Whether the modest QTc-prolonging effect of ziprasidone increases cardiovascular event risk is unknown.

The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC), an open-label, randomized, postmarketing study, enrolled patients with schizophrenia from routine clinical practice settings in 18 countries. The primary outcome was non-suicide mortality in the year after initiation of assigned treatment. A total of 18,154 subjects were randomized to ziprasidone or olanzapine, dosed according to enrolling physician's clinical judgment. A physician-administered baseline questionnaire collected information on demographics, medical and psychiatric history, and concomitant medication use. Brief follow-up questionnaires elicited hospitalization data since the last study visit, vital status, study medication continuation, and concomitant antipsychotic medication(s) use. ZODIAC study subjects reflected the general population of patients with schizophrenia.

The incidence of nonsuicide mortality within one year of initiating therapy was 0.91% for the ziprasidone group and 0.90% for the olanzapine group (both n = 9,077), relative risk (95% confidence interval [CI]) of 1.01 (0.75, 1.37). This finding was robust in numerous secondary and sensitivity analyses. Regarding secondary endpoints, the risk of all-cause mortality or cardiovascular mortality was similar among ziprasidone and olanzapine users; the incidence of all-cause hospitalizations was higher among ziprasidone users. The proportion of patients remaining on treatment at 6 months was lower for the ziprasidone group.

ZODIAC is one of the largest randomized studies conducted to date of patients with schizophrenia. With substantial statistical power, the study found no difference in risk of nonsuicide death associated with the use of ziprasidone vs. olanzapine.