Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

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Article Reviewed:

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Amiodarone as compared with lidocaine for shock-resistant ventricular fibrillation.

Dorian P, Cass D, Schwartz B, et al.

N Engl J Med. 2002;346(12):884-90. [abstract; full-text for subscribers]

Reviewed by Jennifer Keates Baleeiro, MD, and Kathy Meert, MD, Children's Hospital of Michigan, Detroit, MI

Review posted May 3, 2002

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I. What is being studied?:

The study objective:

The study objective was to determine if amiodarone as compared to lidocaine led to higher rates of survival to hospital admission in patients with shock-resistant out-of hospital ventricular fibrillation.

The study design:

The study design was a randomized double blind, placebo controlled clinical trial conducted in Toronto under the auspices of the Toronto Emergency Medical Services system. This system follows treatment protocols in accordance with the American Heart Association guidelines for advanced cardiac life support. The University of Toronto's human subjects review committee approved the study including waiver of informed consent.

The study was sponsored by Wyeth-Ayerst Laboratories, which manufactures amiodarone. However, the investigator-initiated protocol was designed, drafted, executed, analyzed and written by the study authors without contribution from the sponsoring company.

The patients included:

The patients included adults treated out-of-hospital whose ECG demonstrated ventricular fibrillation.

Eligible patients included those with ventricular fibrillation resistant to 3 shocks from an external defibrillator followed by an epinephrine injection, and patients who continued to experience ventricular fibrillation or had recurrent ventricular fibrillation after successful initial defibrillation.

The patients excluded:

The patients excluded were trauma patients, or any patient with an initial cardiac rhythm different from ventricular fibrillation.

The interventions compared:

The interventions compared were the administration of either intravenous amiodarone with lidocaine placebo or intravenous lidocaine with amiodarone placebo.

The outcomes evaluated:

The primary outcome evaluated was survival to admission to a hospital intensive care unit. The secondary outcome was survival to discharge from hospital.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes, the ambulances/EMS response teams used drug kits in a balanced, randomized manner in blocks of four so that the number of patients in the control (lidocaine) and amiodarone groups would be roughly equal.

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

Was followup complete?

All patients were followed until hospital discharge or death. At the end of the study, all 347 patients were accounted for between the control (lidocaine) and amiodarone groups.

Were patients analyzed in the groups to which they were randomized?

All patients were analyzed in the groups to which they were randomized, even if rescue medicine such as open labeled lidocaine was administered. 4 patients in the amiodarone group and 1 patient in the lidocaine group received open labeled lidocaine before study drug administration. 11 patients in the amiodarone group and 10 patients in the lidocaine group received open label lidocaine after study drug administration. The use of open label lidocaine was shown to be nonsignificant in increasing survival to hospital admission.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes, all study personnel were blind to treatment. The assignment of drug treatment was unknown to patients, EMS staff and clinicians in the ICU setting at the 17 community hospitals participating in the protocol.

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

A qualified yes. Although there were no significant differences in the No significant differences between the amiodarone and lidocaine groups were evident at the start of the trial regarding gender, age, history of cardiac disease, initial rhythm, rhythm at time of drug administration, time until EMS response, or the course of resuscitation.

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

All patients received the same standard approach in the field following American Heart Association ACLS guidelines until the experimental intervention of lidocaine versus amiodarone.

The secondary outcome of survival to hospital discharge rests on the assumption that the 17 community hospitals receiving the patients from the EMS teams would treat cardiac patients similarly. All participating hospitals were located in the same geographical area. However, differences in patient care between hospitals may exist.

III. What were the results?

1. How large was the treatment effect?

167 patients were enrolled in the lidocaine group and 180 patients were enrolled in the amiodarone group. The goal for enrollment was 350 patients, (actual 347), 160 in each treatment group plus an additional 30 patients to allow for missing data. The sample size reflected an alpha error of 0.05, a power of 80% and an estimated increase from 25% to 40% survival in patients receiving amiodarone.

20 patients (12%) in the lidocaine group survived to hospital admission, while 41 patients (22.8%) in the amiodarone group survived to hospital admission. The absolute risk reduction was 10.8% (CI .028-.187). The relative risk reduction was 90% (CI 17-208%)

	Calculation	Clinical measure
Baseline risk (lidocaine): X	20/167	0.12 or 12%
Risk with amiodarone: Y	41/180	0.228 or 22.8%
Absolute risk reduction (Risk difference): X-Y	0.228-0.12	0.108 or 10.8%
Relative Risk: Y/X	0.228/0.12	1.9
Relative Risk Reduction (RRR): [X-Y/X] x 100	[0.12-0.228]/0.12 x 100	90%
Number needed to treat: 1/ARR	1/.108	9
Odds ratio		2.17

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

Clinical Significance Measure	Value	Lower 95% confidence boundary	Upper 95% confidence boundary
Absolute Risk Reduction (ARR)	10.8%	2.8%	18.7%
Relative Risk Reduction (RRR)	90%	17%	208%
Odds Ratio	2.17	1.21	3.83
Number Needed to Treat (NTT)	9	5	35

The results suggest that in a similar population the odds ratio for survival would favor the use of amiodarone. Patients are 2.17 (95% CI 1.21 to 3.86) times more likely to survive to hospital admission if amiodarone is used in shock resistant ventricular fibrillation. The benefits of amiodarone are still significant even with adjustment for variables such as age/sex/history of heart disease. A subgroup analysis was conducted to evaluate the effect of amiodarone in patients with early and later EMS response times. Survival to admission was greatest with amiodarone whether the patients were treated within 24 minutes or after 24 minutes of EMS dispatch. (24 minutes was the median response time for EMS teams to deliver the study drugs.)

IV. Will the results help me in caring for my patients?

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

The study focused on adults rather than pediatric patients. Usually, pediatric patients are not found out of hospital experiencing ventricular fibrillation secondary to coronary artery disease. Young patients are generally more likely to arrest secondary to respiratory failure. Pediatric patients may experience dysrhythmias secondary to respiratory arrest or congenital heart disease post surgical repair. Since this study suggests benefits of amiodarone for ventricular fibrillation in an ACLS protocol, it would be reasonable to suggest a pediatric study in-house with the possible use of amiodarone versus lidocaine.

2. Were all clinically important outcomes considered?

The primary outcome of survival to hospital admission was improved by the use of amiodarone. The secondary (and more important) outcome of survival to hospital discharge was considered, however the study was not sufficiently powered to detect a significant difference. Very few patients are successfully discharged from the hospitals after out of hospital ventricular fibrillation. A much larger sample size would be needed to evaluate long-term survival. The quality of life of the survivors was not considered in this study.

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

The benefit of increased survival from a uniformly dismal prognosis of 95% case fatality rate for out of hospital cardiac arrest suggests that amiodarone may be clinically useful. The number needed to treat suggests that 9 patients would need to be administered amiodarone for 1 additional survivor to the hospital. An even greater number of people would need to be treated to achieve improvement in hospital discharge rates. No adverse events due to the administration of amiodarone were reported in the study, so the administration of amiodarone appears justified. A cost-benefit analysis was not performed.

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