Evaluating the evidence using GRADE. Peter Morley E th October 2012

Transcription

1 1 Evaluating the evidence using GRADE Peter Morley E th October 2012

2 2 Conflict of interest disclosure Commercial/industry Evidence Evaluation Expert (ILCOR/AHA) Potential intellectual conflicts Deputy Chair Australian Resuscitation Council (ARC) Chair ALS Committee ARC ARC rep on International Liaison Committee on Resuscitation (ILCOR) Evidence Evaluation Expert (ILCOR/AHA)

3 So what is GRADE? 3

4 4 Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Process to take evidence to guidelines Developed by key international groups Widely accepted internationally

5 5

6 GRADE 6 Offers a transparent and structured process for developing and presenting summaries of evidence, including its quality, for systematic reviews and recommendations in health care. Provides guideline developers with a comprehensive and transparent framework for carrying out the steps involved in developing recommendations. Use is appropriate and helpful irrespective of the quality of the evidence: whether high or very low. Does not eliminate the inevitable need for judgments.

7 7

8 GRADE process adopted by: 8 American College of Physicians The Cochrane Collaboration American College of Chest Physicians European Society of Thoracic Surgeons American Thoracic Society Agency for Healthcare Research and Quality Society of Critical Care Medicine Up to Date WHO NIH NICE Endocrine Society

9 GRADE uptake 9

10 10 Lots of educational material existing

11 Journals Journal of Clinical Epidemiology (2011-2) 12 articles (more to come in series) extensive review, major reference for GRADE methodology BMJ Series (2008) 7 articles initial concepts of GRADE and justification documents Multiple other publications 11

12 Grade (1997) 12

13 13 GRADE (1997) Allows downgrading of quality estimate if involve indirect evidence Population groups? Animals etc! Prognostic or aetiologic studies only useful if their use modifies outcomes! Very good approach to making recommendations

14 14 Grade (1997)

15 15 Comparisons and proposal C2010 Study type/approach C2005 Grade SIGN NH&MRC OCEBM Meta-analyses 1 or 2 1 n/a 1++ to 2++ I 1a or 2a RCTs 1 or 2 High/Mod/Low 1/1+/1++ II 1b or 2b 1 Concurrent controls 2 3 High/Mod/Low 2- to 2++ III-1 or III-2 2b to 4 Retrospective controls 3 4 Low n/a III-3?1c! No controls 4 5 Very low 3 IV 4 Animal/Mechanical/Model 5 6? As for extrap n/a n/a n/a Extrapolations 7 Downgraded n/a n/a n/a 5 YES Covers "non-therapy" studies?1to7 Irrelevant! No Detailed Detailed GRADE approach closest to our needs Not numerical Needs additional non-therapy LOEs OCEBM or NH&MRC

16 16 What are the principles behind GRADE?

17 17 GRADE is outcome-centric Outcome #1 Outcome #2 Outcome #3 Quality: High Quality: Moderate Quality: Low III V II I B Older systems GRADE

18 GRADE: Quality of evidence The extent to which our confidence in an estimate of the treatment effect is adequate to support a particular recommendation. 18 GRADE defines 4 categories of quality: High Moderate Low Very low 18

19 19 Conceptualizing quality High Moderate Low Very low We are very confident that the true effect lies close to that of the estimate of the effect. Our confidence in the effect is limited: The true effect may be substantially different from the estimate of the effect. We are moderately confident in the estimate of effect: The true effect is likely to be close to the estimate of effect, but possibility to be substantially different. We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. 19

20 GRADE Recommendations 20 Strong recommendations strong methods large precise effect few downsides of therapy expect non-variant clinician and patient behavior diminished role for clinical expertise focus on implementation & barriers focused role of patient values and preferences emphasis on compliance and barriers Clinical Experience Research Evidence Weak recommendations weak methods imprecise estimate small effect substantial downsides expect variability in clinician and patient actions clinical expertise important focus on decision-making and implementation patient values and preferences important focus on determining values and preferences relative to decision Patient Values and Preferences

21 So why adopt GRADE? 21

22 22 Apart from international consensus Allows more clarity and consistency when move from evidence to recommendations

23 23 So is this really different to the C2010 approach?

24 24 Differences between processes 2010 ILCOR Identify PICO question Search for studies Clear inclusion exclusion criteria Identify studies for detailed review Identify key (critical) outcomes of relevance 2015 ILCOR (GRADE) Identify PICO question Search for studies Clear inclusion exclusion criteria Identify studies for detailed review Identify key (critical) outcomes of relevance

25 25 Differences between processes 2010 ILCOR Allocate study LOE: from LOE 1 to LOE 5 Allocate methodological quality for each study All studies (with outcomes) into grid according to direction for specific question 2015 ILCOR (GRADE) Allocate study type: RCTs or observational Assess risk of bias for each study All studies (with outcomes) into risk of bias table (including overall risk of bias for each study)

26 26 Assessment of methodological quality (risk of bias) of RCTs: similar 2010: ILCOR Quality RCTs (not clearly documented) Adequacy of randomization Allocation concealment Blinding Loss to follow up Intention to Treat (IT) analysis Groups treated equally? Groups similar at the start? 2015: GRADE Risk of bias RCTs (clearly documented) Adequacy of randomization Allocation concealment Blinding Loss to follow-up, Intention to Treat (IT) analysis Any other risks? Early stopping for positive benefit others

27 Allocation of quality 27 vs downgrading for RCTs: similar 2010: Quality for individual RCT Good studies most/all of the relevant quality items Fair studies have some of the relevant quality items Poor studies have few of the relevant quality items (but sufficient value to include for further review). Excluded insufficient relevant quality items to be included 2015: Overall risk of bias for individual RCT Low (?Good) Unclear (?Fair) High (?Poor)

28 Published (extras at 5) 28

29 29 Remember our evidence table Summary of evidence Evidence Supporting Clinical Question Good Fair Poor Level of evidence A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint B = Survival of event neurological survival Italics = Animal studies D = Intact

30 30

31 Overall risk of bias for study: Low, Moderate or High Low risk of bias = most or all key criteria listed are met, and any violations are not crucial. Moderate risk of bias if have a crucial limitation in one criterion or some in multiple criteria, sufficient to lower the confidence in the estimate of effect. High risk of bias if have a crucial limitation in one or more criteria, sufficient to substantially lower the confidence in the estimate of effect. 31

32 32 Differences between processes 2010 ILCOR Narrative description of key information from all studies 2015 ILCOR (GRADE) Narrative description of key information from all studies Plus specific information regarding evidence for each key outcome Evidence profile table(s) Summary of findings table(s)

33 33 Major difference in approach for GRADE Key outcome measures are allocated a numerical rating Critical 9, 8, 7 Important 6, 5, 4 Limited importance 3, 2, 1 Quality of evidence is assessed (across studies) for each key outcome

34 34 How is the evidence for each outcome collated? Evidence Profile table(s) Summary of Findings table(s) Narrative description Consensus on Science statement

35 Evidence Profile table(s) 35 PICO question Outcome to which evidence applies No of studies that report data for that outcome Study Design (RCT, Observational etc) Risk of bias (: no serious, serious, very serious) Inconsistency (: no serious, serious, very serious) Indirectness (: no serious, serious, very serious) Imprecision (: no serious, serious, very serious) Other including publication bias (Undetected, strongly suspected) Overall Quality of evidence for outcome High, Moderate, Low, Very low

36 Evidence profile table 36

37 Classification across all studies for each outcome 37 Risk of Bias/Inconsistency/Indirectness/Imprecision No serious : Most information is from studies at low risk of bias. Do not downgrade Serious : Most information is from studies at moderate risk of bias. Rate down one level Very serious : Most information is from studies at high risk of bias. Rate down two levels

38 Classification across all studies for each outcome Publication Bias Undetected Strongly suspected Quality of Evidence across all included studies for outcome High Moderate Low Very Low 38

39 39

40 40

41 Quality of evidence for outcome (across all studies) Four final categories High Moderate Low Very low Start with high for RCTs Start with low for observational Can be modified according to a number of factors 41

42 42 RCTs can be downgraded all or most of the studies had sufficient problems to make estimate unreliable or uncertain design and execution (risk of bias) consistency of results directness of comparisons precision publication bias

43 Overall quality of evidence: for each key outcome across studies 43

44 44 What about even lower levels of evidence? Case series (LOE 4) Manikin/Models/Animals (LOE 5)

45 45 Case series Start at low/very low quality Can be upgraded

46 46

47 47 Case series Start at low quality Can be upgraded BUT not if would be downgraded first!

48 48

49 Manikin/Models/Animals (LOE 5) (NB. GRADE not created for these) 49 Starting point depends on methodology BUT RCTs at high quality Observational at low quality Even RCTs can be downgraded Very serious indirectness = -2 Can be explained in comments

50 50 Summary of Findings table: columns PICO Key Outcomes Illustrative comparative risks (categorical or continuous with 95% CI) Control group Intervention group Relative effect (95% CI) No of Participants (studies) Overall quality of the evidence (GRADE) Comments/Footnotes

51 51 Summary of findings table Present a key summary graph or table Citation #1 Citation #2

52 52 Next = CoSTR Consensus on Science statement and Treatment Recommendations

53 53 Differences between processes 2010 Consensus on Science statement (based on listing of levels of evidence for specific outcomes) Treatment recommendation: using behavioral wording, based largely on quality of evidence 2015 Consensus on Science statement (based on overall quality of evidence for critical outcomes ) Treatment recommendation: strong or weak (with behavioral correlates), based on evidence quality (high, moderate, low, very low)

54 54 So how will our Consensus on Science statement and Treatment Recommendations differ? COS: Quality level of evidence (GRADE) TR: Strength of Recommendation (GRADE)

55 55 GRADE Strength of Recommendation Strong: the desirable effects of an intervention clearly outweigh the undesirable effects, or clearly do not. Weak: the trade-offs are less certain either because of low quality evidence or because evidence suggests that desirable and undesirable effects are closely balanced.

56 56 Strong Recommendation For patients most people in your situation would want the recommended course of action and only a small proportion would not; request discussion if the intervention is not offered For clinicians most patients should receive the recommended course of action

57 57 Weak Recommendation For patients most people in your situation would want the recommended course of action, but many would not For clinicians you should recognize that different choices will be appropriate for different patients and that you must help each patient to arrive at a management decision consistent with her or his values and preferences

58 58 So what might a GRADE review for ILCOR look like?

59 59 In adult cardiac arrest (prehospital [OHCA], in-hospital [IHCA]), does the use of an ITD (I) compared with no ITD (C), improve any outcomes (e.g. survival) (O)? Worksheet identifier: TBA Author: Peter Morley Affiliation: ANZCOR Taskforce: ALS/BLS Other Worksheet Authors: TBA

60 60 C2015 PICO Population: adult cardiac arrest (prehospital [OHCA], in-hospital [IHCA]) Intervention: the use of an ITD Comparison: compared with no ITD Outcomes Neurologically intact survival (critical 9) Discharge from hospital alive (critical 8) Return of spontaneous circulation (important 6)

61 61 Inclusion/Exclusion/Articles Found Included all studies with concurrent controls. Excluded review articles, studies with historical controls, animal studies, and studies that did not specifically answer the question. Excluded unpublished studies, studies only published in abstract form, unless accepted for publication. 8 Articles Finally Evaluated

62 62 Risk of Bias in studies table(s) Impedance Threshold Device + Standard CPR (I) vs Standard CPR (C) Study Random -ization Allocation concealment Blinding Loss to follow-up, Intention to Treat (IT) analysis Aufderheide 2005, 734 ITD+SCPR vs ShamITD+SCPR Pirallo 2005, 13 ITD+SCPR vs ShamITD+SCPR Aufderheide 2011, 798 ITD+SCPR vs ShamITD+SCPR Any other risks Outcomes to which these assessments apply Low Low Low Low Discontinued early. Indirectness: 2000 guidelines. All Low Unclear Low Low Changed device halfway into All Low study. Equipment problems Indirectness: 2000 guidelines. Low Low Low Low Indirectness: 2005 guidelines All Low Overall risk of bias for outcome(s) for study** Low Impedance Threshold Device + Active Compression Decompression CPR (I) vs Active Compression Decompression CPR (C) Study Random -ization Allocation concealment Blinding Any other risks Plaisance 2000, 989 ITD+ACD vs ACD Plaisance 2004, 265 ITD+ACD vs ShamITD+ACD Plaisance 2005, 990 ITD+ACD vs ShamITD+ACD Loss to follow-up, IT principle observed or per protocol analysis Low Low Low Low No description primary outcome/power. Indirectness: 1992 guidelines Low Low Low Low Automatic ventilator. Indirectness: 2000 guidelines. Low (order of use) Low Low Low Crossover trial. Indirectness: 2000 guidelines Outcomes to which these assessments apply All All All Overall risk of bias for outcome(s) for study** Low Low Moderate Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per Any other risks Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR protocol analysis Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

63 63 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

64 64 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

65 65 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

66 66 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

67 67 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

68 68 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

69 69 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

70 70 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

71 71 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

72 72 Risk of Bias in studies table: ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Study Wolcke 2003, 2201 ITD+ACD vs SCPR Aufderheide 2011, 301 ITD+ACD vs SCPR Random -ization Allocation concealment Blinding Loss to follow-up, IT principle observed or per protocol analysis Any other risks Low High High Low Indirectness:?1992/2000 guidelines Low Unclear High High: Significant differences in (only real time feedback about CPR outcome quality. Increase enrollment assessor) numbers then stop early. Unclear, some exclusions based on difficultly with airway border on deviation from IT analysis. Outcomes to which these assessments apply All All Overall risk of bias for outcome(s) for study** High High

73 73 Next create an Evidence Profile table

74 Evidence profile table: 74 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 1 Aufderheide Aufderheide Wolcke Study Design RCT RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision) Low (rated down for risk of bias, indirectness and imprecision)

75 Evidence profile table: 75 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 1 Aufderheide Aufderheide Wolcke Study Design RCT RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision) Low (rated down for risk of bias, indirectness and imprecision)

76 Evidence profile table: 76 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) No of studies Author Year 1 st page 1 Aufderheide Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision)

77 Evidence profile table: 77 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) No of studies Author Year 1 st page 1 Aufderheide Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision)

78 Evidence profile table: 78 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) No of studies Author Year 1 st page 1 Aufderheide Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision)

79 Evidence profile table: 79 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) No of studies Author Year 1 st page 1 Aufderheide Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision)

80 Evidence profile table: 80 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) No of studies Author Year 1 st page 1 Aufderheide Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision)

81 Evidence profile table: 81 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) No of studies Author Year 1 st page 1 Aufderheide Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision)

82 Evidence profile table: 82 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) No of studies Author Year 1 st page 1 Aufderheide Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision)

83 Evidence profile table: 83 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) No of studies Author Year 1 st page 1 Aufderheide Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision)

84 84

85 85

86 Overall quality of evidence: for each key outcome across studies 86

87 Evidence profile table: 87 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) No of studies Author Year 1 st page 1 Aufderheide Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious No serious Serious (ARR CI overlap 1%) Undetected (sponsor involvement). More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias and imprecision)

88 88

89 Evidence profile table: 89 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 2 Aufderheide Wolcke Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias, indirectness and imprecision)

90 Evidence profile table: 90 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 2 Aufderheide Wolcke Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias, indirectness and imprecision)

91 Evidence profile table: 91 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 2 Aufderheide Wolcke Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias, indirectness and imprecision)

92 Evidence profile table: 92 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 2 Aufderheide Wolcke Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias, indirectness and imprecision)

93 Evidence profile table: 93 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 2 Aufderheide Wolcke Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias, indirectness and imprecision)

94 Evidence profile table: 94 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 2 Aufderheide Wolcke Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias, indirectness and imprecision)

95 Evidence profile table: 95 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 2 Aufderheide Wolcke Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias, indirectness and imprecision)

96 Evidence profile table: 96 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 2 Aufderheide Wolcke Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias, indirectness and imprecision)

97 Evidence profile table: 97 ITD+ACDCPR vs Standard CPR Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Population: Patients in cardiac arrest Settings: OOHCA Intervention: Impedance Threshold Device + Active Compression Decompression CPR Comparison: Standard CPR Outcome Outcome 2 Survival to hospital discharge Critical (8) No of studies Author Year 1 st page 2 Aufderheide Wolcke Study Design RCT Risk of bias* Very serious (blinding, feedback about CPR quality, exclusions/ IT analysis) Inconsistency* Indirectness* Imprecision* Other (including publication bias)** No serious Serious (Wolcke : 1992/2000 guidelines) Serious (ARR CI overlap 1%) Undetected (sponsor involvement) More pulmonary oedema I 94/840 (11%) vs C 62/813 (7%) Quality of evidence for outcome*** Low (rated down for risk of bias, indirectness and imprecision)

98 98 Next create a summary of findings table

99 99

100 100 Summary of findings table(s) Present a key summary graph or table Citation #1 Citation #2

101 101 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

102 102 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

103 103 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

104 104 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

105 105 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

106 106 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

107 107 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

108 108 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

109 109 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

110 110 Summary of findings table: 1 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 1 Neurologically intact survival (survival to hospital discharge with modified Rankin 3) Critical (9) 47/813 (5.8%) 75/840 (8.9%) Difference 3.15% (0.64 to 5.66) NNT 31.8 OR 1.60 (1.09 to 2.33) 2470 (1)** Low1 Unblinded study with unbalanced control for quality of CPR.

111 111 Summary of findings table: 2 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 2 Survival to hospital discharge Critical (8) 94/920 (10.2%) 123/943 (13%) Difference 2.83% (-0.08 to 5.73) NNT 35.4 OR 1.32 (0.99 to 1.75) 2680 (2)*** Low1 Unblinded studies with unbalanced control for quality of CPR.

112 112 Summary of findings table: 2 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 2 Survival to hospital discharge Critical (8) 94/920 (10.2%) 123/943 (13%) Difference 2.83% (-0.08 to 5.73) NNT 35.4 OR 1.32 (0.99 to 1.75) 2680 (2)*** Low1 Unblinded studies with unbalanced control for quality of CPR.

113 113 Summary of findings table: 2 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 2 Survival to hospital discharge Critical (8) 94/920 (10.2%) 123/943 (13%) Difference 2.83% (-0.08 to 5.73) NNT 35.4 OR 1.32 (0.99 to 1.75) 2680 (2)*** Low1 Unblinded studies with unbalanced control for quality of CPR.

114 114 Summary of findings table: 2 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 2 Survival to hospital discharge Critical (8) 94/920 (10.2%) 123/943 (13%) Difference 2.83% (-0.08 to 5.73) NNT 35.4 OR 1.32 (0.99 to 1.75) 2680 (2)*** Low1 Unblinded studies with unbalanced control for quality of CPR.

115 115 Summary of findings table: 2 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 2 Survival to hospital discharge Critical (8) 94/920 (10.2%) 123/943 (13%) Difference 2.83% (-0.08 to 5.73) NNT 35.4 OR 1.32 (0.99 to 1.75) 2680 (2)*** Low1 Unblinded studies with unbalanced control for quality of CPR.

116 116 Summary of findings table: 2 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 2 Survival to hospital discharge Critical (8) 94/920 (10.2%) 123/943 (13%) Difference 2.83% (-0.08 to 5.73) NNT 35.4 OR 1.32 (0.99 to 1.75) 2680 (2)*** Low1 Unblinded studies with unbalanced control for quality of CPR.

117 117 Summary of findings table: 2 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 2 Survival to hospital discharge Critical (8) 94/920 (10.2%) 123/943 (13%) Difference 2.83% (-0.08 to 5.73) NNT 35.4 OR 1.32 (0.99 to 1.75) 2680 (2)*** Low1 Unblinded studies with unbalanced control for quality of CPR.

118 118 Summary of findings table: 2 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 2 Survival to hospital discharge Critical (8) 94/920 (10.2%) 123/943 (13%) Difference 2.83% (-0.08 to 5.73) NNT 35.4 OR 1.32 (0.99 to 1.75) 2680 (2)*** Low1 Unblinded studies with unbalanced control for quality of CPR.

119 119 Summary of findings table: 2 Topic title: Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) Patient or population: Patients in cardiac arrest Settings: OOHCA Intervention: Use of Impedance Threshold Device in addition to Active Compression Decompression CPR Comparison: Use of Standard CPR Outcomes Illustrative comparative risks* (95% CI) Assumed risk Comparison Corresponding risk Intervention Relative effector (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Outcome 2 Survival to hospital discharge Critical (8) 94/920 (10.2%) 123/943 (13%) Difference 2.83% (-0.08 to 5.73) NNT 35.4 OR 1.32 (0.99 to 1.75) 2680 (2)*** Low1 Unblinded studies with unbalanced control for quality of CPR.

120 120 So what might a 2015 COS statement look like?

121 121 Consensus on Science statements Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) One RCT enrolling over 2000 OOHCAs [Aufderheide 2011, 301]reported improved neurologically intact survival when the unblinded use of an Impedance Threshold Device and Active Compression Decompression CPR was compared with manual standard CPR. Two RCTs enrolling over 2000 OOHCAs [Aufderheide 2011, 301; Wolcke 2003, 2201] were unable to demonstrate any improvements in survival to hospital discharge when the unblinded use of an Impedance Threshold Device and Active Compression Decompression CPR was compared with manual standard CPR.

122 122 What about a Treatment Recommendation?

123 123 GRADE Strength of Recommendation Strong: the desirable effects of an intervention clearly outweigh the undesirable effects, or clearly do not. Weak: the trade-offs are less certain either because of low quality evidence or because evidence suggests that desirable and undesirable effects are closely balanced.

124 124 So what might a 2015 TR look like?

125 Draft Treatment Recommendations Impedance Threshold Device + Active Compression Decompression CPR (I) vs Standard CPR (C) There is insufficient evidence to recommend the routine use of the combination of an Impedance Threshold Device and manual active compression decompression cardiopulmonary resuscitation instead of standard CPR (weak recommendation, low quality of evidence).

126 Grade down Grade up 126 RCT start high, obs. data start low P I C O Outcome Outcome Outcome Outcome Systematic review Critical Critical Important Not Summary of findings & estimate of effect for each outcome High Moderate Low Very low 1. Risk of bias 2. Inconsistency 3. Indirectness 4. Imprecision 5. Publication bias 1. Large effect 2. Dose response 3. Confounders Guideline development Formulate recommendations: For or against (direction) Strong or weak (strength) By considering: Quality of evidence Balance benefits/harms Values and preferences Revise if necessary by considering: Resource use (cost) Rate overall quality of evidence across outcomes based on lowest quality of critical outcomes We recommend using We suggest using We recommend against using We suggest against using

127 Journals Journal of Clinical Epidemiology (2011-2) 12 articles (more to come in series) extensive review, major reference for GRADE methodology BMJ Series (2008) 7 articles initial concepts of GRADE and justification documents Multiple other publications 127

128 128 Online resources Provides numerous webinars, videos, Powerpoint s, and PDFs on the topic of GRADE. General website for all things GRADE Pro: video at site provides 10 minute quick review Con: lacking an executive summary or user guides as have been created for other User Guides to the Medical Literature Software and PDF website Pro: provides both software and PDF tools Con: unknown usability at this point Online tool available to reviewers. Pro: thorough and compreshensive Con: difficult to navigate through

129 ster.ca/ 129