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Plan

Plan. Principles of conventional systematic reviews and meta-analyses Indirect comparisons Network meta-analysis (mixed treatment comparisons meta-analysis). The right question. All cancer therapy for all cancers all antiplatelet agents for all atheroembolic events (heart, head, leg)

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Plan

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  1. Plan Principles of conventional systematic reviews and meta-analyses Indirect comparisons Network meta-analysis (mixed treatment comparisons meta-analysis)

  2. The right question All cancer therapy for all cancers all antiplatelet agents for all atheroembolic events (heart, head, leg) all aspirin doses for stroke 30 to 300 mg. for stroke What is the guide about when it is right to pool?

  3. Pooled Estimate The single best estimate for each outcome. 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. I2 Interpretation 100% Why are we pooling? 75% Very concerned 25% Only a little concerned 50% Getting concerned 0% No worries

  6. Indirect Comparisons Interested in A versus B available data A vs C, B vs C Alendronate (A) Risedronate (B) Placebo (C) • Credibility depends on “similarity assumption”

  7. How often are Indirect Comparisons Accurate? Song BMJ 2003 • Searched for meta-analyses up to 2000 • Both direct and indirect comparisons possible • Indirect comparisons Bucher method • Calculated discrepancies, and SE around discrepancies (log RR or SMD) • also significant versus non-significant

  8. 3 of 44 significantly different equally likely over or underestimate

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

  10. Comparing Multiple Treatments:Introduction to Network Meta-Analyses • Many disease areas where many alternatives exist • Impractical to test each comparator directly • Simultaneous comparison of multiple treatments • “Network meta-analysis”, “mixed treatment comparisons”, “adjusted indirect comparisons”

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

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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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

  22. A Prominent and Debated Example of a NMA

  23. Antidepressants, Results (Bayesian method)

  24. Fundamentals of Network meta-analysisWhat Have we Learned? Network meta-analysis takes advantage of all possible indirect comparisons Some indirect comparisons can be relatively direct, others very indirect If much more data from indirect comparisons with tight loops can dominate pooled comparison More indirect the loop, less the weight in pooled analysis Network meta-analysis can be informative and helpful, but with all the assumptions confidence in estimates will usually be low

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