1. Giuseppe Biondi-Zoccai, MD Sapienza University of Rome, Latina, Italy giuseppe.biondizocca@uniroma1.itgbiondizoccai@gmail.com Stent thrombosis: the meta-analytic view

2. Why should you listen to me? MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis AND (zoccai OR biondi-zoccai)”

3. Why should you listen to me? MEDLINE/PubMed queried on July 30, 2014 for “meta-analysis AND (zoccai OR biondi-zoccai)”

4. METCARDIO, since 2003

5. Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison

6. Learning milestones Scope of the problem Scope of the problem Stent thrombosis Stent thrombosis Meta-analysis Meta-analysis Incidence and impact Incidence and impact Predictors Predictors Prevention and treatment Prevention and treatment

7. Learning milestones Scope of the problem Scope of the problem Stent thrombosis Stent thrombosis Meta-analysis Meta-analysis Incidence and impact Incidence and impact Predictors Predictors Prevention and treatment Prevention and treatment

8. Flashback to 2006: the death/MI/thrombosis iceberg

9. Unavoidability of meta-analysis MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis”

10. Unavoidability of meta-analysis MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis”

11. Unavoidability of meta-analysis MEDLINE/PubMed queried on July 30, 2014 for “stent AND thrombosis AND meta-analysis”

12. Learning milestones Scope of the problem Scope of the problem Stent thrombosis Stent thrombosis Meta-analysis Meta-analysis Incidence and impact Incidence and impact Predictors Predictors Prevention and treatment Prevention and treatment

13. What is stent thrombosis? Schuchman, New Engl J Med 2006

14. Unprecedented and unpredictable Gupta et al, J Invasive Cardiol 2004

15. Failing stents: thrombosis vs restenosis Schuchman, New Engl J Med 2006

16. Camenzind et al, Circulation 2007 Trade-off: thrombosis vs restenosis?

17. Another clinical conundrum BLEEDING THROMBOSIS

18. Mechanisms of thrombosis: Virchow's triad BLOODFLOW VESSEL

19. Mechanisms of stent thrombosis PATIENT FACTORS LESION FACTORS PROCEDURAL & MEDICAL RX FACTORS

20. History of stent thrombosis: 30-day rates from 1991 to 2006

21. What is stent thrombosis? Acute occlusion of a previously patent stent. It is a clinical syndrome (it presents with acute coronary syndrome or sudden death – if silent it cannot be defined stent thrombosis). It is not due to restenosis (i.e. there was no progressively severe restenosis with final occlusion). It is not due to new plaque rupture at distant site, but it may be mistaken with in-stent neo- atherosclerosis and thrombosis.

22. Academic Research Consortium definitions Definite stent thrombosis: – Clinical syndrome (ACS or AMI) – And: angiographic evidence of thrombus or occlusion or pathologic evidence of acute thrombosis Probable stent thrombosis: – Unexplained death < 30 days – or target vessel AMI without angiographic confirmation of thrombosis or other identified culprit lesion Possible stent thrombosis: – Unexplained death after 30 days Cutilip et al, Circulation 2007

23. Timing of stent thrombosis TypeOccurrence*Incidence Acute ST † ≤1 day+ Subacute ST † 2-30 days+++ Late ST2-12 months++ Very late ST>1 year++ *after PCI † defined together as early ST Cutilip et al, Circulation 2007

24. Learning milestones Scope of the problem Scope of the problem Stent thrombosis Stent thrombosis Meta-analysis Meta-analysis Incidence and impact Incidence and impact Predictors Predictors Prevention and treatment Prevention and treatment

25. 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

26. 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

27. 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 educational, psychological and medical treatments. 1980s – Exponential development/use of meta-analytic methods thanks to the availability of advanced scholarly databases and computing systems.

28. 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 G and Rennie D, Users’ Guide to the Medical Literature, 2002

29. Parallel hierarchy of clinical research Biondi-Zoccai et al, HSR Proceedings 2011

30. Minimal glossary Review: viewpoint on a subject quoting different primary authors 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 key goal: systematic review (± meta-analysis) Biondi-Zoccai et al, Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison 2014

31. 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. Biondi-Zoccai et al, Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison 2014

32. Indirect and network meta-analyses An adjusted indirect comparison meta- analysis exploit several randomized trials sharing a common comparator to generate an interaction indirect effect estimate. Network meta-analyses (also called mixed treatment comparisons) combine estimates from direct and indirect meta-analyses to provide more precise effect estimates. Biondi-Zoccai et al, Network Meta-Analysis: Evidence Synthesis with Mixed Treatment Comparison 2014

33. Biondi-Zoccai et al, Minerva Cardioangiol 2008 TREATMENT A TREATMENT B TREATMENT C OR (A vs C) OR (B vs C) OR (A vs B) (A vs B) ln OR a-b = ln OR a-c – ln OR b-c var (ln OR a-b ) = var (ln OR a-c ) – var (ln OR b-c ) Rationale of indirect/network meta-analyses

34. Patients randomized to treatment B vs treatment C Patients randomized to treatment A vs treatment C Small theoretical overlap between patients randomized to A vs C and to B vs C ↓ UNADJUSTED INDIRECT META-ANALYSIS OF A VS B LIKELY UNRELIABLE (multivariable methods recommended) Patients randomized to treatment A vs treatment C Large theoretical overlap between patients randomized to A vs C and to B vs C ↓ UNADJUSTED INDIRECT META-ANALYSIS OF A VS B LIKELY RELIABLE Patients randomized to treatment B vs treatment C Rationale of indirect/network meta-analyses Biondi-Zoccai et al, Minerva Cardioangiol 2008

35. Arguably the most important meta-analysis ever…. Antman et al, JAMA 1992

36. …showing discrepancies among evidence and experts

40. Pros of meta-analysis 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

41. A rather successful pairwise meta- analysis of randomized trials Agostoni et al, J Am Coll Cardiol 2003

42. Cons of meta-analysis 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

43. Appraising a meta-analysis: AMSTAR Shea et al, BMC Med Res Methodol 2007

44. Appraising a meta-analysis: AMSTAR

45. Rules of thumb to appraise a meta-analysis The three rules of thumb to decide whether a meta-analysis can be trusted are: –Were the included studies all based on proper randomization or were observational estimates adjusted for confounders? –Were the included studies clinically and statistically homogeneous? –Are there at least 100 events in any of the two treatment groups for the end-point of interest?

46. Learning milestones Scope of the problem Scope of the problem Stent thrombosis Stent thrombosis Meta-analysis Meta-analysis Incidence and impact Incidence and impact Predictors Predictors Prevention and treatment Prevention and treatment

47. Incidence of stent thrombosis Bangalore et al, Circulation 2012

48. Incidence of stent thrombosis* *median rate (per 1000 patient-years of follow-up): a 9.85 per 1000 patient-years rate equals a 0.985% yearly incidence Bangalore et al, Circulation 2012

49. Comprehensive systematic review on incidence and predictors of stent thrombosis D’Ascenzo et al, Int J Cardiol 2013

50. Incidence of stent thrombosis* *at a median folllow-up of 22 months, with 95% DES penetration D’Ascenzo et al, Int J Cardiol 2013

51. Incidence of DES thrombosis* *at a median folllow-up of 22 months D’Ascenzo et al, Int J Cardiol 2013

52. Prognosis of definite stent thrombosis Kohn et al, PLoS ONE 2013

53. Prognosis of definite stent thrombosis Kohn et al, PLoS ONE 2013

54. Learning milestones Scope of the problem Scope of the problem Stent thrombosis Stent thrombosis Meta-analysis Meta-analysis Incidence and impact Incidence and impact Predictors Predictors Prevention and treatment Prevention and treatment

55. Impact of diabetes mellitus (DM) Qin et al, PLoS ONE 2013

56. Impact of stent length Moreno et al, J Am Coll Cardiol 2005

57. Impact of CYP2C19 polymorphism in those receiving clopidogrel Qin et al, PLoS ONE 2013

58. Most common predictors of definite or probable stent thrombosis* appraised in ≥5 studies and proven independently and significantly associated with ST in ≥50% cohorts; ATD=antiplatelet therapy discontinuation D’Ascenzo et al, Int J Cardiol 2013

59. Most powerful predictors of definite or probable stent thrombosis* *associated with a relative estimate of risk >5.0 or <0.2 for stent thrombosis D’Ascenzo et al, Int J Cardiol 2013

60. Synthesis of predictors* of stent thrombosis *predictors present in ≥10% of included studies D’Ascenzo et al, Int J Cardiol 2013

61. Learning milestones Scope of the problem Scope of the problem Stent thrombosis Stent thrombosis Meta-analysis Meta-analysis Incidence and impact Incidence and impact Predictors Predictors Prevention and treatment Prevention and treatment

62. Impact of bivalirudin Nairooz et al, Am J Cardiol 2014

63. Impact of prolonged DAPT Liu et al, J Cardiovasc Pharmacol 2014

64. Benefits of high-dose clopidogrel Chen et al, PLoS ONE 2013

65. Impact of cilostazol Zhou et al, Exp Ther Med 2013 DAT=dual antiplatelet therapy; TAT=triple antiplatelet therapy

66. Impact of novel antiplatelet agents Biondi-Zoccai et al, Int J Cardiol 2011

67. Impact of novel antiplatelet agents Biondi-Zoccai et al, Int J Cardiol 2011

68. Impact of oral anticoagulants Saheb et al, Chin Med J (Engl) 2013 DAPT=dual antiplatelet therapy; TT=triple antiplatelet therapy (including oral anticoagulant)

69. Impact of novel oral anticoagulants Komocsi et al, Arch Intern Med 2012

70. Benefits of intravascular ultrasound Ahn et al, Am J Cardiol 2014

71. Impact of drug-eluting balloons Frolich et al, BMC Medicine 2013

72. Impact of complex bifurcation stenting Zimarino et al, J Am Coll Cardiol Intv 2013

73. Superiority of EES vs other DES and BMS Palmerini et al, Lancet 2012

74. 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 et al, Lancet 2012

75. 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 et al, Lancet 2012

76. 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 et al, Lancet 2012

77. 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 et al, Lancet 2012

78. 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 et al, Lancet 2012

79. What about death or MI? 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 et al, Lancet 2012

80. Superiority of EES in STEMI as well Palmerini et al, J Am Coll Cardiol 2013

81. Superiority of EES vs BES as well Palmerini et al, J Am Coll Cardiol 2014

82. Take home messages

83. Stent thrombosis is a very important event, despite its slowly decreasing incidence. Meta-analysis represents a unique tool to navigate the scholarly literature maze on stent thrombosis. The meta-analytic take at stent thrombosis suggests that several patient, lesion, and treatment predictors of stent thrombosis can be envisioned, which may have only limited individual precision, but still hold true at a more collective level. We anticipate that stent thrombosis will become again important in the approaching bioresorbable vascular scaffold era. Accordingly, researchers and clinicians must all remain aware of the subtleties of stent thrombosis.

84. Many thanks for your attention! For any query: giuseppe.biondizoccai@uniroma1.it gbiondizoccai@gmail.com For these slides: http://www.metcardio.org/ppts/2014/Biondi- Zoccai_VCU_2014_Stent_thrombosis.pptx For similar slides: http://www.metcardio.org/slides.html http://www.metcardio.org/slides.html