Translational study suggests increases bone formation-use practice • EBM=investigate in appropriate study design in PATIENTS!

  9. Clinical QUESTION Determines Study Design

  10. VSM EBM Literature References Spindler K, Kuhn J, Dunn W • Guide to evaluate paper by EBM • Ref Greenhalgh 2001 How to Read a Paper BMJ publisher • Worksheet (JAAOS) • Manuscript (J.KneeS) • Systematic Review: Autograft choice ACLR AJSM Dec 2004 (cd) • VSM J. Club format: Systematic Reviews using worksheet

  11. How to Approach a ManuscriptMethods Section • Identify and Record the Type of Research (remember clinical question, ie, Ho should determine both type and design!) • Identify and Record the Study Design (see worksheet) • Ask “Is it Appropriate?” Do methods answer proposed clinical question? • Examples: Tx choice RCT vs nonRCT (control group) Prognosis ACLR: risk + predictors OA prospective longitudinal cohort

  12. EBM Literature Review Type of Study Design by HIERARCHY Evidence STUDY DESIGN TYPES – Characteristics LISTED IN HIERARCHY OF EVIDENCE 1. Randomized Controlled Trial – Only those randomized by computer or random number table are acceptable. 2. Cohort – Two or more groups selected basis differences exposure to “agent” and follow up. 3. Case Control – Patient with a particular disease/condition are matched to a control group. 4. Cross-Sectional – Data is collected at a single point in time. 5. Case Reports/Case Series – Medical histories in one or more patients with condition or treatment.

  13. EBM Literature Review Definition of the Types of Bias BIAS 1. Selection Bias – Difference in comparison groups secondary to incomplete or insufficient randomization. 2. Performance Bias – Differences in care provided due to sources other than the intervention being evaluated. 3. Exclusion or Transfer Bias – Differences in groups that occur as a result of patients withdrawing from the trial. 4. Detection Bias – Different evaluations for outcomes best independent examiner or blinding examiner or validated outcome questionnaire self- administered.

  14. EBM Literature Review Study Population Information Allocation of Study Population Insert number (n) POPULATION Group____ Group____ Group____    INTERVENTION ____ ____ ____    FOLLOWUP Initial ____ ____ ____ Final ____ ____ ____ OUTCOMES: 1º ____ ____ ____ 2º ____ ____ ____ 3º ____ ____ ____ Length of Reported Follow-up: Minimal______, Average______ Did the Author Demonstrate Equal Demographics (Age, Gender, etc) in the Groups? □Yes □No Was Post-Treatment Care the Same (e.g. Rehabilitation Protocols) for the Groups? □Yes □No % % %

  15. EBM Literature Review Record Results

  16. EBM Literature Review Should You Change Your Practice? Summary □Yes □No Is there a comparison group in a TREATMENT STUDY? If No, then read for INFORMATION ONLY—THERE IS NO EVIDENCE BASED REASON OR DATA TO CHANGE YOUR PRACTICE. □Yes □No Are the groups compared and equivalent before treatment? If No, then RESULTS MAY NOT BE CAUSED BY THE TREATMENT, BUT BY THE PRE-EXISTING DIFFERENCES IN THE GROUPS. □Yes □No Is the INTERVENTION in the study free from additional proven or suspected variables other than the variable for the 1º hypothesis indicating PERFORMANCE BIAS? If No, the RESULTS MAY NOT BE SPECIFIC TO THE INTERVENTION, AND THE RESULTS ARE OF UNCLEAR SIGNIFICANCE TO TREATMENT. □Yes □No Is the follow-up adequate (>70% of the study population)? If No, there may be EXCLUSION OR TRANSFER BIAS. THE RESULTS COULD CHANGE IF THE FOLLOW-UP WAS BETTER. (It may be more important to know why the drop outs occurred.) □Yes □No Is the statistical evaluation acceptable? Are the statistically significant findings clinical significant? □Yes □No Does the study population reflect your practice population? □Yes □No Do you have adequate training or experience to perform the treatment/technique and expect similar results? If the answers to these questions are Yes, STRONGLY CONSIDER CHANGING YOUR PRACTICE!

  17. How to Use the Literature to Change your PracticeSummary • Understand the Hierarchy of Evidence and choose treatments based on highest levels • Know the Types of Research and Types of Studies • Look for Forms of Bias • Understand P-Values, Power, and Clinical Significance • Recognize Types of Data and Have a General Understanding of the Appropriate Statistics

  18. Systematic Review vs Meta-Analysis

  19. Learn from our Mentors’ Wisdom • How do we progress from past to future? • What other disciplines in medicine can we learn from to guide progress? • Why is this important? • The relatively inexpensive technologic revolution which made Sports Medicine is ending – law of diminishing returns. • The expensive biologic revolution will either “make or break” Orthopaedics and Sports Medicine – we need to understand EBM, CLINICALLY RELEVANT OUTCOMES and foster MULTICENTER STUDIES to SUCCEED.

  20. Use EBM in Epidemiology, Medicine, Cardiology, and Rheumatology • Controlled clinical trials, prospective longitudinal cohorts, and registries provide a mechanism to evaluate EFFICACY, SAFETY, and COST of revolutionary technology, new biologic advances, and determine fundamental shifts in clinical practice quicker and safer than our past masters’ similar conclusions through the use of experience. • Caveat is only a small percentage of sports medicine practice can be based on RCTs given expense and practicality! Therefore, multicenter cohorts and registries are required to advance entire field of SPORTS MEDICINE .

  21. Sample Size Clinical Trails • Estimate from retrospective studies a. also generate hypothesis • Patient participation must be understood • RCT’s 40-60% refuse • Cohort studies have >90% participation • Multivariable modeling 10 patients for each variable (n=10)

  22. SAMPLE SIZE Considerations: • Chris Kaeding OSU: Knee Multi-ligament Reconstruction, Arthroscopy 2005 • Three sites/surgeons decade (OSU, CCF, VSM) • 2286 Knee Ligament “Reconstruction” • ACL/MCL = 193 8.4% • ACL/LCL = 32 1.4% • ACL/PCL = 16 1% • PCL = 9 <1% • Summary PCL or multiligament require 30-50 sites

  23. SAMPLE SIZE Considerations: • MOON: First Year (‘02) • 479 unilateral ACLR • Elite Athletes = 8% (n = 38) (def: pro, semi-pro, NCAA I ) • MOON: First Two Years (’02 + ’03) • 1040 unilateral ACLR • REVISION ACLR 10% CONCLUSION: Elite athlete or revision ACLR require 30-50 sites

  24. Background and Significance • 1997 NIH PA Musculoskeletal Fitness and Sports Medicine • 30 million organized sports • 50% adults exercise • Causes, prevention, and tx these injuries are major health issues • Estimate 175,000 ACLR annually • Physical activity (QOL) focus NIH “Healthy People 2010” • ACL injury threatens ability to be physically active

  25. Design Prospective Longitudinal Cohort Study

  26. Hypothesis: MOON ACLR OUTCOMES Prosp Long Cohort The presence of meniscal and articular cartilage injury and a higher injury severity score (ISS) substantially reduce the potential for long-term functional recovery after ACLR and substantially increases the risk of post-traumatic osteoarthritis. Female gender, mechanism of injury, and demographic variables influence function and development of osteoarthritis to a lesser degree. Conversely, sport, surgeon, or graft type will not predict outcome.

  27. Predictors and Multivariable Statistics • PREDICTORS= Independent risk factors outcome • MULTIVARIABLE STATISTICS = Biostatistics control for confounding variables to determine the most influential risk factors (PREDICTORS) of outcome (FYI: RCT confounders are evenly distributed) • IDENTIFY PROGNOSIS AFTER ACL RECON? • Preferred design = Prospective longitudinal cohort • If highest activity level at two years is most important predictor arthritis (pain + stiffness) 5 years, then potential counsel patients avoid high impact loading. • If identify partial LM best predictor OA at five years, then design RCT of LM substitute! • Note in RCT answer single question and control confounders by random distribution (ie, meniscus tear and articular cartilage injuries)

  28. Predictor Articular cartilage injury Type surg (prim vs rev) Wt at surg Activity level at ACLR Past knee history Past arthroscopic surg Days inj to ACLR Reinjury Dependent Variables Sport-specific scales KOOS* IKDC* Arthritis WOMAC* Quality of Life SF-36* *alternative specific subscales Example: AIM II Outcomes

  29. AIM II Outcomes (cont) • Confounding Variables: Control in statistical modeling • Demographics: age, gender, ht, wt, BMI, wt change • Mechanism: sport, contact, jump, pop, swelling, return to play • Surgery: surgeon, graft type, graft source, surgical exposure • Social status: education, marital status, change in work hours • Meniscus tear and treatment • Additional surgeries

  30. Validated Subjective Outcome Questionnaires • Rigorous methodological testing answer specific patient-relevant questions • SF-36 Quality of Life (Physical and Mental) • WOMAC arthritis (JBJS-Am requires OA) • Sport-Specific: • IKDC: Questionnaire component (AJSM) • KOOS: WOMAC plus two additional domains (QOL, Spts + Rec) • Activity Level: Marx 4 questions at 4 levels (0-16)

  31. Validated Questionnairesas Primary Outcomes for ACLR ? • NSAID trials efficacy tx OA: YES, WOMAC/SF-36 • Medicine, Rheum, Epidemiology: ABSOLUTELY • Total Joint Arthroplasty: YES (WOMAC/SF-36) • Spine: YES, QOL (SF-36) • Impact Publications in Sports Medicine: YES • MoseleyNEJM 2002 Arthroscopy Advanced OA • KnutsenJBJS 2004 Microfx vs ACI

  32. Sports Medicine Paradigm ShiftPatient Relevant Outcomes (PRO) • Do not measure instrumented laxity, but • Can determine what laxity (mm) influences outcome/function • Routine XR OA low correlation PRO, why? • Failed adjust important confounders (activity?) • PRO can establish, for first time, cost effective multicenter outcomes trials • Answer “low frequency” diagnoses or treatments require 30-50 sites. PRO only feasible option (rev ACLR, PCL, OCD, Tx GIV defect, etc.)

  33. What Info Would You Like if You or Your Child Needed ACLR? • Instrumented laxity (KT, stress XR) • Isokinetic strength (Cybex, Biodex, etc) • Activity level at 2 years (Marx) • Validated outcome and/or function (KOOS, IKDC, SF-36, WOMAC) • Sx/Signs OA (WOMAC/MTP XR) • Risk additional surgery, graft failure, contralateral ACL tear • Five- and ten-year follow-up • OR PREDICTORS of 1-7?

  34. Question: Choice AUTOGRAFTACL Reconstruction • Plethora publications! • PAUCITY valid comparisons graft choice • Why clinical shifts? • Autografts • PT = Patellar tendon • HG = Hamstring

  35. PT vs HG Requires • Identical patient inclusions • Equal timing surgery (acute vs chronic) • Same distribution meniscus and articular cartilage injuries • Common rehabilitation guidelines • Results and outcomes measured identically • Control BIAS: Selection/Performance/Transfer/Detection

  36. Marder (AJSM 1991) Aglietti (AJSM 1994) O’Neill (JBJS 1996) Corry (AJSM 1999) Design Surgical technique Rehabilitation Outcomes/Results 1990’s Four Prospective Studies COMPARISON AUTOGRAFT CHOICE Authors Evaluation

  37. Total 37 Outcomes • 7 = Significant differences (p < 0.05) • 1 = Consistent significant difference

  38. Ham weak (Marder)  ROM PT (Aglietti)  Laxity ham (Corry) Both Aglietti and O’Neill All three All three Significant Differences Not Reproduced Result Not Significant

  39. Single Study Significant Results • 10% tib screw removal • NS -- acute vs chronic •  kneeling pain PT •  laxity FEMALES

  40. Conclusion1990’s Studies • Subtle scientific differences except PT increased activity level 75% studies • Surgeons focus attention to detail individual technique, NOT graft • Adopt rational rehab protocols

  41. New Millenium Eight New RCTs(Jan 1, 2000 to Dec 31, 2003) • SELECTION: adequate randomization • PERFORMANCE: modern techniques ACL recon (4 strands, stable fixation methods) • EXCLUSION: >80% f/u 2-3 years • DETECTION: either objective measures and/or five studies independent examiners

  42. SYSTEMATIC REVIEWEnglish Literature AUTOGRAFT Choice • AU: Spindler MD; Kuhn MD; Freedman MD, MPH; Matthews PhD; Dittus MD, MPH; Harrell PhD Ref: AJSM Dec 2004 Systematic Review • INCLUSION: RCT by computer or birth date • PUBLICATIONS: Nine (8 since 2000, plus O’Neill) • How to Read the Literature Worksheet (Greenhalgh T; Lang TA and Secic M; Spindler KP)

  43. Presentation Findings 1.SURGICAL TECHNIQUE • REHABILITATION • RESULTS: • Instrumented Laxity • Isokinetic Strength • Patellofemoral vs Kneeling Pain • Imaging, Activity, Function • Subjective and Composite scales

  44. Surgical Technique and Rehabilitation • Greater consistency PT vs HG • PT: Endoscopic (7), Rear Entry (3) • HG: Endoscopic (6), Primarily 4 strands • Fixation: Identical only 2 but all adequate: minimize Performance Bias • Modern rehabilitation protocols

  45. Summary: RESULTS No PATIENT-RELEVANTOUTCOME measures • 1999 IKDC • KOOS • WOMAC • SF-36

  46. Summary: RESULTS Lack CONSISTENT Evaluation Tools • Exception • Range of motion 100% • Anterior knee pain 100% • Majority Objective Measure • Instrumented laxity 78% (7/9) • Isokinetic strength 78% (7/9)

  47. Summary: RESULTS Sufficient SAMPLE SIZE • Instrumented Laxity • ROM • Isokinetics • Summary • Prevent Type II errors (missing a significant difference)

  48. Results OBJECTIVE Evaluation • Range of Motion • 44% (4/9) loss always PT • Differences degrees 0.5-3.4 • Instrumented Laxity • 43% (3/7) more stable always PT • Differences mm 1.0-3.4 mm • Isokinetic Strength • 43% (3/7) weaker hamstrings always HG • Approximately 7%

  49. Instrumented Laxity at Final Follow-up

  50. Isokinetic Strength at Final Follow-up

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