Tacrine Treatment and Nursing Home Placement: Application of the Cox Proportional Hazards Model With Time-Dependent Cova
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TACRINE TREATMENT AND NURSING HOME PLACEMENT: APPLICATION OF THE COX PROPORTIONAL HAZARDS MODEL WITH TIME-DEPENDENT COVARIATES FRASER SMITH,PHD, AND STEPHEN GRACON, DVM Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan
DAVIDKNOPMAN, MD Department of Neurology, University of Minnesota, Minneapolis, Minnesota
LONSCHNEIDER, MD Department of Psychiany, University of Southern California, Los Angeles, California
Cox proportional hazards regressions with time-dependent covariates were used to determine the effect of continuous, long-term, open-label tacrine hydrochloride (Cognex@) treatment on nursing home placement in patients with Alzheimer 5 disease (AD). The results were compared with those obtained using logistic regression analyses, life table survival plots, and Kaplan-Meier estimates. Patients with probable AD (NlNCDS criteria) initially randomized in a 30-week double-blind, placebo-controlled, parallel-group, high-dose study of tacrine could continue on long-term, open-label treatment at doses up to 160 mg/ahy. The population of interest consisted of patients who remained on tacrine or were off tacrine for only a short period of time (1-60 days) prior to an event. Using last tacrine dose, the Cox proportional hazards regression approach with timedependent covariates demonstrated there was a dose-response trendfavoring higher doses (risk ratio = 1.7, p = 0.056) and a statistically significant difference favoring medium and higher doses combined (risk ratio = 1.8, p = 0.014).
Key Words: Time-dependent covariates; Cox proportional hazards; Survival analysis; Nursing home placement; Tacrine hydrochloride
INTRODUCTION SURVIVAL ANALYSIS TECHNIQUES were used to estimate the delay in time to nursing home placement (NHP) for patients
Reprint address: Fraser Smith, PhD. Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, MI 48105.
with Alzheimer's disease receiving continuous long-term tacrine treatment. Patients initially randomized to a 30-week double-blind, placebo-controlled, parallel group, high-dose study of tacrine (CognexB) (1) could enter a long-term open-label follow-up study (2,3) in which they could receive doses up to 160 mg/day at the discretion of their physician and were followed for approximately two years. This study was conducted at 33 United
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F. Smith,S. Gracon, D. Knopman, and L. Schneider
States centers and consisted of men and women 50 years of age and older with mild to moderate dementia. The analyses in this paper were similar to those used by Smith et al. (3) but were restricted to patients who remained on tacrine or were off tacrine for only 1-60 days prior to an event. The effect of tacrine appears to be dependent on patients continuing treatment-present while on drug and absent when patients go off-with the half life being on the order of several weeks (45). This, in part, motivated the choice of the 60-day win
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