1. Chicago 2014 TFQO: Darren Walters COI #317 EVREV 1: Darren Walters COI #317 EVREV 2: Chris Ghaemmaghami COI #60 Taskforce: Acute Coronary Syndrome In STEMI (P), does fibrinolytic therapy prior to hospital arrival (I), compared with fibrinolytic therapy after hospital arrival (C), change outcomes(O)? ACS 338

2. Chicago 2014 COI Disclosure Chris Ghaemmaghami COI #60 Commercial/industry Potential intellectual conflicts Darren Walters COI #317 Commercial/industry Nil Potential intellectual conflicts Editor IJC, HLC

3. Chicago 2014 2010 Treatment Recommendation In patients with STEMI diagnosed in the prehospital setting, reperfusion may be achieved by administration of fibrinolytics by healthcare providers in the field. Alternately, fibrinolytic therapy may be administered on arrival at hospital. If fibrinolysis is chosen as the reperfusion strategy, it should be started as soon as possible, ideally in the prehospital setting,and should be administered by paramedics, nurses, or doctors using well-established protocols, competency training programs, and quality assurance programs, under medical oversight.

4. Chicago 2014 C2015 PICO Population:Among adults who are suspected of having ST-elevation myocardial infarction outside of a hospital Intervention:does fibrinolytic therapy prior to hospital arrival Comparison:compared with fibrinolytic therapy after hospital arrival Outcomes:change death 9-Critical ICH 8- Critical revascularization 7-Critical major bleeding 6-Important stroke 6-Important reinfarction 5-Important

5. Chicago 2014 Inclusion/Exclusion & Articles Found (“myocardial infarction”[MH] OR AMI[ti] OR “STEMI”[TI] OR “st-elevation”[ti] OR “st elevation”[ti] OR “ST- segment”[TI] OR “ST segment”[TI] OR “infarct*”[ti] OR “myocardial ischemia”[MH] OR “coronary thrombosis”[MH]) AND (“myocardial reperfusion”[MH] OR fibrinoly*[tiab] OR fibrinolytic agents[MH] OR thrombolytic therapy[MH] OR thromboly*[tiab] OR reteplase[TI] OR anistreplase[TI] OR ER-TIMI[TI] OR “tissue plasminogen activator”[TI] OR “tissue plasminogen activator”[MH] OR alteplase[TI] OR rt-PA[TI] OR TPA[TI] OR tenecteplase[TI] OR streptokinase[TI] OR APSAC[TI]) AND (""Emergency medical technicians""[MH] OR ""pre-hospital""[TI] OR ""prehospital""[TI] OR ""ambulance""[TI] OR “ambulances”[MH] OR ""paramedic*""[TI] OR “Emergency medical services”[MH] OR “EMS”[TI] OR “EMT”[TI] OR “out-of- hospital”[TI] OR “out of hospital”[TI] OR “emergency physician*”[TI] OR mobile[TI] OR “before hospital”[TI]) NOT (“animals”[MH] NOT “humans”[MH]) NOT (“editorial”[PT] OR “letter”[PT] OR “comment”[PT] OR “review”[PT] OR “practice guideline”[PT]) NOT ""score""[TI] AND ((("randomized controlled trial"[PT] OR “controlled clinical trial”[PT] OR “clinical trial”[PT] OR “comparative study”[PT] OR random*[TIAB] OR controll*[TIAB] OR “intervention study”[TIAB] OR “experimental study”[TIAB] OR “comparative study”[TIAB] OR trial[TIAB] OR evaluat*[TIAB] OR “Before and after”[TIAB] OR “interrupted time series”[TIAB]) NOT ("animals"[MH] NOT (animals[MH] AND "humans"[MH]))) OR ("Epidemiologic Studies"[Mesh] OR “case control”[TIAB] OR “case-control”[TIAB] OR ((case[TIAB] OR cases[TIAB]) AND (control[TIAB] OR controls[TIAB)) OR “cohort study”[TIAB] OR “cohort analysis”[TIAB] OR “follow up study”[TIAB] OR “follow-up study”[TIAB] OR “observational study”[TIAB] OR “longitudinal”[TIAB] OR “retrospective”[TIAB] OR “cross sectional”[TIAB] OR “cross-sectional”[TIAB] OR questionnaire[TIAB] OR questionnaires[TIAB] OR questionnaires[TIAB] OR survey[TIAB]))) NOT ("letter"[pt] OR "comment"[pt] OR "editorial"[pt]) 279 papers Metanalysis 2 RCTs, 3 non-RCTs 60 excluded

6. Chicago 2014 Previousmet analysis by Morrison JAMA 2000 (6 RCTs) EMIP 1993 included NSTEMI unable to sub stratify data GREAT 1992 no ST elevation –suspicion of STEMI Roth 1990 used alternate monthly rotational allocations Cochrane review includes 3 studies Reviewed the worksheet ACS-018B 2010 COSTAR 32 studies. Inclusion/Exclusion & Articles Found

7. Chicago 2014 2015 Proposed Treatment Recommendations We suggest using pre-hospital fibrinolysis in comparison to in-hospital fibrinolysis for STEMI to reduce the risk of all cause in-hospital mortality based on a low level of evidence.

8. Chicago 2014 Risk of Bias in studies RCT bias assessment StudyYearDesign Total Patien ts Populati on Industry Funding Allocation: Generation Allocation: Concealment Blinding: Participants Blinding: Assessors Outcome: Complete Outcome: Selective Other Bias Castaigne 1989RCT100OHCA NoUnclearHigh highHighLowUnclear Schofer 1990RCT78OHCA NolowLow UnclearHighLow Weaver 1993RCT360OHCA nolowLowHighLowUnclearHighLow

9. Chicago 2014 Forest plot and risk of bias

10. Chicago 2014 Forest Plot bleeding

11. Chicago 2014 Forrest plot ICH

12. Chicago 2014 Forrest plot CVA

13. Chicago 2014 Evidence profile table(s)

14. Chicago 2014 Evidence profile table(s)

15. Chicago 2014 Evidence profile table(s)

16. Chicago 2014 Reviewed non randomised studies 2009- 2014 85 studies First pass 7 studies in detail Armstrong 2010STREAM vs PCI Bata 2009WEST vs PCI Castle 2007retrospective decision analsyis Khan 2009actuarial survival only Koeth 2009 eligible for rct vs ineligible Smith 2011 no outcomes paramedic decisions Zeymer 2009non RCT cohort comparison

17. Chicago 2014 Forrest plot incl non RCT Mortality

18. Chicago 2014 Forrest plot incl non RCT Bleeding CVA

19. Chicago 2014 Re infarction Forrest plot incl non RCT

20. Chicago 2014 Proposed Consensus on Science statements Insert Summary statement(s) from SEERs* For the important outcome of “all cause hospital mortality” we have identified low quality evidence (downgraded for bias allocation and concealment) from three RCTs enrolling 538 patients showing benefit (OR 0.46 95% CI 0.23 – 0.93). For the outcome of Bleeding complications a moderate level of evidence from 2 RCTS enrolling 438 patients showed no benefit (OR 0.96 95% CI 0.40-2.32) For the outcome of stroke a low level of evidence from one study enrolling 360 patients showed no benefit (OR 2.14 95% CI 0.39-11.84) For the outcome of intracranial haemorhage a moderate level of evidence was found from 2 studies enrolling 438 patients showed no benefit (OR 2.14 95% CI 0.39-11.84) For other outcomes no evidence from RCTs was found. For reinfarction a low level of evidence from one non RCT showed enrolling 778 patients showed no benefit (OR 1.09 95% CI 0.55- 2.15)

21. Chicago 2014 Draft Treatment Recommendations We suggest using pre-hospital fibrinolysis in comparison to in hospital fibrinolysis for STEMI to reduce the risk of all cause in hospital mortality based on a low level of evidence.