Joyce A. Cramer

A systematic review of the associations between dose regimens and medication compliance

BACKGROUND Previous reviews of the literature on medication compliance have confirmed the inverse relationship between number of daily doses and rate of compliance. However, compliance in most of these studies was based on patient self-report, blood-level monitoring, prescription refills, or pill count data, none of which are as accurate as electronic monitoring (EM). OBJECTIVE In this paper, we review studies in which compliance was measured with an EM device to determine the associations between dose frequency and medication compliance. METHODS Articles included in this review were identified through literature searches of MEDLINE, PsychInfo, HealthStar, Health & Psychosocial Instruments, and the Cochrane Library using the search terms patient compliance, patient adherence, electronic monitoring, and MEMS (medication event monitoring systems). The review was limited to studies reporting compliance measured by EM devices, the most accurate compliance assessment method to date. Because EM was introduced only in 1986, the literature search was restricted to the years 1986 to 2000. In the identified studies, data were pooled to calculate mean compliance with once-daily, twice-daily, 3-times-daily, and 4-times-daily dosing regimens. Because of heterogeneity in definitions of compliance, 2 major categories of compliance rates were defined: dose-taking (taking the prescribed number of pills each day) and dose-timing (taking pills within the prescribed time frame). RESULTS A total of 76 studies were identified. Mean dose-taking compliance was 71% +/- 17% (range, 34%-97%) and declined as the number of daily doses increased: 1 dose = 79% +/- 14%, 2 doses = 69% +/- 15%, 3 doses = 65% +/- 16%, 4 doses = 51% +/- 20% (P < 0.001 among dose schedules). Compliance was significantly higher for once-daily versus 3-times-daily (P = 0.008), once-daily versus 4-times-daily (P < 0.001), and twice-daily versus 4-times-daily regimens (P = 0.001); however, there were no significant differences in compliance between once-daily and twice-daily regimens or between twice-daily and 3-times-daily regimens. In the subset of 14 studies that reported dose-timing results, mean dose-timing compliance was 59% +/- 24%; more frequent dosing was associated with lower compliance rates. CONCLUSIONS A review of studies that measured compliance using EM confirmed that the prescribed number of doses per day is inversely related to compliance. Simpler, less frequent dosing regimens resulted in better compliance across a variety of therapeutic classes.

Comparison of Carbamazepine, Phenobarbital, Phenytoin, and Primidone in Partial and Secondarily Generalized Tonic–Clonic Seizures

We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.

A Comparison of Valproate with Carbamazepine for the Treatment of Complex Partial Seizures and Secondarily Generalized Tonic–Clonic Seizures in Adults

BACKGROUND Valproate is approved for use primarily in patients with absence seizures, but the drug has a broad spectrum of activity against seizures of all types. Partial or secondarily generalized tonic-clonic seizures are often difficult to control adequately with standard treatment, usually carbamazepine or phenytoin. METHODS We conducted a multicenter, double-blind trial that compared valproate with carbamazepine in the treatment of 480 adults with complex partial seizures (206 patients) or secondarily generalized tonic-clonic seizures (274 patients). The patients were randomly assigned to treatment with carbamazepine or divalproex sodium (valproate) at doses adjusted to achieve blood levels in the middle of the therapeutic range. Patients were followed for one to five years or until seizures became uncontrollable, treatment had unacceptable adverse effects, or both these events occurred. RESULTS For the control of secondarily generalized tonic-clonic seizures, carbamazepine and valproate were comparably effective (in 136 patients and 138 patients, respectively). For complex partial seizures, four of five outcome measures favored carbamazepine (100 patients) over valproate (106 patients): the total number of seizures (2.7 vs. 7.6, P = 0.05), the number of seizures per month (0.9 vs. 2.2, P = 0.01), the time to the first seizure (P less than 0.02), and the seizure-rating score (P = 0.04). Carbamazepine was also superior according to a composite score that combined scores for the control of seizures and for adverse effects (P less than 0.001). Valproate was associated more frequently than carbamazepine with a weight gain of more than 5.5 kg (12 lb) (20 percent vs. 8 percent, P less than 0.001), with hair loss or change in texture (12 percent vs. 6 percent, P = 0.02), and with tremor (45 percent vs. 22 percent, P less than 0.001). Rash was more often associated with carbamazepine (11 percent vs. 1 percent, P less than 0.001). CONCLUSIONS Valproate is as effective as carbamazepine for the treatment of generalized tonic-clonic seizures, but carbamazepine provides better control of complex partial seizures and has fewer long-term adverse effects.

Development of the Quality of Life in Epilepsy Inventory

Summary: We developed an instrument to measure health‐related quality of life (HRQOL) in epilepsy. A 99‐item inventory was constructed from the RAND 36‐Item Health Survey (generic core), with 9 additional generic items, 48 epilepsy‐targeted items, and 6 other items concerning attitudes toward epilepsy and self‐esteem. We administered the 99‐item inventory to 304 adults with epilepsy at 25 epilepsy centers. Patients and patient‐designated proxies completed the inventory and were retested 1–91 days later. A multitrait scaling analysis of these data led to retention of 86 items distributed in 17 multiitem scales (Cronbachs alpha ranged from 0.78 to 0.92). Factor analysis of the 17 multiitem scales yielded four underlying dimensions of health: an epilepsy‐targeted dimension, a cognitive factor, mental health, and physical health. Construct validity was supported by significant patient‐proxy correlations for all scales and correlations between neuropsychologic tests and self‐reported emotional and cognitive function (all p values < 0.05). There were significant negative correlations between the four factor scores derived from the HRQOL scales and neurotoxicity, systemic toxicity, and health care utilization (except for the correlation between mental health factor and health care utilization; all p values < 0.05). Patients who were seizure‐free in the preceding year reported better HRQOL for the overall score, three of the four factor scores, and 8 of the 17 scale scores than did patients with a high frequency of seizures. Relative validity analysis showed that the epilepsy‐targeted factor and three of its four component scales were more sensitive to categorization of patients by severity of seizure frequency and type than scales tapping physical health, mental health, or cognitive function. These cross‐sectional data support the reliability and validity of this measure of HRQOL in epilepsy. The addition of an epilepsy‐targeted supplement to the generic core improved the sensitivity to severity of epilepsy. The 86 items included in the field testing were supplemented by three additional items to form the Quality of Life in Epilepsy (QOLIE‐89) inventory.

A Comparison of Clozapine and Haloperidol in Hospitalized Patients with Refractory Schizophrenia

BACKGROUND Clozapine, a relatively expensive antipsychotic drug, is widely used to treat patients with refractory schizophrenia. It has a low incidence of extrapyramidal side effects but may cause agranulocytosis. There have been no long-term assessments of its effect on symptoms, social functioning, and the use and cost of health care. METHODS We conducted a randomized, one-year, double-blind comparative study of clozapine (in 205 patients) and haloperidol (in 218 patients) at 15 Veterans Affairs medical centers. All participants had refractory schizophrenia and had been hospitalized for the disease for 30 to 364 days in the previous year. All patients received case-management and social-rehabilitation services, as clinically indicated. RESULTS In the clozapine group, 117 patients (57 percent) continued their assigned treatment for the entire year, as compared with 61 (28 percent) of the patients in the haloperidol group (P<0.001). As judged according to the Positive and Negative Syndrome Scale of Schizophrenia, patients in the clozapine group had 5.4 percent lower symptom levels than those in the haloperidol group at all follow-up evaluations (mean score, 79.1 vs. 83.6; P=0.02). The differences on a quality-of-life scale were not significant in the intention-to-treat analysis, but they were significant among patients who did not cross over to the other treatment (P=0.003). Over a one-year period, patients assigned to clozapine had fewer mean days of hospitalization for psychiatric reasons than patients assigned to haloperidol (143.8 vs. 168.1 days, P=0.03) and used more outpatient services (133.6 vs. 97.9 units of service, P=0.03). The total per capita costs to society were high --

Development and Cross‐Cultural Translations of a 31‐Item Quality of Life in Epilepsy Inventory

58,151 in the clozapine group and

Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis

60,885 in the haloperidol group (P=0.41). The per capita costs of antipsychotic drugs were

Development of the Quality of Life in Epilepsy Inventory for Adolescents: The QOLIE‐AD‐48

3,199 in the clozapine group and

Depression and comorbidity in community-based patients with epilepsy or asthma.

367 in the haloperidol group (P<0.001). Patients assigned to clozapine had less tardive dyskinesia and fewer extrapyramidal side effects. Agranulocytosis developed in three patients in the clozapine group; all recovered fully. CONCLUSIONS For patients with refractory schizophrenia and high levels of hospital use, clozapine was somewhat more effective than haloperidol and had fewer side effects and similar overall costs.

A Brief Questionnaire to Screen for Quality of Life in Epilepsy The QOLIE‐10

Summary: Purpose: We report the development of a questionnaire to assess health‐related quality of‐life (HRQOL) in people with epilepsy and the process of cross‐cultural translations of the questionnaire.