PHILADELPHIA – The potential for harmful side effects associated with anti-psychotic medications for treating schizophrenia is a frustration for mental-health professionals who must balance this with the positive benefits of drugs. For example, the issue of the antipsychotic drug ziprasidone lengthening the QTc interval, a possible indicator of life-threatening heart arrhythmias, has demanded much attention among clinicians since the drug was introduced in 2001.
Ziprasidone (marketed as Geodon and Zeldox by Pfizer Inc.) was the fifth second-generation anti-psychotic to gain Food and Drug Administration (FDA) approval. These second-generation drugs have been thought to be associated with a lower risk of suicides, better functional capacity, and an improved quality of life for people with schizophrenia. (It is well known that patients with schizophrenia suffer an overall increased risk of death.) But questions remained as to whether the modest QTc prolongation caused by ziprasidone would translate into increased mortality for the patients using it.
A study published online this month in the American Journal of Psychiatry in advance of print publication in February 2011 showed no difference in nonsuicide mortality between people taking ziprasidone and another second-generation anti-psychotic in real-world use.
Because the number of patients exposed to ziprasidone at the time of marketing authorization was too small to allow for estimation of QTc-related effects on mortality, and because such studies would not reflect real-world prescribing practices, the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) was initiated to provide safety assurance for the use of the drug. ZODIAC was a post-approval commitment by the drug’s manufacturer, Pfizer, Inc., to the FDA.
ZODIAC is an international, multimember, randomized trial designed to examine the risks of nonsuicidal mortality and hospitalization associated with ziprasidone and olanzapine, another second-generation anti-psychotic approved by the FDA for the treatment of schizophrenia and bipolar disorder. Brian Strom, MD, director of the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine, chaired the steering committee that designed and directed the ZODIAC study. Strom is also chair of the Department of Biostatistics and Epidemiology and Vice Dean for Institutional Affairs in the School of Medicine.
Olanzapine (marketed as Zyprexa and other brands names by Eli Lilly and Comp.) was selected for comparison in the study because it was not linked to QTc prolongation in the literature or in a controlled pharmacokinetic study of several agents compared with ziprasidone. The main objective of ZODIAC was to evaluate nonsuicide mortality, which limited the study’s ability to provide data on drug efficacy.
ZODIAC, an open-label, randomized trial, enrolled over 18,000 patients with schizophrenia in 18 countries. The primary outcome measure was nonsuicide mortality in the year after initiation of treatment. Patients were randomly assigned to receive treatment with either ziprasidone or olanzapine and followed for one year by unblinded investigators providing usual care. A physician-administered questionnaire was used to collect baseline demographic information, medical and psychiatric history, and concomitant medication use. Follow-up information on hospitalizations and emergency department visits, patients’ vital status, and current antipsychotic drug status was also collected.
A total of 205 deaths occurred overall in the study population. Despite the known risk of QTc prolongation with ziprasidone treatment, the findings did not show that ziprasidone is associated with an elevated risk of nonsuicidal mortality relative to olanzapine in real-world use. However the study was not designed to examine the risk of rare cardiac events associated with lengthening of the QTc interval.
“We could not disprove that the drug caused abnormal heart rhythms, but that was not the goal of the study,” says Strom. “Our goal was to determine whether there was a difference in risk of nonsuicide death, and there was not.”
Editor’s notes:
Pfizer funded the ZODIAC study. Penn received financial support from Pfizer in connection with the scientific oversight of the study and the development of the manuscript of the study. Dr. Strom has also served as a consultant to Pfizer on topics not related to the data in the AJP paper.
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $3.6 billion enterprise.
Penn’s School of Medicine is currently ranked #2 in U.S. News & World Report’s survey of research-oriented medical schools, and is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $367.2 million awarded in the 2008 fiscal year.
Penn Medicine’s patient care facilities include:
The Hospital of the University of Pennsylvania — the nation’s first teaching hospital, recognized as one of the nation’s top 10 hospitals by U.S. News & World Report.
Penn Presbyterian Medical Center — named one of the top 100 hospitals for cardiovascular care by Thomson Reuters for six years.
Pennsylvania Hospital — the nation’s first hospital, founded in 1751, nationally recognized for excellence in orthopaedics, obstetrics & gynecology, and psychiatry & behavioral health.
Additional patient care facilities and services include Penn Medicine at Rittenhouse, a Philadelphia campus offering inpatient rehabilitation and outpatient care in many specialties; as well as a primary care provider network; a faculty practice plan; home care and hospice services; and several multispecialty outpatient facilities across the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2009, Penn Medicine provided $733.5 million to benefit our community.
