Twelve-month frequency of drug-metabolizing enzyme and transporter-based drug-drug interaction potential in patients receiving oral enzyme-targeted kinase inhibitor antineoplastic agents.

OBJECTIVE: To describe 12-month rates and patterns of coprescription of drugs that potentially create drug-drug interactions (DDIs) through shared metabolic or transport pathways for 9 enzyme-targeted kinase inhibitor oral antineoplastic drugs (OADs). PATIENTS AND METHODS: We used a deidentified pharmacy claims database identifying patients prescribed dasatinib, erlotinib, everolimus, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, or sunitinib between January 1, 2008, and May 31, 2010. Coprescribing was 1 or more overlapping days of supply between the OAD and potential DDI drugs during the 12-month period beginning on the OAD index date. Product labels identified the cytochrome P450 metabolic enzymes used and whether P-glycoprotein was used by the OADs. Drugs that induce and/or inhibit these pathways were identified from the label and online resources. RESULTS: Sample sizes ranged from 96 (pazopanib group) to 4617 (imatinib group). Coprescribing rates with drugs that may decrease OAD effectiveness were 359/1546 (23%) (sunitinib group) to 1851/3263 (57%) (erlotinib group). Coprescribing rates with drugs that may increase OAD toxicity were 364/1546 (24%) (sunitinib group) to 71/96 (74%) (pazopanib group). Patients coprescribed DDI drugs had a median of 1 to 4 more medications present on the OAD index date than those not coprescribed a DDI drug. Most groups coprescribed DDI drugs had a median of 180 or more OAD days of supply during follow-up. The proportion of OAD days of supply with overlapping days of DDI drugs ranged from 7% to 85%. Generally, oncologists prescribed the OAD and nononcologists the DDI drug. CONCLUSION: Coprescription of drugs that induce or inhibit metabolic pathways used by enzyme-targeted kinase inhibitor OADs is high. The clinical consequences need further study.

A decade of postmenopausal hormone therapy prescribing in the United States: long-term effects of the Women's Health Initiative.

OBJECTIVE: Nearly a decade ago, landmark clinical trials revealed an increase in the risks associated with hormone therapy in postmenopausal women, leading to early changes in prescribing patterns. Long-term prescribing patterns in the United States after these trials are unknown. The objective of this study was to describe changes in hormone therapy prescribing including dose, formulation, patient age, and prescriber specialty from 2000 to 2009. METHODS: A national pharmacy claims database was used to describe the annual prevalence and incidence rates of hormone therapy prescribing from 2000 to 2009 in women 50 years and older. RESULTS: Throughout the decade, a number of prescribing trends were observed: a continuous decline in hormone therapy overall, an initial drop in new therapy that stabilized after 2003, a decline in oral formulations and increase in vaginal formulations, a decline in standard- and high-dose and an increase in low-dose oral formulations, and an increase in the proportion of women who received hormone therapy from gynecologists. CONCLUSIONS: Overall prescribing of hormone therapy continued to decline during the past decade, suggesting a long-term impact of the Women's Health Initiative findings. During this same time, treatment regimens shifted to favor vaginal and lower-dose oral formulations.

A large pharmacy claims-based descriptive analysis of patients with migraine and associated pharmacologic treatment patterns.

PURPOSE: To investigate drug use, prescribing patterns, and comorbidities among patients with migraine in a large pharmacy claims database. METHODS: 104,625 migraine subjects (identified according to the criteria in the International Classification of Diseases, Ninth Revision [ICD-9] for migraine or migraine-specific acute medication use) and an equal number of control patients were selected from a de-identified claims database; the prevalence of patients with migraine-specific claims was determined. Patient demographics, migraine-related medication use, other psychotropic medication use, and comorbidities over a 12-month period were compared between the migraine population and the control group and between migraine subgroups. RESULTS: Of the study population, 3.5% had a migraine diagnosis according to the ICD-9 or received a migraine-specific acute medication. Compared with controls, migraine patients had significantly greater disease comorbidity and higher use of prescription nonsteroidal anti-inflammatory drugs and controlled painkillers; they were also more likely to receive medications used to prevent migraines and other nonmigraine psychotropic medications, such as anxiolytics and hypnotics. Among migraine patients, 66% received acute migraine-specific medication while only 20% received US Food and Drug Administration-approved migraine preventive therapy. Notably, one-third of high triptan users did not receive any kind of preventive medication. Multiple medical and psychiatric comorbidities were observed at higher rates among migraine sufferers. In addition to significantly higher utilization of antidepressants compared with controls, migraine patients also received significantly more other psychotropic drugs by a factor of 2:1. CONCLUSION: Acute migraine medications are commonly used and frequently dispensed at rates that raise concern of overuse; high use is often seen without any preventive medications. Furthermore, use of US Food and Drug Administration-approved preventive medications is low. Finally, patients with migraine are significantly more likely to receive other psychotropic medications. These findings suggest efforts to optimize the management of migraines could address appropriate use of triptans, increased and more effective use of migraine preventive medications, and better understanding of the use of other psychotropics.

Adherence to statins, subsequent healthcare costs, and cardiovascular hospitalizations.

Statins are the primary agents used to decrease low-density lipoprotein cholesterol. Although adherence to statins improves the clinical outcomes, the affect of statin adherence on healthcare costs has not been well studied. To examine the relation among statin adherence, subsequent hospitalizations, and healthcare costs, we conducted a retrospective cohort study of 381,422 patients, aged 18 to 61 years, using an integrated pharmacy and medical claims database. We measured adherence using the medication possession ratio (MPR) for 12 months and the healthcare costs and cardiovascular disease-related hospitalizations during the subsequent 18 months. Of those studied, 258,013 (67.6%) were adherent (MPR ≥80%), 65,795 (17.3%) had an MPR of 60% to 79%, and 57,614 (15.1%) had an MPR of <60%. The adjusted all-cause total healthcare costs were lowest in the adherent group at $10,198 ± $39.4 (mean ± SE) versus $10,609 ± $77.7 (p <0.001) for an MPR of 60% to 79%, and $11,102 ± $84.3 (p <0.001) for an MPR of <60%. The adherent group had greater statin costs at $838 ± $1.0 versus $664 ± $2.0 (p <0.001) and $488 ± $2.2 (p <0.001). When evaluated by 5 levels of MPR, 0% to 59% and increments of 10% >60%, the adjusted total healthcare costs were lowest for the MPR 90% to 100% group and significantly greater statistically (p <0.001) for each lower level of adherence. Compared to the statin-adherent patients, cardiovascular disease-related hospitalizations were more likely for the patients with an MPR of 60% to 79% (odds ratio 1.12, 95% confidence interval 1.08 to 1.16) and an MPR of 0% to 59% (odds ratio 1.26, 95% confidence interval 1.21 to 1.31). In conclusion, statin adherence is associated with reductions in subsequent total healthcare costs and cardiovascular disease-related hospitalizations.

General mortality from 1944 through 1994 for a silicon-based chemical company.

The objective of this study is to reevaluate the statistically significant elevated risk of lung cancer among men with >or=20 years of employment at Dow Corning Corporation, a manufacturer of silicon-based materials. The cohort included 712 deaths among 8266 employees who were hired from 1943 to 1992 with follow-up through 1994. Standardized mortality ratios (SMRs) were calculated for 63 causes of death. Analysis confirmed a statistically significant increased mortality from cancer of the bronchus, trachea, and lung among men, prior to 1985, who jointly classified with >or=30 years of work duration and >or=30 years since first employed. SMRs for lung cancer after 1985, however, were not statistically significant and were inconsistent across work duration and years since first employed intervals. The study provides no evidence for elevated mortality among Dow Corning workers since the 1991 cohort mortality study. This study describes the updated mortality experience of a large employee cohort from a major silicon-based manufacturer. It illustrates that a well-designed mortality study can be a key component of employee health surveillance efforts in an industrial setting with potential hazardous workplace exposures.

The association between fibrate use, change in high-density lipoprotein cholesterol, and the risk of cardiovascular disease: a retrospective chart review involving up to 8 years of follow-up.

BACKGROUND: Clinical trials have indicated that the use of fibric acid derivatives confers a benefit against cardiovascular disease (CVD) in selected populations. However, whether fibrates provide a CVD risk reduction independent of changes in the traditional lipoprotein fractions and other known CVD risk factors is not clear. OBJECTIVE: This study examined whether the use of fibrate therapy in a general clinical setting provided cardiovascular benefits independent of changes in the traditional lipoprotein fractions. METHODS: This was a matched, retrospective cohort study. From the electronic records of a large health maintenance organization in the northwestern United States, we identified a population that had newly initiated fibrate pharmacotherapy between January 1, 1996, and December 31, 2000. We then identified a comparator group of patients not using fibrates, matching them to fibrate users based on high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels, age, sex, and year of HDL-C and TG measurement. Subjects were followed until a CVD hospitalization, termination from the health plan, or December 31, 2003, whichever came first. We then used multivariate analysis accounting for differences in followup to identify predictors of CVD incidence. RESULTS: The study population included 1722 matched pairs (56.6% male; mean [SD] age, 57.3 [11.1] years). The patients who had newly initiated fibrate pharmacotherapy had low baseline HDL-C levels (mean, 37.4 mg/dL) and very high TG levels (617 mg/dL). The 2 groups were similar overall, with the only significant differences between fibrate users and nonfibrate controls being a greater prevalence of diabetes (37.7% vs 34.3%, respectively; P=0.040) and greater use of angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (56.6% vs 51.6%, respectively; P=0.003), beta-blockers (53.7% vs 49.0%; P=0.006), calcium channel blockers (25.1% vs 20.9%; P=0.004), and niacin (11.7% vs 7.4%; P<0.001). Overall, CVD risk was 26% lower for every 5-mg/dL increment in HDL-C. After adjustment for age, sex, smoking history, diabetes, existing diagnosis of CVD, weight, systolic blood pressure, baseline HDL-C, change in HDL-C, total cholesterol, TG, and use of statins, niacin, and other CVD drugs, fibrate use did not confer an additional CVD risk reduction. CONCLUSIONS: In this cohort with low baseline HDL-C levels and very high TG levels, fibrate use did not confer an independent CVD risk reduction after adjustment for CVD risk factors. Given the current obesity epidemic in the United States and the corresponding rise in the number of patients with the metabolic syndrome, the apparent risk reduction observed in association with higher HDL-C levels should not be ignored.

The independent correlation between high-density lipoprotein cholesterol and subsequent major adverse coronary events.

BACKGROUND: There is substantial evidence from clinical trials that lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular risk. There is less evidence for the salutatory effects of raising high-density lipoprotein cholesterol (HDL-C). The predictive strength of an initial HDL-C measurement and its change over time for major adverse coronary events is not well understood. METHODS: We identified a cohort of all 6928 patients in an urban primary care practice who had two or more lipid measurements between January 1985 and December 1997. We used bivariable and multivariable (Cox proportional hazards) techniques to identify independent predictors of subsequent major adverse coronary events (hospitalization for myocardial infarction or acute coronary syndrome) after the second set of lipid measurements. RESULTS: The time between first and second lipid measurements averaged 2.6 years. During a mean of 5.1 +/- 3.2 years of observation after their second lipid measurements, 2167 (31%) patients had an acute coronary event. Patients having events were significantly older, more often white, male, and smokers and more often had antecedent diabetes, hypertension, coronary heart disease, and myocardial infarctions. Adjusting for covariates, a 10-mg/dL higher initial HDL-C was associated with an 11% (95% CI 7%-14%) lower risk of coronary events. A 10-mg/dL increase in HDL-C between lipid measurements was associated with a 7% (95% CI 3%-10%) lower risk of events. Neither initial or change in triglycerides nor LDL-C predicted subsequent coronary events. CONCLUSION: High-density lipoprotein cholesterol measurements and change in HDL-C predicted major adverse coronary events in this urban practice, which provides support studying interventions targeting HDL-C for cardiovascular risk reduction.

Antidiabetic therapy and the risk of heart failure in type 2 diabetic patients: an independent effect or confounding by indication.

PURPOSE: This study assesses the effect of the type of antidiabetic treatment on the risk of developing congestive heart failure (CHF) in type 2 diabetes. METHODS: The study was derived from the U.K.-based General Practice Research Database (GPRD) comprised of 3.5 million subjects followed between 1987 and 2001. A total of 21 888 type 2 diabetic patients were identified. A 6:1 matched nested case-control design was employed. Conditional logistic regression was used to derive adjusted odds ratios (ORs) for the association of drug treatment with CHF controlling for diabetes duration and for diseases known to affect the risk of CHF. Antidiabetic drug exposure was defined as the receipt of at least one prescription for an antidiabetic medication within the 3 months prior to the date of CHF diagnosis. RESULTS: There were 1301 incident cases of CHF in the cohort, matched to 7788 controls. After risk factor adjustment, there was a 1.2-fold increase in the risk of CHF for sulphonylureas (SUs) (OR = 1.17; 95%CI = 1.00-1.37) and metformin monotherapies (OR = 1.22; 95%CI = 0.97-1.52), a 1.6-fold increase with combinations of metformin and SUs (OR = 1.62; 95%CI = 1.30-2.02), a 2.2-fold increase with oral tricombinations (OR = 2.16; 95%CI = 0.96-4.86) and a 1.5-fold increase for insulin compared to no exposure (OR = 1.52; 95%CI = 1.06-2.17). Compared to SUs, bicombinations of metformin and SUs showed a statistically significant 1.4-fold increase in the odds of CHF (OR = 1.38; 95%CI = 1.13-1.69). CONCLUSIONS: All antidiabetic medications were associated with an increased likelihood of CHF compared to no antidiabetic exposure. The risk of CHF increased with the complexity of the antidiabetic regimen suggesting that it is the diabetes severity, which imparts risk and not necessarily the antidiabetic regimen itself.

Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report.

OBJECTIVE: To describe the changes in demographics, antidiabetic treatment, and glycemic control among the prevalent U.S. adult diagnosed type 2 diabetes population between the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and the initial release of NHANES 1999-2000. RESEARCH DESIGN AND METHODS: The study population was derived from NHANES III (n = 1,215) and NHANES 1999-2000 (n = 372) subjects who reported a diagnosis of type 2 diabetes with available data on diabetes medication and HbA(1c). Four therapeutic regimens were defined: diet only, insulin only, oral antidiabetic drugs (OADs) only, or OADs plus insulin. Multiple logistic regression was used to examine changes in antidiabetic regimens and glycemic control rates over time, adjusted for demographic and clinical risk factors. The outcome measure for glycemic control was HbA(1c). Glycemic control rates were defined as the proportion of type 2 diabetic patients with HbA(1c) level <7%. RESULTS: Dietary treatment in individuals with diabetes decreased as the sole therapy from 27.4 to 20.2% between the surveys. Insulin use also decreased from 24.2 to 16.4%, while those on OADs only increased from 45.4 to 52.5%. Combination of OADs and insulin increased from 3.1 to 11.0%. Glycemic control rates declined from 44.5% in NHANES III (1988-1994) to 35.8% in NHANES 1999-2000. CONCLUSIONS: Treatment regimens among U.S. adults diagnosed with type 2 diabetes have changed substantially over the past 10 years. However, a decrease in glycemic control rates was also observed during this time period. This trend may contribute to increased rates of macrovascular and microvascular diabetic complications, which may impact health care costs. Our data support the public health message of implementation of early, aggressive management of diabetes.

Silicone gel breast implant rupture rates: research issues.

Documenting the rate of rupture of silicone breast implants appears to be deceptively easy. Largely because of the phenomenon of "silent rupture," it isn't. The authors explore the various technical biases (selection, misclassification, and confounding) and methodological problems that have plagued much of the research conducted to date. By means of a series of illustrations, they argue that explantation has limited utility. Noninvasive techniques have to be used to gather the proper type of data on the timing and frequency of these events. Only with the proper incidence data will researchers be able to identify better the different mechanisms underlying implant rupture and the relative importance of each. The authors recommend that better and standardized definitions of implant rupture be developed, that greater recognition be given to the technical biases and a greater effort be made to eliminate them from investigations of implant rupture, and that more research be conducted by multidisciplinary teams. Because of the growing awareness of the complexity of this issue, the authors also recommend that properly constituted advisory teams be used to provide comprehensive oversight of future research projects from beginning to end.