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Absolute Risk Reduction, Number Needed to Treat, Back-of-the-Envelope Cost Effectiveness Analysis, Treatment Thresholds

Using Randomized Trials to Quantify Treatment Effects. Absolute Risk Reduction, Number Needed to Treat, Back-of-the-Envelope Cost Effectiveness Analysis, Treatment Thresholds Revisited. 10 November 2011 Michael A. Kohn, MD, MPP. (+ Natural experiments and instrumental variables – Tom Newman).

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Absolute Risk Reduction, Number Needed to Treat, Back-of-the-Envelope Cost Effectiveness Analysis, Treatment Thresholds

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  1. Using Randomized Trials to Quantify Treatment Effects Absolute Risk Reduction, Number Needed to Treat, Back-of-the-Envelope Cost Effectiveness Analysis, Treatment Thresholds Revisited 10 November 2011 Michael A. Kohn, MD, MPP (+ Natural experiments and instrumental variables – Tom Newman)

  2. Problem-Writing Assignment • Due in section next week (11/17/2011)! • Include answers • (Best if answers are separate, so we can try the question first without the answer.)

  3. EBM is about using research studies to help in two related areas Diagnosis: Evaluate a test and then use it to determine whether a patient has a given disease. (Chs. 2, 3, 4, 5, 8) Treatment: Determine if a treatment is beneficial in patients with a given disease, and if so, whether the benefits outweigh the costs and risks. (Chs. 9, 10) In screening programs (Ch. 6), diagnosis and treatment are the most closely intertwined. Prognostic testing (Ch. 7) requires longitudinal studies and evaluation of calibration as well as discrimination.

  4. Quantifying the Benefit of a Treatment: Take Home Points • RCT Checklist • Need baseline incidence of bad outcome*. • Number Needed to Treat =NNT= 1/ARR • Number Needed to (treat to) Harm = NNH = 1/ARI • Back-of-the-envelope CEA: Treatment cost per bad outcome prevented = Treatment Cost x NNT *Unless the RR is 1 and RRR is 0.

  5. RCT Checklist

  6. RCT Checklist for Study Validity* Design and conduct • Randomization to address issues of confounding • Blinding of patients and clinicians to prevent differential co-interventions • Blinding of outcome assessors to prevent bias • Patient-Oriented Effect Measures (POEMs) vs. surrogate outcomes • Decompose composite outcomes • Good follow-up to eliminate differential losses to follow-up *For checklist on study validity, see Chapter 1B1 “Therapy”, in Guyatt and Rennie (eds.), Users Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice; AMA Press; 2002.

  7. RCT Checklist for Study Validity* Analysis • Intention-to-treat analysis (once randomized always analyzed) • Compare entire randomization groups, not subgroups • Between groups rather than within groups comparison *For checklist on study validity, see Chapter 1B1 “Therapy”, in Guyatt and Rennie (eds.), Users Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice; AMA Press; 2002.

  8. RCTs (2 orthopedic, 3 CV, and 0 pediatric treatments) • Hip replacement versus screws for hip fractures in the elderly. • Immediate arthroscopy versus immobilization and PT in first shoulder dislocation. • ApoA-I Milano vs. placebo in acute coronary syndrome. • Aspirin versus placebo in suspected acute myocardial infarction: ISIS-2. • Intravascular gamma radiation vs. placebo to prevent re-blockage after cleaning out a blocked coronary artery bypass graft.

  9. Randomization, Intention-to-Treat Analysis, and Follow-up: Hip Replacement vs. Screws • Pt is an 81-year-old woman with a hip fracture • Pt’s son is a physician. He asks about hip replacement vs. screws. Pubmed search  Parker MJ, Khan RJ, Crawford J, Pryor GA. Hemiarthroplasty versus internal fixation for displaced intracapsular hip fractures in the elderly. A randomised trial of 455 patients. J Bone Joint Surg Br. Nov 2002;84(8):1150-1155.

  10. Displaced Femoral Neck Fracture = Hip Fracture

  11. Internal Fixation = Screws

  12. Hemiarthroplasty = Hip Replacement

  13. Randomization, Intention-to-Treat Analysis, and Follow-up: Hip Replacement vs. Screws Randomized controlled trial of the effects of hip replacement vs. screws on re-operation and other outcomes in > 70-year-old patients with displaced, hip fractures. Parker MH et al. Bone Joint Surg Br. 84(8):1150-1155.

  14. Randomization: Hip Replacement vs. Screws Why do a randomized experiment? Why not do an observational study comparing mortality, re-operation rates, etc. between patients who had hip replacements and patients who had screws? Parker MH et al. Bone Joint Surg Br. 84(8):1150-1155.

  15. Intention-to-Treat: Hip Replacement vs. Screws Some patients randomized to the hip replacement group ended up getting screws. Why not include these patients’ outcomes in the screws group or at least exclude them from the hip replacement group? Parker MH et al. Bone Joint Surg Br. 84(8):1150-1155.

  16. How to analyze those who were assigned to hip replacement but received screws?* Intention to Treat: Analyze in the hip replacement group (reduces effect size, bias towards the null) Per Protocol: Exclude from analysis (bias in favor of hip replacement) As Treated: Analyze in the screws group (bias in favor of hip replacment) *Generally they are older, weaker, or sicker than the rest of the group.

  17. Losses to Follow-Up: Hip Replacement vs. Screws.* If each treatment group had 20% loss to follow-up, there could still be bias. What if those in the screws group were lost to follow-up because they got better and those in the hip replacement group were lost because they died? *In fact, there were no losses to follow-up in this study.

  18. Patient Oriented Endpoints, Blinding: Arthroscopy versus Immobilization for 1st Shoulder Dislocation • Pt is a 34-year-old man who dislocated his shoulder while surfing at Ocean Beach. • He asks about early arthroscopic stabilization versus immobilization and PT. Pubmed search  Kirkley A, Griffin S, Richards C, Miniaci A, Mohtadi N. Prospective randomized clinical trial comparing the effectiveness of immediate arthroscopic stabilization versus immobilization and rehabilitation in first traumatic anterior dislocations of the shoulder. Arthroscopy. Jul-Aug 1999;15(5):507-514

  19. Outcomes Affected by Treatments* • Dichotomous (e.g., recurrent dislocation) • Continuous (e.g., Western Ontario Shoulder Disability Index {WOSI}) Endpoints • Patient relevant (e.g., ability to return to sports) • Surrogate (e.g., MRI findings) * Example: Arthroscopy vs. conservative tx for 1st Anterior Shoulder Dislocation (Arthroscopy. 1999 Jul-Aug;15(5):507-14. )

  20. Blinding • Blinding of Patients and Clinicians • Eliminates differential co-interventions • Blinding of Outcome Assessment • Eliminates biased outcome assessment (including placebo effect)

  21. Blinding Blinding less important when opportunity for cointerventions that affect outcomes is minimal, and outcome is not subjective. • Hip Replacement vs Screws for hip fracture, with endpoints of mortality and re-operation: patients, clinicians, and outcome assessors not blinded. • Arthroscopy vs. non-operative management of shoulder dislocation, with endpoints of re-dislocation, and WOSI*: patients not blinded, but clinicians and outcome assessors (therapists) were blinded. *Western Ontario Shoulder Disability Index

  22. Between-groups Comparison: ApoA-I Milano vs. Placebo to Reduce Atheroma Volume in Acute Coronary Syndrome Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. Jama 2003;290(17):2292-2300.

  23. Between-groups Comparison: ApoA-I Milano vs. Placebo to Reduce Atheroma Volume in Acute Coronary Syndrome

  24. Sub-group Analysis: ISIS II* 30-day mortality *Lancet 1988;2(8607):349-360.

  25. Sub-group Analysis: ISIS II* 30-day mortality *Lancet 1988;2(8607):349-360.

  26. Composite Endpoints: Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. “At 12 months, … the rate of major cardiac events was 49 percent lower (32 percent vs. 63 percent, P<0.001). “ Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts." N Engl J Med346(16): 1194-9.

  27. Composite Endpoints: Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. “Major Cardiac Event” = Death or MI or Revascularization Procedure

  28. Composite Endpoints: Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts." N Engl J Med346(16): 1194-9.

  29. Composite Endpoints: Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. Can’t tell from paper. Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts." N Engl J Med346(16): 1194-9.

  30. Composite Endpoints: Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. Could have been… Mortality or MI worse but composite endpoint better.

  31. DONE: RCT Checklist for Study Validity* • Randomization to address issues of confounding • Blinding of patients and clinicians to prevent differential co-interventions • Blinding of outcome assessors to prevent bias • Patient-Oriented Effect Measures (POEMs) vs. surrogate outcomes • Take care with composite outcomes • Good follow-up to eliminate differential losses to follow-up • Intention-to-treat analysis (once randomized always analyzed) • Between groups rather than within groups comparison • Compare entire randomization groups, not subgroups *For checklist on study validity, see Chapter 1B1 “Therapy”, in Guyatt and Rennie (eds.), Users Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice; AMA Press; 2002. (Or try http://www.cche.net/usersguides/therapy.asp#Valid )

  32. RCTs • Hip replacement versus screws for hip fractures in the elderly. • Immediate arthroscopy versus immobilization and PT in first shoulder dislocation. • ApoA-I Milano vs. placebo in acute coronary syndrome. • Aspirin versus placebo in suspected acute myocardial infarction: ISIS-2. • Intravascular gamma radiation vs. placebo to prevent re-blockage after cleaning out a blocked coronary artery bypass graft.

  33. Effect Size (Dichotomous Outcomes*) RR RRR ARR NNT ARI NNH * Not going to discuss continuous outcomes today

  34. Hip Replacement vs. Screws This study was properly randomized but not blinded, used an intention-to-treat analysis, and had NO losses to follow-up. Results follow…

  35. Reduced Re-operation

  36. Measures of Treatment Effect RR= Risk Ratio = RR < 1 means treatment is beneficial RRR = Relative Risk Reduction = 1-RR

  37. Beware of the Odds Ratio RR = Risk Ratio = (a/b) (a/c) OR = Odds Ratio = ------- = -------- = ad/bc (c/d) (b/d) In the hip replacement vs. screws example, the baseline risk of reoperation (with screws) is 40%, so the baseline odds are 67%. The risk (or odds) with replacement is about 5% , so RR ≈ 5/40 ≈ 1/8; but the OR ≈ 5/67 ≈ 1/13.

  38. Beware of the Odds Ratio Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. “The risk of a major cardiac event was significantly lower in the iridium-192 group than in the placebo group (odds ratio, 0.27; 95 percent confidence interval, 0.13 to 0.57; P<0.001) “ Waksman, R., A. E. Ajani, et al. (2002). "Intravascular gamma radiation for in-stent restenosis in saphenous-vein bypass grafts." N Engl J Med346(16): 1194-9.

  39. Beware of the Odds Ratio Irradiation to prevent re-blockage after cleaning out a blocked coronary artery bypass graft. RR = (19/60)/(38/60) = 0.50 OR = (19/41)/(38/22) = 0.27

  40. Measures of Treatment Effect ARR = Absolute Risk Reduction = c/(c+d) - a/(a+b) NNT = Number Needed to Treat (to prevent 1 bad outcome) = 1/ARR

  41. Q: What does the 34% reduction mean?

  42. Nimotop® Ad Graph RR = 21.8%/33% = .66 RRR = 1-0.66 = 34% ARR = 33% - 21.8% = 11.2% 33% 22%

  43. 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Original figure To scale 11%

  44. Why is NNT = 1/ARR? 100 SAH patients treated 67 no stroke anyway 33 strokes with no treatment 11 strokes prevented 22 strokes with with treatment 22 strokes with Nimotop®

  45. Why is NNT 1/ARR? Treat 100 SAH patients; prevent 11 strokes. 100/11 = 1/11% = 1/ARR = 9 patients treated per stroke prevented.

  46. Number Needed to Treat … • With what? • To prevent what? • In whom?

  47. NNT Practice In patients < 30 years old with first-time acute anterior shoulder dislocation, prompt arthroscopic surgery (vs. standard conservative therapy) reduces the 2-year re-dislocation rate by almost 33% in absolute terms (from about 50% to about 17%).* How many first-time dislocation patients do we need to treat with arthroscopy to prevent one having re-dislocation at 2 years?

  48. NNT Practice ISIS- 2*. Aspirin therapy (one month of 160 mg/day) in patients with acute myocardial infarction (AMI) reduced 30-day cardiovascular mortality from 11.8% in the placebo group to 9.3% in the aspirin group. *Lancet 1988;2(8607):349-360.

  49. NNT Practice How many AMI patients do we need to treat with aspirin to prevent one CV death at 30 days? *Lancet 1988;2(8607):349-360.

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