1. Sanjay Kaul, MD, FACC George A. Diamond MD, FACC Division of Cardiology Cedars-Sinai Medical Center and Geffen School of Medicine at UCLA Los Angeles, California From Clinical Trial Evidence to Practice Guidelines Lost in Translation From Clinical Trial Evidence to Practice Guidelines Lost in Translation

2. Complexity of American Strategy in Afghanistan “When we understand that slide, we’ll have won the war” - General McChrystal

3. Complexity of Evidence-Based Medicine Lost in a jungle of evidence, we need a compass

4. Evidence to Guidelines Lost in Translation Key Issues for Discussion Establish the scientific evidence - Appraise and synthesize the evidence Elucidate the clinical context - Clinical importance vs. statistical significance - Clinically relevant weighted outcomes Encourage optimal processes of care - Quality initiatives - Reimbursement initiatives

5. Appraisal of Evidence Design and Methods Appraisal of Evidence Design and Methods  Quality Important limitations - Study design or execution (bias) - Lack of randomization - Lack of concealment - ITT principle violated - Inadequate blinding - Loss to follow-up - Early stopping for benefit - Inconsistency of results - Indirectness of results - Imprecision - Publication bias  Quality Special strengths - Randomized, controlled, prospective, double-blind trials - Large, consistent, and precise treatment effect - RR 2.0 (large) - RR 5.0 (very large) - Minimal confounding & bias

6. Synthesis of Evidence ACC/AHA Clinical Practice Guidelines Synthesis of Evidence ACC/AHA Clinical Practice Guidelines Class I (“Useful & Effective”) (Benefit >>> risk) (Highly recommended) Class II (“Conflicting Evidence”) Class III (“Not useful/ effective, may be harmful”) (No benefit/Harm) (Not recommended) IIa (Benefit >>risk) (Reasonably recommended) IIb (Benefit ? risk) (May be considered) Level A (Multiple randomized clinical trials) Level B (Single randomized trial or nonrandomized studies Level C (Consensus opinion, case studies, or standard of care)

7. Evidence to Guidelines Lost in Translation Self-evident Truths Does empirical evidence trump expert opinion?

8. Tricoci P et al. JAMA 2009 Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines Level of Evidence A Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines Level of Evidence A

9. Tricoci P et al. JAMA 2009 Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines Level of Evidence C Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines Level of Evidence C

10. ACC/AHA Clinical Practice Guidelines Paucity of High-Quality Evidence Class I (Benefit >>> risk) (Highly recommended) Class IIClass III (Risk ? Benefit) (Not recommended) IIa (Benefit >>risk) (Reasonably recommended) IIb (Benefit ? risk) (May be considered) Level A (Multiple randomized clinical trials) 19% based on high-level evidence 41% of guidelines are based on Class II recommendations (”uncertain evidence”) Level B (Single randomized trial or nonrandomized studies Level C (Consensus opinion, case studies, or standard of care) 48% of guidelines are based on level C evidence (“codification of expert opinion“) Tricoci P et al. JAMA 2009 Recommendations are largely developed from lower levels of evidence or expert opinion. “Exercise caution when considering recommendations not supported by solid evidence”

11. “…it seems unlikely that substantial change will occur because many guideline developers seem set in their ways. If all that can be produced are biased, minimally applicable consensus statements, perhaps guidelines should be avoided completely. Unless there is evidence of appropriate changes in the guideline process, clinicians and policy makers must reject calls for adherence to guidelines. Physicians would be better off making clinical decisions based on valid primary data” Shaneyfelt and Centor, JAMA 2009 Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines Caveat Emptor, Caveat Lector Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines Caveat Emptor, Caveat Lector Guidelines that are driven by scientifically documented, high-quality evidence are more likely to be accepted by the stakeholders, thereby reducing the variability in care and improving the quality and cost of care

12. 2009 ACC/AHA Focused Updates for STEMI/PCI Paucity of High-Quality Evidence 2009 ACC/AHA Focused Updates for STEMI/PCI Paucity of High-Quality Evidence Class I (Benefit >>> risk) (Highly recommended) Class IIClass III (Risk ? Benefit) (Not recommended) IIa (Benefit >>risk) (Reasonably recommended) IIb (Benefit ? risk) (May be considered) Level A (Multiple randomized clinical trials) 12% based on high-level evidence 50% of guidelines are based on Class II recommendations (“conflicting evidence”) Level B (Single randomized trial or nonrandomized studies Level C (Consensus opinion, case studies, or standard of care) 44% of guidelines are based on level C evidence (“filtered expert opinion”) Kushner FG, Hand M et al. 2009 Focused Updates, JACC/Circulation 2009

13. The Laws of Diminishing Objectivity in the Interpretation of Evidence vehemence  evidence -1 Peter McCulloch The Lancet, 2004;363;9004 vehemence  eminence 2

14. Establish the scientific evidence - Appraise and synthesize the evidence Elucidate the clinical context - Clinical importance vs. statistical significance - Clinically relevant weighted outcomes Optimal processes of care - Quality initiatives - Reimbursement initiatives Evidence to Guidelines Lost in Translation Key Issues for Discussion

15. Effect size - Absolute risk difference (NNT or NNH) - Relative risk difference Risk ratio Odds ratio Hazard ratio Statistical certainty/precision - Hypothesis testing (P value) - Estimation (confidence interval) ? Clinical importance Little or no explicit guidance ACC/AHA Clinical Practice Guidelines Metrics for Assessing Strength of Evidence ACC/AHA Clinical Practice Guidelines Metrics for Assessing Strength of Evidence

16. 1 P value  Effect Size  Sample Size Statistical significance  Clinical importance! Disconnect Between Statistical Significance and Clinical Importance

17. Boersma et al, Lancet 2002;359:189-1198. GUSTO IV PRISM PRISM-Plus PURSUIT PARAGON A PARAGON B POOLED Trial (IIb/IIIa) Placebo 2b/3a 7800 3232 1570 9461 1513 5169 28,745 N 8.0 7.0 11.9 15.7 11.7 11.4 12.5 8.7 5.7 8.7 14.2 10.3 10.5 11.3 BetterWorse 0.1 1 10 Death / MI at 30 days Risk Ratio & 95% CI (%) 0.91 (0.86, 0.99) P=0.015 P=0.339 Breslow-Day Homogeneity ARR = 1.2% RRR = 9% Statistical Significance vs. Clinical Importance GP IIb/IIIa Inhibitors in UA/NSTEMI Statistical Significance vs. Clinical Importance GP IIb/IIIa Inhibitors in UA/NSTEMI

18. What Does a P(ee) Value of 0.05 Mean? ‘Fisherian’ P value of 0.05 is arbitrary and originally based on n=30 ! Always demand a P value of 200 as strong evidence against the null hypothesis of zero difference Al Feinstein The plain fact is that in 1925 Ronald Fisher gave scientists a mathematical machine for turning “baloney into breakthroughs”, and “flukes into funding”. Robert Matthews

19. 1 P value  Effect Size  Sample Size Lack of statistical significance  lack of clinical importance! Disconnect Between Statistical Significance and Clinical Importance

20. Oler A et al, JAMA 1996;276:811-15 0.11.010 Risk Ratio & 95% CIASA+UFH ASA TrialN Theroux243 RISC399 ATACS214 Holdright285 Cohen 1990 69 Gurfinkel 143 1.6%3.3% 1.4%3.7% 3.8%8.3% 27.3%30.5% 0% 3% 5.7%9.6% ASA+UFH Better ASA Better Overall 1335 7.9% 10.4% 0.67 (0.44-1.02) P=0.06 Death/MI ARR = 2.5% RRR = 33% Statistical Significance vs. Clinical Importance Unfractionated Heparin in UA/NSTEMI Statistical Significance vs. Clinical Importance Unfractionated Heparin in UA/NSTEMI

21. MDD (minimum detectable difference, “  ”) - The “minimum difference” the study is powered to detect - Utilized for sample size estimation - May or may not reflect a clinically important difference MCID (minimum clinically important difference) The “minimum acceptable difference” to change the behavior of the clinician, patient, payer or policy maker, given the side effects, costs and inconveniences of therapeutic interventions Statistical Significance vs. Clinical Importance

22. Guideline Criteria for Clinical Importance Impact of Outcome, Harm, and Cost on MCID Guideline Criteria for Clinical Importance Impact of Outcome, Harm, and Cost on MCID Very lowLowModerateHigh Harm Very lowLowModerateHigh Cost Mortality Irreversible morbidity Reversible Morbidity Surrogate Endpoint Outcome severity Small Large MCID (RRR) 0% 50%

23. Statistical Significance vs. Clinical Importance MCID Threshold for UA/NSTEMI ACS Statistical Significance vs. Clinical Importance MCID Threshold for UA/NSTEMI ACS “In ACS, a relative reduction of 15% in recurrent clinical events has recently been considered clinically important (GUSTO I); this level is far below the perceived threshold that drove the sample size calculations for clinical trials just a decade ago. As we develop more incrementally beneficial therapies, it is likely that the minimally important clinical difference will become even smaller.” Califf and DeMets Circulation. 2002;106:1015

24. 1.0 Risk Ratio (95% CI) 0.85 MCID Statistically significant, clinically important Statistically not significant, may be clinically important Statistically significant, not clinically important Statistically not significant, clinically not important A B C D E Statistically significant, may be clinically important MCID = minimal clinically important difference = 15% RRD Sackett, D Statistical Significance vs. Clinical Importance Strength of Evidence Statistical Significance vs. Clinical Importance Strength of Evidence

25. InterventionControl (%) Rx (%) Summary risk ratio (95% CI) P Value NNT (95% CI) Interpretation of Confidence Intervals (MCID = 15% RRR) Aspirin (N=2,856) 12.85.50.43 (0.33-0.56) <0.0114 (11-19) Statistically significant and clinically important (E) UFH (N=1,353) 10.47.90.67 (0.44-1.02) 0.0644 (∞-18) Statistically not significant, maybe clinically important (B) Enoxaparin (Early invasive) 12.812.10.96 (0.88-1.05) 0.35171 (∞-59) Statistically not significant, clinically not important (A) Clopidogrel (CURE) 11.49.30.82 (0.74-0.92) <0.0154 (35-120) Statistically significant, maybe clinically important (D) GP IIb/IIIa (Early invasive) 14.511.80.81 (0.70-0.94) 0.00737 (21-139) Statistically significant, maybe clinically important (D) Statistical Significance vs. Clinical Importance Class I, LOE A Recommendations for UA/NSTEMI Impact on Death or MI Statistical Significance vs. Clinical Importance Class I, LOE A Recommendations for UA/NSTEMI Impact on Death or MI Aspirin is the only intervention listed as a performance measure!

26. Establish the scientific evidence - Appraise and synthesize the evidence Elucidate the clinical context - Clinical importance vs. statistical significance - Clinically relevant weighted outcomes Encourage optimal processes of care - Quality initiatives - Reimbursement initiatives Evidence to Guidelines Lost in Translation Key Issues for Discussion

27. Endpoints in Cardiovascular Clinical Trials MACE vs MICE Endpoints in Cardiovascular Clinical Trials MACE vs MICE Death Cardiac arrest Large MI Disabling Stroke Emergency CABG Major Adverse Cardiac Events “Hard” but infrequent Silent CK/Tn Release Restenosis Reintervention Recurrent angina Rehospitalization Groin hematoma Minor Inconvenient Cardiac Events “Soft” but prevalent

28. Cardioprotective Effects of Antihistamines Means to an End or an End to Means Cardioprotective Effects of Antihistamines Means to an End or an End to Means Placebo Antihistamine % patients Death Recurrent MI Itching p < 0.05

29. Cardioprotective Effects of Stenting Clinical Outcomes at 1 Year in Stent PAMI D/MI/Stroke/TVR P < 0.005 Stent (N=449) PTCA (N=444) 2.9 2.5 P = 0.7 MI 10.7 20.9 P < 0.0005 TVR 5.6 3.1 0 5 10 15 20 25 Stent (N=452) PTCA (N=448) P = 0.07 Death % Individual Components 0.5 P = 0.83 Stroke Benefit driven by the “least robust” but the “most prevalent” component

30. Validity of the Composite Endpoint Components should be of comparable frequency Components should be of comparable clinical importance Components should be comparably responsive to therapy Montori VM et al. Br Med J 2005; 330:594-596

31. Composite analysis 0.001.002.003.004.00 TVR Stroke MI Death Odds ratio 1.81 (0.93-3.53) 1.17 (0.52-2.65) 0.99 (0.14-7.05) 0.45 (0.31-0.66) 0.62 (0.45-0.86) OR (95% CI) 5.6% 2.9% 0.5% 10.7% 16.9% Stent 3.1% 2.5% 0.5% 20.9% 24.8% PTCA Cardioprotective Effects of Stenting Validity of the Composite Endpoint in Stent PAMI Cochran’s Q = 14.64 Hetero P = 0.002 I 2 = 80% (46-92%) Composite: Variable gradient in clinical importance, frequency and treatment effect across components

32. Cardioprotective Effects of Stenting Weighted Analysis of Composite Endpoint Cardioprotective Effects of Stenting Weighted Analysis of Composite Endpoint Weight of TVR Global P value Weights Death = 1 MI = 1 Stroke = 1 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 0.100.200.300.400.500.600.700.800.901.00 Composite endpoint becomes significant at a TVR weight of >0.7!

33. Class I (Benefit >>> risk) (Highly recommended) Class IIClass III (Risk ? Benefit) (Not recommended) IIa (Benefit >>risk) (Reasonably recommended) IIb (Benefit ? risk) (May be considered) Level A (Multiple randomized clinical trials) Level B (Single randomized trial or nonrandomized studies 60mg prasugrel load ASAP, 10 mg daily x 12m Level C (Consensus opinion, case studies, or standard of care) Withhold prasugrel 7 days prior to CABG or surgery Pts with h/o TIA or stroke; active bleeding ACC/AHA Guideline Recommendations Prasugrel During Primary PCI for STEMI ACC/AHA Guideline Recommendations Prasugrel During Primary PCI for STEMI Kushner FG, Hand M et al. 2009 Focused Updates, JACC/Circulation 2009

34. Benefit-Risk Balance in TRITON (All ACS Cohort) 1000 Patients Treated with prasugrel instead of clopidogrel Benefit-Risk Balance in TRITON (All ACS Cohort) 1000 Patients Treated with prasugrel instead of clopidogrel Prasugrel vs Clopidogrel Benefit 24 endpoints prevented - 3 CV deaths - 0 strokes - 21 nonfatal MIs - 4 PPMIs - 17 MI events - 13 clinically relevant MIs Risk 30 excess TIMI bleeds - 2 bleeding deaths - 3 TIMI Major bleeds - 5 TIMI Minor bleeds - 20 TIMI Minimal bleeds or 29 excess moderate/severe bleeds - 2 bleeding deaths - 9 transfusions - 6 nonfatal serious bleeds - 12 nonfatal moderate bleeds or 17 excess serious bleeds ? 3-6 excess cancer (1 cancer death)

35. Judgments about Strength of Recommendation Prasugrel for Patients with ACS Undergoing PCI FACTORSCOMMENTS Balance between desirable and undesirable effects “The net benefits are uncertain” Quality of the evidence“Quality of the evidence is high.” Patient values and preferences “All patients and care providers would not accept efficacy-safety trade-off.” Alternatives available. Costs (resource use) “The cost is high for treatment for long duration.” Does the evidence favor Class I (benefit >>> risk) recommendation for prasugrel?

36. Establish the scientific evidence - Appraise and synthesize the evidence Elucidate the clinical context - Clinical importance vs. statistical significance - Clinically relevant weighted outcomes Encourage optimal processes of care - Quality initiatives - Reimbursement initiatives Evidence to Guidelines Lost in Translation Key Issues for Discussion

37. Quality Matters Linking Guidelines Adherence and Mortality Peterson et al, JAMA 2006;295:1863-1912 Every 10%  in guidelines adherence  10%  in mortality (OR=0.90, 95% CI: 0.84-0.97) Every 10%  in guidelines adherence  10%  in mortality (OR=0.90, 95% CI: 0.84-0.97)

38. Risk-adjusted hospital deaths declined by 0.7 percentage points (95% CI, -1.7 to 0.3) in NSTE ACS patients. The rate of congestive heart failure and pulmonary edema decreased by 6.5% (95% CI, -8.4 to -4.7). Changes in Clinical Outcomes for NSTE ACS Patients n = 2213 p =.02 for linear trend p <.001 n =1566n = 2228 n = 1564 GRACE: Outcome Measures over Time NSTE ACS Fox et al. JAMA. 2007; 297:1892-1900

39. ACC Improvement Initiatives Continuous Quality Improvement Translating Science into Practice PLAN DO STUDY ACT Education and Training

40. Fuel High-quality evidence Boost Implementation Design, process evaluation The Role of Evidence-Based Guidelines in Improving Clinical Practice Turbocharging the Guidelines The Role of Evidence-Based Guidelines in Improving Clinical Practice Turbocharging the Guidelines

41. Number of recommendations: >250 Number of pages: 157 Number of figures: 21 Number of tables: 26 Last update: 2002 Writing committee members: 15 Reviewers: 40 (6 different layers from evaluation to publication) Conflict-of-interest disclosure - Writing committee members: 14/15 - Reviewers: 30/40 J Am Coll Cardiol 2007; DOI:10.1016/j.jacc.2007.02.028 2007 ACC/AHA Guideline Recommendations Acute Coronary Syndromes 2007 ACC/AHA Guideline Recommendations Acute Coronary Syndromes

42. Quality - Rigorous and standardized methodology (GRADE) - Emphasize clinical importance over statistical significance - Transparent and explicit benefit-risk assessment Efficiency - User-friendly and parsimonious (avoid the 160 page report) Timeliness - Keep pace with advances (annual updates) Dissemination - Direct clinical relevance (at point of care via EMR) - Guide and inform clinical practice (performance measures) - Financial incentives (evidence-based reimbursement) Evidence to Guidelines Framework for Refinement Evidence to Guidelines Framework for Refinement

43. Firewall between systematic review & guideline development Multidisciplinary guideline developers: methodologists, clinical content experts, patient representatives Avoid LOE C recommendations (best suited as “advisories”) Minimize conflicts of interest (COI) for writers/reviewers “Zero tolerance” COI policy for chairs PIs of guideline-relevant trials should only serve as advisors Evidence to Guidelines Framework for Refinement Evidence to Guidelines Framework for Refinement

44. Evidence-Based Medicine ACC Improvement Initiatives Turbocharging guidelines (18 currently available, 9 in development, 6 being updated) Transform and transfer guidelines at the point of care - Just in time strategies (Vivisimo, Cardio Compass) Appropriate use criteria (Noninvasive imaging, CABG/PCI) Quality initiatives (D2B, H2H, FOCUS) Registries - NCDR (CathPCI, ICD, CARE, ACTION-GWG, IMPACT, PINNACLE) Physician incentives (PQRI, ACO) Patient involvement (CardioSmart)

45. Treat as “guides”, not “rules” Patient-specific, not disease-specific Pragmatic/assistive, not prescriptive/directive Flexible and adapted to local practice Based on empirical high-quality evidence, not “codified” or “filtered” expert clinical opinion Drive the standard of care, not be driven by them Inform clinical judgment, not replace it Framework for Increased Adherence to Clinical Practice Guidelines and to EBM Framework for Increased Adherence to Clinical Practice Guidelines and to EBM

46. Clinical Judgment “Evidence-Based” Not “Evidence-Bound” Three Key Dimensions “Evidence-Based” Not “Evidence-Bound” Three Key Dimensions Scientific evidence Patient preference

48. RRR 95%CI P (2-tailed) 18% 2%-32% 0.028 RRR 95%CI P (2-tailed) 18% 2%-32% 0.028 19.4 15.9 Event Rate (%) 1106 1114 N N Conservative Invasive Conclusion: Early invasive is superior to early conservative strategy The difference may be clinically important as the 95% CI contains the critical threshold of 25% RRR (  ) Sample size estimation: Study powered to detect a minimum clinically important difference (  ) of 25% risk reduction Objective: Evaluate impact of early invasive over early conservative strategy in management of ACS Foundations of Classical Statistical Inference TACTICS-TIMI 18 Foundations of Classical Statistical Inference TACTICS-TIMI 18

49. Major advantage of the Bayesian over the classical frequentist approach is that the probability for any given threshold of clinical importance can be explicitly quantified 0 20 40 60 80 100 110100 Probability (%) Risk reduction threshold (%) 17% Threshold Analysis Bayesian analysis provides a transparent, patient- and physician- centric and domain-specific estimate of clinical importance Foundations of Bayesian Inference TACTICS-TIMI 18 Foundations of Bayesian Inference TACTICS-TIMI 18  = 25% Pr d>0 = 99% Pr d>25% = 17%

50. 0.73 (0.62-0.86) 0.65 (0.52-0.80) 0.79 (0.69-0.89) 0.75 (0.68-0.84) OR (95% CI) 0.000.501.001.502.00 Composite MI Stroke CV Death Odds ratio 6.1% vs 8.1% 3.4% vs 4.9% 9.9% vs 12.3% 14.1% vs 17.6% Ramipril vs placebo Cardioprotective Effect of Ramipril Validity of the Composite Endpoint in HOPE Cardioprotective Effect of Ramipril Validity of the Composite Endpoint in HOPE Q = 2.35 P = 0.31 I 2 = 15% (0-91%) Composite: Comparable gradient in clinical importance and treatment effect across components

51. Complexity of Evidence-Based Guidelines Illusion of understanding? Illusion of control?

52. "Yes, I have tricks in my pocket, I have things up my sleeve. But I am the opposite of a stage magician. He gives you illusion that has the appearance of truth. I give you truth in the pleasant disguise of illusion." Tennessee Williams (The Glass Menagerie)

53. Caveats in Interpretation of Meta-analysis “Although it challenges logic that one could obtain new accurate information from the quantitative integration of a number of very diverse studies, the numerous meta-analyses published speak for themselves. Used in the proper setting, I think they can make a valuable contribution. The job of the Journal will be to ensure that those published are in this setting and are methodologically sound.” J Am Coll Cardiol, 2008; 52:237-238 Anthony N DeMaria, MD Editor-in-Chief, JACC Has the Journal lived up to its ideals?

54. Separate systematic review from guideline development Multidisciplinary guideline developers: methodologists, clinical content experts, patient representatives Avoid LOE C recommendations (best suited as “advisories”) Minimize conflicts of interest (COI) for writers/reviewers “Zero tolerance” COI policy for chairs PIs of guideline-relevant trials should only serve as advisors Turbocharging the Guidelines ACC Improvement Initiatives Turbocharging the Guidelines ACC Improvement Initiatives

55. Do we practice evidence-based medicine or reimbursement-based medicine? Fee for Service or Fee for Appropriate Service? What is the Gold Standard? Fee for Service or Fee for Appropriate Service? What is the Gold Standard?

56. PCI for Stable CAD Disconnect Between Policy and Practice PCI for Stable CAD Disconnect Between Policy and Practice Number of PCIs performed for stable CAD - ~ 500,000/yr at cost of $20K per PCI ($10 billion) Appropriateness of PCI - Presence of ischemic symptoms - Objective evidence of ischemia by stress testing - Failed trial of optimal medical therapy and lifestyle Rx The real-world practice - 20% of pts referred for PCI are asymptomatic (ACC-NCDR) - 30-50% of pts have not had a stress test (Topol / Lin et al.); untold (?60-70%) number of stress tests are “ negative ” - 30% of pts not taking anti-ischemic meds (Samuels et al.)

57. Reimbursement for PCI - $20K per PCI Score based on appropriateness - Presence of ischemic symptoms (1/3) - Objective evidence of ischemia by stress testing (1/3) - Failed trial of optimal medical therapy and lifestyle Rx (1/3) Sliding-scale reimbursement - 20% reward for a score of 1 - 20% discount for a score of 2/3 - 60% discount for a score of 1/3 - 100% discount for a score of 0 Evidence-Based Reimbursement for Stable CAD A Financial Incentive for Health Care Reform Evidence-Based Reimbursement for Stable CAD A Financial Incentive for Health Care Reform Diamond and Kaul, Circulation Cardiovasc Qual Outcomes 2009; Archives of Int Med 2009

58. SymptomsStress test TreatmentScorePaymentPatientsReimbursement +++1$24K15,000$0.36B ++-2/3$16K85,000$1.36B +-+2/3$16K45,000$0.72B -++2/3$16K3,750$0.06B +--1/3$8K255,000$2.04B -+-1/3$8K21,250$0.17B --+1/3$8K11,250$0.09B ---0063,750$0B Total500,000$4.8B Evidence-Based Reimbursement for Stable CAD A Financial Incentive for Health Care Reform Evidence-Based Reimbursement for Stable CAD A Financial Incentive for Health Care Reform 80% of patients complain of ischemic symptoms 50% of patients undergo stress testing; 50% of these are ischemic 15% of patients are receiving OMT 13% reduction in caseload and 52% reduction in reimbursement

59. InterventionControl (%) Rx (%) Summary risk ratio (95% CI) P Value NNT (95% CI) Interpretation of Confidence Intervals (MCID = 15% RRR) Aspirin (N=2,856) 12.85.50.43 (0.33-0.56) <0.0114 (11-19) Statistically significant and clinically important (E) UFH (N=1,353) 10.47.90.67 (0.44-1.02) 0.0644 (∞-18) Statistically not significant, maybe clinically important (B) Enoxaparin (Early invasive) 12.812.10.96 (0.88-1.05) 0.35171 (∞-59) Statistically not significant, clinically not important (A) Clopidogrel (CURE) 11.49.30.82 (0.74-0.92) <0.0154 (35-120) Statistically significant, maybe clinically important (D) GP IIb/IIIa (Early invasive) 14.511.80.81 (0.70-0.94) 0.00737 (21-139) Statistically significant, maybe clinically important (D) Early statin (A-to-Z) 12.411.10.89 (0.74-1.07) 0.2187 (∞-33) Statistically not significant, maybe clinically important (B) Statistical Significance vs. Clinical Importance Class I, LOE A Recommendations for UA/NSTEMI Impact on Death or MI Statistical Significance vs. Clinical Importance Class I, LOE A Recommendations for UA/NSTEMI Impact on Death or MI