Predictors of very low adherence with medications for osteoporosis: towards development of a clinical prediction rule.

UNLABELLED: We developed a clinical prediction rule score to predict medication non-adherence for women prescribed osteoporosis treatment. When combined into a summative score, 62% with seven or more points on the score demonstrated very low adherence. This compares with 17% subjects with fewer than seven points (c-statistic = 0.74). INTRODUCTION: Medication non-adherence is extremely common for osteoporosis; however, no clear methods exist for identifying patients at risk of this behavior. We developed a clinical prediction rule to predict medication non-adherence for women prescribed osteoporosis treatment. METHODS: Women undergoing bone mineral density testing and fulfilling WHO criteria for osteoporosis were invited to complete a questionnaire and then followed for 1 year. Adjusted logistic regression models were examined to identify variables associated with very low adherence (medication possession ratio <20%). The weighted variables, based on the logistic regression, were summed, and the score was compared with the proportion of subjects with very low adherence. RESULTS: One hundred forty two women participated in the questionnaire and were prescribed an osteoporosis medication. After 1 year, 36% (n = 50) had very low adherence. Variables associated with very low adherence included prior non-adherence with chronic medications, agreement that side effects are concerning, agreement that she is taking too many medications, lack of agreement that osteoporosis is a worry, lack of agreement that a fracture will cause disability, lack of agreement that medications help her stay active, and frequent use of alcohol. When combined into a summative score, 36 of the 58 subjects (62%) with seven or more points on the score demonstrated very low adherence. This compares with 14 of the 84 (17%) subjects with fewer than seven points (c-statistic = 0.74). CONCLUSION: We developed a brief clinical prediction rule that was able to discriminate between women likely (and unlikely) to experience very low adherence with osteoporosis medications.

Sex differences in gout epidemiology: evaluation and treatment.

BACKGROUND: Little is known about the characteristics, evaluation and treatment of women with gout. OBJECTIVE: To examine the epidemiological differences and differences in treatment between men and women in a large patient population. METHODS: The data from approximately 1.4 million people who were members of seven managed care plans in the USA for at least 1 year between 1 January 1999 and 31 December 2003 were examined. Adult members who had pharmacy benefits and at least two ambulatory claims specifying a diagnosis of gout were identified. In addition, men and women who were new users of urate-lowering drugs (ULDs) were identified to assess adherence with recommended surveillance of serum urate levels within 6 months of initiating urate-lowering treatment. RESULTS: A total of 6133 people (4975 men and 1158 women) with two or more International Classification of Disease-9 codes for gout were identified. As compared with men with gout, women were older (mean age 70 (SD 13) v 58 (SD 14), p<0.001) and had comorbidities and received diuretics more often (77% v 40%; p<0.001). Only 37% of new users of urate-lowering treatment had appropriate surveillance of serum urate levels post-initiation of urate-lowering treatment. After controlling for age, comorbidities, gout treatments, number of ULD dispensings and health plan, women were more likely (odds ratio 1.36, 95% confidence interval 1.11 to 1.67) to receive the recommended serum urate level testing. CONCLUSIONS: Women with gout were older, had greater comorbidities and more often used diuretics and received appropriate surveillance of serum urate levels, suggesting that the factors leading to gout as well as monitoring of treatment are very different in women and men.

Contraindicated use of cisapride: impact of food and drug administration regulatory action.

CONTEXT: Cisapride, a gastrointestinal tract promotility agent, can cause life-threatening cardiac arrhythmias in patients susceptible either because of concurrent use of medications that interfere with cisapride metabolism or prolong the QT interval or because of the presence of other diseases that predispose to such arrhythmias. In June 1998, the US Food and Drug Administration (FDA) determined that use of cisapride was contraindicated in such patients and informed practitioners through additions to the boxed warning in the label and a "Dear Health Care Professional" letter sent by the drug's manufacturer. OBJECTIVE: To evaluate the impact of the FDA's 1998 regulatory action regarding contraindicated use of cisapride. DESIGN AND SETTING: Analysis of data for the 1-year periods before (July 1997-June 1998) and after (July 1998-June 1999) the regulatory action from the population-based, pharmacoepidemiology research databases of 2 managed care organizations (sites A and B) and a state Medicaid program (site C). PARTICIPANTS: Patients with at least 180 days of prior enrollment in 1 of the 3 sites who were prescribed cisapride at least once in the period before (n = 24 840) or after (n = 22 459) regulatory action. Patients could be included in both cohorts. MAIN OUTCOME MEASURES: Proportion of cisapride users in each period for whom cisapride use was contraindicated by the product label, based on computerized patient medical encounter records. RESULTS: In the year prior to regulatory action, cisapride use was contraindicated for 26%, 30%, and 60% of users in study sites A, B, and C, respectively. In the year after regulatory action, use was contraindicated for 24%, 28%, and 58% of users, a reduction in contraindicated use of approximately 2 per 100 cisapride users at each site. When the analysis was restricted to new users of cisapride after regulatory action, only minor reductions in contraindicated use were found. CONCLUSION: The FDA's 1998 regulatory action regarding cisapride use had no material effect on contraindicated cisapride use. More effective ways to communicate new information about drug safety are needed.

The diffusion of a novel therapy into clinical practice: the case of sildenafil.

BACKGROUND: Erectile dysfunction is a common condition, yet in the past most affected men did not seek medical treatment. OBJECTIVE: To examine how sildenafil (Viagra), a new medication for the treatment of erectile dysfunction, has been incorporated into general medical practice. SUBJECTS AND METHODS: The study population consisted of all male members of a group-model Massachusetts health maintenance organization (HMO) whose first prescription for sildenafil was dispensed during the first 24 weeks of its availability through the HMO as a plan benefit (April 24, 1998, through October 8, 1998). Data collected on each member in the study population included age, specialty of the prescribing physician, initial dose, use of prior treatments for erectile dysfunction, receipt of medications known to predispose to impotence, filling of a second prescription for sildenafil, and concomitant medical conditions (including hypertension, ischemic heart disease, hyperlipidemia, diabetes mellitus, and history of radical prostatectomy). Cross tabulations and logistic regression models were constructed to evaluate the potential associations between filling a second prescription for sildenafil and other characteristics of sildenafil users. RESULTS: We identified 899 members who filled a first-time sildenafil prescription in the 24-week period of interest. The majority of sildenafil prescriptions that were filled for the first time (85%) occurred in the first 12 weeks of its availability. Most sildenafil users (84%) were between 45 and 74 years of age (average age, 61 years; age range, 23 to 90 years), and approximately 40% had documentation of prior treatment for erectile dysfunction. Use was highest among those aged 55 to 64 years, with almost 5% of all male HMO members in that age group having received at least 1 sildenafil prescription. Our cohort of sildenafil users was significantly more likely to have hypertension (P<.01), hyperlipidemia (P<.01), and diabetes mellitus (P<.01) than persons who participated in a widely publicized clinical trial of the medication. Prescribing physicians were predominantly primary care physicians (78% were internists, and 11% were family practitioners). More than 60% of sildenafil users filled a second prescription within 3 months of the first prescription; in multivariate analyses, factors associated with filling a second prescription included younger age and prior treatment for erectile dysfunction. CONCLUSIONS: Sildenafil was rapidly adopted into the clinical practice of primary care physicians for the treatment of erectile dysfunction in the managed care setting. The patients for whom the drug was prescribed in the general practice setting differed across many medical characteristics from study subjects who participated in clinical trials of the drug. Arch Intern Med. 2000;160:3401-3405.

Evaluation of a formulary switch from conjugated to esterified estrogens in a managed care setting.

BACKGROUND: Formulary switches between agents in the same therapeutic class have become commonplace in the managed care setting as a strategy to reduce costs. OBJECTIVES: We evaluated the impact of a formulary switch from conjugated to esterified estrogen tablets at the Fallon Community Health Plan, a mixed-model health maintenance organization. DESIGN: A retrospective study was conducted with the use of the automated database of the health plan. SUBJECTS: Study subjects were members of the health plan during the period from May 1, 1995, to December 31, 1997, who were dispensed > or =1 estrogen replacement product. From this population, a cohort of users of conjugated estrogens during the period from May 1, 1995, to October 31, 1995, was selected. MEASURES: The cumulative incidence of switching from conjugated to esterified estrogen tablets and subsequent discontinuations of esterified estrogens was evaluated. The frequencies of ambulatory encounters during the 6 months before and after a switch or discontinuation were compared. RESULTS: During the period after promotion of the formulary switch, 2,149 of 2,984 patients (72%) originally dispensed conjugated estrogen tablets switched to esterified estrogen tablets. Among those patients switching to esterified estrogens, an excess of 20 office visits per 100 patients was noted in the postswitch period (P = 0.005). The risk of switching back to conjugated estrogen tablets was 15% by 2 years. CONCLUSIONS: The findings of this study suggest that plan efforts were successful in switching most users of conjugated estrogens to esterified estrogens. The switch was associated with an increase in utilization of health care services.

Evaluating the predictive value of osteoarthritis diagnoses in an administrative database.

OBJECTIVE: To assess the positive and negative predictive values of osteoarthritis (OA) diagnoses contained in an administrative database. METHODS: We identified all members (> or =18 years of age) of a Massachusetts health maintenance organization with documentation of at least one health care encounter associated with an OA diagnosis during the period 1994-1996. From this population, we randomly selected 350 subjects. In addition, we randomly selected 250 enrollees (proportionally by the age and sex of the 350 subjects) who did not have a health care encounter associated with an OA diagnosis. Trained nurse reviewers abstracted OA-related clinical, laboratory, and radiologic data from the medical records of both study groups (all but 1 chart was available for review). Pairs of physician reviewers evaluated the abstracted information for both groups of subjects and rated the evidence for the presence of OA according to 3 levels: definite, possible, and unlikely. RESULTS: Among the group of patients with an administrative diagnosis of OA, 215 (62%) were rated as having definite OA, 36 (10%) possible OA, and 98 (28%) unlikely OA, according to information contained in the medical record. The positive predictive value of an OA diagnosis was 62%. In those without an administrative OA diagnosis, 44 (18%) were assigned a rating of definite OA. The negative predictive value of the absence of an administrative OA diagnosis was 78%. CONCLUSION: Use of administrative data in epidemiologic and health services research on OA may lead to both case misclassification and under ascertainment.

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.

The effect of an Rx-to-OTC switch on medication prescribing patterns and utilization of physician services: the case of H2-receptor antagonists.

BACKGROUND: Prescription medications are being switched to over-the-counter (OTC) status with increasing frequency. Information is limited regarding the impact of OTC availability on the use of prescription forms of those products and on the utilization of health care services. OBJECTIVES: To determine the impact of OTC availability of H2-receptor antagonists on medication prescribing patterns and utilization of physician services among a population of chronic users of those agents. DESIGN: A retrospective study was conducted to evaluate changes in the number of prescriptions filled for H2-receptor antagonists and other gastrointestinal agents (proton pump inhibitors, gastric motility agents, and sucralfate), and ambulatory medical encounters with physicians during a one-year period before (July 1, 1994-June 30, 1995) and after OTC availability of H2-receptor antagonists (July 1, 1995-June 30, 1996). Changes in the prescription drug costs for gastrointestinal agents were also estimated. SUBJECTS: Members of the Fallon Community Health Plan, a mixed-model HMO located in Central and Eastern Massachusetts (July 1, 1994-June 30, 1996) who were dispensed at least one H2-receptor antagonist during each quarter for the period between July 1, 1994 through June 30, 1995. MEASURES: Mean absolute differences in the frequencies of drug dispensings and ambulatory encounters and prescription drug costs during the pre-OTC (July 1, 1994-June 30, 1995) and post-OTC switch (July 1, 1995-June 30, 1996) periods were calculated. RESULTS: For the one-year period after OTC availability H2-receptor antagonists, we estimated that the mean absolute number of prescriptions dispensed for H2-receptor antagonists was reduced by 1.5 prescriptions (P < 0.001) and the mean number of prescriptions dispensed for all gastrointestinal agents was reduced by 1.3 prescriptions (P < 0.001) among chronic users of these agents. The number of dispensings of gastrointestinal agents was similarly reduced in the population of chronic users with a diagnosis of gastroesophageal reflux disease (GERD). OTC availability was not associated with an increase in physician visits, overall or for GERD-related conditions. CONCLUSIONS: The findings of this study suggest that the prescription-to-OTC switch of H2-receptor antagonists reduced the number of prescriptions for those agents dispensed among a population of chronic users of those drugs in a managed care setting without increasing physician visits.

Effectiveness of antihyperlipidemic drug management in clinical practice.

Although randomized clinical trials have convincingly shown the efficacy of antihyperlipidemic drugs, both discontinuation of antihyperlipidemic drugs and failure to achieve goal lipid levels would be expected to attenuate the effect of these drugs on reducing the rates of hospitalization for coronary events. This study compares the rates of hospitalization and low-density lipoprotein cholesterol (LDL-C) levels during and after discontinuation of antihyperlipidemic drug therapy. A retrospective cohort study was conducted among 2369 patients at 2 health maintenance organizations (HMOs) during the period 1988 to 1994. Rates of coronary heart disease (CHD)-related hospitalization and non-CHD-related hospitalization and the LDL-C levels between 14 and 180 days after the initiation or discontinuation of drug therapy were compared for periods of antihyperlipidemic drug use and nonuse. The rate ratio for CHD hospitalization during periods of antihyperlipidemic drug use compared with periods of nonuse was 1.02 (95% CI, 0.74 to 1.40), excluding the first 6 months after initiation or discontinuation and controlling for patient sex, age, history of CHD, hypertension, diabetes, and HMO site. By contrast, the adjusted rate ratio was 0.70 (95% CI, 0.61 to 0.80) for non-CHD hospitalization. The percentage of patients with a history of CHD who achieved LDL-C levels <130 mg/dL was 27% < or =6 months after initiation of antihyperlipidemic drug therapy compared with 18% during gaps in drug therapy (P = 0.04). This study failed to demonstrate the effectiveness of lipid-lowering therapy in reducing CHD hospitalizations in community settings, apparently because most recipients either discontinued therapy or failed to achieve the desired LDL-C reduction while receiving therapy. These results indicate the need for interventions to improve patient compliance and management of lipid disorders.

Comparative safety evaluation of non-narcotic analgesics.

Both spontaneous reports and single outcome studies may distort the overall safety evaluation of drugs. We identified epidemiologic studies, published from January 1970 to December 1995, that investigated the association of serious adverse effects with aspirin, diclofenac, acetaminophen, and dipyrone to determine and compare the excess mortality associated with short-term drug use. The estimated excess mortality due to community-acquired agranulocytosis, aplastic anemia, anaphylaxis, and serious upper gastrointestinal complications was 185 per 100 million for aspirin, 592 per 100 million for diclofenac, 20 per 100 million for acetaminophen, and 25 per 100 million for dipyrone. The estimates were largely influenced by the excess mortality associated with upper gastrointestinal complications. A relative risk estimate of 300 or more for the association of dipyrone with agranulocytosis would have been necessary for the excess mortality of dipyrone to be comparable to that of aspirin or diclofenac. Based on published epidemiologic evidence used to determine the excess mortality associated with short-term use of these four non-narcotic analgesics, the current regulatory ranking of the drugs appears inappropriate.

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.

Discontinuations of antihyperlipidemic drug therapy: assessment by means of automated databases.

Discontinuations of drugs used in the treatment of chronic conditions such as hyperlipidemia often signal adverse drug effects or therapeutic ineffectiveness. Discontinuations of antihyperlipidemic drug therapy among 2369 patients were evaluated using the computerized files and written medical records of two health maintenance organizations (HMOs) in Massachusetts for the period 1988 to 1990. Three methods were assessed for the identification of potential discontinuations of drug therapy using the automated databases. Overall, 75% of discontinuations flagged by the automated databases were confirmed in the medical charts. (1) In new users, 618 of the 635 (97%) drugs identified as drug switches by the computerized HMO pharmacy files were confirmed as discontinuations by the medical charts. (2) Of 620 eligible HMO members 332 (54%) identified with greater than 6 months between the last refill for an antihyperlipidemic drug and the end of the study stopped the drug therapy according to the medical chart. (3) Of 219 eligible drug therapies flagged with an 'inactive' or with an 'omit' status in the clinical encounter files 198 (90%) were discontinued according to the medical chart. This study demonstrates the utility of clinical automated databases to facilitate the study of drug discontinuations in primary care settings, reducing the cost and the amount of time required for the evaluation.

Discontinuation of antihyperlipidemic drugs--do rates reported in clinical trials reflect rates in primary care settings?

BACKGROUND: Discontinuation rates for drugs used to treat chronic conditions may affect the success of therapy. However, the discontinuation rates reported in clinical trials may not reflect those in primary care settings. METHODS: We conducted a cohort study using computerized research files and medical records on 2369 new users of antihyperlipidemic therapy at two health maintenance organizations (HMOs) from 1988 through 1990. The rates of drug discontinuation in these primary care settings were compared with the rates reported in clinical trials published from 1975 through 1993, located with the Medline data base. RESULTS: In the HMOs, the one-year probability of drug discontinuation was 41 percent for bile acid sequestrants (95 percent confidence interval, 38 to 44 percent), 46 percent for niacin (95 percent confidence interval, 42 to 51 percent), 15 percent for lovastatin (95 percent confidence interval, 11 to 19 percent), and 37 percent for gemfibrozil (95 percent confidence interval, 31 to 43 percent). For the bile acid sequestrants, niacin, and gemfibrozil, the risks of discontinuation were substantially higher in the HMOs than in randomized clinical trials, in which the summary estimates of this risk were 31 percent, 4 percent, and 15 percent, respectively, for trials of one year or longer. The rates of discontinuation in open-label studies were similar to those in the HMOs. CONCLUSIONS: The discontinuation rates reported in randomized clinical trials may not reflect the rates actually observed in primary care settings. The effectiveness and tolerability of antihyperlipidemic medications should be studied further in populations that typically use the agents.