Tissue Plasminogen Activator During Cardiac Arrest: No Better Than Placebo?

Overall Study Question

This study was conducted to determine the efficacy of administration of tissue plasminogen activator (t-PA) during cardiopulmonary resuscitation (CPR) in adults with undifferentiated pulseless electrical activity (PEA) not responsive to initial therapy. Adults (>16 years of age) who had more than 1 minute of PEA and were unresponsive to initial therapy (endotracheal intubation and ventilation with 100% oxygen, 500 mL of normal saline and 1 mg of intravenous (IV) epinephrine) outside the hospital were eligible for the study. The primary endpoint was survival to hospital discharge. The secondary endpoints included return of spontaneous circulation (ROSC), length of hospital stay, hemorrhage and neurological outcome.

Are the Results of the Study Valid?

1. Was assignment of patients randomized?

Yes. Patients were randomized to receive either tPA 100 mg IV over 15 minutes or matching placebo.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes. 233 patients met inclusion criteria and were randomized (117 tPA and 116 placebo). All patients were included in the final analysis.

3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?

Yes. The study was double-blinded. The appearance of the tPA and placebo before and after reconstitution was indistinguishable.

4. Were the groups similar at the start of the trial?

Yes. The baseline characteristics of the tPA and placebo groups were similar.

5. Aside from the experimental intervention, were the groups treated equally?

Yes. There were no differences in the further treatment of patients assigned to tPA or placebo.  Once infusion of the study drug commenced, the infusion was completed regardless of weather a pulse developed.  Resuscitative efforts were continued for a minimum of 15 minutes after the infusion was completed, and further treatment was at the discretion of the CPR leader.

What were the Results?

1. How large was the treatment effect?

The primary endpoint, survival to hospital discharge, occurred in 1(0.9%) patient treated with tPA compared to none (0%) who received placebo. The absolute difference in survival between the tPA group and placebo group was 0.9% (95% confidence interval [CI] -2.6 to 4.3, p=ns).

The secondary endpoint of ROSC occurred in 21.4% of patients in the tPA group and 23.3% of patients in the placebo group (p=ns).

2. How precise was the estimate of the treatment effect?

The 95% CI for the primary endpoint of survival to hospital discharge included zero indicating a non-statistically significance result (0.9%, 95% CI -2.6-4.3, p=ns).

Will the Results Help Me in Caring for My Patients?

1. Can the results be applied to my patient care?

Yes. The use of tPA in a patient population consisting of undifferentiated PEA does not appear to be beneficial in improving overall survival.

2. Were all clinically important outcomes considered?

Yes. In cardiac arrest research the ultimate endpoint is overall survival which was the primary endpoint in this trial.

3. Are the likely treatment benefits worth the potential harms and costs?

No.

Commentary

There are several case series which describe neurologically normal survival in patients with prolonged cardiac arrest following the administration of fibrinolytics. However, a majority of these reports represent select patient populations in which the patients were known or likely to be experiencing cardiac arrest secondary to a thromboembolic event such as myocardial infarction and massive pulmonary embolism.  In a non-randomized, prospective study using historical controls found that treatment with tPA significantly increased the rate of ROSC and hospital admission. In a non-randomized, retrospective, case-control study, tPA was found to improve rates of ROSC, 24-hour survival and survival to hospital discharge.

This is the first trial which involved the prospective randomization of a population of undifferentiated cardiac arrest patients to receive tPA or placebo and found no evidence that tPA during CPR improved the likelihood of either survival or ROSC.  It is difficult to determine the reason why this study had such a low survival rate, although this may be explained by the undifferentiated patient population enrolled.  The fact that there appears to be no benefit to patients in cardiac arrest with undifferentiated PEA leads the clinician to conclude that this strategy is not advantageous.  However, as the authors clearly state, the results of this trial cannot be generalized to a highly selective population of patients with cardiac arrest with a known or suspected pulmonary embolism or myocardial infarction meeting criteria for the administration of fibrinolytics.

Original Citation

Abu-Laban RB, Christieson JM, Innes GD, van Beek CA, Wanger KP, McKnight RD, MacPhail IA, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med 2002;346:1552-8.

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