1. Dallas 2015 TFQO: Karen Woolfrey COI #261 EVREV 1: Karen Woolfrey COI 261 EVREV 2: Daniel Pichel COI # 513 Taskforce: ACS ACS 335: Pre-hospital ADP- Receptor Antagonist in STEMI

2. Dallas 2015 COI Disclosure EVREV 1 COI# 261 Commercial/industry No conflicts of Interest Potential intellectual conflicts No conflicts of Interest EVREV 2 COI# 513 Commercial/industry No conflicts of Interest Potential intellectual conflicts No conflicts of Interest

3. Dallas 2015 2010 Treatment Recommendation Clopidogrel: “ Administration of clopidogrel in addition to standard care (aspirin, anticoagulants, and/or reperfusion) for patients determined to have moderate to high-risk non-ST elevation ACS and STEMI is recommended. The ideal oral loading dose of clopidogrel in patients /-75 years of age has not yet been delineated, but may range from 75 to 600 mg”.

4. Dallas 2015 2010 Treatment Recommendation Prasugrel: “May be administered after angiography to patients with NSTEMI presenting with stenoses amenable to PCI. ED or prehospital administration of clopidogrel should be withheld even in patients who are not at high risk for bleeding (age <75 years, no history of previous stroke or TIA, and body weight >60 kg), pending consideration of prasugrel administration following angiography. In patients who are not at high risk for bleeding with planned PCI, prasugrel (60 mg oral loading dose) may be substituted for clopidogrel for patients determined to have STEMI less than 12 hours after the initial symptoms. Prasugrel is not recommended in STEMI patients receiving fibrinolysis”.

5. Dallas 2015 2010 Treatment Recommendation Ticagrelor: “Administration of ticagrelor (180-mg oral loading dose) in addition to standard care (aspirin, anticoagulants, and/or reperfusion) determined to have non-ST elevation ACS or STEMI managed with early invasive strategy by hospital personnel may be an option instead of clopidogrel. The risks and/or benefits of ticagrelor in STEMI patients managed with fibrinolysis is unknown”.

6. Dallas 2015 C2015 PICO Population: Patients with suspected ST-Elevation Myocardial Infarction (STEMI) identified outside the hospital (pre-hospital) Intervention: Pre-hospital administration of an ADP- receptor antagonist (Clopidogrel, Prasugrel, or Ticagrelor) Comparison: Upstream administration in the hospital Outcomes: 30-day mortality (9); major bleeding(6)

7. Dallas 2015 Inclusion/Exclusion & Articles Found Only randomized control trials (RCT) were included Exclusions No in-hospital comparator group Studies that did not randomize patients in the pre- hospital setting The search yielded a total of 159 RCT 15 articles reviewed (11 full text articles; 4 conference abstracts) 12 excluded (5-no comparator; 1-no clinical outcome; 5- not relevant; 1-no pre-hospital group) 3 RCT were included for bias assessment

8. Dallas 2015 Draft Treatment Recommendations We have insufficient confidence in the treatment effect to recommend a change in practice (weak recommendation, very low quality of evidence) In making this recommendation we place a higher value on not recommending new resource allocation to an unproven intervention over uncertain benefits of mortality

9. Dallas 2015 Risk of Bias in studies

10. Dallas 2015 30-day Mortality (9)

11. Dallas 2015 Major Bleeding (6)

12. Dallas 2015 30-day Mortality (9)

13. Dallas 2015 Major Bleeding (6)

14. Dallas 2015 Proposed Consensus on Science statements For the critical outcome of 30-day mortality, we have identified very low quality of evidence (downgraded for imprecision and reporting bias) from three RCTs (Zeymer 2012, 305; Ducci 2013, 4814; Montalescot 2014; 1) enrolling 2365 patients showing no differential benefit to pre-hospital administration of an ADP-receptor antagonist compared to in hospital administration (OR 1.58 95% CI 0.90-2.78)

15. Dallas 2015 Proposed Consensus on Science statements For the important outcome of major bleeding, we have identified very low quality of evidence (downgraded for imprecision and reporting bias) from three RCTs (Zeymer 2012, 305; Ducci 2013, 4814; Montalescot 2014, 1) enrolling 2365 patients showing no differential benefit to pre-hospital administration of an ADP-receptor antagonist compared to in hospital administration (OR 1.12 95% CI 0.72-1.74)

16. Dallas 2015 Draft Treatment Recommendations In pre-hospital identified STEMI patients with a planned primary PCI approach, we have insufficient confidence in the treatment effect for pre-hospital administration of an ADP-receptor antagonist compared to in-hospital administration to recommend a change in existing practice (very low quality of evidence, weak recommendation) In making this recommendation we place a higher value on not recommending new resource allocation to an unproven intervention over uncertain benefits of mortality

17. Dallas 2015 Knowledge Gaps Specific research required RCT comparing the ADP-receptor antagonists use in pre-hospital setting in STEMI Are these agents recommended in STEMI managed by fibrinolysis?