Monitoring of Drugs With a Narrow Therapeutic Range in Ambulatory Care

Published Online: May 01, 2006
Marsha A. Raebel, PharmD; Nikki M. Carroll, MS; Susan E. Andrade, ScD; Elizabeth A. Chester, PharmD; Jennifer Elston Lafata, PhD; Adrianne Feldstein, MD; Margaret J. Gunter, PhD; Winnie W. Nelson, PharmD; Steven R. Simon, MD, MPH; K. Arnold Chan, MD, ScD; Robert L. Davis, MD, MPH; and Richard Platt, MD

Objectives: To describe the proportion of patients receiving drugs with a narrow therapeutic range who lacked serum drug concentration monitoring during a 1-year period of therapy and to identify patient characteristics associated with lack of monitoring.

Study Design: Retrospective cohort.

Methods: Ambulatory patients (n = 17 748) at 10 health maintenance organizations who were receiving ongoing continuous drug therapy with digoxin, carbamazepine, divalproex sodium, lithium carbonate, lithium citrate, phenobarbital sodium, phenytoin, phenytoin sodium, primidone, quinidine gluconate, quinidine sulfate, procainamide hydrochloride, theophylline, theophylline sodium glycinate, tacrolimus, or cyclosporine for at least 12 months between January 1, 1999, and June 30, 2001, were identified. Serum drug concentration monitoring was assessed from administrative data and from medical record data.

Results: Fifty percent or more of patients receiving digoxin, theophylline, procainamide, quinidine, or primidone were not monitored, and 25% to 50% of patients receiving divalproex, carbamazepine, phenobarbital, phenytoin, or tacrolimus were not monitored. Younger age was associated with lack of monitoring for patients prescribed digoxin (adjusted odds ratio, 1.86; 95% confidence interval, 1.39-2.48) and theophylline (adjusted odds ratio, 1.58; 95% confidence interval, 1.23-2.04), while older age was associated with lack of monitoring for patients prescribed carbamazepine (adjusted odds ratio, 0.59; 95% confidence interval, 0.44-0.80) and divalproex (adjusted odds ratio, 0.50; 95% confidence interval, 0.38-0.66). Patients with fewer outpatient visits were also less likely to be monitored (P< .001).

Conclusions: A substantial proportion of ambulatory patients receiving drugs with narrow intervals between doses resulting in beneficial and adverse effects did not have serum drug concentration monitoring during 1 year of use. Clinical implications of this finding need to be evaluated.

(Am J Manag Care. 2006;12:268-274)

The goal of therapeutic drug monitoring is to guide dosing by means of drug concentration measurements. Therapeutic drug monitoring is useful for drugs that lack correlation between dose and pharmacodynamic properties, for drugs that have nonlinear correlations between dose and effect, and for drugs that have a narrow therapeutic range (NTR) between the dose necessary to achieve beneficial effects and the dose that causes serious adverse effects when there is a direct concentration-effect relationship. Individualizing the drug dosage and the dosing interval can minimize the toxicity and maximize the therapeutic benefit of NTR drugs.1 The first step toward individualizing therapy is to evaluate the drug concentration in the body, often from a serum sample. Although there is controversy about whether monitoring should be routine, as well as about the frequency and timing of therapeutic drug monitoring to maximize beneficial drug effects,2-4 there is general agreement that therapeutic drug monitoring is useful in avoiding drug toxicity. For example, drug concentration monitoring is recommended as a quality-of-care indicator for patients taking phenytoin, phenobarbital, divalproex sodium, and carbamazepine.5,6 Concentration monitoring of many NTR drugs is routinely available at healthcare laboratories, but little is known about the frequency of monitoring among ambulatory patients.

We undertook a study to assess drug concentration monitoring in ambulatory patients receiving NTR drugs. The objectives of this study were to describe the proportion of patients dispensed NTR drugs who did not have drug concentration monitoring during a 1-year therapy period and to identify patient characteristics associated with lack of monitoring. The results of this study provide information to guide thoughtful establishment of quality-of-care indicators related to NTR drug monitoring in ambulatory patients.


Study Population and Design

This retrospective cohort study of ongoing NTR drug therapy was designed to assess rates and correlates of serum drug concentration monitoring among ambulatory members of 10 health maintenance organizations in geographically diverse US locations. We studied monitoring practices for the following NTR drugs: carbamazepine, cyclosporine, digoxin, lithium, phenytoin, phenobarbital, primidone, procainamide hydrochloride, quinidine, tacrolimus, theophylline, and divalproex (valproic acid). The first study objective was to assess the proportion of ambulatory patients receiving continuous ongoing therapy with an NTR drug who did not have at least 1 drug serum concentration monitored within a 1-year period. The second study objective was to evaluate possible associations between lack of NTR drug monitoring and patient age, sex, outpatient visits, chronic diseases, diagnoses, selected socioeconomic status variables, and hospitalizations. Finally, the accuracy of using automated data in identifying drug concentration monitoring was assessed.

The participating organizations comprise the HMO Research Network Center for Education and Research in Therapeutics, which has been described elsewhere.7 In brief, the center includes staff, group, network, independent practice association, and mixed-model health maintenance organizations that serve racially and ethnically diverse populations and in 2000 provided healthcare for approximately 7 million people in more than 1000 locations. The institutional review board of each participating organization approved this study.

The study sample was drawn from a data set of 2 020 037 individuals, consisting of approximately 200 000 randomly selected health plan members from each of the 10 organizations. The sampling scheme and demographic distribution of this population have been previously described.8 We identified patients who received an NTR drug of interest between January 1, 1999, and May 31, 2000, and who had continuous health plan membership with pharmacy benefits during the study period, disregarding gaps of less than 60 days. The study sample was limited to prevalent users who had continued drug dispensings of and ongoing therapy with an NTR drug. To avoid inadvertent inclusion of new drug users in the study cohort, prevalent ongoing therapy was defined as beginning with the second dispensing of that drug in the data set and continuing from the second dispensing date for 12 months or longer. Continued dispensings were present when no interval between prescription refills was greater than the dispensed days' supply plus 1.5 times the dispensed days' supply. A dispensing gap was ignored if it was less than 1.5 times the dispensed days' supply. For example, a patient dispensed a 30-day supply met the criterion of continued dispensings if no more than 75 days (30 days + [1.5 × 30 days]) elapsed between the date of one dispensing and the date of the subsequent dispensing. NTR drug dispensings were identified using National Drug Code numbers. For all eligible patients, we used automated health plan data to ascertain dates of health plan membership and drug dispensings.

Identification and Categorization of Drug Concentration Monitoring

Lack of laboratory monitoring was defined as failure to perform drug concentration monitoring within the 1-year period of ongoing therapy, allowing up to a 1-month grace period (ie, monitoring within 13 months was considered as monitoring within 1 year). To accommodate patients entering the cohort between January 1, 1999, and May 31, 2000, monitoring data were collected for January 1, 1999, through June 30, 2001. Whether the laboratory test was performed was assessed from the presence of an administrative claim for the test. The laboratory test date was the date the test was performed or the result was reported. Laboratory test codes were defined at each site according to that site's method of coding the test (eg, Current Procedural Terminology codes). One site was unable to contribute drug concentration monitoring data for carbamazepine, digoxin, cyclosporine, and phenytoin.

Medical records were randomly selected for review to assess the accuracy of administrative data. Because of resource limitations, this review included medical records of patients dispensed cyclosporine, digoxin, and carbamazepine. Medical record abstraction was considered the gold standard, and abstraction data were compared with administrative data to determine the sensitivity, specificity, positive predictive value, and negative predictive value of administrative information about drug concentration monitoring.

Identification and Definition of Other Patient Characteristics

The health maintenance organization automated databases were used to identify the patient age (on the date of the first NTR drug dispensing), sex, outpatient visits, chronic diseases, diagnoses, and hospitalizations. The presence of specific chronic diseases was determined using the Chronic Disease Score method by Clark et al.9 To evaluate characteristics that predicted lack of monitoring, hospitalizations and outpatient visits that occurred within 6 months before the study period were identified. Outpatient visits include clinic appointments, visits for laboratory testing only, and emergency department visits. Geocoding was used to provide surrogate patient-level measures of socioeconomic status. Residential street address was combined with census-block level data from the 2000 US Census data to construct proxies of patient race, education, and poverty.10

Statistical Analysis

The number of unique patient-drug therapy combinations and the number of patients were tabulated. Descriptive statistics were computed to characterize patients, drug dispensings, and drug concentration monitoring for each drug cohort. The proportions of patients taking each NTR drug who received drug concentration monitoring and those who did not receive drug concentration monitoring were tabulated overall and by health plan, age group, sex, outpatient visits, hospitalizations, Chronic Disease Score, race, education, and poverty categories. Statistical significance of differences was tested using the Wilcoxon rank sum test or the χ2 test.

The association between patient characteristics and drug concentration monitoring was evaluated using generalized estimating equation logistic regression modeling, with site as a cluster variable.11 The initial generalized estimating equation model for each drug included the following variables with P < .05 in the univariate analysis: age group, sex, outpatient visits (in increments of 5 visits), hospitalizations, the presence or absence of selected diagnoses, and the 3 linear socioeconomic status variables. The Chronic Disease Score was not included in any of the initial models because it was correlated with outpatient visits. We used the backward selection method for all generalized estimating equation models. Customary residual and effect statistics were examined to assess model fit and to evaluate outliers. Analyses were performed using SAS version 8.2 or 9.1 (SAS Institute Inc, Cary, NC).


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