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Stent thrombosis: evidence from a network meta-analysis

Stent thrombosis: evidence from a network meta-analysis. Giuseppe Biondi Zoccai, MD Department of Medico-Surgical Sciences and Biotechnologies Sapienza University of Rome gbiondizoccai@gmail.com. LEARNING GOALS. What is stent thrombosis (ST)? What are network meta-analyses (NMA)?

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Stent thrombosis: evidence from a network meta-analysis

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  1. Stent thrombosis: evidence from a network meta-analysis Giuseppe Biondi Zoccai, MD DepartmentofMedico-SurgicalSciences and Biotechnologies Sapienza UniversityofRome gbiondizoccai@gmail.com

  2. LEARNING GOALS • What is stent thrombosis (ST)? • What are network meta-analyses (NMA)? • NMA of ST • Goals • Methods • Results • Implications

  3. LEARNING GOALS • What is stent thrombosis (ST)? • What are network meta-analyses (NMA)? • NMA of ST • Goals • Methods • Results • Implications

  4. WHAT IS STENT THROMBOSIS D’Ascenzo et al, submitted

  5. DEFINITIONS OF STENT THROMBOSIS Cutlip et al, Circulation 2007

  6. DEFINITIONS OF STENT THROMBOSIS Cutlip et al, Circulation 2007

  7. DEFINITIONS OF STENT THROMBOSIS Cutlip et al, Circulation 2007

  8. TIMING OF STENT THROMBOSIS Cutlip et al, Circulation 2007

  9. INCIDENCE OF DES THROMBOSIS very late total acute subacute late D’Ascenzo et al, Int J Cardiol 2012

  10. PREDICTORS OF STENT THROMBOSIS D’Ascenzo et al, Int J Cardiol 2011

  11. IMPACT OF STENT THROMBOSIS Chechi et al, J Am Coll Cardiol 2008

  12. LEARNING GOALS • What is stent thrombosis (ST)? • What are network meta-analyses (NMA)? • NMA of ST • Goals • Methods • Results • Implications

  13. FAMOUS QUOTES “If I have seen further it is by standing on the shoulders of giants” Isaac Newton “The great advances in science usually result from new tools rather than from new doctrines” Freeman Dyson

  14. FAMOUS QUOTES “I like to think of the meta-analytic process as similar to being in a helicopter. On the ground individual trees are visible with high resolution. This resolution diminishes as the helicopter rises, and in its place we begin to see patterns not visible from the ground” Ingram Olkin

  15. BABY STEPS OF META-ANALYSIS • 1904 - Karl Pearson (UK): correlation between inoculation of vaccine for typhoid fever and mortality across apparently conflicting studies • 1931 – Leonard Tippet (UK): comparison of differences between and within farming techniques on agricultural yield adjusting for sample size across several studies • 1937 – William Cochran (UK): combination of effect sizes across different studies of medical treatments • 1970s – Robert Rosenthal and Gene Glass (USA), Archie Cochrane (UK): combination of effect sizes across different studies of, respectively, educational and psychological treatments • 1980s– exponential development/use of meta-analytic methods

  16. MINIMAL GLOSSARY • Review: viewpoint on a subject quoting different primary authors • Overview: as above • Qualitative review: deliberately avoids a systematic approach • Systematic review: deliberately uses a systematic approach to study search, selection, abstraction, appraisal and pooling • Quantitative review: uses quantitative methods to appraise or synthesize data • Meta-analysis: uses specific statistical methods for data pooling and/or exploratory analysis • Individual patient data meta-analysis: uses specific stastistical methods for data pooling or subgroup exploration exploiting individual patient data → Our focus:systematic review + meta-analysis

  17. SYSTEMATIC REVIEW AND META-ANALYSES • What is a systematic review? • A systematic appraisal of the methodological quality, clinical relevance and consistency of published evidence on a specific clinical topic in order to provide clear suggestions for a specific healthcare problem • What is a meta-analysis? • A quantitative synthesis that, preserving the identity of individual studies, tries to provide an estimate of the overall effect of an intervention, exposure, or diagnostic strategy

  18. EBM HIERARCHY OF EVIDENCE • N of 1 randomized controlled trial • Systematic reviews of homogeneous randomized trials • Single (large) randomized trial • Systematic review of homogeneous observational studies addressing patient-important outcomes • Single observational study addressing patient-important outcomes • Physiologic studies (eg blood pressure, cardiac output, exercise capacity, bone density, and so forth) • Unsystematic clinical observations Guyatt and Rennie, Users’ guide to the medical literature, 2002

  19. PROS • Application to any clinical research question • Systematic searches for clinical evidence • Explicit and standardized methods for search and selection of evidence sources • Thorough appraisal of the internal validity of primary studies • Quantitative synthesis with increased statistical power • Increased external validity by appraising the effect of an intervention (exposure) across different settings • Test subgroup hypotheses (eg with patient-level reviews) • Explore clinical and statistical heterogeneity Lau et al, Lancet 1998

  20. REASONS FOR META-ANALYSIS FAILURE • Duplicate efforts may lead to discordant results • Funding or conflicts of interest may bias • Studies/events might not be found • Studies may be of low quality/internal validity • Studies may be heterogeneous/inconsistent, ie “mixing apples with oranges” provides unreal fruits • Studies may not be relevant to current individual practice • Selection based on publication may bias • Analysis with highly sensitive but unrobust tests may bias LeLorier et al, New Engl J Med 1997; Lau et al, Lancet 1998; Rosen, BMC BMC Health Services Research 2009

  21. ARGUABLY THE MOST IMPORTANT META-ANALYSIS EVER…. Antman et al, JAMA 1992

  22. …SHOWING DISCREPANCIES AMONG EVIDENCE AND EXPERTS

  23. STANDARD (PAIR-WISE) META-ANALYSES Incosistency P for effect P for heterogeneity Hsia et al, Ann Surg 2008

  24. INDIRECT AND NETWORKMETA-ANALYSES Biondi-Zoccai et al, HSR Proceedings 2011

  25. PARALLEL HIERARCHY OF CLINICAL RESEARCH

  26. LEARNING GOALS • What is stent thrombosis (ST)? • What are network meta-analyses (NMA)? • NMA of ST • Goals • Methods • Results • Implications

  27. NETWORK META-ANALYSIS (NMA) OF STENT THROMBOSIS (ST)

  28. NMA OF ST: BACKGROUND

  29. NMA OF ST: GOALS

  30. LEARNING GOALS • What is stent thrombosis (ST)? • What are network meta-analyses (NMA)? • NMA of ST • Goals • Methods • Results • Implications

  31. NMA OF ST: DESIGN

  32. NMA OF ST: DESIGN

  33. NMA OF ST: SEARCH AND SELECTION

  34. NMA OF ST: ANALYSIS

  35. NMA OF ST: ANALYSIS

  36. LEARNING GOALS • What is stent thrombosis (ST)? • What are network meta-analyses (NMA)? • NMA of ST • Goals • Methods • Results • Implications

  37. NMA OF ST: PROFILE 2602 potentially relevant articles FDA approved stents (BMS, SES, PES, End-ZES, Res-ZES, CoCr-EES, PtCr-EES) 49 RCTs 50,844 pts 2441 excluded 2117 not a comparison of DES 324 post-hoc, subgroup, follow-up, or pooled analyses Review of title and abstract 161 articles needing full review 112 excluded 84 not an RCT 13 DES not FDA approved 11 no ARC definition 4 DES pooled Full-text review 49 articles meeting criteria

  38. NMA OF ST: NETWORK 9 studies PES BMS 9 studies 4 studies 8 studies 1 study 5 studies 2 studies 6 studies End-ZES SES 6 studies CoCr-EES 2 studies 1 study Res-ZES Pt-Cr-EES

  39. NMA OF ST: RESULTS 30-day definite stent thrombosis Odds Ratio [95%] CoCr-EES vs BMS CoCr-EES vs PES CoCr-EES vs SESCoCr-EES vs End-ZES CoCr-EES vs Res-ZES PtCr-EES vs BMS PtCr-EES vs PES PtCr-EES vs End-ZES PtCr-EES vs Res-ZES SES vs BMS 0.21 (0.11-0.42) 0.27 (0.14-0.51) 0.40 (0.21-0.79) 0.22 (0.09-0.54) 0.07 (0.00-0.46) 0.06 (0.00-0.68) 0.07 (0.00-0.83) 0.06 (0.00-0.73) 0.02 (0.00-0.43) 0.54 (0.30-0.90) 1 10 0.1 0.01 Favors Stent 2 Favors Stent 1

  40. NMA OF ST: RESULTS Odds Ratio [95%] 30d – 1yr definite stent thrombosis CoCr-EES vs BMS CoCr-EES vs PES CoCr-EES vs End-ZES End-ZES vs SES 0.27 (0.08-0.74) 0.24 (0.08-0.62) 0.13 (0.02-0.56) 4.06 (1.11-18.54) 1 100 0.1 0.01 10 Favors Stent 1 Favors Stent 2

  41. NMA OF ST: RESULTS Odds Ratio [95%] 1-year definite stent thrombosis CoCr-EES vs BMS CoCr-EES vs PES CoCr-EES vs SESCoCr-EES vs Res-ZES CoCr-EES vs End-ZES SES vs BMS End-ZES vs SES 0.23 (0.13-0.41) 0.28 (0.16-0.48) 0.41 (0.24-0.70) 0.14 (0.03-0.47) 0.21 (0.10-0.44) 0.57 (0.36-0.88) 1.92 (1.07-3.90) 1 10 0.1 0.01 Favors Stent 1 Favors Stent 2

  42. NMA OF ST: RESULTS Odds Ratio [95%] 2-year definite stent thrombosis CoCr-EES vs BMS CoCr-EES vs PES 0.35 (0.17-0.69) 0.34 (0.19-0.62) 1 10 0.1 0.01 Favors Stent 1 Favors Stent 2

  43. NMA OF ST: RESULTS

  44. NMA OF ST: RESULTS

  45. NMA OF ST: RESULTS

  46. NMA OF ST: RESULTS Odds Ratio IV Random, 95% CI Log (odds ratio) SE Weight Definite stent thrombosis 32.4% 67.6% 100.00% 0.24 (0.09-0.66) 0.24 (0.12-0.49) 0.24 (0.14-0.43) Direct estimate Indirect estimate Total (95% CI) Test for overall effect Z=4.82 (p<0.00001) -1.427 -1.421 0.519 0.359 Definite or probable thrombosis 39.4% 60.6% 100.00% Direct estimate Indirect estimate Total (95% CI) Test for overall effect Z=4.48 (p<0.00001) 0.38 (0.18-0.80) 0.33 (0.18-0.53) 0.35 (0.22-0.55) -0.968 -1.122 0.377 0.304 Statistical inconsistency (I2): 0% for both comparisons 1 10 0.001 0.1 IV = inverse variance SE = standard error Favors CoCr-EES Favors BMS

  47. POTENTIAL OF EVEROLIMUS-ELUTING STENTS Verheye et al, J Am Coll Cardiol 2007

  48. POTENTIAL OF EVEROLIMUS-ELUTING STENTS Kolandaivelu et al, Circulation 2011

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