1. www.metcardio.org 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

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

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

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

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

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

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

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

9. www.metcardio.org totalacutesubacutelate very late INCIDENCE OF DES THROMBOSIS D’Ascenzo et al, Int J Cardiol 2012

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

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

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

13. www.metcardio.org 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. www.metcardio.org 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. www.metcardio.org 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. www.metcardio.org 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. www.metcardio.org 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. www.metcardio.org EBM HIERARCHY OF EVIDENCE 1.N of 1 randomized controlled trial 2.Systematic reviews of homogeneous randomized trials 3.Single (large) randomized trial 4.Systematic review of homogeneous observational studies addressing patient-important outcomes 5.Single observational study addressing patient-important outcomes 6.Physiologic studies (eg blood pressure, cardiac output, exercise capacity, bone density, and so forth) 7.Unsystematic clinical observations Guyatt and Rennie, Users’ guide to the medical literature, 2002

19. www.metcardio.org 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. www.metcardio.org 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. www.metcardio.org

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

24. www.metcardio.org …SHOWING DISCREPANCIES AMONG EVIDENCE AND EXPERTS

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

26. www.metcardio.org INDIRECT AND NETWORK META-ANALYSES Biondi-Zoccai et al, HSR Proceedings 2011

27. www.metcardio.org PARALLEL HIERARCHY OF CLINICAL RESEARCH

28. www.metcardio.org LEARNING GOALS What is stent thrombosis (ST)? What are network meta-analyses (NMA)? NMA of ST – Goals – Methods – Results – Implications

29. www.metcardio.org NETWORK META-ANALYSIS (NMA) OF STENT THROMBOSIS (ST)

30. www.metcardio.org NMA OF ST: BACKGROUND

31. www.metcardio.org NMA OF ST: GOALS

32. www.metcardio.org LEARNING GOALS What is stent thrombosis (ST)? What are network meta-analyses (NMA)? NMA of ST – Goals – Methods – Results – Implications

33. www.metcardio.org NMA OF ST: DESIGN

34. www.metcardio.org NMA OF ST: DESIGN

35. www.metcardio.org NMA OF ST: SEARCH AND SELECTION

36. www.metcardio.org NMA OF ST: ANALYSIS

37. www.metcardio.org NMA OF ST: ANALYSIS

38. www.metcardio.org LEARNING GOALS What is stent thrombosis (ST)? What are network meta-analyses (NMA)? NMA of ST – Goals – Methods – Results – Implications

39. www.metcardio.org NMA OF ST: PROFILE FDA approved stents (BMS, SES, PES, End-ZES, Res-ZES, CoCr-EES, PtCr-EES) 49 RCTs 50,844 pts 2602 potentially relevant articles 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

40. www.metcardio.org NMA OF ST: NETWORK 9 studies PES BMS SES End-ZES Res-ZESPt-Cr-EES CoCr-EES 1 study 8 studies 1 study 4 studies 9 studies 6 studies 2 studies 5 studies

41. www.metcardio.org NMA OF ST: RESULTS Odds Ratio [95%] 30-day definite stent thrombosis CoCr-EES vs BMS CoCr-EES vs PES CoCr-EES vs SES CoCr-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) Favors Stent 1 101 0.1 0.01 Favors Stent 2

42. www.metcardio.org 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) Favors Stent 1 100 10 1 0.1 0.01 Favors Stent 2

43. www.metcardio.org NMA OF ST: RESULTS Odds Ratio [95%] 1-year definite stent thrombosis CoCr-EES vs BMS CoCr-EES vs PES CoCr-EES vs SES CoCr-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) Favors Stent 1Favors Stent 2 101 0.1 0.01

44. www.metcardio.org 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) Favors Stent 1 101 0.1 0.01 Favors Stent 2

45. www.metcardio.org NMA OF ST: RESULTS

46. www.metcardio.org NMA OF ST: RESULTS

47. www.metcardio.org NMA OF ST: RESULTS

48. www.metcardio.org NMA OF ST: RESULTS IV = inverse variance SE = standard error Odds Ratio IV Random, 95% CI 101 0.1 0.001 Favors CoCr-EESFavors BMS Weight SE Log (odds ratio) Definite stent thrombosis Direct estimate Indirect estimate Total (95% CI) Test for overall effect Z=4.82 (p<0.00001) Definite or probable thrombosis Direct estimate Indirect estimate Total (95% CI) Test for overall effect Z=4.48 (p<0.00001) -1.427 -1.421 -0.968 -1.122 0.519 0.359 0.377 0.304 32.4% 67.6% 100.00% 39.4% 60.6% 100.00% 0.24 (0.09-0.66) 0.24 (0.12-0.49) 0.24 (0.14-0.43) 0.38 (0.18-0.80) 0.33 (0.18-0.53) 0.35 (0.22-0.55) Statistical inconsistency (I 2 ): 0% for both comparisons

49. www.metcardio.org POTENTIAL OF EVEROLIMUS-ELUTING STENTS Verheye et al, J Am Coll Cardiol 2007

50. www.metcardio.org POTENTIAL OF EVEROLIMUS-ELUTING STENTS Kolandaivelu et al, Circulation 2011

51. www.metcardio.org LEARNING GOALS What is stent thrombosis (ST)? What are network meta-analyses (NMA)? NMA of ST – Goals – Methods – Results – Implications

52. www.metcardio.org IMPLICATIONS The largest and most comprehensive study comparing the rates of ARC definite and definite or probable stent thrombosis between different types of DES and between DES and BMS has the following implications: – CoCr-EES were associated with significantly lower rates of 1-year and 2-year definite stent thrombosis than were BMS, a result not present with other DES.

53. www.metcardio.org IMPLICATIONS – The reduction in stent thrombosis with CoCr-EES compared with BMS was apparent both early and late (occurring before 30 days and between 31 days and 1 year). – CoCr-EES were also associated with significantly lower 1-year rates of definite stent thrombosis than were other first and second generation DES, including PES, SES, PC-ZES, and Re-ZES.

54. www.metcardio.org IS THIS A PARADIGM SHIFT?

55. www.metcardio.org THE REPLY IS YOURS… IF YOU NEEDED A STENT TODAY, WHICH STENT WOULD YOU CHOOSE?

56. www.metcardio.org For these and further slides on these topics please feel free to visit the metcardio.org website: http://www.metcardio.org/slides.html http://www.metcardio.org/slides.html