Reduction of oral mucositis by filgrastim (r-metHuG-CSF) in patients receiving chemotherapy.

Mucositis, the inflammation and necrosis of mucosal membranes, is a serious and debilitating consequence of many cancer therapies. We were interested in the potential role of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor, r-metHuG-CSF) in the reduction of mucositis. Patients with newly diagnosed small-cell lung cancer (SCLC) were treated with CAE chemotherapy (cyclophosphamide, doxorubicin, and etoposide) and placebo or filgrastim. If patients had an episode of febrile neutropenia, they received unblinded filgrastim in subsequent CAE cycles. Oral mucositis was considered to have occurred if a patient reported any clinical sign or symptom of oral mucositis with or without oral candidiasis. Oral mucositis was analyzed using the unadjusted chi-square test, and time to first episode of mucositis was analyzed using the stratified log-rank test as well as the Cox proportional hazards regression model. During cycle 1, placebo-treated patients had more episodes of mucositis (47%) compared with those patients randomized to filgrastim (28%). Across all cycles of treatment, 70% of placebo-treated patients experienced mucositis, compared with 53% of patients randomized to filgrastim. A significant reduction in the incidence of chemotherapy-related oral mucositis occurred across multiple cycles of treatment in patients treated with filgrastim.

Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial.

OBJECTIVE: To determine if filgrastim (recombinant human methionyl granulocyte colony-stimulating factor) used in addition to standard inpatient antibiotic therapy accelerated recovery from infection associated with chemotherapy-induced neutropenia. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Hematology and oncology wards of four teaching hospitals. PATIENTS: 218 patients with cancer who had fever (temperature > 38.2 degrees C) and neutropenia (neutrophil count < 1.0 x 10(9)/L) after chemotherapy. INTERVENTION: Patients were randomly assigned to receive filgrastim (12 micrograms/kg of body weight per day) (n = 109) or placebo (n = 107) beginning within 12 hours of empiric therapy with tobramycin and piperacillin. Patients received treatment and remained in the study until the neutrophil count was greater than 0.5 x 10(9)/L and until 4 days without fever (temperature < 37.5 degrees C) had elapsed. MEASUREMENTS: Days of neutropenia and fever and days in the study (hospitalization); time to resolution of fever and febrile neutropenia; and frequency of the use of alternative antibiotics. RESULTS: Compared with placebo, filgrastim reduced the median number of days of neutropenia (3.0 compared with 4.0 days of a neutrophil count of < 0.5 x 10(9)/L; P = 0.005) and the time to resolution of febrile neutropenia (5.0 compared with 6.0 days; P = 0.01) but not days of fever (3.0 days for both groups). The frequency of the use of alternative antibiotics was similar in the two groups (46% compared with 41%; P = 0.48). The median number of days patients were hospitalized while on study was the same (8.0 days; P = 0.09); however, filgrastim decreased the risk for prolonged hospitalization (> 11 days, 4th quartile) by half (relative risk, 2.1 [95% CI, 1.1 to 4.1]; P = 0.02). In exploratory subset analyses, filgrastim appeared to provide the greatest benefit in patients with documented infection and in patients presenting with neutrophil counts of less than 0.1 x 10(9)/L. CONCLUSIONS: Filgrastim treatment used with antibiotics at the onset of febrile neutropenia in patients with cancer who have received chemotherapy accelerated neutrophil recovery and shortened the duration of febrile neutropenia.

Variations in the use of medication for the treatment of childhood asthma in the Michigan Medicaid population, 1980 to 1986.

Asthma is a leading cause of morbidity in the United States and is a leading cause of disability in children. Prevalence has been shown to be highest in male children, blacks, and urban residents. Racial and residential differences have been attributed to economics. Medicaid claims data allow for the comparison of asthma morbidity and treatment of patients with different demography but of low socioeconomic status. Michigan Medicaid claims data for recipient children between 5 and 14 years of age were used to ascertain demographic factors associated with asthma treatment from 1980 through 1986. A cross-sectional analysis was used. Black asthmatics were found to receive medical care more frequently, but to obtain asthma drugs less frequently than other groups. The prevalence of different prescription asthma preparations also varied by race and residence. Black, urban residents obtained fixed-combination drugs more frequently and steroids less frequently than other groups. Rural patients, in general, had fewer medical contacts but obtained more prescription products per provider contact, whether black or white. Possible reasons for this variation are discussed.

Trends in the prevalence of asthma hospitalization in the 5- to 14-year-old Michigan Medicaid population, 1980 to 1986.

BACKGROUND: Despite advances in therapy, morbidity and mortality rates as a result of pediatric asthma appear to have increased during the past decade. Epidemiologic evidence suggests that these increases disproportionately affected black children and the urban poor. METHODS: With use of data from the Medicaid Management Information System, we estimated the prevalence of asthma hospitalization in the 5- to 14-year-old Michigan Medicaid population for the period 1980 to 1986. RESULTS: Large increases were seen between 1980 and 1984, with leveling off or a slight decline thereafter. In 5- to 9-year-old children, the prevalence of asthma hospitalization increased from 2.3 per 1000 persons in 1980 to 4.5 per 1000 in 1984. Ten- to 14-year-old children demonstrated an increase of 2.2 per 1000 in 1980 to 3.2 per 1000 in 1984. Comparable trends occurred in all strata defined by age, race, residency, and gender. However, the largest increases were noted in urban black children, in which the rate more than doubled from 3.2 per 1000 in 1980 to 7.1 per 1000 in 1984. The adjusted relative risk for asthma hospitalization associated with being male was 1.6 (95% CI: 1.5, 1.7), with being black was 2.2 (95% CI: 2.1, 2.4), and with living in an urban county was 1.1 (95% CI: 1.04, 1.4). CONCLUSIONS: Within this relatively homogeneous low socioeconomic population, black race remained a strong predictor for asthma hospitalization, whereas urban residence was only minimally associated with this outcome.

Oral contraceptive estrogen dose and the risk of deep venous thromboembolic disease.

Despite the well-recognized association between oral contraceptives and deep venous thromboembolism, little is known about the risks associated with currently marketed formulations containing less than 50 micrograms of estrogen. To assess the venous thrombogenicity of low-estrogen oral contraceptives (those containing less than 50 micrograms of estrogen) relative to intermediate-dose (50 micrograms of estrogen) and high-dose (greater than 50 micrograms of estrogen) formulations, we conducted a cohort study of oral contraceptive users between the ages of 15 and 44 years in the Michigan Medicaid population. The period of the study was from 1980 through the third quarter of 1986. A total of 2,739,400 oral contraceptive prescriptions received by 234,218 women were analyzed. Using the low-estrogen cohort as the referent group, the age and calendar period adjusted relative risk of venous thromboembolism in users of intermediate-dose formulations was 1.5 (95% confidence interval (CI) 1.0-2.1, p = 0.04), and the relative risk in users of high-dose formulations was 1.7 (95% CI 0.9-3.0, p = 0.06). These data provide evidence that the dose-response relation between oral contraceptive estrogen and venous thromboembolism extends from 50 to 30 micrograms of estrogen, the dose range of currently marketed formulations.

Trends in the content and use of oral contraceptives in the United States, 1964-88.

Drug marketing and physician survey data were used to examine trends in the use and hormonal content of oral contraceptives in the United States between 1964 and 1988. Retail prescriptions for oral contraceptives peaked at approximately 68 million in 1973 and have remained between 50 million and 60 million since 1981. Despite this relative consistency in the number of prescriptions, physician "mentions" of oral contraceptives have increased by approximately 75 percent. This increase may reflect closer monitoring of women on oral contraceptives. Use of multiphasic formulations has steadily risen, accounting for 37 percent of the oral contraceptive prescriptions in 1988. Mean estrogen and progestin doses in all types of formulations have steadily declined. A change in the type of estrogen and progestin used in preparations has coincided with this decline in dose. The association between age and use of high-dose formulations seen in the past was no longer evident in 1988. The data demonstrate that oral contraceptive formulations in wide use today differ in hormone content from those of the past, when most of the major studies addressing the risks associated with oral contraceptive use were completed. There is therefore a need to determine the risks and long-term effects associated with these newer formulations.

Oral contraceptive oestrogen and progestin potencies and the incidence of deep venous thromboembolism.

To assess possible differences in the incidence of venous thrombosis and pulmonary embolism associated with oral contraceptives of varying hormonal potencies, the authors conducted a retrospective cohort study in the 15-44 year old Michigan Medicaid population. Cohorts were defined by the progestin- and oestrogen-potencies of oral contraceptives in use at the time of follow-up as classified by an oral contraceptive potency scheme. Using the low-oestrogen-/low-progestin-potency formulations for reference (rate ratio = 1), adjusted rate ratios of 0.8 (95% CI: 0.5 to 1.3, P = 0.41) and 0.6 (95% CI 0.4 to 1.2, P = 0.13) were observed for intermediate-progestin-potency and high-progestin-potency formulations, respectively. Adjusted rate ratios of 1.4 (95% CI: 0.8 to 2.3, P = 0.21) and 2.6 (95% CI: 1.2 to 5.5, P = 0.01) were observed for intermediate- and high-oestrogen-potency formulations. These data suggest a dose-response relationship between oral contraceptive oestrogen potency and venous thromboembolism, whereas no such evidence for a dose-response relationship between oral contraceptive progestin potency and venous thrombo-embolism was found.

Prevalence and treatment of asthma in the Michigan Medicaid patient population younger than 45 years, 1980-1986.

The prevalence and outpatient treatment of asthma were studied in the Michigan Medicaid patient population by use of computerized physician, hospital, and pharmacy reimbursement data to mark and track asthma-related medical transactions. Asthma cases were defined as patients with evidence of at least two diagnoses and prescription drug transactions consistent with asthma. More than 52,000 cases were thus identified. The period prevalence of asthma was estimated on a year-by-year basis. The prevalence of asthma in the population increased from 2.0 per 100 Medicaid patients in 1980 to 2.8 per 100 Medicaid patients in 1986. Prevalence decreased with age until the age of 20 years and increased thereafter, and was higher in male children than in female children. In contrast, asthma was more prevalent in female adults than in male adults. Prevalence was higher in black subjects than in other races and higher in urban residents than in rural residents. The total number of reimbursements for antiasthma medications increased from 60,000 per year to 120,000 per year, and the average number of antiasthma prescriptions per Michigan Medicaid asthma case increased at the rate of 6.6% per year during the study interval. Changes in the preferred types of asthma treatment consistent with changes that have occurred in the general population were observed. These data suggest that the relative and absolute occurrence of asthma and asthma treatment in the Michigan Medicaid population is increasing.

Morbidity and mortality among low birth weight infants exposed to an intravenous vitamin E product, E-Ferol.

In April 1984, the US FDA was notified of an unusual clinical syndrome consisting of ascites, liver and renal failure, thrombocytopenia, and death among low birth weight infants exposed to an intravenous vitamin E preparation, E-Ferol. The product, which had not been tested for safety prior to marketing, was voluntarily withdrawn from the market in early April. To further investigate the reported associations, the FDA conducted a retrospective cohort study among seven neonatal intensive care units where the product had been used. Standardized abstraction forms were completed for infants admitted to a unit between Nov 1, 1983, and April 30, 1984. Included in the study were 379 infants weighing 2,000 g or less and surviving at least two days; 148 (39%) had been exposed to E-Ferol. Compared with the unexposed infants, the exposed infants were more likely to die and to have ascites, hepatomegaly, thrombocytopenia, and a combination of clinical events similar to the syndrome initially reported. We conclude that the use of E-Ferol in these neonatal intensive care units was associated with increased morbidity and mortality among exposed infants.

Determinants of wound infection incidence after isolated coronary artery bypass surgery in patients randomized to receive prophylactic cefuroxime or cefazolin.

In this open-label, randomized drug study, we compared two cephalosporin prophylactic regimens, one using cefazolin and one using cefuroxime, in 100 patients having coronary bypass surgery. Additional epidemiological data were collected to identify the patient at higher risk for acquiring an infection. Patients were categorized into four groups: (1) no infection; (2) clinically determined infection without a culture or prescription of additional antibiotics; (3) clinical infection with no or negative wound culture and prescription of additional antibiotics; and (4) clinical infection with positive culture and need for additional antibiotics. Seven cefuroxime patients (13.5%) and 9 cefazolin patients (18.8%; p = 0.471) had a wound that became clinically infected (Groups 2-4). In a univariate analysis, 11 variables were statistically associated with the development of a wound infection. A logistic regression model defined 3 variables at an alpha level of 0.05 and 3 at an alpha level of 0.10 that predicted a wound infection. Patients were identified at high risk of wound infection if they had postoperative weight gain, long operative hospitalization, prolonged use of a Foley catheter, postoperative use of blood products, and operation performed by two specific surgeons. Our results indicated that closer observation of the high-risk patients and a definition of the mechanism of the infections are needed.