Thrombolysis during out-of-hospital cardiac arrest: a lesson in the law of diminishing returns

Intravascular thrombosis plays a fundamental role in the pathophysiology of cardiac arrest. Autopsy results from cases of unsuccessful resuscitation and coronary angiography in survivors of out-of-hospital cardiac arrest suggest that 50-70% of deaths can be attributed to thrombosis in the form of myocardial infarction or pulmonary embolism [2,3]. Ischemia and reperfusion during resuscitation from cardiac arrest cause endothelial cell dysfunction, platelet activation, disseminated intravascular coagulation, relatively low fi brinolysis, and a propensity for microcirculatory clot formation [4,5]. Expanded Abstract Citation Böttiger BW, Arntz HR, Chamberlain DA, Bluhmki E, Belmans A, Danays T, Carli PA, Adgey JA, Bode C, Wenzel V: Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med 2008, 359:2651-2662 [1]. Background Approximately 70% of persons who have an out-of-hospital cardiac arrest have underlying acute myocardial infarction or pulmonary embolism. Therefore, thrombolysis during cardiopulmonary resuscitation may improve survival. Methods Objective: To determine whether thrombolysis with the use of tenecteplase during cardiopulmonary resuscitation can improve survival in adults with witnessed out-of-hospital arrest of presumed cardiac origin. Design: Prospective, randomized, double-blind, placebo-controlled, multicenter trial. Setting: 66 European emergency medical-service systems. Subjects: 1050 adult patients with witnessed out-of-hospital cardiac arrest. Intervention: We randomly assigned adult patients with witnessed out-of-hospital cardiac arrest to receive tenecteplase or placebo during cardiopulmonary resuscitation. Adjunctive heparin or aspirin was not used. Outcomes: The primary end point was 30-day survival; the secondary end points were hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcome. Results After blinded review of data from the fi rst 443 patients, the data and safety monitoring board recommended discontinuation of enrollment of asystolic patients because of low survival, and the protocol was amended. Subsequently, the trial was terminated prematurely for futility after enrolling a total of 1050 patients. Tenecteplase was administered to 525 patients and placebo to 525 patients; the two treatment groups had similar clinical profi les. We did not detect any signifi cant diff erences between tenecteplase and placebo in the primary end point of 30-day survival (14.7% vs. 17.0%; P=0.36; relative risk, 0.87; 95% confi dence interval, 0.65 to 1.15) or in the secondary end points of hospital admission (53.5% vs. 55.0%, P=0.67), return of spontaneous circulation (55.0% vs. 54.6%, P=0.96), 24-hour survival (30.6% vs. 33.3%, P=0.39), survival to hospital discharge (15.1% vs. 17.5%, P=0.33), or neurologic outcome (P=0.69). There were more intracranial hemorrhages in the tenecteplase group. Conclusions When tenecteplase was used without adjunctive antithrombotic therapy during advanced life support for out-ofhospital cardiac arrest, we did not detect an improvement in outcome, in comparison with placebo. (ClinicalTrials.gov number, NCT00157261.)