TITLE: Thrombolytic Drugs for Cardiac Arrest: A Review of the Clinical Effectiveness

Transcription

1 TITLE: Thrombolytic Drugs for Cardiac Arrest: A Review of the Clinical Effectiveness DATE: 28 January 2013 CONTEXT AND POLICY ISSUES While out-of-hospital cardiac arrest is a relatively rare occurrence, with the median incidence estimated to be 52 people per 100,000 individuals in North America, 1 cardiac arrest is associated with considerable mortality. While estimates vary, generally less than 10% of people who experience cardiac arrest will survive to hospital discharge. 1,2 There are a number of causes of cardiac arrest, and approximately 70% of cases of cardiac arrest are caused by acute myocardial infarction or pulmonary embolism. 3,4 Other potential causes of cardiac arrest include non-traumatic bleeding, intoxication, trauma, and malignancy. 4 Treatment for cardiac arrest is focused on basic life support, which involves cardiopulmonary resuscitation (CPR) with chest compressions, with or without rescue breaths, defibrillation with an automated external defibrillator (AED) if the person has ventricular fibrillation or pulseless ventricular tachycardia, and access to emergency medical care as quickly as possible. 5 Basic life support has been proven to improve survival in people with cardiac arrest, but even with administration of basic life support, likelihood of mortality due to cardiac arrest remains high. 1,5 Given that cardiac arrest is associated with considerable mortality, it is clear that strategies for preventing mortality in this population are necessary. Myocardial infarction and pulmonary embolism are two common causes of cardiac arrest, 3,4 and thrombolytics can be used to treat these conditions in certain circumstances, including pulmonary embolism with hypotension and ST-elevation myocardial infarction (STEMI) with symptom onset within the previous 12 hours. 6,7 In addition, cardiac arrest itself initiates systemic coagulation due to ischemia. 8 As a result, those who experience cardiac arrest may benefit from receiving thrombolytic therapy to dissolve blood clots and improve systemic circulation. This purpose of this report is to determine the clinical effectiveness of thrombolytic drugs for the treatment of people experiencing cardiac arrest. Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 RESEARCH QUESTION 1. What is the clinical effectiveness of thrombolytic drugs for the treatment of adult patients experiencing cardiac arrest with a return of spontaneous circulation? KEY FINDINGS Higher quality controlled trials indicate that the use of thrombolytic drugs does not improve survival to hospital discharge and 30-day mortality, and increases the risk of bleeding for patients experiencing a cardiac arrest. METHODS Literature Search Strategy A limited literature search was conducted on key resources including PubMed, The Cochrane Library (2012, Issue 12), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2007 and December 19, Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications for relevancy, and evaluated the relevant full-text publications for the final article selection based on the criteria listed in Table 1. Table 1: Selection Criteria Population Adults experiencing cardiac arrest with return of spontaneous circulation Intervention Comparator Outcomes Study Designs Thrombolytics, including tissue plasminogen activator (t-pa) (alteplase, reteplase, and tenecteplase), anistreplase, streptokinase, and urokinase Standard care, placebo, or each other Improved clinical outcomes, mortality, or length of hospital stay Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and non-randomized studies Exclusion Criteria Studies were excluded if they did not meet the selection criteria, if they were duplicate publications or were included in a selected systematic review, or were published prior to January 1, Critical Appraisal of Individual Studies The Downs and Black checklist 9 was used to critically appraise the observational studies included in this report, and the Assessment of Multiple Systematic Reviews (AMSTAR) tool was Thrombolytic Drugs for Cardiac Arrest 2

3 used to critically appraise the systematic review. 10 Summary scores were not calculated for the included studies, rather, a review of the strengths and limitations of each included study were described. SUMMARY OF EVIDENCE Quantity of Research Available The literature search identified 254 citations. After screening titles and abstracts, 238 citations were excluded and 16 potentially relevant manuscripts were retrieved for full-text review. The grey literature search did not identify any additional relevant publications. Of the 16 potentially relevant manuscripts, 13 did not meet the selection criteria, and three publications were included in this review, as outlined in a PRISMA flowchart (Appendix 1). Among the three publications included, one was a systematic review of controlled trials, 11 and two were observational studies. 12,13 Summary of Study Characteristics Details on study design, critical appraisal, and study findings are located in Appendices 2, 3, and 4, respectively. Study Design One systematic review of controlled trials, 11 and two observational studies were included in this review. 12,13 Among the observational studies, both were retrospective cohort designs. Country of Origin One observational study was from Austria, 13 and one study was from France. 12 The systematic review originated in Canada, 11 and included five controlled studies from Australia, 14 Austria, 15 Canada, 16 and the United States. 17 The fifth study 18 in the systematic review was a multicentre study involving sites in Austria, Belgium, France, Germany, Italy, the Netherlands, Norway, Spain, Sweden, and Switzerland. Patient Population The controlled trials from the systematic review 11 included patients who failed to respond to advanced cardiac life support regardless of cause of cardiac arrest, 14,16,17 or those with presumed cardiac causes of cardiac arrest. 15,18 In the observational studies, Renard et al. included people with non-traumatic out-of-hospital cardiac arrest, 12 and Richling included patients with cardiac arrest due to acute STEMI. 13 Among the studies included, there were no studies that specifically looked at use of thrombolytics in people after return of spontaneous circulation (ROSC), rather, ROSC was an outcome measure in the five studies included in the systematic review Interventions and Comparators Thrombolytics that were evaluated in the included studies were alteplase, reteplase, tenecteplase, and t-pa (type not specified) Placebo was the comparator in the randomized controlled trials included in the systematic review. 14,16,18 One observational study compared Thrombolytic Drugs for Cardiac Arrest 3

4 thrombolysis to percutaneous coronary intervention (PCI), 13 and standard resuscitation care was used as the comparator in the other observational studies. 12,15,17 Thrombolytics were administered by an out-of-hospital emergency physician or mobile intensive care unit prior to hospital arrival, 12,18 immediately after admission to the emergency department, 13,14,17 in those who failed to achieve ROSC after 15 minutes of standard advanced life support, 15 or in those with pulseless electrical activity for at least one minute and no palpable pulse for more than 3 minutes during rescuscitation. 16 Clinical Outcomes A number of outcomes were assessed to identify the clinical effectiveness of thrombolytics in cardiac arrest, including best-achieved functional neurologic recovery within 6 months after cardiac arrest, 13 mortality at 6 months after cardiac arrest, 13 and survival to hospital admission. 12 The studies included in the systematic review assessed 30 day survival, 18 ROSC, survival to hospital admission. 14,15,17,18 survival to 24 hours, 15,17 length of hospital stay, 16 survival to hospital discharge, neurologic outcome, risk of bleeding Summary of Critical Appraisal Studies included in the systematic review were identified through a comprehensive literature search conducted up to August 2010, and the authors utilized duplicate data extraction to report data from each study. 11 In addition, the authors stated they had no conflicts of interest to disclose. There were a number of limitations associated with the systematic review, including one reviewer to assess the search results for study relevancy and inclusion, no report of the number of studies identified in the literature search or after the relevancy assessment, lack of thorough reporting of the study characteristics, no assessment of individual study quality, and no assessment of publication bias. 11 Strengths of the study by Renard et al. included the reporting of a clear study objective, clear reporting of the outcome measurement, clear description of important demographic and clinical characteristics of the included patients, identification of controls and treated subjects from the same population, and appropriate statistical analyses with comparisons adjusted for differences in known confounding variables. 12 Limitations included no randomization of individuals to thrombolysis or standard care, lack of blinding of outcome assessors to treatment group, and lack of reporting of potential side effects in those who receive thrombolytics compared to those who received standard care. 12 In the study by Richling et al., the study objective was clearly reported, controls and treated subjects were recruited from the same population, important demographic and clinical characteristics of the included patients were clearly described, and the statistical analyses were appropriate and comparisons were adjusted for differences in known confounding variables. 13 The limitations included no randomization of individuals to thrombolysis or standard care, no report of potential side effects in those who received thrombolytics compared to those who received standard care, and the inclusion of individuals who had cardiac arrest due to an acute STEMI, therefore results likely are not generalizable to those with cardiac arrest not due to acute STEMI. 13 Thrombolytic Drugs for Cardiac Arrest 4

5 Summary of Findings What is the clinical effectiveness of thrombolytic drugs for the treatment of adult patients experiencing cardiac arrest with a return of spontaneous circulation? While three of the five studies included in the systematic review demonstrated an increased likelihood of ROSC, the studies also consistently demonstrated no survival difference between those who received thrombolytics compared to those who received placebo or standard care. 11 The largest RCT included in the systematic review evaluated 1050 patients (525 in the treatment group and 525 in the placebo group) with cardiac arrest of presumed cardiac origin, and found no difference in likelihood of 24 hour or 30 day survival, but a significant increase in the likelihood of intracranial hemorrhage in those who received tenecteplase compared to placebo (2.7% vs. 0.4%, relative risk: 6.95; 95% CI: 1.59 to 30.41). 18 Renard and colleagues found that use of thrombolytic therapy increased the likelihood of surviving to hospital admission in those with non-traumatic out-of-hospital cardiac arrest (47.7% vs. 23.6%, adjusted odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.09 to 2.68). 12 They found a statistically significant interaction between shock with an AED and thrombolytic therapy; in those who were not initially shocked with an AED, if a person received thrombolytic therapy, they were 3.6 times more likely to survive to hospital admission compared to those who did not receive thrombolytic therapy (adjusted OR: 3.61; 95% CI: 1.88 to 6.96). 12 In those who were initially shocked with an AED, there was no significant difference in survival to hospital admission (adjusted OR: 1.08; 95% CI: 0.61 to 1.92). 12 In a population of people with cardiac arrest due to acute STEMI, no difference was found in functional neurologic recovery or survival at 6 months in those who received thrombolytics compared to those who received PCI. 13 The authors concluded that thrombolytics may be an option for those with cardiac arrest due to acute STEMI in which PCI is not readily available. 13 Limitations There are limitations in the currently available evidence that must be noted. The studies identified for this report did not look at the impact of thrombolytic administration after ROSC on patient outcomes, but most studies included ROSC as an endpoint. In addition, some of the studies used different study populations (for example, cardiac arrest due to presumed or confirmed cardiac causes) and different thrombolytic agents, making the results difficult to compare between studies. However, results were consistent across studies in terms of lack of benefit on survival, so this may indicate that thrombolytic agents as a class do not improve survival in different populations. Only one of the included studies involved patients from Canada, however, it is unlikely that the results of other studies included in this report would not apply to the Canadian population. Four of the studies, including two from the systematic review, did not randomize study participants to treatment or control, and are therefore subject to bias, including confounding by indication and residual confounding. Four of the studies had sample sizes of less than 200 people, limiting the power to detect differences in hard endpoints like survival. Thrombolytic Drugs for Cardiac Arrest 5

6 CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING Based on the evidence included in this review, it appears that while thrombolytics may increase the likelihood of ROSC and survival to hospital admission, they do not increase the likelihood of survival to hospital discharge or 30 days after cardiac arrest compared to placebo or standard care. In addition, use of thrombolytics increased bleed risk, including intracranial hemorrhage, compared to placebo. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Thrombolytic Drugs for Cardiac Arrest 6

7 REFERENCES 1. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA Sep 24;300(12): Available from: 2. Rea TD, Eisenberg MS, Sinibaldi G, White RD. Incidence of EMS-treated out-of-hospital cardiac arrest in the United States. Resuscitation Oct;63(1): Spaulding CM, Joly LM, Rosenberg A, Monchi M, Weber SN, Dhainaut JF, et al. Immediate coronary angiography in survivors of out-of-hospital cardiac arrest. N Engl J Med Jun 5;336(23): Kuisma M, Alaspaa A. Out-of-hospital cardiac arrests of non-cardiac origin. Epidemiology and outcome. Eur Heart J Jul;18(7): Berg RA, Hemphill R, Abella BS, Aufderheide TP, Cave DM, Hazinski MF, et al. Part 5: adult basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation Nov 2;122(18 Suppl 3):S685-S Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of patients with acute myocardial infarction). J Am Coll Cardiol Aug 4;44(3):E1-E Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest Feb;141(2 Suppl):e419S-e494S. 8. Bottiger BW, Motsch J, Bohrer H, Boker T, Aulmann M, Nawroth PP, et al. Activation of blood coagulation after cardiac arrest is not balanced adequately by activation of endogenous fibrinolysis. Circulation Nov 1;92(9): Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health [Internet] Jun [cited 2013 Jan 10];52(6): Available from: Shea BJ, Hamel C, Wells GA, Bouter LM, Kristjansson E, Grimshaw J, et al. AMSTAR is a reliable and valid measurement tool to assess the methodological quality of systematic reviews. J Clin Epidemiol Oct;62(10): Perrott J, Henneberry RJ, Zed PJ. Thrombolytics for cardiac arrest: case report and systematic review of controlled trials. Ann Pharmacother Dec;44(12): Thrombolytic Drugs for Cardiac Arrest 7

8 12. Renard A, Verret C, Jost D, Meynard JB, Tricehreau J, Hersan O, et al. Impact of fibrinolysis on immediate prognosis of patients with out-of-hospital cardiac arrest. J Thromb Thrombolysis Nov;32(4): Richling N, Herkner H, Holzer M, Riedmueller E, Sterz F, Schreiber W. Thrombolytic therapy vs primary percutaneous intervention after ventricular fibrillation cardiac arrest due to acute ST-segment elevation myocardial infarction and its effect on outcome. Am J Emerg Med Jun;25(5): Fatovich DM, Dobb GJ, Clugston RA. A pilot randomised trial of thrombolysis in cardiac arrest (The TICA trial). Resuscitation Jun;61(3): Bottiger BW, Bode C, Kern S, Gries A, Gust R, Glatzer R, et al. Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial. Lancet May 19;357(9268): Abu-Laban RB, Christenson JM, Innes GD, van Beek CA, Wanger KP, McKnight RD, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med May 16;346(20): Bozeman WP, Kleiner DM, Ferguson KL. Empiric tenecteplase is associated with increased return of spontaneous circulation and short term survival in cardiac arrest patients unresponsive to standard interventions. Resuscitation Jun;69(3): Bottiger BW, Arntz HR, Chamberlain DA, Bluhmki E, Belmans A, Danays T, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med Dec 18;359(25): Thrombolytic Drugs for Cardiac Arrest 8

9 APPENDIX 1: Selection of Included Studies 254 citations identified from electronic literature search and screened 238 citations excluded 16 potentially relevant articles retrieved for scrutiny (full text, if available) 0 potentially relevant reports retrieved from other sources (grey literature, hand search) 16 potentially relevant reports 13 reports excluded: - irrelevant population (1) - irrelevant outcomes (1) - no control group (case series) (2) - already included the selected systematic review (2) - other (review articles, editorials) (7) 3 reports included in review Thrombolytic Drugs for Cardiac Arrest 9

10 APPENDIX 2: Characteristics of Included Studies First Author, Publication Year, Country Systematic Review Perrott, 2010, Canada 11 Study Design and Length Systematic review Observational Studies Renard, Retrospective 2011, cohort study France 12 Richling, 2007, Austria month study period ( ) Retrospective cohort study 13.5 year study period ( ) Patient Characteristics Included 5 controlled trials (2 were prospective observational studies; 3 were RCTs) involving 1,544 cases of cardiac arrest. Publication years were 2001, 2002, 2004, 2006, and Non-traumatic OHCA, age > 18 years Thrombolytic provided by an out-of-hospital emergency physician with EMS Witnessed cardiac arrest due to acute STEMI Intervention Comparator Clinical Outcomes Measured t-pa (type not specified) used in 2 studies, tenecteplase in 3 studies Alteplase (50mg single bolus) or tenecteplase (100 IU/kg single bolus) (n = 107 combined without a description of who received each thrombolytic) Reteplase 100mg in a front-loaded regimen or tenecteplase in a weight-adjusted dosage after admission to emergency and a diagnosis of acute STEMI (n = 101 combined without a description who received each thrombolytic) RCTs: placebo Observational studies: standard resuscitation care No thrombolytics (n = 1154) PCI (n = 46) ROSC; survival to hospital admission; 24 hour survival; survival to hospital discharge; risk of bleeding events Primary outcome: survival to hospital admission Secondary: impact of AED shock administration on survival to hospital admission for those with and without thrombolytics Primary outcome: bestachieved functional neurologic recovery, based on cerebral performance category (on a scale of 1 5 with 1 equal to conscious with little or no disability and 5 equal to brain death), within 6 Thrombolytic Drugs for Cardiac Arrest 10

11 First Author, Publication Year, Country Study Design and Length Patient Characteristics Intervention Comparator Clinical Outcomes Measured months after cardiac arrest Secondary outcome: mortality at 6 months after cardiac arrest AED: automated external defibrillator; CPR: cardiopulmonary resuscitation; EMS: emergency medical services; OHCA: out of hospital cardiac arrest; PCI: percutaneous coronary intervention; RCT: randomized controlled trial; ROSC: return of spontaneous circulation; STEMI: ST-elevation myocardial infarction; tpa: tissue plasminogen activator Thrombolytic Drugs for Cardiac Arrest 11

12 APPENDIX 3: Critical Appraisal of Included Studies First Author, Strengths Publication Year Systematic Review Perrott, Duplicate data extraction Comprehensive literature search of three databases (MEDLINE, Embase, and Google Scholar) up to August Authors reported no conflict of interest. Observational Studies Renard, Study objective clearly reported Outcome clearly reported in the methods section of the manuscript. Important demographic and clinical characteristics of the included patients were clearly described. Included all patients who presented with a non-traumatic out-of-hospital cardiac arrest from , therefore the patient population is likely generalizable. Controls and treated subjects were recruited from the same population. The main findings of the study are clearly described. Statistical analyses were appropriate and comparisons adjusted for differences in known confounding variables. Richling, Study objective clearly reported Controls and treated subjects were recruited from the same population. Study endpoints clearly defined. Important demographic and clinical characteristics of the included patients were clearly described. The main findings of the study are clearly described. Statistical analyses were appropriate and comparisons adjusted for differences in known confounding variables. STEMI: ST-elevation myocardial infarction Limitations No specific inclusion criteria were reported. Only a list of the five included studies was reported, without mention of how many studies were identified from the original search or after the relevancy assessment. No formal assessment of study quality. No assessment of publication bias. No mention of losses to follow up or if missing data existed, and how it was handled in the analysis. No report of potential side effects in those who receive thrombolytics compared to those who received standard care. No randomization of individuals to thrombolysis or standard care. Outcome assessors were not blinded to treatment group. Included individuals who had cardiac arrest due to an acute STEMI, therefore results are not generalizable to those with cardiac arrest not due to acute STEMI. No randomization of individuals to thrombolysis or standard care. No mention of losses to follow up or if missing data existed, and how it was handled in the analysis. No report of potential side effects in those who received thrombolytics compared to those who received standard care. Outcome assessors were not blinded to treatment group. Thrombolytic Drugs for Cardiac Arrest 12

13 APPENDIX 4: Results of Included Studies First Author, Main Study Findings Publication Year Systematic review Perrott, 3/5 studies demonstrated a significant increase in ROSC in those who received thrombolytics compared to those who received placebo/standard care. 2/5 studies demonstrated a significant increase in likelihood of hospital admission in those who received thrombolytics compared to those who received placebo/standard care. No significant difference was found between those who received thrombolytics compared to those who received placebo/standard care in 24 hour survival (evaluated in 3 studies) or survival to hospital discharge (evaluated in 5 studies). A total of 94 bleeding events were reported in the 5 studies, 59 in the thrombolytics group and 35 in the placebo group. Observational Studies Renard, Survival to hospital admission: 51/107 (47.7%) who received thrombolysis 272/1154 (23.6%) who did not receive thrombolysis Study authors performed a multivariate propensity score-matched logistic regression to estimate the impact of thrombolytic therapy on likelihood of hospital admission (47.7% in the thrombolytic group compared to 23.6% in the standard care group): Adjusted OR: 1.7; 95% CI: Adjusted for differences in age, gender, bystander presence and action, etiology, AED shock administration, and delay between alarm and AED switch on. Authors Conclusions From a clinical decision-making perspective, controlled trials have shown that there is a lack of benefit and potential harm to administering thrombolysis in a patient with undifferentiated cardiac arrest (p. 2012) The authors suggest that those with a cardiac arrest due to pulmonary embolus may benefit from use of thrombolytics: Clinicians should be cognizant of current evidence and not write off a potentially beneficial intervention in a patient who is part of a population that has not been adequately studied and who likely has a better than average change of benefiting from this therapy. (p. 2012) This study showed that fibrinolytic therapy was associated with more frequent survival to hospital admission. (p. 407) In our study population, the influence of shock administration by first responder AED, the variables that influence the doctor s decision to administer fibrinolytics and the choice of a pragmatic endpoint are three essential points that need further research. (p. 408) Patients who did not receive external shock from an AED: thrombolytics associated with a greater likelihood of survival to hospital admission: Adjusted OR: 3.61; 95% CI: Patients who did receive external shock from an AED: survival to hospital admission was not impacted by administration of thrombolytics: Adjusted OR: 1.08; 95% CI: Thrombolytic Drugs for Cardiac Arrest 13

14 First Author, Main Study Findings Publication Year Richling, CPC 1 or 2 (56% in those who received thrombolysis compared to 48% in those who received primary PCI): Adjusted OR: 1.24; 95% CI: Survival at 6 months (68% in those who received thrombolysis compared to 55% in those who received primary PCI): Adjusted OR: 1.74; 95 % CI: Comparisons were adjusted for differences in location of cardiac arrest, cooling, age, and sex. Authors Conclusions In patients with cardiac arrest due to acute STEMI, we found no evidence that PCI offers an important advantage compared with thrombolysis. (p. 549) Although the study was retrospective and too small to draw a definitive conclusion, it may be an acceptable option to use thrombolysis as a reperfusion strategy in such patients. This applies especially in hospitals where immediate PCI is not available. (p. 549) AED: automated external defibrillator; CI: confidence interval; CPC: cerebral performance category; OR: odds ratio; PCI: percutaneous coronary intervention; SD: standard deviation; STEMI: ST-elevation myocardial infarction; VF: ventricular fibrillation Thrombolytic Drugs for Cardiac Arrest 14