Does levonorgestrel-releasing intrauterine system increase breast cancer risk in peri-menopausal women? An HMO perspective.

PURPOSE: To evaluate the association between levonorgestrel-releasing intrauterine system (LNG-IUS) use and breast cancer (BC) risk. METHODS: A cohort of all Maccabi Healthcare Services (MHS) female members aged 40-50 years between 1/2003 and 12/2013 was used to identify LNG-IUS users as "cases," and 2 age-matched non-users as "controls." Exclusion criteria included: prior BC diagnosis, prior (5 years pre-study) and subsequent treatment with other female hormones or prophylactic tamoxifen. Invasive tumors were characterized by treatments received (chemotherapy, hormonal therapy, trastuzumab, or combination thereof). RESULTS: The analysis included 13,354 LNG-IUS users and 27,324 controls (mean age: 44.1 ± 2.6 vs. 44.9 ± 2.8 years; p < 0.0001). No significant differences in 5-year Kaplan-Meier (KM) estimates for overall BC risk or ductal carcinoma in situ occurrence were observed between groups. There was a trend towards higher risk for invasive BC in LNG-IUS users (5-year KM-estimate: 1.06% vs. 0.93%; p = 0.051). This difference stemmed primarily from the younger women (40-45 years; 0.88% vs. 0.69%, p = 0.014), whereas in older women (46-50 years), it was non-significant (1.44% vs. 1.21%; p = 0.26). Characterization of invasive BC by treatment demonstrated that LNG-IUS users had similar proportions of tumors treated with hormonal therapy, less tumors treated with trastuzumab, (7.5% vs. 14.5%) and more tumors treated with chemotherapy alone (25.8% vs. 14.9%; p = 0.041). CONCLUSIONS: In peri-menopausal women, LNG-IUS was not associated with an increased total risk of BC, although in the subgroup of women in their early 40's, it was associated with a slightly increased risk for invasive tumors.

Trends in annual drug expenditure - a 16 year perspective of a public healthcare maintenance organization.

BACKGROUND: Modern drug therapy accounts for a major share of health expenditure and challenges public provider resources. The objective of our study was to compare drug expenditure trends for ten major drug classes over 16 years at Maccabi Healthcare Services (MHS), the 2(nd) largest healthcare organization in Israel. METHODS: A retrospective analysis of drug expenditure per HMO beneficiary between the years 1998-2014. Trends in annual mean drug expenditures per MHS member were compared among 10 major drug classes. RESULTS: Average annual drug expenditure per beneficiary increased during the study period from 429.56 to 474.32 in 2014 (10.4 %). Ten drug classes accounted for 58.0 % and 77.8 % of total drug cost in 1998 and 2014, respectively. The overall distribution of drug expenditure among drug classes differed significantly between 1998 and 2014 (p < 0.001), mainly due to the increase in expenditure for cancer drugs, from 6.8 % of total drug cost to 30.3 %. In contrast, expenditures for cardiovascular drugs decreased during the same period from 16.0 to 2.7 %. Moreover, the median annual increase in net drug costs per HMO member during 1998-2014 was largest for cancer drugs (NIS 6.18/year; IQR, 1.70-9.92/year), about two-fold that of immunosuppressants, the second fastest growing drug class (NIS 2.81; IQR, 0.58-7.43/year). CONCLUSIONS: The continuous rise in anti-cancer drug expenditure puts a substantial burden on the medication budgets of public health organizations. Coordinated measures involving policy makers, physicians, and pharmaceutical companies will be required for efficient cost containment.

A Novel Computational Tool for Mining Real-Life Data: Application in the Metastatic Colorectal Cancer Care Setting.

BACKGROUND: Randomized clinical trials constitute the gold-standard for evaluating new anti-cancer therapies; however, real-life data are key in complementing clinically useful information. We developed a computational tool for real-life data analysis and applied it to the metastatic colorectal cancer (mCRC) setting. This tool addressed the impact of oncology/non-oncology parameters on treatment patterns and clinical outcomes. METHODS: The developed tool enables extraction of any computerized information including comorbidities and use of drugs (oncological/non-oncological) per individual HMO member. The study in which we evaluated this tool was a retrospective cohort study that included Maccabi Healthcare Services members with mCRC receiving bevacizumab with fluoropyrimidines (FP), FP plus oxaliplatin (FP-O), or FP plus irinotecan (FP-I) in the first-line between 9/2006 and 12/2013. RESULTS: The analysis included 753 patients of whom 15.4% underwent subsequent metastasectomy (the Surgery group). For the entire cohort, median overall survival (OS) was 20.5 months; in the Surgery group, median duration of bevacizumab-containing therapy (DOT) pre-surgery was 6.1 months; median OS was not reached. In the Non-surgery group, median OS and DOT were 18.7 and 11.4 months, respectively; no significant OS differences were noted between FP-O and FP-I, whereas FP use was associated with shorter OS (12.3 month; p <0.002; notably, these patients were older). Patients who received both FP-O- and FP-I-based regimens achieved numerically longer OS vs. those who received only one of these regimens (22.1 [19.9-24.0] vs. 18.9 [15.5-21.9] months). Among patients assessed for wild-type KRAS and treated with subsequent anti-EGFR agent, OS was 25.4 months and 18.7 months for 124 treated vs. 37 non-treated patients (non-significant). Cox analysis (controlling for age and gender) identified several non-oncology parameters associated with poorer clinical outcomes including concurrent use of diuretics and proton-pump inhibitors. CONCLUSIONS: Our tool provided insights that confirmed/complemented information gained from randomized-clinical trials. Prospective tool implementation is warranted.

Database evaluation of the effects of long-term rosiglitazone treatment on cardiovascular outcomes in patients with type 2 diabetes.

Recent meta-analyses suggest an increased risk of acute myocardial infarction (AMI) in patients with type 2 diabetes mellitus (T2DM) treated with rosiglitazone. These meta-analyses have drawn considerable criticisms. Retrospective observational studies do not consistently support this association. The objective of this study was to compare rates of adverse cardiovascular outcomes in T2DM patients treated with rosiglitazone alone or combined with metformin or metformin alone. This retrospective study, using the health maintenance organization database, included patients who were dispensed rosiglitazone (alone or with metformin) for at least 6 months as follows: rosiglitazone alone (n = 745), rosiglitazone and metformin (n = 2753), and metformin alone (n = 11 938). Adverse cardiovascular outcomes were new diagnosis of AMI, acute coronary syndrome (ACS), coronary revascularization (CRV), congestive heart failure (CHF), and all-cause mortality. Mean on-treatment follow-up was 30 months. After adjustment for covariates found to be significant in univariate analyses, rosiglitazone was associated only with CHF (hazard ratio [HR] = 2.23; 95% confidence interval [CI]: 1.41-1.95) with no increase of risk for AMI (HR = 1.13; 95%CI: 0.60-2.12), ACS (HR = 0.85; 95% CI: 0.57-1.26), coronary revascularization (HR = 1.22; 95% CI:0.82-1.54), or all-cause mortality (HR = 1.15; 95% CI: 0.85-1.56). In this community-based cohort, 30 months of therapy with rosiglitazone treatment was associated with increased risk of CHF but was not associated with increased risk of AMI, ACS, coronary revascularization, or all-cause mortality.

Use of a homeopathic preparation for "infantile colic" and an apparent life-threatening event.

OBJECTIVE: An apparent life-threatening event (ALTE) caused by ingestion of drugs or toxins has been reported rarely among infants. None of these agents was homeopathic medication. We report 11 infants who presented with an ALTE after ingestion of Gali-col Baby, a homeopathic agent indicated for "infantile colic." METHODS: A retrospective case-control study was conducted. Charts of all infants who were younger than 1 year and were admitted with an ALTE from January 2005 through August 2008 to the pediatric division at the Barzilai Medical Center were reviewed. Age-matched infants who were admitted on the same dates for a reason other than ALTE served as a control group. Information on medications administered before admission was recorded. RESULTS: During the study period, 36 635 children visited the pediatric emergency department of the Barzilai Medical Center. There were 11 057 admissions to the pediatric division during this period, 115 of which were because of an ALTE. Eleven of these infants received Gali-col Baby before the event as opposed to none in the control group (P < .005). Three infants received a significant overdose, compared with the manufacturer's recommended dosage. After a thorough investigation, no other presumptive causes for ALTE were found among the 11 infants. CONCLUSIONS: Gali-col Baby is associated with an ALTE in some infants. There are no published controlled trials on the efficacy or safety of its use; therefore, better control and supervision of Gali-col Baby and probably other homeopathic medications are needed to prevent possible serious adverse effects.

Database assessment of the effectiveness of brand versus generic rosiglitazone in patients with type 2 diabetes mellitus.

BACKGROUND: To compare the effectiveness of brand rosiglitazone maleate (BRM) versus generic rosiglitazone HCl (GRH) in patients with type 2 diabetes mellitus, using computerized records of a healthcare organization. Retrospective, longitudinal database analysis. MATERIAL/METHODS: Comparison of HbA1C reduction in patients starting treatment with either BRM (n=740) or GRH (n=306) in the years 2004-2005. RESULTS: BRM users were older (63.5+/-11 vs. 61.7+/-10 years p<0.001) and presented more cardiovascular disorders (38% vs. 25%, p<0.001) with no differences in gender distribution, rates of hypertension or use of concomitant oral hypoglycemic drugs. Use of concomitant insulin was more frequent (17.7% vs. 6.2%, p<0.0001), rates of dispensed rosiglitazone doses >4 mg/d (65.3% vs. 48.5%, p<0.001) and treatment duration was longer (9.3+/-6.2 vs. 5.2+/-2.2 months, p<0.001) with the generic formulation. Baseline HbA1C levels were higher (9.0+/-1.5 vs. 8.6+/-1.2%, p<0.001) and the absolute decrease in HbA1C levels was greater in the GRH group (-1.2+/-1.6% vs. -0.5+/-1.7%, p<0.001). On multiple regression analysis, the decrease in HbA1C (dependent variable) was associated mainly with initial HbA1C level (partial r2=0.30). Rosiglitazone formulation (partial r2=0.02), age, treatment duration and concomitant insulin (partial r2=0.006) were all significant but minor predictors, with no effect of rosiglitazone daily dose. Mean regression-predicted decreases in HbA1C (with 95% CL) were not significantly different between the two rosiglitazone formulations: -1.6% (-4.3% to +1.1%) for GRH and -1.1% (-3.8% to +1.6%) for BRM. CONCLUSIONS: In this retrospective database analysis, we found no evidence of different effectiveness of generic vs. brand rosiglitazone in lowering HbA1C levels.