1. www.metcardio.org Why are drug-eluting stents safer than bare-metal stents? Giuseppe Biondi Zoccai, MD Sapienza University of Rome, Rome, Italy METCARDIO, Ospedaletti, Italy giuseppe.biondizoccai@uniroma1.it 10 th International Cardiology Congress – Patras – 4-6 May 2012

2. www.metcardio.org LEARNING GOALS Current paradigm Why could drug-eluting stents possibly be safer than bare-metal stents? The case for network meta-analyses Stent thrombosis with drug-eluting versus bare-metal stents: evidence from a network meta-analysis Paradigm shift

3. www.metcardio.org LEARNING GOALS Current paradigm Why could drug-eluting stents possibly be safer than bare-metal stents? The case for network meta-analyses Stent thrombosis with drug-eluting versus bare-metal stents: evidence from a network meta-analysis Paradigm shift

4. www.metcardio.org WHAT IS STENT THROMBOSIS?

5. www.metcardio.org totalacutesubacutelate very late INCIDENCE OF STENT THROMBOSIS* *at a median folllow-up of 18 months D’Ascenzo et al, Int J Cardiol 2012

6. www.metcardio.org PREDICTORS OF STENT THROMBOSIS* *number of studies confirming the independent role of the predictor D’Ascenzo et al, Int J Cardiol 2012

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

8. www.metcardio.org 2006: ANNUS HORRIBILIS FOR DRUG-ELUTING STENTS

9. www.metcardio.org Nordmann et al, Eur Heart J 2006 Camenzind, ESC/WCC 2006 Bavry et al, Am J Med 2006 2006: ANNUS HORRIBILIS FOR DRUG-ELUTING STENTS

10. www.metcardio.org LEARNING GOALS Current paradigm Why could drug-eluting stents possibly be safer than bare-metal stents? The case for network meta-analyses Stent thrombosis with drug-eluting versus bare-metal stents: evidence from a network meta-analysis Paradigm shift

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

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

13. www.metcardio.org RISK OF STENT THROMBOSIS WITH EVEROLIMUS-ELUTING VERSUS BARE-METAL STENTS Sabate, ESC 2011 Kaiser et al, New Engl J Med 2010

14. www.metcardio.org POTENTIAL OF ZOTAROIMUS-ELUTING STENTS Guagliumi et al, J Am Coll Cardiol Intv 2010

15. www.metcardio.org LEARNING GOALS Current paradigm Why could drug-eluting stents possibly be safer than bare-metal stents? The case for network meta-analyses Stent thrombosis with drug-eluting versus bare-metal stents: evidence from a network meta-analysis Paradigm shift

16. www.metcardio.org META-ANALYSES “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

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

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

20. www.metcardio.org Hsia et al, Ann Surg 2008 P for effect Inconsistency P for heterogeneity STANDARD (PAIR-WISE) META-ANALYSES Point estimate 95% confidence interval Summary estimate

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

22. www.metcardio.org PARALLEL HIERARCHY OF CLINICAL RESEARCH Biondi-Zoccai et al, HSR Proceedings 2011

23. www.metcardio.org LEARNING GOALS Current paradigm Why could drug-eluting stents possibly be safer than bare-metal stents? The case for network meta-analyses Stent thrombosis with drug-eluting versus bare-metal stents: evidence from a network meta-analysis Paradigm shift

24. www.metcardio.org NETWORK META-ANALYSIS OF STENT THROMBOSIS Palmerini, Biondi-Zoccai et al, Lancet 2012

25. www.metcardio.org GOAL We aimed to perform direct, indirect and combined (i.e. network) meta-analyses of the risk of stent thrombosis with all FDA approved coronary stents: – Bare-metal stents (BMS); Cobalt-chromium everolimus-eluting stents (CoCr-EES); Endeavor zotarolimus-eluting stents (End-ZES); Paclitaxel- eluting stents (PES); Platinum-chromium everolimus-eluting stents (PtCr-EES); Resolute zotarolimus-eluting stents (Res-ZES); Sirolimus- eluting stents (SES) Palmerini, Biondi-Zoccai et al, Lancet 2012

26. www.metcardio.org SEARCH AND SELECTION Randomized trials of FDA approved coronary stents reporting on stent thrombosis according to the Academic Research Consortium (ARC) definitions were searched in multiple databases (including MEDLINE/PubMed). Authors and experts were queried for additional data and insights on other potentially pertinent studies. Palmerini, Biondi-Zoccai et al, Lancet 2012

27. www.metcardio.org END-POINTS Primary end-point: – 1-year definite stent thrombosis Secondary end-points: – Definite stent thrombosis occurring before 30 days, after 30 days, and within 2 years – Definite or probable stent thrombosis (at the above time points) – Death, cardiac death and myocardial infarction within 2 years Palmerini, Biondi-Zoccai et al, Lancet 2012

28. www.metcardio.org ANALYSIS Direct (pair-wise) meta-analyses were performed with a random-effect method computing odds ratios (OR) with 95% confidence intervals (95%CI). Indirect and network meta-analyses were performed with a random-effect method within a Bayesian hierarchical framework, also computing OR and 95%CI. Palmerini, Biondi-Zoccai et al, Lancet 2012

29. www.metcardio.org ANALYSIS Small study effects were appraised by funnel plot inspection. Statistical consistency in pair-wise and network analyses was appraised with I 2. Sensitivity analyses were conducted using a fixed-effect method and restricted to several subgroups of interest. RevMan and WinBUGS were used for computations. Palmerini, Biondi-Zoccai et al, Lancet 2012

30. www.metcardio.org REVIEW 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 RCTs meeting criteria Palmerini, Biondi-Zoccai et al, Lancet 2012

31. www.metcardio.org EVIDENCE NETWORK 9 studies PES BMS SES End-ZES Res-ZESPtCr-EES CoCr-EES 1 study 8 studies 1 study 4 studies 9 studies 6 studies 2 studies 5 studies Palmerini, Biondi-Zoccai et al, Lancet 2012

32. www.metcardio.org 1-YEAR DEFINITE STENT THROMBOSIS Odds Ratio [95%] 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 Palmerini, Biondi-Zoccai et al, Lancet 2012

33. www.metcardio.org 30-DAY DEFINITE STENT THROMBOSIS Odds Ratio [95%] 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 Palmerini, Biondi-Zoccai et al, Lancet 2012

34. www.metcardio.org 30-DAY TO 1-YEAR DEFINITE STENT THROMBOSIS Odds Ratio [95%] 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 (1.11-18.5) Favors Stent 1 100 10 1 0.1 0.01 Favors Stent 2 Palmerini, Biondi-Zoccai et al, Lancet 2012

35. www.metcardio.org 2-YEAR DEFINITE STENT THROMBOSIS Odds Ratio [95%] 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 Palmerini, Biondi-Zoccai et al, Lancet 2012

36. www.metcardio.org OTHER RESULTS FOR DEFINITE STENT THROMBOSIS Palmerini, Biondi-Zoccai et al, Lancet 2012

37. www.metcardio.org Palmerini, Biondi-Zoccai et al, Lancet 2012 OTHER RESULTS FOR DEFINITE STENT THROMBOSIS

38. www.metcardio.org Palmerini, Biondi-Zoccai et al, Lancet 2012 OTHER RESULTS FOR DEFINITE OR PROBABLE STENT THROMBOSIS

39. www.metcardio.org STATISTICAL CONSISTENCY 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 Palmerini, Biondi-Zoccai et al, Lancet 2012

40. www.metcardio.org WHAT ABOUT DEATH OR MYOCARDIAL INFARCTION? CoCr-EES were also associated with a significantly lower risk of myocardial infarction (OR=0.61 [0.47-0.79]). These differences were supported by favorable trends for all cause death (OR=0.83 [0.65-1.03]) and cardiac death (OR=0.82 [0.58- 1.13]). Palmerini, Biondi-Zoccai et al, Lancet 2012

41. www.metcardio.org LEARNING GOALS Current paradigm Why could drug-eluting stents possibly be safer than bare-metal stents? The case for network meta-analyses Stent thrombosis with drug-eluting versus bare-metal stents: evidence from a network meta-analysis Paradigm shift

42. www.metcardio.org IMPLICATIONS The largest and most comprehensive appraisal of the risk of stent thrombosis with different types of coronary stents 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 any other DES.

43. www.metcardio.org IMPLICATIONS – Decreases in stent thrombosis with CoCr- EES compared with BMS were apparent both early and late (occurring before 30 days and between 31 days and 1 year). – CoCr-EES were also associated with lower 1- year rates of definite stent thrombosis than were other 1 st and 2 nd generation DES, including PES, SES, PC-ZES, and Re-ZES. – These benefits were associated with lower rates of myocardial infarction.

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

45. www.metcardio.org THE REPLY IS YOURS… IF I NEEDED A STENT TODAY, WHICH STENT SHOULD I CHOOSE?

46. www.metcardio.org Many thanks for your attention 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

47. www.metcardio.org

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

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

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

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