Tenecteplase study halted

Sep 6 2006

World Congress of Cardiology 2006 - Thrombolytic Therapy, given during cardiopulmonary resuscitation (CPR) in out-ofhospital cardiac arrests, may be no better than placebo.

One of the largest trials ever conducted into the condition was halted early because of the low chance of patients benefiting. However, researchers say thrombolysis may still be considered in some cases.

The Thrombolysis in Cardiac Arrest (TROICA) Trial was due to enrol 1,300 patients in ten European countries. It was stopped by the data safety monitoring board in July 2006, because of the low chance of the drug, tenecteplase, showing superiority over placebo.

By then, 1,050 patients had been included in this randomised, double-blind study. The new analysis was presented at yesterday’s Hot Line II session. It included 827 patients, of whom 412 received tenecteplase and 415, placebo.

The results were unexpected. There was no significant difference in primary or secondary endpoints. Thirty-day survival was 18.2% for the tenecteplase group, compared with 20.2% for placebo (p=0.512). Hospital admission was 59.0% for the treated patients, and 59.5% for the controls (p= 0.931). There was little difference in rates of return of spontaneous circulation, 24-hour survival, and survival to day 30 or hospital discharge.

Adverse events were higher in the treated group, but again, the differences were not significant. Symptomatic intracranial haemorrhage occurred in 1% of the tenecteplase patients, and 0% among controls (p=0.133); major bleeds in 8.9% of the tenecteplase patients versus 7.4% of controls (p=0.528).

Bernd Böttiger (Heidelberg, Germany) led the project: “The results were somewhat disappointing. We had several pilot studies – not done by our group, but by others around the world – that showed benefit with this particular agent during cardiopulmonary resuscitation.”

There had been a strong rationale for the study: up to 70% of out-of-hospital cardiac arrest patients have underlying acute myocardial infarction or pulmonary embolism.

Thrombolytic therapy is indicated for both conditions. Cardiac arrest is associated with systemic coagulation and, again, dissolving clots with thrombolytic therapy was expected to be beneficial.

It is possible that thrombolysis is not generally effective in cardiac arrests. Böttiger said it could also be that the tenecteplase was given at the wrong time, too early or too late; or that it interacted with other treatments such as vasopressors given during CPR. Further, there could be a need for adjunctive therapy:

“It is possible that tenecteplase opened the coronary arteries and maybe they re-occluded afterwards because we didn’t use a concomitant therapy like heparin because it is not recommended in the guidelines for CPR. We can only speculate”.

The work has no bearing on current indications for thrombolytic therapy, he said, and might still be considered for patients with pulmonary embolism. Sub-group analysis in this study revealed that patients with pulmonary embolism were more likely to be stabilised when given tenecteplase than placebo, but there were too few patients to reach a conclusion. Even so, this condition cannot be picked up outside of hospital.

Böttiger said that more research was needed: “First of all, we have to analyse all the information from the trial in more depth. This is a new analysis completed two or three weeks ago. I am still convinced that this concept has a future but we have to look into the details of our results to come up with future proposals.

“We need to totally understand what is going on in reperfusion after cardiac arrest.

Cardiac arrest remains a high mortality symptom with no specific treatment even when the event is witnessed.”