Dallas 2015 TFQO: Jonathan Witt (COI #418) EVREVs: Steve Lin (COI #137), Thomas Pellis (COI #186) and Katie Dainty (COI #) Taskforce: ALS ALS 428 : Antiarrhythmic drugs for cardiac arrest

Dallas 2015 COI Disclosure (specific to this systematic review) Commercial/industry None Potential intellectual conflicts None

Dallas CoSTR Consensus on Science There was little evidence to suggest a survival-to-discharge advantage with any antiarrhythmic drug used during resuscitation from out-of-hospital or in- hospital cardiac arrest. Two randomized trials demonstrated the benefit of amiodarone over standard of care, which included lidocaine in 80% of cases, or routine use of lidocaine for shock refractory or recurrent VT/VF for the end point of survival to hospital admission, but not to survival to hospital discharge. A retrospective review demonstrated improved survival to admission with lidocaine (compared with standard treatment) for patients in VF out of hospital (LOE 4). A retrospective review found procainamide was associated with increased survival to 1 hour postarrest in patients with VF in hospital (LOE 4). Four randomized, controlled trials did not show any increase in ROSC or survival when magnesium was compared with placebo for patients in VF in out-of- hospital, ICU, and emergency department (ED) settings (LOE 1). Treatment Recommendation Amiodarone may be considered for those who have refractory VT/VF, defined as VT/VF not terminated by defibrillation, or VT/VF recurrence in out-of- hospital cardiac arrest or in-hospital cardiac arrest. There is inadequate evidence to support or refute the use of lidocaine in the same settings.

Dallas 2015 C2015 PICO P: Adults who are in cardiac arrest in any setting I: Does antiarrhythmic drugs (e.g. lidocaine, amiodarone, other) administration C: Compared with not using antiarrhythmic drugs (no drug or placebo) O: Change Survival with Favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year, Survival only at discharge, 30 days, 60 days, 180 days AND/OR 1 year, ROSC

Dallas 2015 Inclusion/Exclusion & Articles Found Inclusions/Exclusions Included RCTs and non-RCTs evaluating antiarrhythmics given during cardiac arrest resuscitation compared to no antiarrhythmics Excluded studies comparing antiarrhythmic vs. antiarrhythmic (e.g. amiodarone vs. lidocaine) 2052 articles initially identified, and 8 studies included (5 RCTs and 3 non-RCTs)

Dallas Proposed Treatment Recommendations There are no studies that show improved survival to hospital discharge or functional survival with the use of antiarrhythmics in cardiac arrest patients refractory to VF/pVT. We suggest the use of amiodarone in adult patients who suffer OHCA with refractory VF/pVT to improve rates of ROSC (Weak recommendation; high confidence in effect estimate). Clinicians might consider lidocaine or nifekalant in adult patients who suffer OHCA and IHCA, respectively (Weak recommendation, very low confidence in effect estimates). We suggest against the use of magnesium in adult patients who are in OHCA in any rhythm (Strong recommendation, moderate confidence in effect estimate).

Dallas 2015 Risk of Bias in studies SEERS not updated to insert risk of bias tables

Dallas 2015 Key data from key studies Reference: Kudenchuk et al., 1999 P: OHCA with VF/VT refractory to 3 defibrillations I: Amiodarone 300mg C: Placebo (polysorbate 80) O: ROSC 64% vs 41%; p=0.03 Survival to admission 44% vs 34%; p=0.03 Suvival to discharge 13.4% vs 13.2%; p=ns Neuro 53% vs 50% of survivors; p=ns

Dallas 2015 Evidence profile tables

Dallas 2015 Evidence profile tables

Dallas 2015 Evidence profile tables

Dallas 2015 Evidence profile tables

Dallas 2015 Proposed Consensus on Science statements Amiodarone (I) versus no amiodarone (C) For the important outcome of ROSC, we have identified one RCT (GRADE: high) of 504 patients who suffered from OHCA with an initial rhythm of (or developing) VF or pulseless VT refractory to 3 shocks showing an improved rate of ROSC with administration of amiodarone (300 mg after 1 mg of adrenaline) compared with no drug (64% vs 41%; p=0.03) [Kundenchuk 1999]. For the critical outcome of survival at discharge, we have identified one RCT (GRADE: high) of 504 patients who suffered from OHCA with an initial rhythm of (or developing) VF or pulseless VT refractory to 3 shocks showing a similar rate of survival with administration of amiodarone (300 mg after 1 mg of adrenaline) compared with no drug (13.4% vs 13.2%; p=ns) [Kundenchuk 1999]. For the critical outcome of survival with favorable neurological/functional outcome at discharge, we have identified one RCT (GRADE: high) of 504 patients who suffered from OHCA with an initial rhythm of (or developing) VF or pulseless VT refractory to 3 shocks showing a similar rate of survival with favorable neurological outcome with administration of amiodarone (300 mg after 1 mg of adrenaline) compared with no drug (53% vs 50% of survivors; p=ns) [Kundenchuk 1999].

Dallas 2015 Proposed Consensus on Science statements Lidocaine (I) versus no lidocaine (C) For the important outcome of ROSC, we identified 2 retrospective observational single center studies (GRADE: very low; very serious risk of bias) with conflicting results: Herlitz [1997] et al. showed in 290 patients who suffered from OHCA with VF refractory to 3 shocks an improved rate of ROSC with administration of lidocaine (50 mg, repeatable up to 200 mg) compared with no drug (45% vs 23%; p<0.001). Harrison [1981] showed in 116 patients who suffered from OHCA with VF refractory to 3 shocks a similar rate of ROSC with administration of lidocaine (100 mg) compared with no drug (55% vs 54%; p=ns). For the critical outcome of survival at discharge, we have identified 2 retrospective observational studies (GRADE: very low; very serious risk of bias) with consistent results: Herlitz [1997] et al. showed in a single center study of 290 patients who suffered from OHCA with VF refractory to 3 shocks a similar rate of survival rate of survival with administration of lidocaine (50 mg, repeatable up to 200 mg) compared with no drug (14% vs 8%; p=ns). Harrison [1981] showed in a single center study of 116 patients who suffered from OHCA with VF refractory to 3 shocks a similar rate of survival with administration of lidocaine (100 mg) compared with no drug (11% vs 2%; p=ns).

Dallas 2015 Proposed Consensus on Science statements Nifekalant (I) versus no nifekalant (C) For the critical outcome of survival at discharge, we have identified one retrospective single center study (GRADE: very low; downgraded due to very serious risk bias, very serious indirectness and confounding) of 63 patients who suffered from cardiac arrest upon or during hospitalization with VF/VT due to coronary artery disease showing improved survival with administration of nifekalant (loading dose 0.27 mg/kg followed by infusion of 0.26 mg/kg/h) comparing with no drug in historical controls with an adjusted OR for cardiac death of 0.26 (95% CI ; P = 0.041) [Ando 2005].

Dallas 2015 Proposed Consensus on Science statements Magnesium (I) versus no magnesium (C) For the important outcome of ROSC, we have identified 3 double-blind RCT (GRADE: moderate; downgraded due to imprecision in small study sample sizes) with consistent results: Fatovich [1997] et al. showed in a single center study of 67 patients who suffered OHCA (but with ongoing CPR at ED arrival) with all rhythms a similar rate of ROSC with administration of magnesium (5 g (20 mmol) bolus) comparing with no drugs (23% vs 22%, p=0.97). Allegra [2001] et al. showed in a multi-center study of 109 patients who suffered OHCA with VF refractory to 3 shocks a similar rate of ROSC with administration of magnesium (2 g (8 mmol) bolus) comparing with no drugs (25% vs 19%, p=0.39). Hassan [2002] et al. showed in a single center study of 105 patients who suffered OHCA with VF refractory to 3 shocks or recurrent a similar rate of ROSC with administration of magnesium (2 g (8 mmol) bolus, repeatable once) comparing with no drugs (17% vs 13%, p=0.56).

Dallas 2015 Proposed Consensus on Science statements For the critical outcome of survival at discharge, we have identified 4 double-blind RCT (GRADE: moderate; downgraded due to imprecision in small study sample sizes) with consistent results: Thel [1997] et al. showed in a single centre study of 156 patients who suffered IHCA (only ICU and general wards) with all initial rhythms (50% in VF/VT) and of all causes a similar survival with administration of magnesium (2 g (8 mmol) bolus followed infusion of 8 g (32 mmol) in 24 h) comparing with no drugs (21% vs 21%, p=ns). After multivariate adjustment, the OR for survival was similar (1.22, 95% CI ). Fatovich [1997] et al. showed in a single center study of 67 patients who suffered OHCA (but with ongoing CPR at ED arrival) with all rhythms a similar survival with administration of magnesium (5 g (20 mmol) bolus) comparing with no drugs (1 vs 0 patients, p=0.46). Allegra [2001] et al. showed in a multi-center study of 109 patients who suffered OHCA with VF refractory to 3 shocks a similar survival with administration of magnesium (2 g (8 mmol) bolus) comparing with no drugs (3.6% vs 3.7%, p=1.0; unadjusted RR of increased survival 0.98, 95% CI ). Hassan [2002] et al. showed in a single center study of 105 patients who suffered OHCA with VF refractory to 3 shocks or recurrent a similar survival with administration of magnesium (2 g (8 mmol) bolus, repeatable once) comparing with no drugs (4% vs 2%, p=0.99). Multivariate logistic regression was not possible due to the low number of survivors (respectively 2 and 1 patient).

Dallas 2015 Proposed Consensus on Science statements For the critical outcome of survival with favorable neurological/functional outcome at discharge, we have identified one single centre double-blind RCT (GRADE: moderate) of 156 patients who suffered IHCA (only ICU and general wards, no ED etc.) with all initial rhythms (50% in VF/VT) and of all causes showing a similar survival with favorable neurological outcome with administration of magnesium (2 g (8 mmol) bolus followed infusion of 8 g (32 mmol) in 24 h) comparing with no drugs (favorable return to independent living 14.5% vs 7.5%, p=ns; median GCS at hospital discharge 15 (IQR 15-15) vs 15 (IQR 15-15), p=ns) [Thel 1997].

Dallas 2015 Draft Treatment Recommendations There are no studies that show improved survival to hospital discharge or functional survival with the use of antiarrhythmics in cardiac arrest patients refractory to VF/pVT. We suggest the use of amiodarone in adult patients who suffer OHCA with refractory VF/pVT to improve rates of ROSC (Weak recommendation; high confidence in effect estimate). Clinicians might consider lidocaine or nifekalant for in adult patients who suffer OHCA and IHCA, respectively (Weak recommendation, very low confidence in effect estimates). We suggest against the use of magnesium in adult patients who are in OHCA in any rhythm (Strong recommendation, moderate confidence in effect estimate).

Dallas 2015 Knowledge Gaps There is a need for sufficiently powered RCTs to detect a difference in survival to hospital discharge or favorable neurological outcomes

Dallas 2015 Next Steps This slide will be completed during Task Force Discussion (not EvRev) and should include: Consideration of interim statement Person responsible Due date Essential slide (one slide only). Estimated time <30 sec