Multicenter epidemiologic and health services research on therapeutics in the HMO Research Network Center for Education and Research on Therapeutics.

Research and education programs in therapeutics that combine the data, organizational capabilities, and expertise of several managed care organizations working in concert can serve an important role when a single organization is not large enough to address a question of interest, when diversity in populations or delivery systems is required, and when it is necessary to establish consistency of results in different settings. Nine members of the HMO Research Network, a consortium of health maintenance organizations (HMOs) that perform public domain research, have formed a Center for Education and Research on Therapeutics (CERT), sponsored by the Agency for Healthcare Research and Quality, to conduct multicenter research in therapeutics. The CERT uses a distributed organizational model with shared leadership, in which data reside at the originating organization until they are needed to support a specific study. Extraction of data from the host computer systems, and some manipulation of data, is typically accomplished through computer programs that are developed centrally, then modified for use at each site. For complex studies, pooled analysis files are created by a coordinating center, and then analysed by investigators throughout the HMOs. It is also possible to contact HMO members when necessary. This multicenter environment has several benefits, addressing: (1) a wide array of questions about the safety and effectiveness of therapeutics, (2) the impact of efforts to change clinicians' and patients' behavior, and (3) pharmacoeconomic and pharmacogenetic questions.

Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women.

BACKGROUND: Inhibitors of hydroxymethylglutaryl-coenzyme A reductase (statins) increase new bone formation in rodents and in human cells in vitro. Statin use is associated with increased bone mineral density of the femoral neck. We undertook a population-based case-control study at six health-maintenance organisations in the USA to investigate further the relation between statin use and fracture risk among older women. METHODS: We investigated women aged 60 years or older. Exposure, outcome, and confounder information was obtained from automated claims and pharmacy data from October, 1994, to September, 1997. Cases had an incident diagnosis of non-pathological fracture of the hip, humerus, distal tibia, wrist, or vertebrae between October, 1996, and September, 1997. Controls had no fracture during this period. We excluded women with records of dispensing of drugs to treat osteoporosis. FINDINGS: There were 928 cases and 2747 controls. Compared with women who had no record of statin dispensing during the previous 2 years, women with 13 or more statin dispensings during this period had a decreased risk of non-pathological fracture (odds ratio 0.48 [95% CI 0.27-0.83]) after adjustment for age, number of hospital admissions during the previous year, chronic disease score, and use of non-statin lipid-lowering drugs. No association was found between fracture risk and fewer than 13 dispensings of statins or between fracture risk and use of non-statin lipid-lowering drugs. INTERPRETATION: Statins seem to be protective against non-pathological fracture among older women. These findings are compatible with the hypothesis that statins increase bone mineral density in human beings and thereby decrease the risk of osteoporotic fractures.

Relationship between modifiable health risks and short-term health care charges.

CONTEXT: If physical inactivity, obesity, and smoking status prove to contribute significantly to increased health care charges within a short period of time, health plans and payers may wish to invest in strategies to modify these risk factors. However, few data are available to guide such resource allocation decisions. OBJECTIVE: To examine the relationship of modifiable health risks to subsequent health care charges after controlling for age, race, sex, and chronic conditions. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of a stratified random sample of 5689 adults (75.5% of total sample of 7535) aged 40 years or older who were enrolled in a Minnesota health plan and completed a 60-item questionnaire. MAIN OUTCOME MEASURE: Resource use as measured by billed health care charges from July 1, 1995, to December 31, 1996, compared by health risk (physical activity, body mass index [BMI], and smoking status). RESULTS: The mean annual per patient charge in the total study population was $3570 (median, $600), and 15% of patients had no charges during the study period. After adjustment-for age, race, sex, and chronic disease status, physical activity (4.7% lower health care charges per active day per week), BMI (1.9% higher charges per BMI unit), current smoking status (18% higher charges), and history of tobacco use (25.8% higher charges) were prospectively related to health care charges over 18 months. Never-smokers with a BMI of 25 kg/m2 and who participated in physical activity 3 days per week had mean annual health care charges that were approximately 49% lower than physically inactive smokers with a BMI of 27.5 kg/m2. CONCLUSIONS: Our data suggest that adverse health risks translate into significantly higher health care charges within 18 months. Health plans or payers seeking to minimize health care charges may wish to consider strategic investments in interventions that effectively modify adverse health risks.

The sensitivity and specificity of forecasting high-cost users of medical care.

OBJECTIVES: This study compares the ability of 3 risk-assessment models to distinguish high and low expense-risk status within a managed care population. Models are the Global Risk-Assessment Model (GRAM) developed at the Kaiser Permanente Center for Health Research; a logistic version of GRAM; and a prior-expense model. GRAM was originally developed for use in adjusting Medicare payments to health plans. METHODS: Our sample of 98,985 cases was drawn from random samples of memberships of 3 staff/group health plans. Risk factor data were from 1992 and expenses were measured for 1993. Models produced distributions of individual-level annual expense forecasts (or predicted probabilities of high expense-risk status for logistic) for comparison to actual values. Prespecified "high-cost" thresholds were set within each distribution to analyze the models' ability to distinguish high and low expense-risk status. Forecast stability was analyzed through bootstrapping. RESULTS: GRAM discriminates better overall than its comparators (although the models are similar for policy-relevant thresholds). All models forecast the highest-cost cases relatively well. GRAM forecasts high expense-risk status better than its comparators within chronic and serious disease categories that are amenable to early intervention but also generates relatively more false positives within these categories. CONCLUSIONS: This study demonstrates the potential of risk-assessment models to inform care management decisions by efficiently screening managed care populations for high expense-risk. Such models can act as preliminary screens for plans that can refine model forecasts with detailed surveys. Future research should involve multiple-year data sets to explore the temporal stability of forecasts.

Health-based payment and computerized patient record systems.

Health care information technology is changing rapidly and dramatically. A small but growing number of clinicians, especially those in staff and group model HMOs and hospital-affiliated practices, are automating their patient medical records in response to pressure to improve quality and reduce costs. Computerized patient record systems in HMOs track risks, diagnoses, patterns of care, and outcomes across large populations. These systems provide access to large amounts of clinical information; as a result, they are very useful for risk-adjusted or health-based payment. The next stage of evolution in health-based payment is to switch from fee-for-service (claims) to HMO technology in calculating risk coefficients. This will occur when HMOs accumulate data sets containing records on provider-defined disease episodes, with every service linked to its appropriate disease episode for millions of patients. Computerized patient record systems support clinically meaningful risk-assessment models and protect patients and medical groups from the effects of adverse selection. They also offer significant potential for improving quality of care.

Building health plan databases to risk adjust outcomes and payments.

OBJECTIVES: To highlight the types and sources of data on medical risk and outcomes routinely collected by managed care organizations over time; to summarize the quality and consistency of these data; and to describe some of the difficulties that arise in collecting, pooling, and using these data. DESIGN: Synthesis of the experiences of two risk-adjustment modeling projects in assembling large volumes of demographic, diagnostic, and expense data from several health maintenance organizations (HMOs) over multiple years. SETTING: Six large HMOs from the Northwest, North Central, and Northeast regions of the USA. INTERVENTIONS: Health plans were approached to participate in a risk-adjustment study, presented with an extensive variable-by-variable data request, and, if willing to participate, asked to specify a desired process for extracting, copying, and transferring selected variables to the study site for purposes of research. Depending on local circumstances, three different approaches were used: (i) health plan staff obtained the data and organized them into the requested study format; (ii) study staff were provided access to health plan data systems to perform the extractions directly; and (iii) health plans hired contract programmers to perform the extractions under the direction of the study team. Key measures of risk and cost were extracted and merged into analysis files. MAIN OUTCOME MEASURES: Complete and consistent eligibility maps, demographic information, inpatient and outpatient diagnoses, and total health plan expense for each enrollee. RESULTS: We have been successful in collecting and integrating complete utilization, morbidity, demographic, and cost data on total memberships of five large HMOs as well as a subset from a sixth HMO, all for multiple years. CONCLUSION: While HMOs vary greatly in the quality and comprehensiveness of their data systems, these attributes have been improving across the board over time. Automated health plan data systems represent potentially valuable sources of data on health risks and outcomes and can be used to benchmark disease management programs and risk adjust capitation payments and medical outcomes.

Lamotrigine and severe skin eruptions.

Lamotrigine is an important new addition to the drugs used to treat people with seizure disorders, but disconcerting are reports of a higher than expected incidence of severe skin reaction among children. Using automated data from three HMOs, we conducted a retrospective investigation of children (<15 years) exposed to lamotrigine from 1 January 1995 to 30 June 1997. The outcome of interest was hospitalization for a severe skin reaction (e.g. erythema multiforme). Lamotrigine was dispensed to 124 children (56% female, mean age 8.7 years); the mean number of dispensings per person was 10. Of those exposed, 59 (47%) were hospitalized at least once during the study period, mainly for convulsions and epilepsy. There were no hospitalizations for or with a diagnosis of severe skin reactions. Our investigation revealed no evidence to support a causal relationship between lamotrigine and severe skin reactions. However, because our sample size was small we had power to detect only a very strong association between lamotrigine and severe skin disease. Taken alone, our study does not establish the risks of lamotrigine. These results should be viewed as a contribution to the totality of evidence that will be used to assess the safety of lamotrigine.

The effect of increased prescription drug cost-sharing on medical care utilization and expenses of elderly health maintenance organization members.

OBJECTIVES: The nature and extent of prescription drug benefits for the elderly are a continuing concern for health-care managers and policy makers. This study examined the impact of increased prescription drug cost-sharing on the drug and medical care utilization and expenses of the elderly. METHODS: Two groups of well-insured Medicare risk-based members of a large health maintenance organization (HMO) had their copayments increased in different years during a 3-year period. Four 2-year analysis periods were established for comparing these elderly groups. During one analysis period, copayments did not change in either group. RESULTS: Moderate increases of from $1 to $3, from $3 to $5 per copayment, and from 50% per dispensing to 70% per dispensing with a maximum payment per dispensing resulted in lower annual per capita prescription drug use and expenses. No consistent annual changes were observed in either medical care utilization (office visits, emergency room visits, home health-care visits, hospitalizations) or total medical care expenses across analysis periods. CONCLUSIONS: No consistent relationships were observed between increased copayments per dispensing and medical care utilization and expense. Future research needs to address the impact on the classes of medications received and related health status, and the impact of larger increases in copayments per dispensing on medical care and health-related factors.

The impact of increasing patient prescription drug cost sharing on therapeutic classes of drugs received and on the health status of elderly HMO members.

OBJECTIVE: To assess the impact of increased prescription drug copayments on the therapeutic classes of drugs received and health status of the elderly. HYPOTHESES TESTED: Increased prescription drug copayments will reduce the relative exposure to, annual days use of, and prescription drug costs for drugs used in self-limiting conditions, but will not affect drugs used in progressive chronic conditions and will not reduce health status. STUDY DESIGN: Each year over a three-year period, one or the other of two well-insured Medicare risk groups in an HMO setting had their copayments per dispensing increased. Sample sizes ranged from 6,704 to 7,962. DATA SOURCES/DATA COLLECTION: Automated administrative data systems of the HMO were used to determine HMO eligibility, prescription drug utilization, and health status. ANALYSIS DESIGN: Analysis of variance or covariance was employed to measure change in dependent variables. FINDINGS: Relative exposure, annual days of use, and prescription drug costs for drugs used in self-limiting conditions and in progressive chronic conditions were not affected in a consistent manner across years by increases in prescription drug copayment. Health status may have been adversely affected. Larger increases in copayments appeared to generate more changes. CONCLUSIONS: Small changes in copayments did not appear to substantially affect outcomes. Large changes in copayments need further examination.

A role for Mac-1 (CDIIb/CD18) in immune complex-stimulated neutrophil function in vivo: Mac-1 deficiency abrogates sustained Fcgamma receptor-dependent neutrophil adhesion and complement-dependent proteinuria in acute glomerulonephritis.

Mac-1 (alphambeta2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fcgamma receptors to facilitate immune complex (IC)-stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1-FcgammaR interactions in IC-mediated injury in vivo, we induced a model of Fc-dependent anti-glomerular basement membrane (GBM) nephritis in wild-type and Mac-1-deficient mice by the intravenous injection of anti-GBM antibody. The initial glomerular PMN accumulation was equivalent in Mac-1 null and wild-type mice, but thereafter increased in wild-type and decreased in mutant mice. The absence of Mac-1 interactions with obvious ligands, intercellular adhesion molecule 1 (ICAM-1), and C3 complement, is not responsible for the decrease in neutrophil accumulation in Mac-1- deficient mice since glomerular PMN accumulation in mice deficient in these ligands was comparable to those in wild-type mice. In vitro studies showed that spreading of Mac-1-null PMNs to IC-coated dishes was equivalent to that of wild-type PMNs at 5-12 min but was markedly reduced thereafter, and was associated with an inability of mutant neutrophils to redistribute filamentous actin. This suggests that in vivo, Mac-1 is not required for the initiation of Fc-mediated PMN recruitment but that Mac-1-FcgammaR interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1-FcgammaR interactions in vivo. PMN-dependent proteinuria, maximal in wild-type mice at 8 h, was absent in Mac-1 mutant mice at all time points. Complement C3-deficient mice also had significantly decreased proteinuria compared to wild-type mice. Since Mac-1 on PMNs is the principal ligand for ic3b, an absence of Mac-1 interaction with C3 probably contributed to the abrogation of proteinuria in Mac-1-null mice.

Brain endothelium lack one of two pathways of P-selectin-mediated neutrophil adhesion.

P-selectin, an endothelial leukocyte adhesion receptor, is rapidly translocated to the cell surface upon release from storage granules called Weibel-Palade bodies and is also transcriptionally upregulated upon cytokine stimulation of endothelial cells (ECs). These two pathways of surface expression are coincident with the rapid and cytokine-inducible pathway of neutrophil adhesion to ECs. Constitutive P-selectin expression is largely absent in cultured murine brain microvascular EC (BMEC) monolayers, but interleukin-1beta and tumor necrosis factor-alpha stimulation for 4 hours leads to dramatic P-selectin upregulation. The functional relevance of differential P-selectin expression in these cells was examined by studying BMECs derived from wild-type mice and P-selectin-deficient mice. We show that P-selectin deficiency does not affect Weibel-Palade body formation or their release in response to short-acting agonists. However, in the absence of P-selectin, the brain endothelium is unable to support neutrophil adhesion after stimulation with these agonists, which may contribute to the immune privilege status of the brain. We show that P-selectin does play a major role in supporting neutrophil adhesion in the cytokine-induced pathway in BMECs in the context of other cytokine-inducible endothelial-leukocyte adhesion receptors, E-selectin, ICAM-1, and VCAM-1.

Influence of Helicobacter pylori on gastric mucosal adaptation to naproxen in man.

Our objective was to determine whether H. pylori influences gastric mucosal injury and adaptation caused by naproxen. Twenty-four healthy volunteers, 12 H. pylori-positive and 12 H. pylori-negative, were given a 28-day course of naproxen 500 mg twice a day. They were each gastroscoped to assess gastric mucosal damage and mucosal blood flow before and at 1, 7, and 28 days during treatment. Maximal gastric mucosal damage (median grade + IQR) occurred during the first 24 hr in both groups and was of similar magnitude (H. pylori-positive: 2.5, 2.0-3.0 P < 0.01; H. pylori-negative: 2.0, 1.0-3.0 P < 0.01). This damage was associated with a fall in antral but not corpus mucosal blood flow. With continued NSAID administration, gastric damage resolved confirming adaptation (H. pylori-positive 1.0, 0-2.0, H. pylori-negative: 1.0, 0-1.0) and antral mucosal blood flow returned to baseline in both groups by day 28. These observations suggest that initial gastric mucosal injury is not influenced by H. pylori colonization and adaptation occurs regardless of its presence.

Chronic disease, functional health status, and demographics: a multi-dimensional approach to risk adjustment.

OBJECTIVE: The goal of this study was to develop unbiased risk-assessment models to be used for paying health plans on the basis of enrollee health status and use propensity. We explored the risk structure of adult employed HMO members using self-reported morbidities, functional status, perceived health status, and demographic characteristics. DATA SOURCES/STUDY SETTING: Data were collected on a random sample of members of a large, federally qualified, prepaid group practice, hospital-based HMO located in the Pacific Northwest. STUDY DESIGN: Multivariate linear nonparametric techniques were used to estimate risk weights on demographic, morbidity, and health status factors at the individual level. The dependent variable was annual real total health plan expense for covered services for the year following the survey. Repeated random split-sample validation techniques minimized outlier influences and avoided inappropriate distributional assumptions required by parametric techniques. DATA COLLECTION/EXTRACTION METHODS: A mail questionnaire containing an abbreviated medical history and the RAND-36 Health Survey was administered to a 5 percent sample of adult subscribers and their spouses in 1990 and 1991, with an overall 44 percent response rate. Utilization data were extracted from HMO automated information systems. Annual expenses were computed by weighting all utilization elements by standard unit costs for the HMO. PRINCIPAL FINDINGS: Prevalence of such major chronic diseases as heart disease, diabetes, depression, and asthma improve prediction of future medical expense; functional health status and morbidities are each better than simple demographic factors alone; functional and perceived health status as well as demographic characteristics and diagnoses together yield the best prediction performance and reduce opportunities for selection bias. We also found evidence of important interaction effects between functional/perceived health status scales and disease classes. CONCLUSIONS: Self-reported morbidities and functional health status are useful risk measures for adults. Risk-assessment research should focus on combining clinical information with social survey techniques to capitalize on the strengths of both approaches. Disease-specific functional health status scales should be developed and tested to capture the most information for prediction.

Cultured murine cerebral microvascular endothelial cells contain von Willebrand factor-positive Weibel-Palade bodies and support rapid cytokine-induced neutrophil adhesion.

OBJECTIVE: To obtain cultures of rodent brain microvascular endothelium (BMEC) that retain endothelial cell-specific markers and functions for two purposes: investigating whether these cultures contain endothelial cell-specific storage granules or Weibel-Palade bodies and have the ability to rapidly bind neutrophils upon cytokine induction; and setting the groundwork for future studies examining endothelium derived from mice strains with targeted deficiencies in endothelial adhesion molecules. METHODS: Capillaries were obtained by collagenase/dispase digestion and subsequent density centrifugation of either rodent brain or meninges. The yield was then plated onto fibronectin-coated dishes. For some studies, pure murine endothelial cultures were obtained by flow-cytometric sorting, using uptake of fluorescently labeled diI-acetylated low-density lipoprotein as a marker for endothelium. Endothelial cell-specific markers were analyzed via immunofluorescence, immunoprecipitation and light microscopy. Cytokine-induced neutrophil adhesion and associated upregulation of leukocyte adhesion molecules were measured as described previously for human umbilical vein endothelial cells. RESULTS: BMEC possess numerous von Willebrand factor-containing Weibel-Palade bodies and synthesize and secrete all multimeric forms of von Willebrand factor. They take up diI-acetylated low-density lipoproteins, contain platelet-endothelial cell adhesion molecules and form capillary-like structures on three-dimensional extracellular matrix substrates. Sorted murine brain microvascular endothelial cells treated with IL-1 beta or TNF-alpha for 4 h show an increase in surface expression of the cytokine-inducible leukocyte adhesion molecules E-selectin, VCAM-1, and ICAM-1, and they support rapid neutrophil adhesion, which is, on average, three times greater than that of nonstimulated cells. CONCLUSIONS: The brain microvascular endothelial cultures described here exhibit many of the markers of endothelial cells including the presence of Weibel-Palade bodies. The localization of von Willebrand factor almost exclusively to Weibel-Palade bodies indicates that murine cerebral endothelium has evolved an efficient mechanism for storage of this platelet adhesion protein, which plays an important role in hemostasis. In addition, this is the first demonstration of rapid neutrophil adhesion to murine brain microvascular endothelial cells. Finally, the reproducible culture and the characterization of murine BMEC makes feasible future studies on endothelium isolated from gene-targeted mice.

Gastric mucosal adaptation to etodolac and naproxen.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) frequently cause damage to the gastroduodenal mucosa, principally by suppressing mucosal prostaglandin synthesis. However, such acute mucosal injury usually resolves, despite continued NSAID administration, by a process known as adaptation. Newer NSAIDs, such as etodolac, have been developed to minimize effects on prostaglandin synthesis. AIM: To determine whether etodolac causes less acute damage than naproxen, and whether the damage produced resolves with continued NSAID administration. METHODS: Twenty-four healthy volunteers were given a 28-day course of either etodolac 300 mg b.d. or naproxen 500 mg b.d. Gastroduodenal damage was assessed using a modified Lanza scoring system and mucosal blood flow with laser doppler flowmetry at endoscopy before NSAID administration and during days 1, 7 and 28 of continued intake. RESULTS: Maximum gastric damage (median grade and interquartile range, IQR) occurred during the first 24 h of administration, being greater with naproxen (2.0, IQR 1.0-3.0) than etodolac (1.0, IQR 1.0-1.5; P = 0.03). Such damage was associated with a fall in antral blood flow in the naproxen group (mean +/- S.E.M.) from 54.5 +/- 3.4 to 43.8 +/- 3.4 arbitrary units (P = 0.07) and a slight increase in mucosal blood flow in the etodolac group from 43.5 +/- 2.24 to 49.5 +/- 3.6 arbitrary units. With continued intake this damage resolved in all subjects taking etodolac and in eight of 14 subjects on naproxen. Resolution in the naproxen group was associated with a return to normal of antral blood flow. CONCLUSIONS: These observations suggest that etodolac causes less mucosal damage than naproxen and that adaptation occurs to both.