BARCELONA — Routine thrombolytic therapy in patients with refractory out-of-hospital cardiac arrest failed to show even a glimmer of benefit in the 1,050-patient Thrombolysis in Cardiac Arrest trial, the first major randomized double-blind study to examine the issue.
“These results are very unexpected,” a disappointed TROICA Chairman Dr. Bernd W. Boettiger admitted at the joint meeting of the European Society of Cardiology and the World Heart Federation. “Cardiac arrest remains a high-mortality syndrome with no specific treatment,” added Dr. Boettiger, professor of anesthesiology at the University of Heidelberg (Germany) and chairman-elect of the European Resuscitation Council.
TROICA involved 1,050 patients in 10 European countries with witnessed cardiac arrest of presumed cardiac origin who didn't experience prompt return of spontaneous circulation after initiation of CPR. Following administration of atropine in accord with standard CPR protocol, patients were randomized to fibrinolytic therapy with tenecteplase or placebo given in the field by EMS personnel or physicians as CPR continued.
The primary end point was 30-day survival. It was 18.2% in the tenecteplase arm and 20.2% with placebo, a nonsignificant difference. About 59% of both groups were admitted to the hospital. The two groups did not differ significantly in any other outcomes, including symptomatic intracranial hemorrhage or major bleeding.
The rationale for TROICA, a Boehringer Ingelheim-funded trial, lies in the well-established fact that 65%–70% of all out-of-hospital cardiac arrests are due to underlying acute MI or pulmonary embolism, both of which are approved indications for thrombolytic therapy. Cardiac arrest also entails activation of a cascade of systemic coagulation, and thrombolytic therapy dissolves blood clots. Roughly a half dozen prior small, nonrandomized studies suggested benefit for thrombolysis during CPR.
One possible explanation for the negative results in TROICA is that thrombolytic therapy was administered either too early or too late. Another is that the tenecteplase was rendered less effective by the derangements in pH and blood glucose, and other changes that characterize cardiac arrest, or perhaps by having vasopressors on board.
“I am still convinced the rationale is sound for a thrombolytic approach during CPR, maybe combined with an adjunctive anticoagulant like heparin,” Dr. Boettiger said in an interview.
For now, he will consider using thrombolysis in out-of-hospital cardiac arrest on a case-by-case basis, mainly in patients with suspected pulmonary embolism. There was a suggestion in TROICA that thrombolysis produced better outcomes in that patient subset.
Dr. Frans Van de Werf, professor of cardiology at the University of Leuven (Belgium), speculated that another possible explanation for TROICA's failure might be that the blood flow generated during prolonged CPR was insufficient to bring the thrombolytic agent to the thrombus. He stressed that the TROICA results have absolutely no bearing on the currently approved indications for thrombolytic therapy: ST-elevation MI, pulmonary embolism, and ischemic stroke.