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Network Meta-analysis

Network Meta-analysis. What is a network meta-analysis? GRADE approach to confidence in estimates Determining credibility of NMA. Comparing Multiple Treatments: Introduction to Network Meta-Analyses . Many disease areas where many alternatives exist

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Network Meta-analysis

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  1. Network Meta-analysis What is a network meta-analysis? GRADE approach to confidence in estimates Determining credibility of NMA

  2. Comparing Multiple Treatments:Introduction to Network Meta-Analyses • Many disease areas where many alternatives exist • Clinicians/patients need to know about relative merits • Impractical to test each comparator directly • Simultaneous comparison of multiple treatments • “Network meta-analysis”, “mixed treatment comparisons”, “adjusted indirect comparisons”

  3. Conventional meta-analysisPooled Estimate assumption Single best estimate of treatment effect Assumes effect similar across Patients Interventions Outcomes Methodology “Homogeneity assumption”

  4. ' ' ' ' ' ' ' ' 0.1 1 10 Relative Risk with 95% CI for Vitamin D Non-vertebral Fractures Favors Vitamin D Favors Control Chapuy et al, (2002) 0.85 (0.64, 1.13) Chapuy et al, (1994) 0.79 (0.69, 0.92) Lips et al, (1996) 1.10 (0.87, 1.39) Dawson-Hughes et al, (1997) 0.46 (0.24, 0.88) Pfeifer et al, (2000) 0.48 (0.13, 1.78) Meyer et al, (2002) 0.92 (0.68, 1.24) Trivedi et al, (2003) 0.67 (0.46, 0.99) Pooled Random Effect Model 0.82 (0.69 to 0.98) p= 0.05 for heterogeneity, I2=53% Relative Risk 95% CI

  5. Indirect Comparisons Interested in A versus B available data A vs C, B vs C Alendronate (A) Risedronate (B) Placebo (C) • Less confidence than direct? • Why?

  6. Vulnerability of Indirect comparison • Effect modifiers • Patients • Optimal interventions • Comparator • Cointerventions • Outcome measures • Risk of bias

  7. Combine direct and indirect comparisons • - additional assumption mediators same in direct and indirect • - “consistency” or “coherence” assumption

  8. Network Meta-analysis Case Study: Which Approach to Nicotine Addiction Works Best

  9. Network Meta-analysis Case Study Combines effect estimates from direct and indirect comparisons Placebo Nicotine replacement treatment (NRT) Varenicline Antidepressants + NRT Antidepressants

  10. Comparison with Antidepressants Varenicline NRT + antidepressant NRT Treatments 1.35 1.34 1.16 1.04 NRT + NRT (1.04 - 1.75) (1.00 - 1.78) (0.85 - 1.58) (0.71 - 1.52) 1.30 1.30 1.29 1.29 1.12 NRT + antidepressant (0.98 (0.98 - - 1.73) 1.73) (0.96 (0.96 - - 1.74) 1.74) (0.81 - 1.55) 1.17 1.17 1.16 1.16 Varenicline (0.98 (0.98 - - 1.39) 1.39) (0.97 (0.97 - - 1.38) 1.38) 1.01 Antidepressants (0.88 - 1.15) 4 4 .5 .75 1 1.33 2 .5 .75 1 1.33 2 4 .5 .75 1 1.33 2 .5 .75 1 1.33 2 Odds ratio Odds ratio Odds ratio Odds ratio

  11. NRT+NRT buspirone rimonabant clonidine antidepressants +NRT varenicline Direct Comparison 1.12 1 comparison 1.54, I2=46% 5 comparisons 0.73, I2=0% 2 comparisons 1.28, I2=0% 3 comparisons 1.85, I2=13% 67 comparisons NRT 1.36, I2=0% 2 comparisons control 1.63, I2=0% 4 comparisons 1.14, I2=63% 6 comparisons 4.85 1 comparison 1.88, I2=19% 29 comparisons 2.68, I2=82% 5 comparisons Direct evidence (3 trials) 1.28 1 comparison Antide- pressants 1.34 (0.71, 2.56) I-squared=43.7% 1.70, I2=0% 3 comparisons .5 1 1 1 . 5 2 2.5 NRT superior Antidepressants superior

  12. NRT+NRT buspirone rimonabant clonidine antidepressants +NRT varenicline Indirect Comparison 1 1.12 1 comparison 1.54, I2=46% 5 comparisons 0.73, I2=0% 2 comparisons 1.28, I2=0% 3 comparisons 1.85, I2=13% 67 comparisons NRT 1.36, I2=0% 2 comparisons control 1.63, I2=0% 4 comparisons 1.14, I2=63% 6 comparisons 4.85 1 comparison Indirect evidence 1.88, I2=19% 29 comparisons 2.68, I2=82% 5 comparisons 1.01 (0.81,1.27) Direct evidence (3 trials) 1.28 1 comparison Antide- pressants 1.34 (0.71, 2.56) I-squared=43.7% 1.70, I2=0% 3 comparisons .5 1 1 1 . 5 2 2.5 NRTsuperior Antidepressants superior

  13. NRT+NRT buspirone rimonabant clonidine antidepressants +NRT antidepressants +NRT Indirect Comparison 2 1.12 1 comparison 1.54, I2=46% 5 comparisons 0.73, I2=0% 2 comparisons 1.28, I2=0% 3 comparisons 1.85, I2=13% 67 comparisons NRT 1.36, I2=0% 2 comparisons control 1.63, I2=0% 4 comparisons 1.14, I2=63% 6 comparisons 1.14, I2=63% 6 comparisons 4.85 1 comparison 2.68, I2=82% 5 comparisons Indirect evidence 1.88, I2=19% 29 comparisons 0.85 (0.38, 1.92) Direct evidence (3 trials) 1.28 1 comparison Antide- pressants varenicline 1.34 (0.71, 2.56) I-squared=43.7% 1.70, I2=0% 3 comparisons .5 1 1 1 . 5 2 2.5 NRTsuperior Antidepressants superior

  14. 5 Paths to Indirectly CompareAntidepressants vs NRT NRT+NRT buspirone NRT rimonabant placebo and nonplacebo control clonidine antidepressants +NRT varenicline antidepressants 1 2 3 1 comparison 4 5 comparisons 2 comparisons 5 3 comparisons 67 comparisons 2 comparisons 3 comparisons 4 comparisons 6 comparisons 1 comparison 5 comparisons 29 comparisons 1 comparison 3 comparisons

  15. NRT+NRT buspirone NRT rimonabant placebo and nonplacebo control clonidine antidepressants +NRT varenicline antidepressants 5 Paths to Indirectly Compare Antidepressants vs NRT 1 1.01 (0.81, 1.27) 2 0.85 (0.38, 1.92) 3 0.89 (0.29, 2.77) 1 comparison 4 1.56 (0.54, 4.49) 5 comparisons 2 comparisons 5 1.31 (0.25, 6.76) 3 comparisons 67 comparisons 2 comparisons 3 comparisons 4 comparisons 6 comparisons 1 comparison 5 comparisons 29 comparisons 1 comparison 3 comparisons

  16. Comparative effectiveness of NRT vs. Antidepressants on prolonged abstinence (≥6 months) Indirect evidence NRT+NRT buspirone Path 1.12 1 comparison 1 1.01 (0.81, 1.27) 2 1.54, I2=46% 5 comparisons 0.85 (0.38, 1.92) 0.73, I2=0% 2 comparisons 1.28, I2=0% 3 comparisons 1.85, I2=13% 67 comparisons 3 rimonabant 0.89 (0.29, 2.77) 4 1.56 (0.54, 4.49) NRT 1.36, I2=0% 2 comparisons 5 1.31 (0.25, 6.76) control Direct evidence 1.63, I2=0% 4 comparisons .5 1 1 1.5 2 2.5 1.34, I2=44% 3 comparisons 1.14, I2=63% 6 comparisons NRT superior Antidepressants superior 4.85 1 comparison 2.68, I2=82% 5 comparisons clonidine 1.88, I2=19% 29 comparisons 3 trials pooled 1.28 1 comparison Antide- pressants 1.34 (0.71, 2.56) varenicline I-squared = 43.7% 1.70, I2=0% 3 comparisons .5 1 1 1.5 2 2.5 NRT superior Antidepressants superior

  17. Comparative effectiveness of NRT vs. Antidepressants on prolonged abstinence (≥6 months) Indirect evidence NRT+NRT buspirone Path 1.12 1 comparison 1 1.01 (0.81, 1.27) 2 1.54, I2=46% 5 comparisons 0.85 (0.38, 1.92) 0.73, I2=0% 2 comparisons 1.28, I2=0% 3 comparisons 1.85, I2=13% 67 comparisons 3 rimonabant 0.89 (0.29, 2.77) 4 1.56 (0.54, 4.49) NRT 1.36, I2=0% 2 comparisons 5 1.31 (0.25, 6.76) control Direct evidence 1.63, I2=0% 4 comparisons .5 1 1 1.5 2 2.5 1.34, I2=44% 3 comparisons 1.14, I2=63% 6 comparisons NRT superior Antidepressants superior 4.85 1 comparison 2.68, I2=82% 5 comparisons clonidine 1.88, I2=19% 29 comparisons 0.98 (95% 0.85-1.13) 3 trials pooled 1.28 1 comparison Antide- pressants 1.34 (0.71, 2.56) varenicline I-squared = 43.7% 1.70, I2=0% 3 comparisons .5 1 1 1.5 2 2.5 NRT superior Antidepressants superior

  18. Comparative effectiveness of NRT vs. Antidepressants on prolonged abstinence (≥6 months) Indirect evidence pooled estimate 1.01 (95% 0.88-1.15) NRT+NRT buspirone Path 1.12 1 comparison 1 1.01 (0.81, 1.27) 2 1.54, I2=46% 5 comparisons 0.85 (0.38, 1.92) 0.73, I2=0% 2 comparisons 1.28, I2=0% 3 comparisons 1.85, I2=13% 67 comparisons 3 rimonabant 0.89 (0.29, 2.77) 4 1.56 (0.54, 4.49) NRT 1.36, I2=0% 2 comparisons 5 1.31 (0.25, 6.76) control Direct evidence 1.63, I2=0% 4 comparisons .5 1 1 1.5 2 2.5 1.34, I2=44% 3 comparisons 1.14, I2=63% 6 comparisons NRT superior Antidepressants superior 4.85 1 comparison 2.68, I2=82% 5 comparisons clonidine 1.88, I2=19% 29 comparisons 0.98 (95% 0.85-1.13) 3 trials pooled 1.28 1 comparison Antide- pressants 1.34 (0.71, 2.56) varenicline I-squared = 43.7% 1.70, I2=0% 3 comparisons .5 1 1 1.5 2 2.5 NRT superior Antidepressants superior

  19. Confidence in Estimates

  20. Approach Example Step 1: Present direct and indirect estimate for each comparison of the evidence network Step 2: Rate the confidence in the direct and indirect estimate Step 3: Present the NMA estimate Step 4: Rate the confidence in the NMA estimate

  21. Approach Example Step 1: Present direct and indirect estimate for each comparison of the evidence network Step 2: Rate the confidence in the direct and indirect estimate Step 3: Present the NMA estimate Step 4: Rate the confidence in the NMA estimate

  22. Starting level of indirect • Intutitively lower confidence • Previous GRADE guidance start at moderate • NMA enthusiasts argue no different • New guidance: Start at high • Only rate down for lack of similarity (intransivity)

  23. Placebo n=41,548 Teriparatide (PTH) n=1,093 Ibandronate n=1,912 Hip Fractures # of trials =40 Risedronate # of participants =139,647 n=6,850 # of hip fracture =2,567 Zoledronate n=4,954 Vitamin D and Calcium n=46,933 Denosumab n=3,933 Calcium n=3,896 Vitamin D n=12,469 Alendronate n=5,084 Raloxifene n=10,975

  24. Placebo n=41,548 Teriparatide (PTH) n=1,093 Ibandronate n=1,912 Hip Fractures # of trials =40 Risedronate # of participants =139,647 n=6,850 # of hip fracture =2,567 Zoledronate n=4,954 Vitamin D and Calcium n=46,933 Denosumab n=3,933 Dominant link Calcium n=3,896 Vitamin D n=12,469 Alendronate n=5,084 Raloxifene n=10,975

  25. Confidence in indirect estimate Lowest of direct estimates A versus B comparison of interest Through C dominant link A versus C high; B versus C moderate or low Confidence based on B versus C

  26. Approach Example Step 1: Present direct and indirect estimate for each comparison of the evidence network Step 2: Rate the confidence in the direct and indirect estimate Step 3: Present the NMA estimate Step 4: Rate the confidence in the NMA estimate

  27. Approach Example Step 1: Present direct and indirect estimate for each comparison of the evidence network Step 2: Rate the confidence in the direct and indirect estimate Step 3: Present the NMA estimate Step 4: Rate the confidence in the NMA estimate

  28. Confidence in NMA estimate If only direct or indirect use that If both use higher

  29. Confidence in NMA estimate • Direct and indirect very different • Terminology differs • Ours (for now) • Heterogeneity for direct • Transitivity for indirect • Incoherence for direct versus indirect

  30. Judging incoherence Difference in point estimates Extent of overlap in confidence intervals P-value for test of incoherence

  31. P-value for test of incoherence 0.02

  32. Credibility of the Process of NMA • Usual criteria for systematic review • Explicit sensible questions • Search exhaustive • Selection and assessment reproducible • Present results ready for clinical application • Address confidence in effect estimates

  33. Presentation of Results • Often presented with rankings • Potentially very misleading • Small difference between ranks • Everything low or very low confidence • First ranked lower than others

  34. Conclusion • NMA will play important role in EBCP • Needs usual criteria for SR/MA credibility • If includes confidence in estimates interpretable • If no confidence very difficult to interpret • Probably shouldn’t bother

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