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PURPOSE The incidence of cardiometabolic risk factors in breast cancer (BC) survivors has not been well described. Thus, we compared risk of hypertension, diabetes, and dyslipidemia in women with and without BC. METHODS Women with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California (KPNC) were identified and matched 1:5 to noncancer controls on birth year, race, and ethnicity. Cumulative incidence rates of hypertension, diabetes, and dyslipidemia were estimated with competing risk of overall death. Subdistribution hazard ratios (sHRs) were estimated by Fine and Gray regression, adjusted for cardiovascular disease–related risk factors, and stratified by treatment and body mass index (BMI). RESULTS A total of 14,942 BC cases and 74,702 matched controls were identified with mean age 61.2 years and 65% non-Hispanic White. Compared with controls, BC cases had higher cumulative incidence rates of hypertension (10.9% v 8.9%) and diabetes (2.1% v 1.7%) after 2 years, with higher diabetes incidence persisting after 10 years (9.3% v 8.8%). In multivariable models, cases had higher risk of diabetes (sHR, 1.16; 95% CI, 1.07 to 1.26) versus controls. Cases treated with chemotherapy (sHR, 1.23; 95% CI, 1.11 to 1.38), left-sided radiation (sHR, 1.29; 95% CI, 1.13 to 1.48), or endocrine therapy (sHR, 1.23; 95% CI, 1.12 to 1.34) continued to have higher diabetes risk. Hypertension risk was higher for cases receiving left-sided radiation (sHR, 1.11; 95% CI, 1.02 to 1.21) or endocrine therapy (sHR, 1.10; 95% CI, 1.03 to 1.16). Normal-weight (BMI < 24.9 kg/m2) cases had higher risks overall and within treatment subgroups versus controls. CONCLUSION BC survivors at KPNC experienced elevated risks of diabetes and hypertension compared with women without BC depending on treatments received and BMI. Future studies should examine strategies for cardiometabolic risk factor prevention in BC survivors.

PURPOSE To examine cardiovascular disease (CVD) and mortality risk in women with breast cancer (BC) by cancer therapy received relative to women without BC. METHODS The study population comprised Kaiser Permanente Northern California members. Cases with invasive BC diagnosed from 2005 to 2013 were matched 1:5 to controls without BC on birth year and race/ethnicity. Cancer treatment, CVD outcomes, and covariate data were from electronic health records. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs of CVD incidence and mortality by receipt of chemotherapy treatment combinations, radiation therapy, and endocrine therapy. RESULTS A total of 13,642 women with BC were matched to 68,202 controls without BC. Over a 7-year average follow-up (range < 1-14 years), women who received anthracyclines and/or trastuzumab had high risk of heart failure/cardiomyopathy relative to controls, with the highest risk seen in women who received both anthracyclines and trastuzumab (HR, 3.68; 95% CI, 1.79 to 7.59). High risk of heart failure and/or cardiomyopathy was also observed in women with BC with a history of radiation therapy (HR, 1.38; 95% CI, 1.13 to 1.69) and aromatase inhibitor use (HR, 1.31; 95% CI, 1.07 to 1.60), relative to their controls. Elevated risks for stroke, arrhythmia, cardiac arrest, venous thromboembolic disease, CVD-related death, and death from any cause were also observed in women with BC on the basis of cancer treatment received. CONCLUSION Women with BC had increased incidence of CVD events, CVD-related mortality, and all-cause mortality compared with women without BC, and risks varied according to the history of cancer treatment received. Studies are needed to determine how women who received BC treatment should be cared for to improve cardiovascular outcomes.

Purpose: Studies comparing the effect of aromatase inhibitor (AI) and tamoxifen use on cardiovascular disease (CVD) risk factors in hormone-receptor positive breast cancer (BC) survivors report conflicting results. We examined associations of endocrine therapy use with incident diabetes, dyslipidemia, and hypertension. Methods: The Pathways Heart Study examines cancer treatment exposures with CVD-related outcomes in Kaiser Permanente Northern California members with BC. Electronic health records provided sociodemographic and health characteristics, BC treatment, and CVD risk factor data. Hazard ratios (HR) and 95% confidence intervals (CI) of incident diabetes, dyslipidemia, and hypertension in hormone-receptor positive BC survivors using AIs or tamoxifen compared with survivors not using endocrine therapy were estimated using Cox proportional hazards regression models adjusted for known confounders. Results: In 8,985 BC survivors, mean baseline age and follow-up time was 63.3 and 7.8 years, respectively; 83.6% were postmenopausal. By treatment, 77.0% used AIs, 19.6% used tamoxifen, and 16.0% used neither. Postmenopausal women who used tamoxifen had an increased rate (HR: 1.43, 95% CI: 1.06-1.92) of developing hypertension relative to those who did not use endocrine therapy. Tamoxifen use was not associated with incident diabetes, dyslipidemia, or hypertension in premenopausal BC survivors. Postmenopausal AI users had higher hazard rates of developing diabetes (HR: 1.37, 95% CI: 1.05-1.80), dyslipidemia (HR: 1.58, 95% CI: 1.29-1.92) and hypertension (HR: 1.50, 95% CI: 1.24-1.82) compared with non-endocrine therapy users. Conclusion: Hormone-receptor positive BC survivors treated with AIs may have higher rates of developing diabetes, dyslipidemia, and hypertension over an average 7.8 years post-diagnosis.

OBJECTIVES: It is important to understand relationships of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension, given their high baseline risk of adverse outcomes. We assessed associations of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension by pre-pregnancy body mass index categories. STUDY DESIGN: We identified 14,369 women with chronic hypertension using electronic health records from 3 integrated health care delivery systems (2005-2014). Gestational weight gain-for-gestational age charts were used to calculate gestational weight gain z-scores, which account for gestational age. Modified Poisson regression models using generalized estimating equations were used to calculate relative risks and 95% confidence intervals, adjusted for sociodemographic and medical characteristics. MAIN OUTCOME MEASUREMENTS: Preeclampsia, preterm delivery, cesarean delivery, neonatal intensive care unit admission, birthweight (extracted from the electronic health record) RESULTS: In women with normal weight or overweight, low gestational weight gain (z-score1) was associated with 40-90% greater risk of preeclampsia and 59-113% greater risk of LGA. In women with obesity, low GWG was associated with 27-54% lower risk of several adverse pregnancy outcomes, including preeclampsia and cesarean delivery. CONCLUSIONS: In women with chronic hypertension and normal weight or overweight, moderate gestational weight gain may confer the lowest risk of adverse outcomes. In women with chronic hypertension and obesity, low gestational weight gain may be necessary for the lowest risk of adverse pregnancy outcomes.

Nearly 30% of individuals with gestational diabetes (GDM) do not achieve glycemic control with lifestyle modification alone and require medication treatment. Oral agents, such as glyburide, have several advantages over insulin for the treatment of GDM, including greater patient acceptance; however, the effectiveness of glyburide for the treatment of GDM remains controversial.To compare the perinatal and neonatal outcomes associated with glyburide vs insulin using causal inference methods in a clinical setting with information on glycemic control.The population-based cohort study included patients with GDM who required medication treatment from 2007 to 2017 in Kaiser Permanente Northern California. Machine learning and rigorous casual inference methods with time-varying exposures were used to evaluate associations of exposure to glyburide vs insulin with perinatal outcomes. Data analysis was conducted from March 2018 to July 2017.Time-varying exposure to glyburide vs insulin during pregnancy.Outcomes evaluated separately included neonatal hypoglycemia, jaundice, shoulder dystocia, respiratory distress syndrome (RDS), neonatal intensive care unit (NICU) admission, size-for-gestational age, and cesarean delivery. Inverse probability weighting (IPW) estimation was used to separately compare perinatal outcomes between those initiating glyburide and insulin. This approach was combined with Super Learning for propensity score estimation to account for both baseline and time-dependent confounding in both per-protocol (primary) and intention-to-treat (secondary) analyses to evaluate sustained exposure to the same therapy.From 2007 to 2017, 11 321 patients with GDM (mean [SD] age, 32.9 [4.9] years) initiated glyburide or insulin during pregnancy. In multivariate models, the risk of neonatal respiratory distress was 2.03 (95% CI, 0.13-3.92) per 100 births lower and the risk of NICU admission was 3.32 (95% CI, 0.20-6.45) per 100 births lower after continuous exposure to glyburide compared with insulin. There were no statistically significant differences in glyburide vs insulin initiation in risk for neonatal hypoglycemia (0.85 [95% CI, -1.17 to 2.86] per 100 births), jaundice (0.02 [95% CI, -1.46 to 1.51] per 100 births), shoulder dystocia (-1.05 [95% CI, -2.71 to 0.62] per 100 births), or large-for-gestational age categories (-2.75 [95% CI, -6.31 to 0.80] per 100 births).Using data from a clinical setting and contemporary causal inference methods, our findings do not provide evidence of a difference in the outcomes examined between patients with GDM initiating glyburide compared with those initiating insulin.

BACKGROUND: Mail order pharmacy (MOP) use has been linked to improved medication adherence and health outcomes among patients with diabetes. However, no large-scale intervention studies have assessed the effect of encouraging MOP use on medication adherence. OBJECTIVE: To assess an intervention to encourage MOP services to increase its use and medication adherence. DESIGN: Randomized encouragement trial. PATIENTS: 63,012 diabetes patients from three health care systems: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Hawaii (KPHI), and Harvard Pilgrim Health Care (HPHC) who were poorly adherent to at least one class of cardiometabolic medications and had not used MOP in the prior 12 months. INTERVENTION: Patients were randomized to receive either usual care (control arm) or outreach encouraging MOP use consisting of a mailed letter, secure email message, and automated telephone call outlining the potential benefits of MOP use (intervention arm). HPHC intervention patients received the letter only. MEASUREMENTS: We compared the percentages of patients that began using MOP and that became adherent to cardiometabolic medication classes during a 12-month follow-up period. We also conducted a race/ethnicity-stratified analysis. RESULTS: During follow-up, 10.6% of intervention patients began using MOP vs. 9.3% of controls (p

In studies based on electronic health records (EHR), the frequency of covariate monitoring can vary by covariate type, across patients, and over time, which can limit the generalizability of inferences about the effects of adaptive treatment strategies. In addition, monitoring is a health intervention in itself with costs and benefits, and stakeholders may be interested in the effect of monitoring when adopting adaptive treatment strategies. This paper demonstrates how to exploit non‐systematic covariate monitoring in EHR‐based studies to both improve the generalizability of causal inferences and to evaluate the health impact of monitoring when evaluating adaptive treatment strategies. Using a real world, EHR‐based, comparative effectiveness research (CER) study of patients with type II diabetes mellitus, we illustrate how the evaluation of joint dynamic treatment and static monitoring interventions can improve CER evidence and describe two alternate estimation approaches based on inverse probability weighting (IPW). First, we demonstrate the poor performance of the standard estimator of the effects of joint treatment‐monitoring interventions, due to a large decrease in data support and concerns over finite‐sample bias from near‐violations of the positivity assumption (PA) for the monitoring process. Second, we detail an alternate IPW estimator using a no direct effect (NDE) assumption. We demonstrate that this estimator can improve efficiency but at the potential cost of increase in bias from violations of the PA for the treatment process.

Few studies have examined factors that determine bisphosphonate (BP) continuation beyond 5 years in clinical practice.To investigate factors associated with BP continuation among women who completed 5 years of BP therapy.Women who received 5 consecutive years of oral BP treatment entered the cohort during 2002-2014 and were followed up to 5 additional years. Multivariable logistic regression was used to evaluate the association of demographic and clinical factors with adherent treatment continuation.The cohort included 19,091 women with a median age of 72 years. Baseline and time-varying factors associated with increased odds of BP continuation after 5 years were (a) most recent bone mineral density (BMD) T-score -2 to -2.4 (OR = 1.31, 95% CI = 1.25-1.38), T-score -2.5 to -2.9 (OR = 1.48, 95% CI = 1.39-1.57), and T-score ≤ -3.0 (OR = 1.57, 95% CI = 1.47-1.68) versus T-scores above -2.0; (b) index date before 2008 (OR =1.35, 95% CI = 1.29-1.41); and (c) diabetes mellitus (OR = 1.08, 95% CI = 1.01-1.16). In contrast, factors associated with decreased odds of BP continuation were (a) recent hip (OR = 0.61, 95% CI = 0.52-0.71) or humerus (OR = 0.79, 95% CI = 0.66-0.94) fracture or fracture other than hip, wrist, spine, or humerus (OR = 0.90, 95% CI = 0.84-0.97); (b) Charlson Comorbidity Index score2 (OR = 0.91, 95% CI = 0.84-0.98); (c) history of rheumatoid arthritis (OR = 0.89, 95% CI = 0.80-0.99); (d) Hispanic (OR = 0.89, 95% CI=0.85-0.94) or Asian (OR = 0.90, 95% CI = 0.85-0.94) race/ethnicity; and (e) use of proton pump inhibitors (OR = 0.65, 95% CI = 0.59-0.71). Patient age and fracture before BP initiation were not associated with treatment continuation.Clinical factors predicting continued BP treatment beyond 5 years include low BMD T-score, absence of recent fracture, and earlier era of treatment. Use of proton pump inhibitors was associated with lower likelihood of BP continuation. Other clinical and demographic factors were also noted to have variable effects on BP treatment continuation.This study was supported by a grant from the National Institute on Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (NIH; R01AG047230, S1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Kaiser Permanente. Lo has received previous research funding from Amgen and Sanofi, unrelated to the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, unrelated to the current study. Ettinger has served as an expert witness for Teva Pharmaceuticals, unrelated to the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. The other authors have nothing to disclose. These data were presented at the 2018 Annual Meeting of the American Society of Bone and Mineral Research (ASBMR), September 28-October 1, 2018, Montreal, Quebec, Canada.

Background Persons living with human immunodeficiency virus (HIV; PLWH) experience a high burden of cancer. It remains unknown which cancer types are reduced in PLWH with earlier initiation of antiretroviral therapy (ART). Methods We evaluated AIDS-free, ART-naive PLWH during 1996–2014 from 22 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. PLWH were followed from first observed CD4 of 350–500 cells/µL (baseline) until incident cancer, death, lost-to-follow-up, or December 2014. Outcomes included 6 cancer groups and 5 individual cancers that were confirmed by chart review or cancer registry linkage. We evaluated the effect of earlier (in the first 6 months after baseline) versus deferred ART initiation on cancer risk. Marginal structural models were used with inverse probability weighting to account for time-dependent confounding and informative right-censoring, with weights informed by subject’s age, sex, cohort, baseline year, race/ethnicity, HIV transmission risk, smoking, viral hepatitis, CD4, and AIDS diagnoses. Results Protective results for earlier ART were found for any cancer (adjusted hazard ratio [HR] 0.57; 95% confidence interval [CI], .37–.86), AIDS-defining cancers (HR 0.23; 95% CI, .11–.49), any virus-related cancer (HR 0.30; 95% CI, .16–.54), Kaposi sarcoma (HR 0.25; 95% CI, .10–.61), and non-Hodgkin lymphoma (HR 0.22; 95% CI, .06–.73). By 15 years, there was also an observed reduced risk with earlier ART for virus-related NADCs (0.6% vs 2.3%; adjusted risk difference −1.6; 95% CI, −2.8, −.5). Conclusions Earlier ART initiation has potential to reduce the burden of virus-related cancers in PLWH but not non-AIDS-defining cancers (NADCs) without known or suspected viral etiology.

This cohort study sought to estimate the differences in risk of delivering infants who were small or large for gestational age (SGA or LGA, respectively) according to exercise during the first trimester of pregnancy (vs. no exercise) among 2,286 women receiving care at Kaiser Permanente Northern California in 2013–2017. Exercise was assessed by questionnaire. SGA and LGA were determined by the sex- and gestational-age-specific birthweight distributions of the 2017 US Natality file. Risk differences were estimated by targeted maximum likelihood estimation, with and without data-adaptive prediction (machine learning). Analyses were also stratified by prepregnancy weight status. Overall, exercise at the cohort-specific 75th percentile was associated with an increased risk of SGA of 4.5 (95% CI: 2.1, 6.8) per 100 births, and decreased risk of LGA of 2.8 (95% CI: 0.5, 5.1) per 100 births; similar findings were observed among the underweight and normal-weight women, but no associations were found among those with overweight or obesity. Meeting Physical Activity Guidelines was associated with increased risk of SGA and decreased risk of LGA but only among underweight and normal-weight women. Any vigorous exercise reduced the risk of LGA in underweight and normal-weight women only and was not associated with SGA risk.

Assigning drug exposure is a necessary first step in examining bisphosphonate (BP) treatment in observational studies using pharmacy data.To determine whether the choice of adherence level using the proportion of days covered (PDC) affected BP exposure assignment.10,381 female health plan members who initiated oral BP therapy between 2002 and 2010 and had received 5 consecutive years of treatment were identified and subsequently followed up to 5 additional years. In each 90-day interval of follow-up, a woman was considered "on treatment" if she received the drug for more than a predetermined PDC based on pharmacy days supply and "off treatment" if she received the drug for less than that PDC. Women who continued on therapy above the PDC threshold during follow-up were considered continuously on therapy. Women who were off treatment during the first 90-days of follow-up were classified as off therapy and were followed to determine if they remained continuously off treatment. This study evaluated the extent to which varying the PDC threshold (≥ 0.5, ≥ 0.6, and ≥ 0.7) affected the proportion of women classified as "continuously on" or "continuously off" BP during follow-up.Under PDC thresholds of 0.5, 0.6, and 0.7, 48%, 43%, and 36% of women who remained on follow-up were categorized as continuously on treatment at year 2 of follow-up, and 18%, 14%, and 12% were categorized as continuously on treatment by the end of follow-up. Using these same PDC thresholds, 9%, 12%, and 15% of women were categorized as off therapy during the first quarter of follow-up and were highly likely to remain off therapy: 4%, 5%, and 5% were classified as continuously off therapy at year 2, and 4% of women were classified as such by the end of follow-up for all 3 thresholds.A PDC of 0.6 was chosen as a practical threshold for drug adherence. Varying the PDC to 0.5 or 0.7 resulted in modest changes in the proportions of women considered continuously on BP therapy.This study was supported by a grant from the National Institute of Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (R01AG047230, S1). Lo has received previous research funding from Amgen and Sanofi, outside of the current study. Chandra has received previous research funding from Amgen outside of the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, outside of the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. Ettinger previously served as an expert witness for Teva Pharmaceuticals.

Introduction: Incidence of heart failure (HF), specifically with preserved ejection fraction (HFpEF), is rising in the general population, yet is understudied. To provide a population-based estimate of HF in breast cancer (BC) survivors, we compared risk of HF in women with and without BC history in the Kaiser Permanente Northern California (KPNC) integrated health system. Methods: Data were extracted from KPNC electronic health records. All invasive BC cases diagnosed from 2005-2013 were identified and matched 1:5 with non-BC controls on birth year, race/ethnicity, and KPNC membership at BC diagnosis. Cox regression models assessed the hazard of HF by EF status: HFpEF (EF ≥ 45%), HF with reduced EF (HFrEF; EF < 45%), and unknown EF. Women with prior history of HF were excluded. Models were adjusted for factors known to affect BC risk or CVD and for prevalent CVD at BC diagnosis. We also examined case subgroups who received cardiotoxic chemotherapy, left-sided radiation therapy, and/or endocrine therapy, versus their controls. Results: A total of 14,804 women diagnosed with invasive BC and with no history of HF were identified and matched to 74,034 women without BC history. Women were on average 61 years at BC diagnosis and 65% white. Women with HFpEF were older and more likely to have hypertension (p Conclusions: Increased surveillance is warranted for women with BC receiving cardiotoxic chemotherapy for development of both HFrEF and HFpEF.

Purpose: Studies on long-term cardiovascular disease (CVD) risk in breast cancer (BC) survivors are limited. We examined CVD risk associated with exposure to specific BC therapies and explored whether body mass index (BMI) or prevalent CVD risk factors at BC diagnosis modified these associations. Methods: The Pathways Heart Study is a prospective cohort study examining incident CVD outcomes and risk factors in women with BC at Kaiser Permanente Northern California (KPNC). Eligible women were diagnosed with stage I-IV invasive BC from 2005-2013, ≥21 years old, and KPNC members ≥12 months at diagnosis. KPNC records provided demographic and BC therapy characteristics. Incident CVD outcomes [ischemic heart disease, heart failure/cardiomyopathy (HF/CM), stroke] were assessed from ICD9/10 codes. Multivariable Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) of each CVD outcome by cancer therapy received compared to not receiving that therapy, excluding those with prevalent CVD. Separate regression models included interaction terms for cancer therapy by overweight, obesity, diabetes, dyslipidemia, and hypertension to test whether the CVD outcome risk varied by presence of these factors at diagnosis. Results: Among 4,181 BC survivors with mean age of 59.6±12.0 years and mean follow-up of 7.9±3.5 years (range: 0.04-13.3), cancer therapies were not associated with incident CVD. However, CVD risks varied by BMI and prevalence of CVD risk factors at BC diagnosis. Normal weight (NW) women who received anthracyclines had higher risk of ischemic heart disease and HF/CM relative to NW women not receiving these therapies; interaction terms indicated HF/CM risk was statistically different than risks for obese women (Table). NW women who received cyclophosphamide or left-sided radiation had higher risk of HF/CM and stroke relative to NW women not receiving these therapies; these risks were statistically different from obese (for cyclophosphamide) or overweight (for radiation) women. Relative to women not receiving these therapies, higher HRs for HF/CM were observed among non-diabetic women who received cyclophosphamide (2.03, CI: 1.22-3.37), non-dyslipidemic women who received anthracyclines (3.65, CI: 1.69-7.87), and non-hypertensive women who received either anthracyclines (4.04, CI: 1.81-9.03) or cyclophosphamide (2.66, CI: 1.23-5.74) (P for interaction range: 0.04 to 0.06). Conclusion: Certain chemotherapy drugs may increase the risk of CVD in NW BC survivors; overweight and obese BC survivors may experience less risk than NW women. While chemotherapy also appears to increase HF/CM risk for women without diabetes, dyslipidemia, and hypertension, these conditions are more prevalent among overweight/obese women. Analysis within these subgroups is needed and forthcoming. Table. Adjusted HRs (95% CI) of CVD outcomes among breast cancer survivors receiving select cancer therapies* stratified by BMI status at diagnosisBMI Ischemic heart diseaseHeart failure/CardiomyopathyStrokeAnthracycline, n=1283Normal4.22 (1.59, 11.2)5.27 (2.54, 10.9)1.89 (0.79, 4.53)Overweight1.66 (0.73, 3.77)2.17 (1.15, 4.11)0.40 (0.16, 0.99)Obese1.26 (0.56, 2.85)1.1 (0.54, 2.27)a0.33 (0.13, 0.83)aCyclophosphamide, n=1705Normal1.63 (0.61, 4.31)3.28 (1.59, 6.75)2.21 (1.01, 4.84)Overweight1.59 (0.75, 3.39)1.63 (0.9, 2.97)0.73 (0.34, 1.58)Obese0.85 (0.39, 1.86)0.75 (0.38, 1.47)a0.31 (0.13, 0.71)aLeft-Side Radiation, n=1331Normal1.44 (0.56, 3.69)2.04 (1.0, 4.18)2.38 (1.28, 4.42)Overweight1.47 (0.68, 3.16)0.68 (0.34, 1.34)b0.72 (0.37, 1.4)bObese1.32 (0.73, 2.38)1.30 (0.79, 2.16)1.05 (0.61, 1.82)*Cancer therapies with non-significant findings (i.e., Trastuzumab, taxanes, aromatase inhibitors, Tamoxifen, and any-side radiation) are not shown.ap≤0.05 normal weight v. obese; bp≤0.05 normal weight v. overweight Citation Format: Heather Greenlee, Eileen Rillamas-Sun, Carlos Iribarren, Richard Cheng, Romain Neugebauer, Jamal S. Rana, Mai Nguyen-Huynh, Zaixing Shi, Cecile A. Laurent, Valerie S. Lee, Janise M. Roh, Hanjie Shen, Dawn L. Hershman, Lawrence H. Kushi, Marilyn L. Kwan. Cardiovascular disease risk of breast cancer therapies: The pathways heart study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-01.

Purpose: Endocrine therapy is associated with cardiovascular disease among breast cancer (BC) survivors, with observed opposing effects between aromatase inhibitors (AIs) and tamoxifen. AIs deplete endogenous estrogen levels, while tamoxifen has mixed estrogenic and antiestrogenic activity. Yet, observational studies comparing AI vs. tamoxifen use may be confounded by indication and few have tested their associations with cardiometabolic risk factors. Therefore, we examined the association of AI or tamoxifen use on the incidence of newly diagnosed hypertension, diabetes, and dyslipidemia in a cohort of BC survivors within Kaiser Permanente Northern California (KPNC). Methods: The Pathways Heart Study is an ongoing cohort study within KPNC examining incident CVD outcomes and risk factors in 14,942 women with history of BC. Eligibility was: 1) stage I-IV invasive BC diagnosis between Nov 2005 and Mar 2013; 2) ≥21 years; and 3) active KPNC membership ≥12 months at diagnosis. KPNC records were used to collect demographic, socioeconomic, and health characteristics. Endocrine therapy was collected from outpatient pharmacy data. Incident hypertension, diabetes, and dyslipidemia were identified from ICD-9/10 codes, laboratory results, and/or medication use. Hazard ratios (HR) and 95% confidence intervals (CI) from Cox proportional models were used to determine whether AI and tamoxifen use were associated with incident hypertension, diabetes, and dyslipidemia compared to BC survivors not receiving either of these therapies. For each cardiometabolic risk factor, models adjusted for demographic, socioeconomic, and health characteristics and excluded women with the cardiometabolic risk factor at baseline. Results: Among 14,942 women with a history of BC, mean age at baseline was 61.2±12.8 years and mean follow-up time was 7.0±3.5 years (range 1-13.4). The frequency of use was: AI, n=6,070 (40.6%); tamoxifen, n=1,755 (11.8%); and neither, n=7,117 (47.6%). Regression models showed AI use was associated with increased risk of incident hypertension (HR: 1.1, 95% CI: 1.00-1.21) and increased risk of incident dyslipidemia (HR: 1.18, 95% CI: 1.07-1.3) relative to BC survivors who did not use endocrine therapy. (Table). In contrast, tamoxifen use was associated with decreased risk of dyslipidemia (HR: 0.8, 95% CI: 0.68-0.94) relative to BC survivors who did not use endocrine therapy. Neither AI nor tamoxifen use was associated with risk of incident diabetes. Conclusion: Compared to BC survivors who did not use endocrine therapy, women treated with AIs had a higher risk of incident hypertension and dyslipidemia, while women treated with tamoxifen had a lower risk of dyslipidemia. AIs reduce endogenous estrogen levels, which can alter lipid profiles, although prior studies have been inconsistent, possibly due to differences in steroidal and non-steroidal AIs. More work is needed to understand the implications of these associations on long-term cardiovascular health and how to best manage cardiometabolic risk factors in BC survivors with a history of endocrine therapy use. Table. Adjusted1 hazard ratios (95% confidence intervals) of incident cardiometabolic risk factors among women with a history of breast cancer, by endocrine therapy useNo Endocrine Therapy(n=7,117)Endocrine TherapyAromatase inhibitor(n=6,070)Tamoxifen(n=1,755)Incident HypertensionRef1.10 (1.00, 1.21)0.98 (0.85, 1.14)Incident DiabetesRef0.99 (0.87, 1.13)0.98 (0.80, 1.20)Incident DyslipidemiaRef1.18 (1.07, 1.30)0.80 (0.68, 0.94)1Adjusted for age, race/ethnicity, baseline body mass index, AJCC stage, menopausal status, smoking status, education level, income, chemotherapy, radiation therapy, and prevalent cardiovascular disease. Citation Format: Heather Greenlee, Eileen Rillamas-Sun, Carlos Iribarren, Richard Cheng, Romain Neugebauer, Jamal S. Rana, Mai Nguyen-Huynh, Zaixing Shi, Cecile A. Laurent, Valerie S. Lee, Janise M. Roh, Hanjie Shen, Dawn L. Hershman, Lawrence H. Kushi, Marilyn L. Kwan. Development of cardiometabolic risk factors following endocrine therapy: The pathways heart study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-03.

OBJECTIVES Continuity of patient information across settings can improve transitions after hospital discharge, but outpatient clinicians often have limited access to complete information from recent hospitalizations. We examined whether providers' timely access to clinical information through shared inpatient-outpatient electronic health records (EHRs) was associated with follow-up visits, return emergency department (ED) visits, or readmissions after hospital discharge in patients with diabetes. STUDY DESIGN Stepped-wedge observational study. METHODS As an integrated delivery system staggered implementation of a shared inpatient-outpatient EHR, we studied 241,510 hospital discharges in patients with diabetes (2005-2011), examining rates of outpatient follow-up office visits, telemedicine (phone visits and asynchronous secure messages), laboratory tests, and return ED visits or readmissions (as adverse events). We used multivariate logistic regression adjusting for time trends, patient characteristics, and medical center and accounting for patient clustering to calculate adjusted follow-up rates. RESULTS For patients with diabetes, provider use of a shared inpatient-outpatient EHR was associated with a statistically significant shift toward follow-up delivered through a combination of telemedicine and outpatient laboratory tests, without a traditional in-person visit (from 22.9% with an outpatient-only EHR to 27.0% with a shared inpatient-outpatient EHR; P

Objective: To estimate the effects of exercise during the first trimester on the risks of abnormal screening and gestational diabetes mellitus (GDM). Research Design and Methods: Data come from PETALS, a prospectively followed pregnancy cohort (n= 2,246, 79% minorities) receiving care at Kaiser Permanente Northern California. A Pregnancy Physical Activity Questionnaire was used to assess exercise. Glucose testing results for screening and diagnostic tests were obtained from electronic health records. Inverse probability of treatment weighting and Targeted Maximum Likelihood with data-adaptive estimation (machine learning) of propensity scores and outcome regressions were used to obtain causal risk differences adjusted for potential confounders, including prepregnancy BMI, exercise before pregnancy, and gestational weight gain. Exercise was dichotomized at: 1) the cohort’s 75th percentile for moderate to vigorous intensity exercise (≥ 13.2 MET hours per week, approximately ≥ 264 minutes per week of moderate exercise), 2) current recommendations (≥ 7.5 MET hours per week, or ≥ 150 minutes per week of moderate exercise), and 3) any vigorous exercise. Results: Overall, 24.3% and 6.5% had abnormal screening and GDM, respectively. Exercise meeting or exceeding the 75th percentile decreased the risks of abnormal screening and GDM, by 4.8 (95% CI 1.1, 8.5) and 2.1 (0.2, 4.1) fewer cases per 100, respectively, in adjusted analyses. Conclusions: Exercise reduces the risks of abnormal screening and GDM but the amount needed to achieve these risk reductions is likely higher than current recommendations. Future interventions may consider promoting ≥ 38 minutes per day of moderate intensity exercise to prevent GDM.

Almost 30% of women with gestational diabetes (GDM) fail to achieve glycemic control with lifestyle modification alone and require medication treatment. Currently, the American Diabetes Association recommends insulin as the first line medication treatment for women with GDM. However, oral agents have several advantages including ease of use and acceptance among patients. The safety and efficacy of glyburide for the treatment of GDM remains controversial. We aimed to compare the effectiveness of glyburide and insulin in improving perinatal outcomes. We used rigorous causal inference methods with time-varying exposures and machine learning to evaluate perinatal outcomes of exposure to glyburide versus insulin during pregnancy in a retrospective cohort study of 11,321 women diagnosed with GDM who required medication treatment to achieve glycemic control in Kaiser Permanente Northern California from 2007-2017. For each outcome, Inverse Probability Weighting (IPW) estimation was used to separately compare several perinatal outcomes between glyburide versus insulin initiators. This approach combined with Super Learning for propensity score estimation can account for both baseline and time-dependent confounding in per protocol analyses to evaluate the effect of continuous exposure to the same therapy. Women who used glyburide versus insulin had similar rates of macrosomia, hypoglycemia, hyperbilirubinemia, and cesarean delivery; significantly lower rates of a NICU admission (risk difference -0.03 [95%CI:-0.06;-0.002]) or respiratory distress syndrome (-0.02 [-0.04;-0.001]) and suggestive higher rates of an appropriately sized for gestational age infant (0.04 [-0.002;0.08]) after adjusting for baseline and time-varying covariates. Using data from a real-world clinical setting we find no evidence to suggest that adverse outcomes were higher among glyburide users compared with insulin users. Disclosure M.M. Hedderson: None. A. Ferrara: None. A. Regenstein: None. R. Neugebauer: None. Funding Permanente Medical Group

Background Bisphosphonate (BP) therapy has been associated with atypical femur fracture (AFF). However, the threshold of treatment duration leading to increased AFF risk is unclear. In a retrospective cohort of older women initiating BP, we compared the AFF risk associated with treatment for at least three years to the risk associated with treatment less than three years. Methods We used observational data from a large population of female members of an integrated healthcare system who initiated oral BP during 2002–2014. Women were retrospectively followed for incident AFF confirmed by radiologic adjudication. Demographic data, pharmacologic exposures, comorbidity, bone density, and fracture history were ascertained from electronic health records. Inverse probability weighting was used to estimate risk differences comparing the cumulative incidence (risk) of AFF if women discontinued BP within three years to the cumulative incidence of AFF if women continued BP for three or more years, adjusting for potential time-dependent confounding by the aforementioned factors. Results Among 87,820 women age 45–84 years who initiated BP (mean age 68.6, median T-score − 2.6, 14% with prior major osteoporotic fracture), 16,180 continued BP for three or more years. Forty-six confirmed AFFs occurred during follow-up in the two groups. AFF-free survival was greater for BP treatment p = 0.004 comparing areas under survival curves). At five years, the risk of AFF was 27 per 100,000 (95% confidence interval, CI: 8–46) if women received BP treatment Conclusions Bisphosphonate treatment for 3 or more years was associated with greater risk of AFF than treatment for less than 3 years. Although AFFs are uncommon among BP-treated women, this increased risk should be considered when counseling women about long-term BP use. Future studies should further characterize the dose-response relationship between BP duration and incident AFF and identify patients at highest risk.

Objective To incorporate blood pressure (BP), diagnoses codes, and medication fills from electronic medical records (EMR) to identify pregnant women with hypertension. Study design A retrospective cohort study of singleton pregnancies at three US integrated health delivery systems during 2005–2014. Main outcome measures Women were considered hypertensive if they had any of the following: (1) ≥2 high BPs (≥140/90 mmHg) within 30 days during pregnancy (High BP); (2) an antihypertensive medication fill in the 120 days before pregnancy and a hypertension diagnosis from 1 year prior to pregnancy through 20 weeks gestation (Treated Chronic Hypertension); or (3) a high BP, a hypertension diagnosis, and a prescription fill within 7 days during pregnancy (Rapid Treatment). We described characteristics of these pregnancies and conducted medical record review to understand hypertension presence and severity. Results Of 566,624 pregnancies, 27,049 (4.8%) met our hypertension case definition: 24,140 (89.2%) with High BP, 5,409 (20.0%) with Treated Chronic Hypertension, and 5,363 (19.8%) with Rapid Treatment (not mutually exclusive). Of hypertensive pregnancies, 19,298 (71.3%) received a diagnosis, 9,762 (36.1%) received treatment and 11,226 (41.5%) had a BP ≥ 160/110. In a random sample (n = 55) of the 7,559 pregnancies meeting the High BP criterion with no hypertension diagnosis, clinical statements about hypertension were found in medical records for 58% of them. Conclusion Incorporating EMR BP identified many pregnant women with hypertension who would have been missed by using diagnosis codes alone. Future studies should seek to incorporate BP to study treatment and outcomes of hypertension in pregnancy.

Background People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk. Methods We studied 102 777 PLWH during 1996–2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion. Results Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for Conclusions Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk.

BACKGROUND Cutaneous melanoma incidence may be modestly elevated in people with HIV (PWH) vs. people without HIV. However, little is known about the relationship of immunosuppression, HIV replication, and antiretroviral therapy (ART) with melanoma risk. METHODS PWH of white race in the North American AIDS Cohort Collaboration on Research and Design were included. A standardized incidence ratio was calculated comparing risk with the white general population, standardizing by age, sex, and calendar period. Associations between melanoma incidence and current, lagged, and cumulative measures of CD4 count, HIV RNA level, and ART use were estimated with Cox regression, adjusting for established risk factors such as age and annual residential ultraviolet B (UVB) exposure. RESULTS Eighty melanomas were diagnosed among 33,934 white PWH (incidence = 40.75 per 100,000 person-years). Incidence was not elevated compared with the general population [standardized incidence ratio = 1.15, 95% confidence interval (95% CI) = 0.91 to 1.43]. Higher melanoma incidence was associated with older age [adjusted hazard ratio (aHR) per decade increase = 1.50, 95% CI = 1.20 to 1.89] and higher UVB exposure (aHR for exposure ≥35 vs.

Background The most widely used topical agents for the field-based treatment of multiple actinic keratoses (AKs) are 5-fluorouracil and imiquimod, but their comparative effectiveness has not been assessed in a real-world setting. Objective We compared the effectiveness of 5-fluorouracil and imiquimod in reducing risk for subsequent AKs in a large, integrated health care delivery system in northern California. Methods In this cohort study, we identified adult health plan members who had an AK diagnosed in 2007 and who subsequently filled a prescription for 5-fluorouracil or imiquimod (N = 5700). We followed subjects for subsequent AKs identified by the International Classification of Diseases codes and estimated the 2-year (short-term) and 5-year (long-term) differences in cumulative risk while controlling for potential confounding by pretreatment variables. Results 5-Fluorouracil reduced the short-term incidence of subsequent AKs (cumulative risk difference -4.54% [95% confidence interval, -7.91% to -1.17%]), but there was no statistically significant evidence of a long-term decreased risk (cumulative risk difference -1.43% [95% confidence interval, -3.43% to 0.05%]) compared with that with imiquimod. Limitations This is a retrospective study with limited ascertainment of all relevant potential confounding variables. Conclusion We found that 5-fluorouracil appeared to be significantly more effective than imiquimod in the short-term, but not long-term, prevention of subsequent AKs.

Effective management of diabetes during the coronavirus disease 2019 (COVID-19) pandemic is critical given that hyperglycemia is both a risk factor for infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has been associated with poorer outcomes for those infected (1). Unfortunately, inadequate diabetes self-management due to medication nonadherence is prevalent among patients with diabetes and is a major contributor to poor diabetes outcomes (2,3). Research suggests that mail order pharmacy (MOP) use can improve medication adherence (3). However, there is little data on how the COVID-19 pandemic is related to MOP use. Regrettably, racial/ethnic minority patients with diabetes have poorer medication adherence than White patients, and research shows marked disparities among racial/ethnic minorities in SARS-CoV-2 infection rates and outcomes, but little is known about racial/ethnic differences in MOP use during the COVID-19 pandemic (3,4). The objectives of our study were to 1 ) assess the association between the COVID-19 pandemic shelter-in-place order and MOP use and 2 ) examine these associations by patient race/ethnicity. We conducted a retrospective cohort study using a cohort from a randomized encouragement trial conducted in 2017–2018 at Kaiser Permanente Northern California (KPNC), the Encouraging Mail Order Pharmacy Use to Improve Outcomes and Reduce Disparities …

Key Points Question Among adults with type 2 diabetes receiving long-acting insulin with a glycated hemoglobin A1c level of 6.8% to 8.5%, is there a difference in cardiovascular events and mortality among individuals who do or do not initiate additional treatment with short-acting insulin? Findings In this cohort study of 57 278 adults, addition of short-acting insulin was associated with increased all-cause mortality compared with long-acting insulin alone and a decreased risk of acute myocardial infarction, with limited evidence of a difference in congestive heart failure. Meaning Given the lack of evidence demonstrating an increase in major cardiovascular events or cardiovascular mortality, the increased mortality with the combination of long- and short-acting insulin may be explained by noncardiovascular events or unmeasured confounding., This cohort study assesses the occurrence of overall mortality, cardiovascular mortality, acute myocardial infarction, stroke, and hospitalization for congestive heart failure among adults with type 2 diabetes receiving long-acting insulin alone vs long- plus short-acting insulin treatment., Importance Cardiovascular events and mortality are the principal causes of excess mortality and health care costs for people with type 2 diabetes. No large studies have specifically compared long-acting insulin alone with long-acting plus short-acting insulin with regard to cardiovascular outcomes. Objective To compare cardiovascular events and mortality in adults with type 2 diabetes receiving long-acting insulin who do or do not add short-acting insulin. Design, Setting, and Participants This retrospective cohort study emulated a randomized experiment in which adults with type 2 diabetes who experienced a qualifying glycated hemoglobin A1c (HbA1c) level of 6.8% to 8.5% with long-acting insulin were randomized to continuing treatment with long-acting insulin (LA group) or adding short-acting insulin within 1 year of the qualifying HbA1c level (LA plus SA group). Retrospective data in 4 integrated health care delivery systems from the Health Care Systems Research Network from January 1, 2005, to December 31, 2013, were used. Analysis used inverse probability weighting estimation with Super Learner for propensity score estimation. Analyses took place from April 1, 2018, to June 30, 2019. Exposures Long-acting insulin alone or with added short-acting insulin within 1 year from the qualifying HbA1c level. Main Outcomes and Measures Mortality, cardiovascular mortality, acute myocardial infarction, stroke, and hospitalization for heart failure. Results Among 57 278 individuals (39 279 with data on cardiovascular mortality) with a mean (SD) age of 60.6 (11.5) years, 53.6% men, 43.5% non-Hispanic White individuals, and 4 years of follow-up (median follow-up of 11 [interquartile range, 5-20] calendar quarters), the LA plus SA group was associated with increased all-cause mortality compared with the LA group (hazard ratio, 1.27; 95% CI, 1.05-1.49) and a decreased risk of acute myocardial infarction (hazard ratio, 0.89; 95% CI, 0.81-0.97). Treatment with long-acting plus short-acting insulin was not associated with increased risks of congestive heart failure, stroke, or cardiovascular mortality. Conclusions and Relevance Findings of this retrospective cohort study suggested an increased risk of all-cause mortality and a decreased risk of acute myocardial infarction for the LA plus SA group compared with the LA group. Given the lack of an increase in major cardiovascular events or cardiovascular mortality, the increased all-cause mortality with long-acting plus short-acting insulin may be explained by noncardiovascular events or unmeasured confounding.

Kaposi sarcoma (KS) remains common among HIV-infected persons. To better understand KS etiology and to help target prevention efforts, we comprehensively examined a variety of CD4 T-cell count and HIV-1 RNA viral load (VL) measures, as well as antiretroviral therapy (ART) use, to determine independent predictors of KS risk.North American AIDS Cohort Collaboration on Research and Design.We followed HIV-infected persons during 1996-2009 from 18 cohorts. We used time-updated Cox regression to model relationships between KS risk and recent, lagged, trajectory, and cumulative CD4 count or VL measures, as well as ART use. We used Akaike's information criterion and global P values to derive a final model.In separate models, the relationship between each measure and KS risk was highly significant (P0.0001). Our final mutually adjusted model included recent CD4 count [hazard ratio (HR) for50 vs. ≥500 cells/μL = 12.4; 95% confidence interval (CI): 6.5 to 23.8], recent VL (HR for ≥100,000 vs. ≤500 copies/mL = 3.8; 95% CI: 2.0 to 7.3), and cumulative (time-weighted mean) VL (HR for ≥100,000 vs. ≤500 copies/mL = 2.5; 95% CI: 1.0 to 5.9). Each P-trend was0.0001. After adjusting for these measures, we did not detect an independent association between ART use and KS risk.Our results suggested a multifactorial etiology for KS, with early and late phases of development. The cumulative VL effect suggested that controlling HIV replication promptly after HIV diagnosis is important for KS prevention. We observed no evidence for direct anti-KS activity of ART, independent of CD4 count and VL.

Objective To evaluate the impact of a population-based telephonic wellness coaching program on weight loss. Methods Individual-level segmented regression analysis of interrupted time series data comparing the BMI trajectories in the 12 months before versus the 12 months after initiating coaching among a cohort of Kaiser Permanente Northern California members (n = 954) participating in The Permanente Medical Group Wellness Coaching program in 2011. The control group was a 20:1 propensity-score matched control group (n = 19,080) matched with coaching participants based on baseline demographic and clinical characteristics. Results Wellness coaching participants had a significant upward trend in BMI in the 12 months before their first wellness coaching session and a significant downward trend in BMI in the 12 months after their first session equivalent to a clinically significant reduction of greater than one unit of baseline BMI (P < 0.01 for both). The control group did not have statistically significant decreases in BMI during the post-period. Conclusions Wellness coaching has a positive impact on BMI reduction that is both statistically and clinically significant. Future research and quality improvement efforts should focus on disseminating wellness coaching for weight loss in patients with diabetes and those at risk for developing the disease.

Purpose. Many Americans continue to smoke, increasing their risk of disease and premature death. Both telephone-based counseling and in-person tobacco cessation classes may improve access for smokers seeking convenient support to quit. Little research has assessed whether such programs are effective in real-world clinical populations. Design. Retrospective cohort study comparing wellness coaching participants with two groups of controls. Setting. Kaiser Permanente Northern California, a large integrated health care delivery system. Subjects. Two hundred forty-one patients who participated in telephonic tobacco cessation coaching from January 1, 2011, to March 31, 2012, and two control groups: propensity-score–matched controls, and controls who participated in a tobacco cessation class during the same period. Wellness coaching participants received an average of two motivational interviewing–based coaching sessions that engaged the patient, evoked their reason to consider quitting, and helped them establish a quit plan. Measures. Self-reported quitting of tobacco and fills of tobacco cessation medications within 12 months of follow-up. Analysis. Logistic regressions adjusting for age, gender, race/ethnicity, and primary language. Results. After adjusting for confounders, tobacco quit rates were higher among coaching participants vs. matched controls (31% vs. 23%, p < .001) and comparable to those of class attendees (31% vs. 29%, p = .28). Coaching participants and class attendees filled tobacco-cessation prescriptions at a higher rate (47% for both) than matched controls (6%, p < .001). Conclusion. Telephonic wellness coaching was as effective as in-person classes and was associated with higher rates of quitting compared to no treatment. The telephonic modality may increase convenience and scalability for health care systems looking to reduce tobacco use and improve health.

Embedded researchers could play a central role in developing tools to personalize care using electronic medical records (EMRs). However, few studies have described the steps involved in developing such tools, or evaluated the key factors in success and failure. This case study describes how we used an EMR-derived data warehouse to develop a prototype informatics tool to help oncologists counsel patients with pancreatic cancer about their prognosis. The tool generated real-time prognostic information based on tumor type and stage, age, comorbidity status and lab tests. Our multidisciplinary team included embedded researchers, application developers, user experience experts, and an oncologist leader.This prototype succeeded in establishing proof of principle, but did not reach adoption into actual practice. In pilot testing, oncologists succeeded in generating prognostic information in real time. A few found it helpful in patient encounters, but all identified critical areas for further development before implementation. Generalizable lessons included the need to (1) include a wide range of potential use cases and stakeholders when selecting use cases for such tools; (2) develop talking points for clinicians to explain results from predictive tools to patients; (3) develop ways to reduce lag time between events and data availability; and (4) keep the options presented in the user interface very simple. This case demonstrates that embedded researchers can lead collaborations using EMR-derived data to create systems for real-time personalized patient counseling, and highlights challenges that such teams can anticipate.

Medication non-adherence is a major contributor to poor diabetes outcomes. Observational studies show positive associations between mail order pharmacy (MOP) use and adherence, and suggest that mail order is cost-saving to patients. However, no prospective trials have examined the effect of encouraging MOP use on medication adherence. We conducted a randomized encouragement trial in 2017 in three health plans: Kaiser Permanente (KP) Northern California, KP Hawaii, and Harvard Pilgrim Health Care (HPHC). Patients were eligible if they had diabetes, poor adherence (Proportion of Days Covered Disclosure J. Schmittdiel: None. C.M. Trinacty: None. J. Wharam: None. O. Duru: Advisory Panel; Self; Healthwise. R. Neugebauer: None. S.D. Brown: None. D. Ross-Degnan: None. A.J. Karter: None. W.T. Dyer: None. B. Ramachandran: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

BackgroundFor patients with diabetes, many with multiple complex chronic conditions, using a patient portal can support self-management and coordination of health care services, and may impact the frequency of in-person health care visits.ObjectiveTo examine the impact of portal access on the number of outpatient visits, emergency visits, and preventable hospitalizations.DesignObservational study comparing patients' visit rates with and without portal access, using marginal structural modeling with inverse probability weighting estimates to account for potential bias due to confounding and attrition.SettingLarge integrated delivery system which implemented a patient portal (2006-2007).PatientsWe examined 165,447 patients with diabetes defined using clinical registries. Our study included both patients with diabetes-only and patients with multiple complex chronic conditions (diabetes plus asthma, congestive artery disease, congestive heart failure, or hypertension).MeasurementsWe examined rates of outpatient office visits, emergency room visits, and preventable hospitalizations (for ambulatory care sensitive conditions).ResultsAccess to a patient portal was associated with significantly higher rates of outpatient office visits, in both patients with diabetes only and in patients with multiple complex conditions (pLimitationsObservational study in an integrated delivery system.ConclusionAccess to a patient portal can increase engagement in outpatient visits, potentially addressing unmet clinical needs, and reduce downstream health events that lead to emergency and hospital care, particularly among patients with multiple complex conditions.

BackgroundResearch is needed to better understand relations between immunosuppression and HIV viraemia and risk for non-Hodgkin lymphoma, a common cancer in people living with HIV. We aimed to identify key CD4 count and HIV RNA (viral load) predictors of risk for non-Hodgkin lymphoma, overall and by subtype.MethodsWe studied people living with HIV during 1996-2014 from 21 Canadian and US cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. To determine key independent predictors of risk for non-Hodgkin lymphoma, we assessed associations with time-updated recent, past, cumulative, and nadir or peak measures of CD4 count and viral load, using demographics-adjusted, cohort-stratified Cox models, and we compared models using Akaike's information criterion.FindingsOf 102 131 people living with HIV during the study period, 712 people developed non-Hodgkin lymphoma. The key independent predictors of risk for overall non-Hodgkin lymphoma were recent CD4 count (ie, lagged by 6 months

Key Points Question Is bisphosphonate therapy beyond 5 years associated with lower risk of hip fracture? Findings In this cohort study of 29 685 older women who completed 5 years of bisphosphonate treatment, if women continued treatment for 5 additional years, the risk of hip fracture was not significantly different than if they discontinued after the first 5 years. If women continued for 2 additional years and then discontinued, there was a difference in hip fracture outcome depending on the use of a grace period for discontinuation. Meaning In this study of women who completed 5 years of bisphosphonate treatment, completing an additional 5 years of treatment was not associated with a reduction in hip fracture risk; the potential hip fracture benefit for continuing 2 additional years but not for 5 additional years should be further studied., This cohort study examines the association of discontinuing bisphosphonate at study entry, discontinuing at 2 years, and continuing for 5 additional years with hip fracture among women who completed 5 years of treatment at study entry., Importance Clinical trials have demonstrated the antifracture efficacy of bisphosphonate drugs for the first 3 to 5 years of therapy. However, the efficacy of continuing bisphosphonate for as long as 10 years is uncertain. Objective To examine the association of discontinuing bisphosphonate at study entry, discontinuing at 2 years, and continuing for 5 additional years with the risk of hip fracture among women who had completed 5 years of bisphosphonate treatment at study entry. Design, Setting, and Participants This cohort study included women who were members of Kaiser Permanente Northern and Southern California, 2 integrated health care delivery systems, and who had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, to September 30, 2014. Data analysis was conducted from January 2018 to August 2020. Exposure Discontinuation of bisphosphonate at study entry (within a 6-month grace period), discontinuation at 2 years (within a 6-month grace period), and continuation for 5 additional years. Main Outcomes and Measures The outcome was hip fracture determined by principal hospital discharge diagnoses. Demographic, clinical, and pharmacological data were ascertained from electronic health records. Results Among 29 685 women (median [interquartile range] age, 71 [64-77] years; 17 778 [60%] non-Hispanic White individuals), 507 incident hip fractures were identified. Compared with bisphosphonate discontinuation at study entry, there were no differences in the cumulative incidence (ie, risk) of hip fracture if women remained on therapy for 2 additional years (5-year risk difference [RD], −2.2 per 1000 individuals; 95% CI, −20.3 to 15.9 per 1000 individuals) or if women continued therapy for 5 additional years (5-year RD, 3.8 per 1000 individuals; 95% CI, −7.4 to 15.0 per 1000 individuals). While 5-year differences in hip fracture risk comparing continuation for 5 additional years with discontinuation at 2 additional years were not statistically significant (5-year RD, 6.0 per 1000 individuals; 95% CI, −9.9 to 22.0 per 1000 individuals), interim hip fracture risk appeared lower if women discontinued after 2 additional years (3-year RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 per 1000 individuals; 4-year RD, 9.3 per 1000 individuals; 95% CI, 6.3 to 12.3 per 1000 individuals) but not without a 6-month grace period to define discontinuation. Conclusions and Relevance In this study of women treated with bisphosphonate for 5 years, hip fracture risk did not differ if they discontinued treatment compared with continuing treatment for 5 additional years. If women continued for 2 additional years and then discontinued, their risk appeared lower than continuing for 5 additional years. Discontinuation at other times and fracture rates during intervening years should be further studied.

Evidence is conflicting about the association of abacavir use and cardiovascular disease (CVD) among HIV-infected individuals. Previous studies may have been biased by the preferential initiation or continuation of abacavir in patients with renal dysfunction.We conducted a cohort study in Kaiser Permanente California during 1998-2011, following HIV-infected adults initiating antiretroviral therapy until the earliest of CVD (ie, coronary heart disease or ischemic stroke), health plan disenrollment, death, or end of study. We used inverse-probability weighting to fit marginal structural models to estimate hazard ratios (HRs) for CVD comparing regimens with and without abacavir. Propensity score models included demographics, HIV-specific factors, and CVD risk factors, including alcohol/drug use, smoking, overweight/obesity, diabetes, lipid-lowering and hypertension therapy, and renal dysfunction (ie, estimated glomerular filtration rate60 mL·min·1.73 m).Among 8154 subjects, 178 had ≥1 CVD event, with 24/704 (3.4%) in the abacavir group and 154/7450 (2.1%) in the group initiating regimens without abacavir. Abacavir users had more renal dysfunction at antiretroviral therapy initiation (7.0% vs. 3.3%, P0.001). Compared with patients initiating regimens without abacavir, abacavir users had a 2.2-fold higher risk of CVD in intention-to-treat analysis [HR 2.2, 95% confidence interval (CI): 1.4 to 3.5], a 2.7-fold higher risk when remaining on their initial regimens for ≥1 year (HR 2.7, 95% CI: 1.5 to 5.0), and a 2.1-fold higher risk in per-protocol analysis (HR 2.1, 95% CI: 0.9 to 5.0).Abacavir was associated with an over 2-fold increased risk of CVD, which was not explained by renal dysfunction or other CVD risk factors.

Purpose Several epidemiologic studies suggest that compared to white women, Asians have a greater propensity to suffer an atypical femur fracture (AFF) while taking bisphosphonate therapy. This study examines the relative risk of AFF following bisphosphonate initiation for Asian compared to white women. Methods Using data from a large integrated northern California healthcare delivery system, we examined diaphyseal femur fracture outcomes among women age ≥ 50 years old who initiated oral bisphosphonate therapy during 2002–2007. An AFF was defined by the 2013 American Society of Bone and Mineral Research Task Force criteria. The risk of radiographically-confirmed AFF was examined for Asian compared to white women, adjusting for differences in bisphosphonate exposure and other potential risk factors. Results Among 48,390 women (65.3% white, 17.1% Asian) who newly initiated bisphosphonate therapy and were followed for a median of 7.7 years, 68 women experienced an AFF. The rate of AFF was 18.7 per 100,000 person-years overall and eight-fold higher among Asian compared to white women (64.2 versus 7.6 per 100,000 person-years). Asians were also more likely to have longer bisphosphonate treatment duration compared to whites (median 3.8 versus 2.7 years). The age-adjusted relative hazard for AFF was 8.5 (95% confidence interval 4.9–14.9) comparing Asian to white women, and was only modestly reduced to 6.6 (3.7–11.5) after adjusting for bisphosphonate duration and current use. Conclusions Our study confirms marked racial disparity in AFF risk that should be further investigated, particularly the mechanisms accounting for this difference. These findings also underscore the need to further examine the association of bisphosphonate duration and AFF in women of Asian race, as well as differential risk across Asian subgroups. In the interim, counseling of Asian women about osteoporosis drug continuation should include consideration of their potentially higher AFF risk.

OBJECTIVE This study evaluates an employer-based diabetes/prediabetes screening intervention that invited at-risk employees via letters, secure e-mails, and automated voice messages to complete blood glucose testing at a health plan facility. METHODS Quasi-experimental cohort study among health plan members insured by two employers that received the intervention and three employers that were selected as control sites. RESULTS The proportion of at-risk members that completed a screening was higher in the intervention group than in the control group (36% vs 13%, P

Many breast cancer therapies have adverse effects on the cardiovascular health of patients. Breast cancer patients who are members of racial/ethnic minority and disadvantaged socioeconomic groups suffer disproportionately from cardiotoxicity during and after cancer treatment, leading to disparities in overall survival. These disparities may exist, in part, because of inequality in the management of pre-existing cardiovascular diseases and its risk factors such as hypertension and diabetes. Shared lifestyle risk factors for breast cancer and cardiovascular diseases, including obesity, poorer diet, and lack of physical activity may contribute to disparate outcomes in cardiotoxicity. In addition, patients of racial/ethnic minority and disadvantaged socioeconomic groups may have limited access to cardio-oncology care due to lack of insurance coverage and longer geographic distance from their health care provider. Patients living in disadvantaged neighborhoods may lack healthy food options and exercise facilities, thus are unable to follow a heathier lifestyle. We present evidence from prior studies on these potential mechanisms of disparities in cardiotoxicity and accompanying gaps in research. Finally, we introduce our ongoing Pathways Heart Study (R01 CA21 4057, mPI: Kwan, Greenlee), a large population-based study of nearly 15,000 breast cancer survivors and 75,000 noncancer controls who are members of Kaiser Permanente Northern California, which is an extension of the Pathways Study of 4,505 breast cancer survivors (U01 CA19 5565, mPI: Kushi, Ambrosone). Our study provides a unique opportunity to better understand the individual and health care system level contributors to risk of cardiotoxic outcomes. Citation Format: Zaixing Shi, Heather Greenlee, Romain S. Neugebauer, Carlos Iribarren, Mai N. Nguyen-huynh, Jamal S. Rana, Dawn L. Hershman, Lawrence H. Kushi, Marilyn L. Kwan. Disparities in cardiovascular disease incidence in breast cancer survivors [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr IA28.

12016 Background: Breast cancer (BC) survivors are at increased risk of cardiovascular disease (CVD) following diagnosis, as compared to women without BC. To provide a population-based estimate of CVD risk in BC survivors, we compared risk of CVD events in women with and without BC history enrolled in the Kaiser Permanente Northern California (KPNC) integrated health system. Methods: Data were extracted from KPNC electronic health records. All invasive BC cases diagnosed between 2005-2013 were identified and matched 1:5 with non-BC controls on birth year, race/ethnicity and KPNC membership at date of BC diagnosis. Cox regression models were used to assess differences in the hazard of four major CVD events (ischemic heart disease (IHD), heart failure (HF), cardiomyopathy, and stroke). Models were adjusted for factors known to influence risk of breast cancer or CVD.Other CVD events included arrhythmia, cardiac arrest, carotid disease, myocarditis/pericarditis, transient ischemic attack, valvular disease, and venous thromboembolism (VTE). We additionally examined subgroups of cases who received chemotherapy, radiation, and endocrine therapy, and their controls. Results: A total of 14,942 women with a new diagnosis of invasive BC were identified and matched to 74,702 women without BC history. On average, women were 62.0 years, 28.3 kg/m2BMI, 64.9% non-Hispanic white. Among all cases and controls, there were no significant differences in hazard of developing IHD, cardiomyopathy, and stroke; there was a borderline difference in HF (HR: 1.08, 95% CI: 0.99, 1.19). Cases were more likely to have a cardiac arrest (HR: 1.39, 95% CI: 1.09, 1.78) and develop VTE (HR: 1.97, 95% CI: 1.74, 2.23). Women treated with chemotherapy were more likely than controls to develop HF (HR: 1.44, 95% CI: 1.21, 1.72), cardiomyopathy (HR: 2.01, 95% CI: 1.02, 3.98), and VTE (HR: 3.15, 95% CI: 2.62, 3.79). Women who received radiation therapy were more likely to develop carotid disease (HR: 5.49, 95% CI: 1.22, 24.66) and VTE (HR: 1.65, 95% CI: 1.35, 2.03) than controls. Women who received endocrine therapy were more likely to experience a cardiac arrest (HR: 1.49, 95% CI: 1.07, 2.09) and develop VTE (HR: 1.70, 95% CI: 1.42, 2.03) than controls. Conclusions: Women with BC were at increased risk of heart failure, cardiomyopathy, cardiac arrest, VTE and carotid disease. These risks varied by cancer treatment, with higher risk in those who received chemotherapy. Future studies should explore the effects of chemotherapy class and radiation dose exposure on diverse CVD endpoints in BC survivors.

12017 Background: Women with a history of breast cancer (BC) are at increased long-term risk of dying from cardiovascular disease (CVD). However, the onset of CVD risk factors in women with BC has not been well-described. We compared risk of incident CVD risk factors in women with and without BC enrolled in the Kaiser Permanente Northern California (KPNC) integrated health system. Methods: Data were extracted from KPNC electronic health records. All invasive BC cases diagnosed between 2005-2013 were identified and matched 1:5 with controls on birth year, race/ethnicity and KPNC membership at the date of BC diagnosis. Cox regression models assessed the hazard of incident hypertension (based on diagnosis codes and filled prescriptions), dyslipidemia (based on diagnosis codes, filled prescriptions, and lab values), and diabetes (KPNC Diabetes Registry). Models were adjusted for baseline BMI, menopausal status, smoking status, neighborhood median household income, education, prevalent CVD conditions, and other baseline CVD risk factors. Subgroups of women who received chemotherapy, radiation therapy, and endocrine therapy were compared with controls. Results: A total of 14,942 women with a new diagnosis of invasive BC were identified and matched to 74,702 controls. On average, women were 62.0 years, 28.3 kg/m2BMI, 64.9% non-Hispanic white. Overall, cases were more likely to develop hypertension (HR: 1.18, 95% CI: 1.13, 1.24) and diabetes (HR: 1.23, 95% CI: 1.16, 1.31). Across the board, receipt of any of the three therapies (chemotherapy, radiation therapy and endocrine therapy) was associated with increased risk of hypertension and diabetes, compared to controls. Risk-factor specific hazard ratios for receipt of chemotherapy were (HR 1.18, 95% CI: 1.10, 1.27) and (HR 1.38, 95% CI: 1.26, 1.51), for hypertension and diabetes, respectively. For receipt of radiation therapy, risk-factor specific hazard ratios were (HR: 1.17, 95% CI: 1.09, 1.26) and (HR: 1.15, 95% CI: 1.04, 1.27), for hypertension and diabetes, respectively. Risk-factor specific hazard ratios for receipt of endocrine therapy were (HR: 1.22, 95% CI: 1.14, 1.30) and (HR: 1.16, 95% CI: 1.06, 1.27), for hypertension and diabetes, respectively. Conclusions: The risk of developing hypertension and diabetes is increased in women with BC who received chemotherapy, radiation therapy, and/or endocrine therapy. Future studies should examine the roles of CVD risk factor diagnosis and management on cardiometabolic risk in women with a BC history.

This cohort study examines the association of analogue compared with human insulin use with mortality and major cardiovascular events among adults with type 2 diabetes., Key Points Question Are there significant differences in cardiovascular outcomes in adults with type 2 diabetes who use human insulin compared with those who use analogue insulin? Findings In this cohort study of 127 600 adults with type 2 diabetes, no differences were found in overall mortality, cardiovascular mortality, myocardial infarction, stroke, and hospitalization for congestive heart failure. Meaning In this study, insulin-naive adults with type 2 diabetes treated with human vs analogue insulin had similar rates of major cardiovascular events, mortality due to cardiovascular disease, and overall mortality., Importance The comparative cardiovascular safety of analogue and human insulins in adults with type 2 diabetes who initiate insulin therapy in usual care settings has not been carefully evaluated using machine learning and other rigorous analytic methods. Objective To examine the association of analogue vs human insulin use with mortality and major cardiovascular events. Design, Setting, and Participants This retrospective cohort study included 127 600 adults aged 21 to 89 years with type 2 diabetes at 4 health care delivery systems who initiated insulin therapy from January 1, 2000, through December 31, 2013. Machine learning and rigorous inference methods with time-varying exposures were used to evaluate associations of continuous exposure to analogue vs human insulins with mortality and major cardiovascular events. Data were analyzed from September 1, 2017, through June 30, 2018. Exposures On the index date (first insulin dispensing), participants were classified as using analogue insulin with or without human insulin or human insulin only. Main Outcomes and Measures Overall mortality, mortality due to cardiovascular disease (CVD), myocardial infarction (MI), stroke or cerebrovascular accident (CVA), and hospitalization for congestive heart failure (CHF) were evaluated. Marginal structural modeling (MSM) with inverse probability weighting was used to compare event-free survival in separate per-protocol analyses. Adjusted and unadjusted hazard ratios and cumulative risk differences were based on logistic MSM parameterizations for counterfactual hazards. Propensity scores were estimated using a data-adaptive approach (machine learning) based on 3 nested covariate adjustment sets. Sensitivity analyses were conducted to address potential residual confounding from unmeasured differences in risk factors across delivery systems. Results The 127 600 participants (mean [SD] age, 59.4 [12.6] years; 68 588 men [53.8%]; mean [SD] body mass index, 32.3 [7.1]) had a median follow-up of 4 quarters (interquartile range, 3-9 quarters) and experienced 5464 deaths overall (4.3%), 1729 MIs (1.4%), 1301 CVAs (1.0%), and 3082 CHF hospitalizations (2.4%). There were no differences in adjusted hazard ratios for continuous analogue vs human insulin exposure during 10 quarters for overall mortality (1.15; 95% CI, 0.97-1.34), CVD mortality (1.26; 95% CI, 0.86-1.66), MI (1.11; 95% CI, 0.77-1.45), CVA (1.30; 95% CI, 0.81-1.78), or CHF hospitalization (0.93; 95% CI, 0.75-1.11). Conclusions and Relevance Insulin-naive adults with type 2 diabetes who initiate and continue treatment with human vs analogue insulins had similar observed rates of major cardiovascular events, CVD mortality, and overall mortality.

Aims To evaluate the effectiveness of automated symptom and side effect monitoring on quality of life among individuals with symptomatic diabetic peripheral neuropathy. Methods We conducted a pragmatic, cluster randomized controlled trial (July 2014 to July 2016) within a large healthcare system. We randomized 1834 primary care physicians and prospectively recruited from their lists 1270 individuals with neuropathy who were newly prescribed medications for their symptoms. Intervention participants received automated telephone-based symptom and side effect monitoring with physician feedback over 6 months. The control group received usual care plus three non-interactive diabetes educational calls. Our primary outcomes were quality of life (EQ-5D) and select symptoms (e.g. pain) measured 4-8 weeks after starting medication and again 8 months after baseline. Process outcomes included receiving a clinically effective dose and communication between individuals with neuropathy and their primary care provider over 12 months. Interviewers collecting outcome data were blinded to intervention assignment. Results Some 1252 participants completed the baseline measures [mean age (sd): 67 (11.7), 53% female, 57% white, 8% Asian, 13% black, 20% Hispanic]. In total, 1179 participants (93%) completed follow-up (619 control, 560 intervention). Quality of life scores (intervention: 0.658 ± 0.094; control: 0.653 ± 0.092) and symptom severity were similar at baseline. The intervention had no effect on primary [EQ-5D: -0.002 (95% CI -0.01, 0.01), P = 0.623; pain: 0.295 (-0.75, 1.34), P = 0.579; sleep disruption: 0.342 (-0.18, 0.86), P = 0.196; lower extremity functioning: -0.079 (-1.27, 1.11), P = 0.896; depression: -0.462 (-1.24, 0.32); P = 0.247] or process outcomes. Conclusions Automated telephone monitoring and feedback alone were not effective at improving quality of life or symptoms for people with symptomatic diabetic peripheral neuropathy. Trial registration ClinicalTrials.gov (NCT02056431).