Analyzing the Meta-analysis : Thrombolytics vs. Heparin for PE

1. Analyzing the Meta-analysis:Thrombolytics vs. Heparin for PE • Tiffany Eng • EBM September 19, 2012

2. Agenda • 10:30 How to critically appraise a meta-analysis • 10:45 Small Groups • 11:20 Discussion • 11:40 Bringing it all together

3. What is a Systemic Review ? • identifies all studies for a specific focused question • appraises the methods of the studies • summarizes the results • presents key findings • identifies reasons for different results across studies • cites limitations of current knowledge

4. What is a Meta-analysis? • the process of mathematically combining results of multiple studies to produce an overall summary of treatment effect

5. Strengths • It’s an EFFICIENT way to familiarize yourself with the best available research. • It determines whether findings are CONSISTENT & GENERALIZABLE across populations, settings, and whether findings vary by subgroup.

6. Strengths • Mathematically combining a series of well-conducted studies increases the sample size and ENHANCES THE STATISTICAL POWER of the analysis and reduces the confidence interval. • If the treatment effect in small trials shows a nonsignificant trend toward efficacy, pooling the results may show the benefit of therapy.

7. Limitations • A meta-analaysis is only as good as the methods of the primary studies. • It does not overcome flaws in design and execution of the primary studies.

8. Limitations • publication bias: studies that report dramatic effects are more likely to be identified, summarized and subsequently pooled in meta-analysis than studies that report smaller effect sizes • Sample size, direction and statistical significance, and investigators’ perceptions of whether findings are “interesting” are related to likelihood of publication.

9. Limitations • Combining discordant studies i.e. CONCEPTUAL HOMOGENEITY PRECEDES STATISTICAL HOMOGENEITY

10. Was the review conducted according to a prespecified protocol? • written protocol (prepared in advance) that describes the research question, hypotheses, review method and plan for how the data will be extracted and completed

11. Was the question focused? • patient problem or diagnosis • the intervention • comparison group • primary and secondary outcomes

12. Were the “Right” Types of Studies Eligible for the Review? • What were the inclusion criteria for choosing studies? • Were the inclusion criteria appropriate?

13. Was the Method of Identifying All Relevant Information Comprehensive? • Reviewers should use a search strategy that maximizes the identification of relevant articles. • MEDLINE, EMBASE, Cochrane, CINAHL, ECONOLIT, conference proceedings, abstracts, books.

14. Publication Bias • The search strategy should reduce potential publication bias. • Language bias • Small samples • Funnel plot or “fail-safe N” • The studies published are dominated by drug-company sponsored trials.

15. Was the Data Abstraction from Each Study Appropriate? • Did the reviewers analyze the methodologic quality of the primary studies? • Were the findings of the primary studies valid?

16. How was the information synthesized and summarized? • Did the studies have similar estimated effects? • heterogeneity testing • review team should explain significant differences between primary studies • sensitivity analysis

17. Checklist

18. OBJECTIVE • They compared adverse outcome events (death, recurrent PE, bleeding events) in studies of patients who received thrombolytics vs. heparin therapy for pulmonary embolism.

19. Methods • They selected randomized clinical trials comparing thrombolysis and heparin for treatment of PE from MEDLINE, meeting abstracts, reference lists, review articles. • Data on death and major bleeding events had to be available. • 9 randomized trials met inclusion criteria.

21. Results • 23.2% thrombolysis had adverse outcome- 4.6% died, 12.9% major bleeding, 2.1% fatal bleeds, 6.6% recurrent PE • 25.9% heparin had adverse outcome- 7.7% died, 8.6% major bleeding, 0 fatal bleeds, 10.4% recurrent PE

22. Conclusion • Thrombolysis had a lower composite end point of death/ recurrence than heparin. Excessive bleeding is the trade off.

23. Strengths • clear question • used Medline, meeting abstracts, reference lists • used 9 randomized trials • plotted the odds ratios across all studies

24. Limitations • 2 out of 9 randomized trials were double blind • did not use EMBASE, Cochrane • no prespecified protocol

25. Limitations • no commentary on methods or validity of primary studies • the end point of the primary studies (pulmonary reperfusion as assessed by AGF and LS) was different from the primary end-point of the meta-analysis • 5 out 9 studies had invasive procedures performed and these studies had a higher incidence of major bleed

26. Limitations • only 6 out 9 studies recorded incidence of recurrent PE • 4 out of 9 trials recorded adequate data on major and minor bleeds • trials use different thrombolytic agents w/ different efficacy

27. OBJECTIVE • In patients with presenting with evidence of submassive PE (ECG or echocardiographic evidence of right heart strain), does the addition of thrombolytic therapy to standard treatment with heparin reduce mortality or recurrence of PE without increasing major hemorrhagic complications?

28. Methods • Searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE for rcts assessing effectiveness thrombolytic therapy for submassive PE and reported mortality, recurrent PE, and major hemorrhage • used search terms “pulmonary embolus” and “thombolytic therapy” • human studies • English • had to report death, recurrent PE, major bleeding • 2 studies met these inclusion criteria: Konstantinides et al and Goldhaber et al

30. Results • Konstantinides study showed RR for mortality of 1.56, recurrent PE of 1.17, and major hemorrhage of 0.23. Goldhaber study subgroup analysis did not produce statistically significant findings.

31. Conclusions • The addition of thrombolytics to heparin for submassive PE did not show any significant differences in clinically important outcomes.

32. Strengths • clear specific question • explicit inclusion criteria- searched Cochrane, Medline and Embase from Feb 2006 w/ search history shown in table 1. Studies eliminated if not in English, not conducted on humans, performed before 1990, did not use heparin, did not report outcomes of mortality, recurrent PE, major bleeding or was a review article. • analyzes study design and validity of two chosen primary trials (also see Table 2 and Table 3)

33. Limitations • includes only 2 studies, one with much larger sample size • Were the inclusion criteria appropriately narrow?

34. Meta-analysis of all randomized trials comparing thrombolytic therapy with heparin in patients with acute PE.

35. Methods • searched for published and unpublished randomized trials via MEDLINE & EMBASE January 1980 - January 2003, Cochrane Library with search terms “pulmonary embolism,” “thromboembolism,” “thombolysis,” “fibrinolysis,” “randomized control trial” • Inclusion criteria: 1) proper randomization 2) inclusion of patients with objectively diagnosed PE 3) comparison thrombolysis with heparin for initial treatment of PE 4) use of objective methods to assess 1 or more clinical outcomes, including PE, death and bleeding • Criteria for Assessment of Study Quality: 1) proper generation of treatment allocation sequence 2) proper concealment of allocation sequence 3) blinding of the patient and the investigator assessing clinical outcomes to treatment allocation 4) completeness of follow up

37. Results • Compared with heparin, thrombolytics was associated with a nonsignificant reduction in recurrent PE or death (OR 0.67), nonsignificant increase in major bleeding (OR 1.42), significant increase in nonmajor bleeding (OR 2.63; NNH 8). • Thrombolytics was associated with a significant reduction in recurrent PE or death in trials that also enrolled patients with major (hemodynamically unstable) PE (OR .45 NNT 10) but not in trials that excluded these patients.

38. Conclusion • There was no evidence of benefit of thrombolytics compared with heparin. There may be benefit with patients at highest risk of recurrence or death.

39. Strengths • clear specific question • developed prespecified protocol • searched MEDLINE, EMBASE, Cochrane, bibliographies or journal articles, abstracts from major international meetings

40. Strengths • had specific inclusion criteria: proper randomization, inclusion of patients with objectively diagnosed symptomatic PE, comparison thrombolysis with heparin, objective methods to assess 1 or more clinical outcomes, including PE, death and bleeding • assessed quality of primary studies • completed sensitivity analyses

41. Strengths • completed heterogeneity analyses • fixed effects model analysis results were compared with random effects model results • evaluated for publication bias using inverted funnel plot of treatment effect vs study precision

42. Limitations • the quality of the primary studies is variable: randomization generated with random number tables or programs in 3 studies, 8/11 studies were not double blinded, LTF was not reported in any of the trials • primary studies do not have similar trend in results • total number of patients randomized and total number of outcomes was modest therefore limited statistical power

43. What Next? • What conclusions, if any, can we take away from these articles? • What impact does this have on how we practice medicine?

44. The End... • Thanks to Ben Friedman MD, Vince Nguyen MD, Sam Ayala MD • Shout out LKB MD, NFA MD