1. An Overview of Coronary Drug-Eluting Stents: the Meta-analytic Approach
Giuseppe Biondi-Zoccai
Ospedale S. Giovanni Battista “Molinette”
Università di Torino
Convegno Regionale Piemonte “Aggiornamenti in tema di valvulopatie, resincronizzazione e
malattia coronarica” - Torino, 14 Novembre 2007 (h )

2. Learning goals Why such a fuzz on meta-analyses?
What is a meta-analysis?
Are meta-analyses useful?
How can I appraise the internal and external validity of a meta-analysis?
What are the meta-analysis results on drug-eluting stents?

3. Learning goals Why such a fuzz on meta-analyses?
What is a meta-analysis?
Are meta-analyses useful?
How can I appraise the internal and external validity of a meta-analysis?
What are the meta-analysis results on drug-eluting stents?

4. Do you remember 2005? The rosy future…
Buzzword = ?

6. Do you remember 2005? The rosy future…
Buzzword = Late loss

7. Do you remember 2005? The rosy future…

8. Late 2006 surprise: the death/MI/thrombosis iceberg
Buzzword = ?

10. Late 2006 surprise: the death/MI/thrombosis iceberg
Buzzword = Thrombosis

11. Late 2006 surprise: the death/MI/thrombosis iceberg

12. Learning goals Why such a fuzz on meta-analyses?
What is a meta-analysis?
Are meta-analyses useful?
How can I appraise the internal and external validity of a meta-analysis?
What are the meta-analysis results on drug-eluting stents?

13. Exponential increase in PubMed citations
PubMed search strategy: ("2001"[PDAT] : "2005"[PDAT]) AND (("systematic"[title/abstract] AND "review"[title/abstract]) OR ("systematic"[title/abstract] AND "overview"[title/abstract]) OR ("meta-analysis"[title/abstract] OR "meta-analyses"[title/abstract]))

14. 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

15. 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

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 exploration exploiting individual patient data

17. Systematic review vs meta-analysis
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. Individual patient data meta-analysis
Ideally should be a systematic review and meta-analysis based on individual patient data
Major pros:
a unique database containing primary studies is created and used (consistency checks and homogenous variables are created)
the same analytical tools can be used across studies
subgroup analyses can be performed even for groups that were not reported in the original publications
Major cons:
some studies may have to be excluded (publication bias) because original authors may not provide source data
poses major logistical and financial challenges

19. Systematic review and meta-regression
A meta-regression employs meta-analytic methods to explore the impact of covariates or moderators on the main effect measure or on other
All the limitations of non-RCT studies applies, and thus they should mainly be regarded as hypothesis generating

20. Indirect and network meta-analyses
An indirect comparison meta-analysis exploit several randomized trials sharing a common comparator to generate an interaction indirect effect estimates
Network meta-analyses combine estimates from direct and indirect meta-analyses to provide more precise effect estimates

21. Learning goals Why such a fuzz on meta-analyses?
What is a meta-analysis?
Are meta-analyses useful?
How can I appraise the internal and external validity of a meta-analysis?
What are the meta-analysis results on drug-eluting stents?

22. Meta-analysis: Cons “Exercise in mega-silliness”
“Mixing apples with oranges”
Not original research
Big RCTs definitely better
Pertinent studies might not be found, or may be of low quality or internal validity
Publication and small study bias
Average effect largely unapplicable to individuals
Lau et al, Lancet 1998

23. Cons
Smith et al, BMJ 2003

24. Meta-analysis: Pros 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
Explore clinical and statistical heterogeneit
Lau et al, Lancet 1998

26. A famous cumulative meta-analysis
Antman et al, JAMA 1992

27. Antman et al, JAMA 1992

28. Learning goals Why such a fuzz on meta-analyses?
What is a meta-analysis?
Are meta-analyses useful?
How can I appraise the internal and external validity of a meta-analysis?
What are the meta-analysis results on drug-eluting stents?

29. Should we trust meta-analyses? It depends on their internal validity!

30. Oxman-Guyatt index of internal validity
1. Where the search methods used to find evidence stated?
2. Was the search for evidence reasonably comprehensive?
3. Were the criteria for deciding which studies to include in the overview reported
4. Was bias in the selection of studies avoided
5. Were the criteria used for assessing the validity of the included studies reported?
6. Was the validity of all studies referred to in the text assessed using appropriate criteria
7. Were the methods used to combine the findings of the relevant studies reported?
8. Were the findings of the relevant studies combined appropriately relative to the primary question the overview addresses?
9. Were the conclusions made by the author(s) supported by the data and/or analysis reported in the overview?
Oxman et al, J Clin Epidemiol 1991

31. Biondi-Zoccai
et al, BMJ 2006

32. Steg et al, Arch Intern Med 2007

33. Learning goals Why such a fuzz on meta-analyses?
What is a meta-analysis?
Are meta-analyses useful?
How can I appraise the internal and external validity of a meta-analysis?
What are the meta-analysis results on drug-eluting stents?

34. Synopsis Meta-analyses showing a DES hazard Meta-analyses
suggesting DES safety
Bavry et al, Am J Med 2006
Camenzind et al, Circ 2007
Kastrati et al, NEJM 2007
Nordmann et al, Eur Heart J 2006
Spaulding et al, NEJM 2007*
Stone et al, NEJM 2007*
Dibra et al, J Am Coll Cardiol 2007
Holmes et al, Eur Heart J 2006*
Mauri et al, NEJM 2007*
Pasceri et al, Am Heart J 2007
Stettler et al, Lancet 2007
*likely stemming from the same analysis set
STOP!
GO!

35. Nordmann et al, Eur Heart J 2006

36. Bavry et al, Am J Med 2006

37. Camenzind et al, Circulation 2007

38. Camenzind et al, Circulation 2007

39. Spaulding et al, NEJM 2007

40. Hazard ratio for death
Kastrati et al, NEJM 2007

41. P=0.02
Kastrati et al, NEJM 2007

42. Mauri et al, NEJM 2007

43. Stone et al, NEJM 2007

44. Stone et al, NEJM 2007

45. Meta-analysis on 5 studies-1230 pts with DES implantation for ISR: TLR
Dibra et al, J Am Coll Cardiol 2007

46. Cypher versus Taxus meta-analysis
Schomig et al, JACC 2007

47. Hazards of mixing and duplicating data
Kereiakes et al, JACC 2007

48. Stettler et al, Lancet 2007

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

50. Rationale of indirect/network meta-analyses
Patients randomized to treatment A vs treatment C
Patients randomized to treatment B vs treatment C
Patients randomized to treatment A vs treatment C
Patients randomized to treatment B 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
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)
Biondi-Zoccai et al, Minerva Cardioangiol 2008

51. Meta-analysis on 16 studies-1278 pts
with unprotected left main DES implantation
Agostoni et al (2005, 58 pts)
15,5
Carriè et al (2006, 120 pts)
12.5
Chieffo et al (2005, 85 pts)
32,7
Christiansen et al (2006, 42 pts)
7,1
de Lezo et al (2004, 52 pts)
5,8
Dudek et al (2006, 28 pts)
14,3
Han et al (2006, 138 pts)
10,9
KOMATE (2005, 54 pts)
4,6
Lee et al (2006, 50 pts)
10,6
Study
Lozano et al (2005, 42 pts)
26,2
Migliorini et al (2006, 156 pts)
23,7
Palmerini et al (2006, 94 pts)
25,5
Park et al (2005, 102 pts)
8,8
Price et al (2006, 50 pts)
54,0
Sheiban et al (2006, 85 pts)
9,1
Wood et al (2006, 100 pts)
19,0
Overall estimate (95%CI)
16,5 (11,7-21,3) 15 30 45 60
Rate of mid-term MACE (%)
Biondi-Zoccai et al, Am Heart J 2007

52. Meta-analysis on 16 studies-1278 pts
with unprotected left main DES implantation
Prevalence of non-bifurcational ULM
Log10 transformed MACE
rate at mid-term follow-up 70 60 50 40 30 20 10
-,2
-,4
-,6
-,8
-1,0
-1,2
-1,4
Beta= P=0.001
Biondi-Zoccai et al, Am Heart J 2007

53. Take home messages

54. Take home messages

55. Not all meta-analyses are born equal, nor of equal quality

56. Results of meta-analyses suggest DES are likely associated with a minor increase in stent thrombosis

57. However DES are warranted in patients at higher risk of restenosis or those who can tolerate dual antiplatelet therapy for >6-12 months

58. For further slides on these topics please feel free to visit the metcardio.org website: