Safety of opioid prescribing among older cancer survivors.

BACKGROUND: Cancer survivors receive more long-term opioid therapy (LTOT) than people without cancer, but the safety of LTOT prescribing is unknown. METHODS: Opioid-naive adults aged ≥66 years who had been diagnosed in 2008-2015 with breast, lung, head and neck, or colorectal cancer were identified with data from Surveillance, Epidemiology, and End Results cancer registries linked with Medicare claims. Survivors with 1 or more LTOT episodes (≥90 consecutive days) occurring ≥1 year after their cancer diagnosis and before censoring at hospice entry, another cancer diagnosis, 6 months before death, or December 2016 were included. The safety of prescribing during the first 90 days of the first LTOT episode was measured during follow-up. As a positive safety indicator, the proportion of survivors with concurrent nonopioid pain management was measured. Indicators of less safe prescribing were the proportion of survivors with a high average daily opioid dose (≥90 morphine milligram equivalents) and the proportion of survivors with concurrent benzodiazepine dispensing. Multivariable logistic regression analyses were conducted to identify clinical predictors of each safety outcome. RESULTS: In all, 3628 cancer survivors received LTOT during follow-up (median duration, 4.9 months; interquartile range, 3.5-8.0 months). Seventy-two percent of the survivors received multimodal pain management concurrently with LTOT. Eight percent of the survivors had high-dose opioid prescriptions; 25% of the survivors received benzodiazepines during LTOT. Multivariable analyses identified variations in safety measures by multiple clinical factors, although none were consistently significant across outcomes. CONCLUSIONS: To improve safe LTOT prescribing for survivors, efforts should focus on increasing multimodal pain management and reducing inappropriate benzodiazepine prescribing. Different clinical predictors of each outcome suggest different drivers of safe prescribing.

Baseline representativeness of patients in clinics enrolled in the PRimary care Opioid Use Disorders treatment (PROUD) trial: comparison of trial and non-trial clinics in the same health systems.

BACKGROUND: Pragmatic primary care trials aim to test interventions in "real world" health care settings, but clinics willing and able to participate in trials may not be representative of typical clinics. This analysis compared patients in participating and non-participating clinics from the same health systems at baseline in the PRimary care Opioid Use Disorders treatment (PROUD) trial. METHODS: This observational analysis relied on secondary electronic health record and administrative claims data in 5 of 6 health systems in the PROUD trial. The sample included patients 16-90 years at an eligible primary care visit in the 3 years before randomization. Each system contributed 2 randomized PROUD trial clinics and 4 similarly sized non-trial clinics. We summarized patient characteristics in trial and non-trial clinics in the 2 years before randomization ("baseline"). Using mixed-effect regression models, we compared trial and non-trial clinics on a baseline measure of the primary trial outcome (clinic-level patient-years of opioid use disorder (OUD) treatment, scaled per 10,000 primary care patients seen) and a baseline measure of the secondary trial outcome (patient-level days of acute care utilization among patients with OUD). RESULTS: Patients were generally similar between the 10 trial clinics (n = 248,436) and 20 non-trial clinics (n = 341,130), although trial clinics' patients were slightly younger, more likely to be Hispanic/Latinx, less likely to be white, more likely to have Medicaid/subsidized insurance, and lived in less wealthy neighborhoods. Baseline outcomes did not differ between trial and non-trial clinics: trial clinics had 1.0 more patient-year of OUD treatment per 10,000 patients (95% CI: - 2.9, 5.0) and a 4% higher rate of days of acute care utilization than non-trial clinics (rate ratio: 1.04; 95% CI: 0.76, 1.42). CONCLUSIONS: trial clinics and non-trial clinics were similar regarding most measured patient characteristics, and no differences were observed in baseline measures of trial primary and secondary outcomes. These findings suggest trial clinics were representative of comparably sized clinics within the same health systems. Although results do not reflect generalizability more broadly, this study illustrates an approach to assess representativeness of clinics in future pragmatic primary care trials.

Prevalence and Medication Treatment of Opioid Use Disorder Among Primary Care Patients with Hepatitis C and HIV.

BACKGROUND: Hepatitis C and HIV are associated with opioid use disorders (OUD) and injection drug use. Medications for OUD can prevent the spread of HCV and HIV. OBJECTIVE: To describe the prevalence of documented OUD, as well as receipt of office-based medication treatment, among primary care patients with HCV or HIV. DESIGN: Retrospective observational cohort study using electronic health record and insurance data. PARTICIPANTS: Adults ≥ 18 years with ≥ 2 visits to primary care during the study (2014-2016) at 6 healthcare systems across five states (CO, CA, OR, WA, and MN). MAIN MEASURES: The primary outcome was the diagnosis of OUD; the secondary outcome was OUD treatment with buprenorphine or oral/injectable naltrexone. Prevalence of OUD and OUD treatment was calculated across four groups: HCV only; HIV only; HCV and HIV; and neither HCV nor HIV. In addition, adjusted odds ratios (AOR) of OUD treatment associated with HCV and HIV (separately) were estimated, adjusting for age, gender, race/ethnicity, and site. KEY RESULTS: The sample included 1,368,604 persons, of whom 10,042 had HCV, 5821 HIV, and 422 both. The prevalence of diagnosed OUD varied across groups: 11.9% (95% CI: 11.3%, 12.5%) for those with HCV; 1.6% (1.3%, 2.0%) for those with HIV; 8.8% (6.2%, 11.9%) for those with both; and 0.92% (0.91%, 0.94%) among those with neither. Among those with diagnosed OUD, the prevalence of OUD medication treatment was 20.9%, 16.0%, 10.8%, and 22.3%, for those with HCV, HIV, both, and neither, respectively. HCV was not associated with OUD treatment (AOR = 1.03; 0.88, 1.21), whereas patients with HIV had a lower probability of OUD treatment (AOR = 0.43; 0.26, 0.72). CONCLUSIONS: Among patients receiving primary care, those diagnosed with HCV and HIV were more likely to have documented OUD than those without. Patients with HIV were less likely to have documented medication treatment for OUD.

Prevalence of prescription opioid use during pregnancy in eight US health plans during 2001-2014.

PURPOSE: To estimate prevalence of prescription opioid use during pregnancy in eight US health plans during 2001-2014. METHODS: We conducted a cohort study of singleton live birth deliveries. Maternal characteristics were ascertained from health plan and/or birth certificate data and opioids dispensed during pregnancy from health plan pharmacy records. Prevalence of prescription opioid use during pregnancy was calculated for any use, cumulative days of use, and number of dispensings. RESULTS: We examined prevalence of prescription opioid use during pregnancy in each health plan. Tennessee Medicaid had appreciably greater prevalence of use compared to the seven other health plans. Thus, results for the two groups were reported separately. In the seven health plans (n = 587 093 deliveries), prevalence of use during pregnancy was relatively stable at 9%-11% throughout 2001-2014. In Tennessee Medicaid (n = 256 724 deliveries), prevalence increased from 29% in 2001 to a peak of 36%-37% in 2004-2010, and then declined to 28% in 2014. Use for ≥30 days during pregnancy was stable at 1% in the seven health plans and increased from 2% to 7% in Tennessee Medicaid during 2001-2014. Receipt of ≥5 opioid dispensings during pregnancy increased in the seven health plans (0.3%-0.6%) and Tennessee Medicaid (3%-5%) during 2001-2014. CONCLUSION: During 2001-2014, prescription opioid use during pregnancy was more common in Tennessee Medicaid (peak prevalence in late 2000s) compared to the seven health plans (relatively stable prevalence). Although a small percentage of women had opioid use during pregnancy for ≥30 days or ≥ 5 dispensings, they represent thousands of women during 2001-2014.

Validity of diagnosis and procedure codes for identifying neural tube defects in infants.

PURPOSE: The use of validated criteria to identify birth defects in electronic healthcare databases can avoid the cost and time-intensive efforts required to conduct chart reviews to confirm outcomes. This study evaluated the validity of various case-finding methodologies to identify neural tube defects (NTDs) in infants using an electronic healthcare database. METHODS: This analysis used data generated from a study whose primary aim was to evaluate the association between first-trimester maternal prescription opioid use and NTDs. The study was conducted within the Medication Exposure in Pregnancy Risk Evaluation Program. A broad approach was used to identify potential NTDs including diagnosis and procedure codes from inpatient and outpatient settings, death certificates and birth defect flags in birth certificates. Potential NTD cases were chart abstracted and confirmed by clinical experts. Positive predictive values (PPVs) and 95% confidence intervals (95% CI) are reported. RESULTS: The cohort included 113 168 singleton live-born infants: 55 960 infants with opioid exposure in pregnancy and 57 208 infants unexposed in pregnancy. Seventy-three potential NTD cases were available for the validation analysis. The overall PPV was 41% using all diagnosis and procedure codes plus birth certificates. Restricting approaches to codes recorded in the infants' medical record or to birth certificate flags increased the PPVs (72% and 80%, respectively) but missed a substantial proportion of confirmed NTDs. CONCLUSIONS: Codes in electronic healthcare data did not accurately identify confirmed NTDs. These results indicate that chart review with adjudication of outcomes is important when conducting observational studies of NTDs using electronic healthcare data.

Diabetes and differences in detection of incident invasive breast cancer.

Many women diagnosed with breast cancer have chronic conditions such as diabetes that may impact other health behaviors. Our purpose was to determine if breast cancer screening and detection differs among women with and without diabetes. We conducted a cross-sectional analysis of a retrospective cohort of women aged 52-74 years diagnosed with incident stages I-III breast cancer enrolled in an integrated health plan between 1999 and 2014 with linkage to the Surveillance, Epidemiology and End Results registry (n = 2040). Screening data were taken from electronic health records. We used multivariable modified Poisson regression models with robust standard errors to estimate relative risks (RR) and 95% confidence intervals (CI) for outcomes of (i) receipt of screening in the 2 years prior to diagnosis; (ii) symptom-detected breast cancer; and (iii) diagnosis of locally advanced stage III breast cancer. Compared to women without diabetes, women with diabetes were similar with respect to receipt of screening mammography (78% and 77%), symptom-detected breast cancer (46% and 49%), and stage III diagnosis (7% and 7%). In multivariable models adjusting for age and year of diagnosis, race, BMI, Charlson comorbidity score and depression diagnosis no differences were observed in the outcomes by presence of diabetes. Further investigation is warranted to determine how diabetes acts as a mediating factor in adverse breast cancer outcomes.

Changes in use of opioid therapy after colon cancer diagnosis: a population-based study.

PURPOSE: To describe patterns of opioid use in cancer survivors. METHODS: In a cohort study of colon cancer patients diagnosed during 1995-2014 and enrolled at two Kaiser Permanente regions, we constructed quarterly measures of opioid use from 1 year before cancer diagnosis through 5 years after diagnosis to examine changes in use. Measures included any use, incident use, regular use (use ≥ 45 days in a 91-day quarter), and average daily dose (converted to morphine milligram equivalent, MME). We also assessed temporal trends of opioid use. RESULTS: Of 2,039 colon cancer patients, 11-15% received opioids in the four pre-diagnosis quarters, 68% in the first quarter after diagnosis, and 15-17% in each subsequent 19 quarters. Regular opioid use increased from 3 to 5% pre-diagnosis to 5-7% post diagnosis. Average dose increased from 15 to 17 MME/day pre-diagnosis to 14-22 MME/day post diagnosis (excluding the quarter in which cancer was diagnosed). Among post-diagnosis opioid users, 73-95% were on a low dose (< 20 MME/day). Over years, regular use of opioids increased in survivorship with no change in dosage. CONCLUSION: Opioid use slightly increased following a colon cancer diagnosis, but high-dose use was rare. Research is needed to differentiate under- versus over-treatment of cancer pain.

Cardiovascular medication use and risks of colon cancer recurrences and additional cancer events: a cohort study.

BACKGROUND: Cardiovascular medications may be associated with cancer development, but little is known about their association with cancer recurrence. Medications such as statins and antihypertensives may be commonly used among colon cancer survivors, who are, on average, diagnosed in their mid-60s. We described the associations between statins and antihypertensive medications and colon cancer recurrence in a large, population-based study. METHODS: We conducted a cohort study among adults with stage I-IIIA colon cancer diagnosed in 1995-2014 in two Kaiser Permanente regions, Colorado and Washington. Statin and antihypertensive use were obtained from electronic pharmacy dispensing data. People were classified as medication users on the date of their first dispensing after cohort entry, which started 90 days after completing cancer treatment, continuing through the earliest of death, health plan disenrollment, or chart abstraction. We collected outcome information from medical record abstraction and tumor registries on colon cancer recurrences and second primary cancers. Using Cox proportional hazards multivariable models, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for colon cancer recurrences and any cancer event (recurrences and new primaries at any anatomic site) comparing medication users to non-users. RESULTS: Among 2039 people, 937 (46%) used statins and 1425 (70%) used antihypertensives at any point during a median of 4.9 years of follow-up; 460 people had any additional cancer event, including 152 with a colon cancer recurrence. Statin use was not associated with colon cancer recurrence (HR = 1.09, 95%CI = 0.65-1.85) or any cancer event (HR = 1.12, 95%CI = 0.85-1.47), nor was antihypertensive use associated with recurrence (HR = 0.73, 95%CI = 0.44-1.21) or any cancer event (HR = 0.93, 95%CI = 0.70-1.24). CONCLUSIONS: Our results suggest no association between cardiovascular medication use and the risk of recurrence or any additional cancer, and may provide reassurance to colon cancer survivors.

Use of antidepressants after colon cancer diagnosis and risk of recurrence.

OBJECTIVE: Prior research examining the association between use of antidepressants after colon cancer diagnosis and risk of recurrence is scant. We evaluated this association among colon cancer patients diagnosed at two integrated health care delivery systems in the United States. METHODS: We conducted a cohort study of stage I to IIIA colon cancer patients diagnosed at greater than or equal to 18 years of age at Kaiser Permanente Colorado and Kaiser Permanente Washington during 1995 to 2014. We used pharmacy records to identify dispensings for antidepressants and tumor registry records and patients' medical charts to identify cancer recurrences. Using Cox proportional hazards models, we estimated the adjusted hazard ratio (HR) of colon cancer recurrence comparing patients who used antidepressants after diagnosis to those who did not. We also evaluated the risk associated with use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) separately. RESULTS: Among the 1923 eligible colon cancer patients, 807 (42%) used an antidepressant after diagnosis and 139 had a colon cancer recurrence during an average 5.6 years of follow-up. Use of antidepressants after colon cancer diagnosis was not associated with risk of recurrence (HR: 1.14; 95% confidence interval [CI], 0.69-1.87). The HR for use of SSRIs was 1.22 (95% CI, 0.64-2.30), and for TCAs, it was 1.18 (95% CI, 0.68-2.07). CONCLUSIONS: Our findings suggest that use of antidepressants after colon cancer diagnosis was common and not associated with risk of recurrence. Future larger studies with greater power to examine risk associated with individual antidepressants would be valuable additions to the evidence base.

Risk of second breast cancer events with chronic opioid use in breast cancer survivors.

PURPOSE: Opioids may increase cancer risk and progression through multiple pathways. Our objective was to estimate the association between chronic opioid use and risk of second breast cancer events (SBCEs). METHODS: Cohort study of women greater than or equal to 18 years, diagnosed with early stage breast cancer between January 1, 1990, and December 31, 2008, and enrolled in a large health plan for 1+ years before and after (unless died) diagnosis. SBCEs were defined as evidence of recurrence or second primary breast cancer in the medical chart. Chronic opioid use was defined as 75+ days of use in any moving 90-day window after breast cancer diagnosis and varied to 150+ days in a 180-day window in a sensitivity analysis. Using Cox proportional hazards models, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for SBCE and components of SBCE by chronic opioid use. RESULTS: Almost 10% met the criteria for chronic use and almost a third of users were taking opioids for greater than 3 years. Risk of SBCEs (HR = 1.20; 95% CI, 0.85-1.70), including second primary breast cancer (HR = 1.38; 95% CI, 0.71-2.70), was nonsignificantly higher among chronic users vs nonchronic/nonusers. The HR for recurrence was 1.14 (95% CI, 0.76-2.70). Results of the sensitivity analyses on longer opioid use does support an association with SBCE or recurrence. CONCLUSION: This first US-based study on chronic opioid use and cancer outcomes provides some reassurance on safety. However, the question warrants further exploration in other populations and settings.

Risk of colon cancer recurrence in relation to diabetes.

PURPOSE: To describe the association between diabetes and colon cancer recurrence. METHODS: We conducted a cohort study at two integrated health care delivery systems in the United States. Using tumor registry data, we identified patients aged ≥ 18 years when diagnosed with stage I-IIIA adenocarcinomas of the colon during 1995-2014. Pre-existing diabetes was ascertained via diagnosis codes. Medical records were reviewed for eligibility and to abstract recurrence and covariate information. Recurrence was ascertained beginning 90 days after the end of colon cancer treatment (i.e., cohort entry). Recurrence of any cancer or a new primary cancer at any site was a secondary outcome. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for the associations between diabetes at cohort entry and study outcomes. RESULTS: Among the 1,923 eligible patients, 393 (16.7%) had diabetes at cohort entry. Diabetes was not associated with recurrence (HR 0.87; 95% CI 0.56-1.33) or with any subsequent cancer (HR 1.09; 95% CI 0.85-1.40). When the definition of recurrence included second primary colorectal cancer, risk was non-significantly higher in patients with diabetes than without diabetes. CONCLUSIONS: The risk of colon cancer recurrence appears to be similar in patients with and without diabetes at diagnosis. IMPACT: Future studies should evaluate the association between diabetes and colorectal cancer outcomes, especially second primary colon cancers, in larger populations.

Evidence for Detection Bias by Medication Use in a Cohort Study of Breast Cancer Survivors.

In previous studies, we found modestly decreased and increased risks of second breast cancer events with the use of statins and antibiotics, respectively, after adjustment for surveillance mammography. We evaluated detection bias by comparing receipt of surveillance mammography among users of these 2 disparate classes of medication. Adult women diagnosed with early-stage breast cancer during 1990-2008 (n = 3,965) while enrolled in an integrated health-care plan (Group Health Cooperative; Washington State) were followed for up to 10 years in the Commonly Used Medications and Breast Cancer Outcomes (COMBO) Study. Categories of antibiotic use included infrequent (1-3 dispensings/12 months) and frequent (≥4 dispensings/12 months) use, and categories of statin use included less adherent (1 dispensing/6 months) and adherent (≥2 dispensings/6 months). We examined associations between medication use and surveillance mammography using multivariable generalized estimating equations and evaluated the impact of adjusting for surveillance within Cox proportional hazard models. Frequent antibiotic users were less likely to receive surveillance mammography (odds ratio (OR) = 0.90, 95% confidence interval (CI): 0.82, 0.99) than were nonusers; no association was found among infrequent users (OR = 0.96, 95% CI: 0.90, 1.03). Adherent statin use was associated with more surveillance compared with nonuse (OR = 1.11, 95% CI: 1.01, 1.25), but less adherent statin use was not (OR = 1.03, 95% CI: 0.81, 1.31). No difference in associations between medications of interest and second breast cancer events was observed when surveillance was removed from otherwise adjusted models. The influence of detection bias by medication use warrants further exploration.

Risk of Breast Cancer With Long-Term Use of Calcium Channel Blockers or Angiotensin-Converting Enzyme Inhibitors Among Older Women.

Controversy exists about breast cancer risk associated with long-term use of calcium channel blockers (CCBs) or angiotensin-converting enzyme inhibitors (ACEis), respectively. Our objective in this study was to separately evaluate associations between duration of CCB or ACEi use and breast cancer in hypertensive women aged ≥55 years at 3 sites in the Kaiser Permanente health-care system (1997­2012). Exposures included CCB or ACEi use of 1­12 years' duration, determined from pharmacy dispensings. Outcomes included invasive lobular or ductal carcinoma. Statistical methods included discrete-time survival analyses. The cohort included 19,674 (17.9%) CCB users and 90,078 (82.1%) ACEi users. Two percent (n = 397) of CCB users and 1.9% (n = 1,733) of ACEi users developed breast cancer. Compared with 1­<2 years of use, in adjusted analysis, there was no association between CCB use for 2­<12 years and breast cancer: All 95% confidence intervals included 1. Increasing duration of ACEi use was associated with reduced breast cancer risk: Compared with 1­<2 years of use, the adjusted hazard ratio was 0.76 (95% confidence interval: 0.63, 0.92) for 5­<6 years of use and 0.63 (95% confidence interval: 0.43, 0.93) for 9­<10 years of use. We conclude that among older women with hypertension, long-term CCB use does not increase breast cancer risk and long-term treatment with ACEis may confer protection against breast cancer.

Characteristics associated with nonadherence to medications for hypertension, diabetes, and dyslipidemia among breast cancer survivors.

OBJECTIVE: Comorbidity among breast cancer survivors is prevalent, and adherence to medication management of comorbidities may be important for both chronic disease and cancer-related outcomes. Our objective was to determine characteristics associated with nonadherence to common chronic medications among breast cancer survivors. METHODS: We conducted a retrospective cohort study of 4216 women in an integrated care system diagnosed with early-stage breast cancer between 1990 and 2008 and alive without recurrence or second primary breast cancer in the second-year following diagnosis. Adherence to antihypertensives, oral diabetes medications, and statins was measured during the second-year post-breast cancer diagnosis using medication possession ratios (MPR). Nonadherence was defined as MPR <0.80. We estimated odds ratios (OR) and 95% confidence intervals (CI) for nonadherence to antihypertensives, oral diabetes medications, and statins by various characteristics using multivariable logistic regression. RESULTS: Among 2308 users of antihypertensives (n = 1779), diabetes medications (n = 499) and/or statins (n = 1072), 37% were nonadherent to antihypertensives; 75% were nonadherent to diabetes medications; 39% were nonadherent to statins. In adjusted models, younger age was associated with nonadherence to all three therapeutic classes. Certain cancer treatments were associated with nonadherence to antihypertensives (radiation: OR 1.21, 95% CI 1.01-1.47; endocrine therapy: OR 1.27, 95% CI 1.03-1.52) and diabetes medications (chemotherapy: OR 1.69, 95% CI 1.17-2.21). Less frequent primary care provider visits were associated with higher odds of nonadherence to antihypertensives (OR 1.70, 95% CI 1.19-2.22); and trends showed higher Charlson comorbidity scores associated with greater adherence to diabetes medications (P < 0.001) and statins (P = 0.032). CONCLUSIONS: Nonadherence to medications is high among breast cancer survivors, particularly diabetes medications, and is associated with cancer treatments and other patient characteristics. Additional research is warranted to understand the needs of cancer patients taking chronic medications and explore patient and provider factors influencing adherence.

Validity of Self-Reported Medication Use Compared With Pharmacy Records in a Cohort of Older Women: Findings From the Women's Health Initiative.

Inaccurate self-reported data on medication exposure lead to less reliable study findings. From 2013 to 2015, we assessed the validity of information on medication use collected via a mailed medication inventory among 223 Women's Health Initiative participants who were members of a health-care delivery system. Self-reported information on medication use was compared with pharmacy records for statins, calcium channel blockers, ß-blockers, and bisphosphonates. We assessed sensitivity, specificity, and positive predictive value (PPV) for current medication use. We assessed agreement on duration of use (<2, 2, 3, 4, or ≥5 years) by means of the weighted κ statistic. The mean age of participants was 77 years. Statins, ß-blockers, and calcium channel blockers were each reported by over 15% of women, and bisphosphonates were reported by 4.5%. Compared with pharmacy records, the sensitivity, specificity, and PPV for self-reported use of statins, ß-blockers, and calcium channel blockers were all 95% or greater. The sensitivity and PPV for bisphosphonate use were both 80% (95% confidence interval: 44, 97), and specificity was 99% (95% confidence interval: 97, 100). The κ statistic for duration of use was 0.87 or greater for all 4 medication classes. Compared with pharmacy records, self-reported information on current medication use and duration of use collected via mailed medication inventory among older women had almost perfect agreement for use of statins, ß-blockers, and calcium channel blockers.

Comparative safety of diabetes medications and risk of incident invasive breast cancer: a population-based cohort study.

PURPOSE: Growing evidence suggests that certain commonly used diabetes medications have the potential to differentially alter breast cancer risk. We evaluated the influence of metformin, insulin, and sulfonylureas on risk of incident invasive breast cancer. METHODS: We conducted a retrospective cohort study of women ≥40 years of age enrolled in a health plan between 1996 and 2011. Ever, current (≤12 months), and duration (<1, 1-2.9, ≥3 years) of diabetes medication use were obtained from pharmacy databases and modeled as time varying. Multivariable Cox proportional hazards models adjusting for potential confounders including screening mammography and body mass index were used to estimate hazard ratios (HRs) and 95% Confidence Intervals (CIs). RESULTS: Among 10,050 women with diabetes, 57 % used metformin, 43 % used sulfonylureas, 32 % used insulin, and 301 were diagnosed with breast cancer over median follow-up of 6.7 years. Results suggested no significant decreased risk of breast cancer among metformin users (HR 0.86; 95% CI 0.65-1.12). We found no association between increased breast cancer risk and long-acting insulin (HR 0.95; 95% CI 0.51-1.77), but reduced risk with short-/rapid-acting insulin (HR 0.69; 95% CI 0.50-0.94), and suggestion of a dose-response with increasing duration of short-/rapid-acting insulin use (HR 0.87; 95% CI 0.76-1.00). Estimates for sulfonylurea users suggested increased risk with ever use (HR 1.18; 95% CI 0.90-1.53) and with longer durations of use (≥3 years: HR 1.23; 95% CI 0.88-1.73), but confidence intervals included 1.0. CONCLUSIONS: Our results provide little support for the previously hypothesized decreased risk of breast cancer with metformin use or for an increased risk with insulin use. Implications for possible residual confounding by screening mammography and comorbidity should be considered in breast cancer pharmacoepidemiology studies.

Breast cancer recurrence in relation to antidepressant use.

PURPOSE: Women with breast cancer frequently use antidepressants; however, questions about the effect of these medications on breast cancer recurrence remain. METHODS: We identified 4,216 women ≥18 years with an incident stage I or II breast cancer diagnosed between 1990 and 2008 in a mixed-model healthcare delivery system linked to a cancer registry. Recurrences were ascertained from chart review. Medication exposures were extracted from electronic pharmacy records. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) to assess the association between antidepressant use and breast cancer recurrence and mortality. We also conducted analyses restricted to tamoxifen users. RESULTS: Antidepressants overall, tricyclic antidepressants, and selective serotonin reuptake inhibitors were not associated with risk of breast cancer recurrence or mortality. Women taking paroxetine only (adjusted HR: 1.66; 95 % CI 1.02, 2.71) and trazodone only (adjusted HR: 1.76; 95 % CI 1.06, 2.92), but not fluoxetine only (adjusted HR: 0.92; 95 % CI 0.55, 1.53), had higher recurrence risks than antidepressant nonusers. There was some suggestion of an increased recurrence risk with concurrent paroxetine and tamoxifen use compared with users of tamoxifen only (adjusted HR: 1.49; 95 % CI 0.79, 2.83). CONCLUSIONS: In general, antidepressants did not appear increase risk of breast cancer recurrence, though there were some suggested increases in risk that warrant further investigation in other datasets. Our results combined systematically and quantitatively with results from other studies may be useful for patients and providers making decisions about antidepressant use after breast cancer diagnosis.

Associations between diabetes medication use and risk of second breast cancer events and mortality.

PURPOSE: Diabetes and certain diabetes medications have been shown to influence breast cancer (BC) risk. Less is known about their relation to BC outcomes. Our objective was to evaluate the effects of diabetes and diabetes medications on risk of second breast cancer events (SBCE) and mortality. METHODS: This population-based cohort study was conducted among women diagnosed with early-stage (I-II) BC and enrolled in an integrated health plan. Exposures of interest were diabetes and medication classes including insulin, metformin, and sulfonylureas. Outcomes of interest were SBCE defined as recurrence or second primary BC, BC-specific mortality, and all-cause mortality. We used multivariable Cox proportional hazards models to estimate hazard ratios (HR) and 95 % confidence intervals (CI) for diabetes and medication use while accounting for potential confounders and competing risks. RESULTS: Among 4,216 women, 13 % developed SBCE during a median follow-up of 6.3 years. 610 women had diabetes of which 76 % used oral diabetes medication and/or insulin. Findings suggested that diabetes increased the risk of recurrence (HR = 1.57; 95 % CI 1.09-2.25) but not overall SBCE (HR = 1.29; 95 % CI 0.94-1.76) or second primary BC (HR = 0.74; 95 % CI 0.39-1.41). Among women with diabetes, insulin use was associated with increased risks of recurrence (HR = 1.94; 95 % CI 1.08-3.48) and all-cause mortality (HR = 2.33; 95 % CI 1.70-3.20). Metformin use was associated with lower all-cause mortality (HR = 0.55; 95 % CI 0.38-0.79). CONCLUSIONS: Our findings show an association between diabetes and increased recurrence risk, and risk may be greater among insulin users. Metformin may reduce all-cause mortality among BC survivors. Given the growing breast cancer survivor population, further research in larger, more diverse populations is warranted.

Sedative Hypnotic Medication Use and the Risk of Motor Vehicle Crash.

OBJECTIVES: We sought to estimate the association between sedative hypnotic use and motor vehicle crash risk. METHODS: We conducted a new user cohort study of 409 171 adults in an integrated health care system. Health plan data were linked to driver license and collision records. Participants were aged 21 years or older, licensed to drive in Washington State, had at least 1 year of continuous enrollment between 2003 and 2008, and were followed until death, disenrollment, or study end. We used proportional hazards regression to estimate the risk of crash associated with 3 sedatives. RESULTS: We found 5.8% of patients received new sedative prescriptions, with 11 197 person-years of exposure. New users of sedatives were associated with an increased risk of crash relative to nonuse: temazepam hazard ratio (HR) = 1.27 (95% confidence interval [CI] = 0.85, 1.91), trazodone HR = 1.91 (95% CI = 1.62, 2.25), and zolpidem HR = 2.20 (95% CI = 1.64, 2.95). These risk estimates are equivalent to blood alcohol concentration levels between 0.06% and 0.11%. CONCLUSIONS: New use of sedative hypnotics is associated with increased motor vehicle crash risk. Clinicians initiating sedative hypnotic treatment should consider length of treatment and counseling on driving risk.

Adherence to oral diabetes medications and glycemic control during and following breast cancer treatment.

OBJECTIVES: We evaluated changes in oral diabetes mellitus medication adherence and persistence, as well as glycemic control for the year prior to breast cancer (BC) diagnosis (Year -1), during BC treatment, and in subsequent years. METHODS: Cohort study of 4216 women diagnosed with incident early stage (I and II) invasive BC from 1990-2008, enrolled in Group Health Cooperative. Adherence was measured in prevalent users at baseline (N = 509), during treatment, and 1-3 years post-diagnosis using medication possession ratio (MPR), % adherent (MPR ≥0.80) and discontinuation rates. Laboratory data on glycosylated hemoglobin (HbA1c ) was obtained for the corresponding periods. RESULTS: Compared with Year -1, mean MPR for metformin/sulfonylureas (0.86 vs 0.49, p < 0.001) and % adherent (75.3% vs 24.6%, p < 0.001) declined during BC treatment. MPR and % adherent rose slightly during Years 1-3 post-diagnosis but never returned to baseline. Discontinuation rates increased from treatment to Year +1 (59.3% vs 75.6%, p < 0.001) and remained elevated during subsequent observation periods. Compared with baseline, increased HbA1c (7.0% vs 7.4%, p = 0.001) and % women with high HbA1c >7.0% (34.9% vs 51.1%, p < 0.001) coincided with decreased adherence. CONCLUSION: Diabetes mellitus medication adherence declined following BC diagnosis, whereas discontinuation rates were relatively stable but poor overall. The proportion of adherent users increased only marginally following treatment, whereas the proportion of women meeting goals for HbA1c decreased considerably. These data support the hypothesis that adherence and subsequent glycemic control are sensitive to BC diagnosis and treatment. Confirmatory studies in other settings, on reasons for reduced adherence post-cancer diagnosis, and on subsequent indicators of glycemic control are warranted.