Between November 1994 and February 1997, 3954 consecutive patients were treated for out-of-hospital cardiac arrest from any cause in Seattle and King County and were considered for enrollment in the trial; 3260 of these did not meet the eligibility criteria and did not undergo randomization.

Deviations from the Protocol

Because of the rapidly changing circumstances of resuscitation, a patient's eligibility for the study could change after the inclusion criteria had originally been met. Of the 667 consecutive patients who initially met the study criteria, 160 were not treated with amiodarone or placebo because of spontaneous conversion of their arrhythmia, technical problems, or protocol violations. Moreover, an additional 27 recipients of amiodarone or placebo were discovered, in fact, to be ineligible for the study.

The clinical characteristics of the 27 ineligible patients who were treated and the 160 who were eligible but untreated were similar to those of the eligible, treated patients. As might be expected, the 27 ineligible patients, who had received amiodarone or placebo before their third shock or after a pulse had already been restored, had a higher rate of admission to the hospital (19 of 27, or 70 percent) than the eligible, treated patients (200 of 507, or 39 percent; P=0.003). Sixty-nine of the 160 eligible but untreated patients (43 percent) survived until admission to the hospital, a proportion that did not differ significantly from the proportion of treated, eligible patients who survived until admission to the hospital. The treatment assignment of 3 of the 507 treated, eligible patients was not known (the empty drug vials were lost after use). These three patients were excluded from the analysis; however, the statistical conclusions were the same whether all three were considered to have received amiodarone or all three were considered to have received placebo.

Study Patients

Table 1. Table 1. Clinical Characteristics of the Patients and the Course of Resuscitation before the Administration of Amiodarone or Placebo.

After the exclusions just described, 246 eligible, treated patients (49 percent) were assigned to amiodarone and 258 (51 percent) to placebo, for a total of 504 patients. The treatment groups had similar clinical profiles (Table 1). In 84 percent of patients, the first documented arrhythmia was ventricular fibrillation (including one case of pulseless ventricular tachycardia). In the remaining 16 percent, initial asystole or pulseless electrical activity evolved to ventricular fibrillation during resuscitation. At the actual time of study-drug administration, 88 percent of the patients had ventricular fibrillation and 7 percent had pulseless ventricular tachycardia. In 5 percent (23 patients), the pulseless rhythm was not documented, was ventricular tachycardia at a rate of 150 beats per minute or less, or could have been considered asystole or small-amplitude ventricular fibrillation (<0.1 mV). The clinical characteristics and outcomes of these 23 patients were similar to those of patients in whom ventricular fibrillation or tachycardia was more clearly documented at the time of study-drug administration.

Characteristics before Study-Drug Administration

Table 2. Table 2. Characteristics of Resuscitation and Treatment before and after Assignment to Amiodarone or Placebo.

An average of five shocks were delivered before the administration of amiodarone or placebo (Table 2). More patients in the placebo group had been treated previously for bradycardia or arrhythmias, but these patients were otherwise similar to amiodarone recipients (Table 2). There were no differences between the treatment groups in the time from dispatch until the arrival of the first responders or the paramedics or until the performance of various resuscitation procedures (Table 1). The time from dispatch to the administration of amiodarone or placebo was long (>20 minutes).

Intermediate Outcomes

Among the patients receiving amiodarone, as compared with those receiving placebo, there was a slight reduction in the duration of resuscitation, the number of shocks, and the number of patients needing additional antiarrhythmic drugs for persistent ventricular tachyarrhythmias before arrival at the hospital, but these differences were not significant (Table 2). Among the 298 patients who had a return of spontaneous circulation, recipients of amiodarone were more likely to require treatment for hypotension or bradycardia than recipients of placebo. Among the patients who had pulses on arrival at the hospital, the mean heart rate and blood pressure were lower in amiodarone recipients, but rhythms were similar in the two treatment groups (Table 2).

Survival until Admission to the Hospital

Figure 1. Figure 1. Effect of Treatment with Amiodarone or Placebo on the Rate of Survival to Hospital Admission in All Patients and Subgroups of Patients. VF denotes ventricular fibrillation, PEA pulseless electrical activity, and ROSC return of spontaneous circulation before administration of the study drug. Values above the bars are the percentages of patients who survived to admission.

Of the 504 patients, 197 (39 percent) survived to be admitted to the hospital. Recipients of amiodarone were more likely to be resuscitated and admitted to the hospital than were recipients of placebo (44 percent and 34 percent, respectively; P=0.03), for a relative improvement of 29 percent (Figure 1). After adjustment for other independent predictors of outcome (location of the cardiac arrest, presence or absence of bradycardia or hypotension before the administration of amiodarone or placebo, response time for paramedics, initial rhythm, presence or absence of transient return of spontaneous circulation during the resuscitation attempt, previous treatment with other antiarrhythmic drugs, and sex; P<0.001 to P=0.09), the odds ratio for survival to admission to the hospital in recipients of amiodarone, as compared with recipients of placebo, was 1.6 (95 percent confidence interval, 1.1 to 2.4; P=0.02), which was similar to the unadjusted odds ratio of 1.5 (95 percent confidence interval, 1.04 to 2.1; P=0.03).

Figure 2. Figure 2. Effect of the Length of Time to the Administration of Amiodarone or Placebo on the Rate of Survival to Admission to the Hospital in Patients with Witnessed Cardiac Arrest, According to Quartile of Time from Dispatch. As compared with the placebo group, the amiodarone group had a better outcome at all measured intervals, and the benefit was consistent whether the drug was administered early or late (P=0.008 by the Mantel–Haenszel chi-square test). Values above the bars are the percentages of patients who survived to admission.

Among the 221 patients with witnessed cardiac arrests for whom the interval from dispatch to study-drug administration was known, there was no significant interaction between this interval and the effect of amiodarone on the rate of admission to the hospital. For all lengths of time to treatment, whether the interval was analyzed as a continuous variable or according to quartiles (as in Figure 2), amiodarone recipients were more likely to survive to be admitted to the hospital than those who received placebo (P=0.008 by the Mantel–Haenszel chi-square test).

Subgroup Analyses

Patients whose cardiac arrest was due to ventricular fibrillation were more likely to survive to be admitted to the hospital than those whose initial rhythm was asystole or pulseless electrical activity (44 percent vs. 14 percent; adjusted odds ratio, 5.2; 95 percent confidence interval, 2.5 to 10.6; P<0.001). In addition, patients with a transient return of spontaneous circulation were more likely to survive to be admitted than those who remained pulseless before receiving amiodarone or placebo (53 percent vs. 30 percent; adjusted odds ratio, 2.7; 95 percent confidence interval, 1.7 to 4.5; P<0.001). A multivariate test of interaction showed no significant differences in the response to treatment with amiodarone with respect to either the initial cardiac-arrest rhythm or the presence or absence of a transient return of pulses before study-drug administration, suggesting that the benefit associated with amiodarone was essentially the same among these subgroups (Figure 1).

Women tended to have better outcomes after cardiac arrest than men: 49 of 114 women (43 percent) and 148 of 390 men (38 percent) survived to be admitted to the hospital (adjusted odds ratio, 1.6; 95 percent confidence interval, 0.97 to 2.6; P=0.06). The effect of amiodarone was also significantly modified by sex, independently of age or the other pretreatment variables listed in Table 1 and Table 2. Women treated with amiodarone were more likely than women receiving placebo to survive to be admitted to the hospital (adjusted odds ratio, 4.3; 95 percent confidence interval, 1.03 to 17.8). Among men, the comparable adjusted odds ratio was 1.2 (95 percent confidence interval, 0.8 to 1.9). The interaction between treatment with amiodarone and sex was significant (P=0.008).

Patients who had received an antiarrhythmic medication to treat ventricular fibrillation or tachycardia before receiving the study drug were more likely than those who had not received such medication to survive to be admitted to the hospital (45 percent vs. 37 percent; adjusted odds ratio, 1.8; 95 percent confidence interval, 1.1 to 2.8; P=0.02). However, a multivariate test of interaction found no significant differences in the effect of amiodarone with respect to either previous or subsequent treatment with antiarrhythmic medications, suggesting an equivalent benefit of amiodarone regardless of the use of additional antiarrhythmic drugs.

Survival after Hospital Admission

Blinding was maintained throughout hospitalization, but the treatment of patients after their arrival at the hospital was not standardized. Of the 504 study patients, 67 (13 percent) were discharged alive from the hospital. Of the remaining 130 patients who were admitted to the hospital, 13 patients awakened, and 117 (90 percent) never regained consciousness. In these patients, the identifiable contributing causes of death were cardiovascular in 35 percent, respiratory in 30 percent, and multifactorial or unspecified in the remainder, and the causes of death did not significantly differ between treatment groups.

The proportion of patients who survived until discharge from the hospital did not differ significantly in the amiodarone and placebo groups, regardless of whether the analysis included all treated patients (13.4 percent [33 of 246] and 13.2 percent [34 of 258], respectively), only patients whose presenting arrhythmia was ventricular fibrillation (16 percent and 15 percent), or only those who had a transient return of pulses before treatment (24 percent and 15 percent). More than half of the 67 patients discharged alive after treatment with amiodarone or placebo, all after lengthy resuscitation, resumed independent living activities or returned to their former employment (55 percent [18 of 33] in the amiodarone group and 50 percent [17 of 34] in the placebo group).