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Objective: Type 2 diabetes is associated with increased cardiovascular risk. The role of aggressive glycemic control in preventing cardiovascular events is unclear. A nested case-control study design was used to evaluate the association between average A1C and cardiovascular outcomes.Research Design and Methods: Adults with type 2 diabetes were identified among members of Kaiser Permanente Southern California. Type 2 diabetes was identified based on ICD-9 diagnosis codes and either A1C >7.5% or prescriptions for hypoglycemic agents. Case subjects were defined based on nonfatal myocardial infarction, nonfatal stroke, or death attributed to cardiovascular events during a 3-year window. Four type 2 diabetes control subjects were matched to each case subject based on age, sex, and index date for the corresponding case. A conditional logistic regression model was used to estimate the odds ratio of cardiovascular events and compare three patient groups based on average A1C measured in the preindex period (≤6, >6-8, >8%).Results: A total of 44,628 control subjects were matched to 11,157 case subjects. Patients with an average A1C ≤6% were 20% more likely to experience a cardiovascular event than the group with an average A1C of >6-8% (P < 0.0001). Patients with an average A1C >8% experienced a 16% increase in the likelihood of a cardiovascular event (P < 0.0001). We found evidence of statistical interaction with A1C category and LDL level (P = 0.0002), use of cardiovascular medications (P = 0.02), and use of antipsychotics (P = 0.001).Conclusions: High-risk patients with type 2 diabetes who achieved mean A1C levels of ≤6% or failed to decrease their A1C to <8% are at increased risk for cardiovascular events. [ABSTRACT FROM AUTHOR]

Importance: Anticoagulation management services (AMSs; ie, warfarin clinics) have evolved to include patients treated with direct oral anticoagulants (DOACs), but it is unknown whether DOAC therapy management services improve outcomes for patients with atrial fibrillation (AF)., Objective: To compare outcomes associated with 3 DOAC care models for preventing adverse anticoagulation-related outcomes among patients with AF., Design, Setting, and Participants: This retrospective cohort study included 44 746 adult patients with a diagnosis of AF who initiated oral anticoagulation (DOAC or warfarin) between August 1, 2016, and December 31, 2019, in 3 Kaiser Permanente (KP) regions. Statistical analysis was conducted from August 2021 through May 2023., Exposures: Each KP region used an AMS to manage warfarin but used distinct approaches to DOAC care: (1) usual care (UC) by the prescribing clinician, (2) UC plus an automated population management tool (PMT), or (3) pharmacist-managed AMS care. Propensity scores and inverse probability of treatment weights (IPTWs) were estimated. Direct oral anticoagulant care models were first indirectly compared using warfarin as a common comparator within each region and then directly compared across regions., Main Outcomes and Measures: Patients were followed up until the first occurrence of an outcome (composite of thromboembolic stroke, intracranial hemorrhage, other major bleeding, or death), discontinuation of KP membership, or December 31, 2020., Results: Overall, 44 746 patients were included: 6182 in the UC care model (3297 DOAC; 2885 warfarin), 33 625 in the UC plus PMT care model (21 891 DOAC; 11 734 warfarin), and 4939 in the AMS care model (2089 DOAC; 2850 warfarin). Baseline characteristics (mean [SD] age, 73.1 [10.6] years, 56.1% male, 67.2% non-Hispanic White, median CHA2DS2-VASc [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65-74 years, female sex] score of 3 [IQR, 2-5]) were well balanced after IPTW. Over a median follow-up of 2 years, patients who received the UC plus PMT or AMS care model did not have significantly better outcomes than those who received UC. The incidence rate of the composite outcome was 5.4% per year for DOAC and 9.1% per year for warfarin for those in the UC group, 6.1% per year for DOAC and 10.5% per year for those in the UC plus PMT group, and 5.1% per year for DOAC and 8.0% per year for those in the AMS group. The IPTW-adjusted hazard ratios (HRs) for the composite outcome comparing DOAC vs warfarin were 0.91 (95% CI, 0.79-1.05) in the UC group, 0.85 (95% CI, 0.79-0.90) in the UC plus PMT group, and 0.84 (95% CI, 0.72-0.99) in the AMS group (P = .62 for heterogeneity across care models). When directly comparing patients receiving DOAC, the IPTW-adjusted HR was 1.06 (95% CI, 0.85-1.34) for the UC plus PMT group vs the UC group and 0.85 (95% CI, 0.71-1.02) for the AMS group vs the UC group., Conclusions and Relevance: This cohort study did not find appreciably better outcomes for patients receiving DOAC who were managed by either a UC plus PMT or AMS care model compared with UC.

Background: During the COVID-19 pandemic, opioid-related overdose deaths increased. Although Medication-Assisted Treatment or Recovery (MAT or MAR) is available, initiation and retention rates vary. The goal of this study was to evaluate clinical, demographic, and Social Determinant of Health factors affecting MAR initiation, on-time initiation of medications, and successful retention in the program. The secondary goal was to evaluate the impact of a novel interprofessional practice model incorporating pharmacists., Methods: A retrospective analysis was conducted using electronic health record data from a pilot MAR Program initiated within a California Federally Qualified Healthcare Center., Results: From September 2019 to August 2020, 48 patients enrolled into the program. On-time initiation of medications occurred in 68% of patients and average program retention was 96.4 ± 95.8 days. Patients currently using opioids ( p = 0.005) and those receiving supportive medications ( p = 0.049) had lower odds of on-time MAR initiation. There were no statistically significant factors associated with successful retention in the program. The number of visits with members of the interprofessional team did not significantly affect on-time initiation or successful retention., Conclusions: Current opioid use and receipt of supportive medications were associated with lower on-time medication initiation. Further studies are warranted to explore additional factors which may affect initiation and retention.

Introduction: Studies of hypertension in pregnancy that use electronic health care data generally identify hypertension using hospital diagnosis codes alone. We sought to compare results from this approach to an approach that included diagnosis codes, antihypertensive medications and blood pressure (BP) values., Materials and Methods: We conducted a retrospective cohort study of 1,45,739 pregnancies from 2009 to 2014 within an integrated healthcare system. Hypertensive pregnancies were identified using the "BP-Inclusive Definition" if at least one of three criteria were met: (1) two elevated outpatient BPs, (2) antihypertensive medication fill plus an outpatient hypertension diagnosis, or (3) hospital discharge diagnosis for preeclampsia or eclampsia. The "Traditional Definition" considered only delivery hospitalization discharge diagnoses. Outcome event analyses compared rates of preterm delivery and small for gestational age (SGA) between the two definitions., Results: The BP-Inclusive Definition identified 14,225 (9.8%) hypertensive pregnancies while the Traditional Definition identified 13,637 (9.4%); 10,809 women met both definitions. Preterm delivery occurred in 20.9% of BP-Inclusive Definition pregnancies, 21.8% of Traditional Definition pregnancies and 6.6% of non-hypertensive pregnancies; for SGA the numbers were 15.6, 16.3, and 8.6%, respectively ( p < 0.001 for all events compared to non-hypertensive pregnancies). Analyses in women meeting only one hypertension definition (21-24% of positive cases) found much lower rates of both preterm delivery and SGA., Conclusion: Prevalence of hypertension in pregnancy was similar between the two study definitions. However, a substantial number of women met only one of the study definitions. Women who met only one of the hypertension definitions had much lower rates of adverse neonatal events than women meeting both definitions., Competing Interests: SS reports receiving research funding from Synoos Health that represents a consortium of pharmaceutical companies. TE has done consulting for DiabetOmics Inc., Alynylam Pharmaceuticals, and Ferring Pharmaceuticals. LA has received research funding from Bausch Health Companies. SD has received research funding from GSK pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cheetham, Shortreed, Avalos, Reynolds, Holt, Easterling, Portugal, Zhou, Neugebauer, Bider, Idu and Dublin.)

Objective: To compare maternal and infant outcomes with different antihypertensive medications in pregnancy., Design: Retrospective cohort study., Setting: Kaiser Permanente, a large healthcare system in the United States., Population: Women aged 15-49 years with a singleton birth from 2005-2014 treated for hypertension., Methods: We identified medication exposure from automated pharmacy data based on the earliest dispensing after the first prenatal visit. Using logistic regression, we calculated weighted outcome prevalences, adjusted odds ratios (aORs) and 95% confidence intervals, with inverse probability of treatment weighting to address confounding., Main Outcome Measures: Small for gestational age, preterm delivery, neonatal and maternal intensive care unit (ICU) admission, preeclampsia, and stillbirth or termination at > 20 weeks., Results: Among 6346 deliveries, 87% with chronic hypertension, the risk of the infant being small for gestational age (birthweight < 10th percentile) was lower with methyldopa than labetalol (prevalence 13.6% vs. 16.6%; aOR 0.77, 95% CI 0.63 to 0.92). For birthweight < 3rd percentile the aOR was 0.57 (0.39 to 0.80). Compared with labetalol (26.0%), risk of preterm delivery was similar for methyldopa (26.5%; aOR 1.10 [0.95 to 1.27]) and slightly higher for nifedipine (28.5%; aOR 1.25 [1.06 to 1.46]) and other β-blockers (31.2%; aOR 1.58 [1.07 to 2.23]). Neonatal ICU admission was more common with nifedipine than labetalol (25.9% vs. 23.3%, aOR 1.21 [1.02 to 1.43]) but not elevated with methyldopa. Risks of other outcomes did not differ by medication., Conclusions: Risk of most outcomes was similar comparing labetalol, methyldopa and nifedipine. Risk of the infant being small for gestational age was substantially lower for methyldopa, suggesting this medication may warrant further consideration., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SD received a grant to support this work from the National Institute on Child Health and Human Development. She has also received grant support from GSK for unrelated work. LC received a postdoctoral fellowship from the Group Health Foundation. She is now employed by Genentech (a member of Roche Group). ZBC is now employed by Roche Pharmaceuticals. TRE has consulted for Alnylam Pharmaceuticals, DiabetOmics, and Ferring Pharmaceuticals. SMS has received grant funding through her institutions from Syneos Health for work unrelated to this study. LAA received funding through her institution from Bausch Health Companies and KR from Amgen, Novartis and Merck & Co, all for work unrelated to this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background Direct oral anticoagulants (DOACs) are widely used in patients with nonvalvular atrial fibrillation for stroke prevention. However, long-term adherence to DOACs and clinical outcomes in real-world clinical practice is not well understood. This study evaluated long-term medication adherence patterns to DOAC therapy and clinical outcomes in a large US integrated health care system. Methods and Results We included adult patients with nonvalvular atrial fibrillation who newly initiated DOACs between 2012 and 2018 in Kaiser Permanente Southern California. Long-term (3.5 years) adherence trajectories to DOAC were investigated using monthly proportion of days covered and group-based trajectory models. Factors associated with long-term adherence trajectories were investigated. Multivariable Poisson regression analyses were used to investigate thromboembolism and major bleeding events associated with long-term adherence trajectories. Of 18 920 patients newly initiating DOACs, we identified 3 DOAC adherence trajectories: consistently adherent (85.2%), early discontinuation within 6 months (10.6%), and gradually declining adherence (4.2%). Predictors such as lower CHA 2 DS 2 -VASc (0-1 versus ≥5) and previous injurious falls were associated with both early discontinuation and gradually declining adherence trajectories. Early discontinuation of DOAC therapy was associated with a higher risk of thromboembolism (rate ratio, 1.40; 95% CI, 1.05-1.86) especially after 12 months from DOAC initiation but a lower risk of major bleed compared with consistent adherence (rate ratio, 0.48; 95% CI, 0.30-0.75), specifically during the first 12 months following DOAC initiation. A gradual decline in adherence to DOACs was not statistically significantly associated with thromboembolism outcomes compared with consistent adherence. Conclusions Although a large proportion of patients with nonvalvular atrial fibrillation were adherent to DOAC therapy over 3.5 years, early discontinuation of DOAC was associated a higher risk of thromboembolic events. Future tailored interventions for early discontinuers may improve clinical outcomes.

Importance: Hypertensive disorders of pregnancy are a leading cause of maternal morbidity and mortality. The impact of applying recent guideline definitions for nonpregnant adults to pregnant women is unclear., Objective: To determine whether reclassification of hypertensive status using the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline definition better identifies women at risk for preeclampsia or eclampsia and adverse fetal/neonatal events compared with the current American College of Obstetricians and Gynecologists (ACOG) definition of hypertension., Design, Setting, and Participants: This cohort study used electronic medical record data of women who delivered singleton infants between 2009 and 2014 at a large US regional health system. Data analysis was performed from July 2020 to September 2020., Exposure: Application of ACC/AHA and ACOG guidelines for the definition of chronic and gestational hypertension., Main Outcomes and Measures: The primary maternal end point was the development of preeclampsia or eclampsia, and the primary fetal/neonatal end point was a composite of preterm birth, small for gestational age, and neonatal intensive care unit admission within 28 days of delivery. Net reclassification indices were calculated to examine how well the lower ACC/AHA diagnostic threshold reclassifies outcomes of pregnancy compared with the current ACOG definition of hypertension., Results: Applying the ACC/AHA criteria to 137 389 pregnancies of women (mean [SD] age at time of delivery, 30.1 [5.8] years) resulted in a 14.3% prevalence of chronic hypertension (19 621 pregnancies) and a 13.8% prevalence of gestational hypertension (18 998 pregnancies). A 17.8% absolute increase was found in the overall prevalence of hypertension from 10.3% to 28.1%. The 2.1% of women who were reclassified with chronic rather than gestational hypertension had the highest risk of developing preeclampsia compared with women without hypertension by either criterion (adjusted risk ratio, 13.58; 95% CI, 12.49-14.77). Overall, the use of the ACC/AHA criteria to diagnose hypertension resulted in a 20.8% improvement in the appropriate identification of future preeclampsia, but only a 3.8% improvement of appropriate fetal/neonatal risk classification., Conclusions and Relevance: Using the lower diagnostic threshold for hypertension recommended in the 2017 ACC/AHA guideline increased the prevalence of chronic and gestational hypertension, markedly improved the appropriate identification of women who would go on to develop preeclampsia, and was associated with the identification of adverse fetal/neonatal risk.

Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of 98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. Conclusion: The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Importance: Azithromycin is one of the most commonly prescribed antibiotics in the US. It has been associated with an increased risk of cardiovascular death in some observational studies., Objective: To estimate the relative and absolute risks of cardiovascular and sudden cardiac death after an outpatient azithromycin prescription compared with amoxicillin, an antibiotic not known to increase cardiovascular events., Design, Setting, and Participants: This retrospective cohort study included 2 large, diverse, community-based integrated care delivery systems with comprehensive capture of encounters and prescriptions from January 1, 1998, to December 31, 2014. The cohort included patients aged 30 to 74 years who had at least 12 months of health-plan enrollment prior to antibiotic exposure. The exclusion criteria were absence of prescription benefits, prescription for more than 1 type of study antibiotic within 10 days, hospitalization or nursing home residence, and serious medical conditions. Risk of cardiovascular death associated with azithromycin vs amoxicillin exposure was calculated after controlling for confounding factors using a propensity score. Data were analyzed from December 1, 2016, to March 30, 2020., Exposures: Outpatient prescription of azithromycin or amoxicillin., Main Outcomes and Measures: The primary outcomes were cardiovascular death and sudden cardiac death. An a priori subgroup analysis quantified the effects of azithromycin exposure among patients with increased baseline cardiovascular risk. The secondary outcomes were noncardiovascular death and all-cause mortality., Results: The study included 7 824 681 antibiotic exposures, including 1 736 976 azithromycin exposures (22.2%) and 6 087 705 amoxicillin exposures (77.8%), among 2 929 008 unique individuals (mean [SD] age, 50.7 [12.3] years; 1 810 127 [61.8%] women). Azithromycin was associated with a significantly increased hazard of cardiovascular death (hazard ratio [HR], 1.82; 95% CI, 1.23-2.67) but not sudden cardiac death (HR, 1.59; 95% CI, 0.90-2.81) within 5 days of exposure. No increases in risk were found 6 to 10 days after exposure. Similar results were observed in patients within the top decile of cardiovascular risk (HR, 1.71; 95% CI, 1.06-2.76). Azithromycin was also associated with an increased risk of noncardiovascular death (HR, 2.17; 95% CI, 1.44-3.26) and all-cause mortality (HR, 2.00; 95% CI, 1.51-2.63) within 5 days of exposure., Conclusions and Relevance: These findings suggest that outpatient azithromycin use was associated with an increased risk of cardiovascular death and noncardiovascular death. Causality cannot be established, particularly for noncardiovascular death, owing to the likelihood of residual confounding.

Background: Anticyclic citrullinated peptide (anti-CCP) positivity may be a strong predictor of joint erosion and a potential biomarker for guiding treatment decisions for rheumatoid arthritis (RA). However, limited studies are currently available on the effect of anti-CCP positivity on health care utilization and/or medical costs of RA patients., Objective: To investigate short-term and long-term direct health care expenditures associated with anti-CCP positivity in newly diagnosed RA patients., Methods: A retrospective cohort study was conducted in adult RA patients within a U.S. integrated health care delivery system (January 1, 2007-June 30, 2015). Patients were required to have 2 RA diagnoses and treatment with a conventional or biologic disease-modifying antirheumatic drug (DMARD) within 12 months. The first RA diagnosis date was labeled as the index date, and patients were followed until they left the health plan, died, or reached the end of the study period. Patient demographics, anti-CCP results, comorbid conditions, and health care resource utilization during baseline (12 months before the index date) and follow-up periods were collected. Nationally recognized direct medical costs were assigned to health care utilization to calculate health care costs in 2015 U.S. dollars. The baseline differences between anti-CCP positivity and negativity and differences in censoring during follow-up were addressed using propensity scores. The mean differences in costs were estimated using recycled prediction methods., Results: 2,448 newly diagnosed RA patients were identified and followed for a median of 3.7 years (range = 1-8 years). At baseline, 65.8% of patients were anti-CCP positive. Anti-CCP-positive patients had fewer comorbid conditions at baseline. During the first 12 months of follow-up, median (interquartile range) total health care expenditures for anti-CCP-positive and anti-CCP-negative patients were $6,200 ($3,563-$13,260) and $7,022 ($3,885-$12,995), respectively. After adjusting for baseline differences, total incremental mean cost associated with anti-CCP positivity during the first 12 months was estimated to be $2,163 per patient (P = 0.001). The annual incremental costs in anti-CCP-positive patients became progressively larger over time, from $2,163 during the first year to $5,062 during the fourth year. Anti-CCP positivity was associated with higher prescription, laboratory testing, and rheumatologist utilization. A higher percentage of anti-CCP-positive patients received 1 or more biologic DMARDs (11.6% for anti-CCP-positive vs. 5.7% for anti-CCP negative; P < 0.001) compared with anti-CCP-negative patients during the 12-month follow-up, which resulted in $2,499 in incremental prescription costs (P < 0.001). Total additional burden associated with anti-CCP positivity during the first 4 years was estimated to be $14,089 per patient., Conclusions: In newly diagnosed RA patients, higher economic burden associated with anti-CCP positivity was mainly driven by prescription costs., Disclosures: This research and manuscript were funded by Bristol-Myers Squibb (BMS). Alemao and Connolly are employees and shareholders of BMS and participated in the design of the study, interpretation of the data, review/revision of the manuscript, and approval of the final version of the manuscript. An and Cheetham received a grant from BMS for this research. At the time of this study, An was employed by Western University of Health Sciences, and Cheetham was employed by Kaiser Permanente Southern California. Bider-Canfield, Kang, and Lin have nothing to disclose. Some study results were presented as a poster at the American College of Rheumatology Annual Meeting; November 5, 2017; San Diego, CA, and at the International Society for Pharmacoeconomics and Outcomes Research Meeting; May 19, 2018; Baltimore, MD.

Background: Lipid screening determines eligibility for statins and other cardiovascular risk reduction interventions., Objective: To examine trends in lipid screening among adults aged ≥20 years in a large, multiethnic, integrated health care delivery system in southern California., Methods: Temporal trends in lipid screening were examined from 2009 to 2015 with an index date of September 30 of each year. Lipid screening was defined as the proportion of eligible members each year who (a) had ever been screened among those aged 20-39 years and (b) had been screened in the previous 6 years for those aged ≥ 40 years. Trends were analyzed by age, gender, and the presence of atherosclerotic cardiovascular disease (ASCVD) or diabetes without ASCVD status., Results: More than 2 million individuals were included each year: 5%-6% had ASCVD (includes those with diabetes), 7%-8% had diabetes without ASCVD, and 87% had neither condition. Among the entire population, lipid screening increased from 79.8% in 2009 to 82.6% in 2015 (P < 0.0001). Among those with ASCVD or diabetes, lipid screening was 99% across all years. Among those without ASCVD or DM, screening increased from 76.9% in 2009 to 80.0% in 2015 (P < 0.0001), with higher screening among women compared with men and lower screening among individuals younger than 55 years., Conclusions: Consistently high rates of lipid screening were observed among individuals with ASCVD or diabetes. In individuals without these conditions, screening increased over time. However, there is room to further increase screening rates in adults younger than 55 years., Disclosures: This manuscript and research work was supported by a contractual agreement between the Southern California Permanente Medical Group and Regeneron Pharmaceuticals and Sanofi U.S. Researchers from Regeneron and Sanofi collaborated on the study design, interpretation of data, and writing of the manuscript. Ling Grant, Harrison, Chang, Hsu, Cheetham, Wei, and Reynolds are employed by Kaiser Permanente Southern California. Scott is employed by Southern California Permanente Medical Group. Boklage is employed by Regeneron, and Romo-LeTourneau is employed by Sanofi. Preliminary results from this study were presented at the American Heart Association Scientific Sessions; November 12-16, 2016; New Orleans, LA.

Limited safety data are available on inadvertent exposure to quadrivalent human papillomavirus vaccine (4vHPV) during pregnancy. We conducted a descriptive observational postlicensure safety surveillance study in Kaiser Permanente Southern California and Northern California to assess congenital anomaly and miscarriage among pregnancies exposed to 4vHPV. Using electronic medical records, we identified women who received a dose of 4vHPV between August 2006 and March 2008 within 30 days preconception or any time during a possible pregnancy. A broad algorithm was developed using diagnostic and procedure codes and laboratory tests to identify pregnancy, congenital anomalies, and miscarriages. Medical records of all potential congenital anomaly cases and a random sample of 100 potential miscarriage cases were reviewed to confirm pregnancy exposure and diagnosis. Results were reviewed by an independent Safety Review Committee (SRC). Among the population of 189,629 females who received at least one dose of 4vHPV during the study period, 2,678 females were identified as possibly having a 4vHPV-exposed pregnancy. Among 170 potential congenital anomalies identified, 44 (26%) were found to be both 4vHPV-exposed and confirmed congenital anomaly cases. Among the 633 potential miscarriages identified, the records of a random sample of 100 cases were reviewed, and 9 cases (9%) were confirmed as 4vHPV-exposed miscarriages. The SRC noted no safety signal for congenital anomaly or miscarriage associated with 4vHPV exposure during pregnancy. The rate of major congenital anomaly (3.6%) was in the range of background estimates from the literature. There was no apparent pattern of timing of 4vHPV exposure among 4vHPV-exposed miscarriages.

Context: Hyperuricemia is an independent risk factor for progression of kidney disease., Objective: To determine whether lowering serum uric acid level (sUA) to below 6 mg/dL (target) improves mild to moderate chronic kidney disease (CKD) and whether CKD stage influences the benefit of lowering sUA to target., Design: Retrospective epidemiologic cohort study conducted over 8 years. Estimated glomerular filtration rate (eGFR) was required in the 6 months preceding the index date (defined as first occurrence of sUA < 7 mg/dL), and at least 1 sUA and eGFR were required during follow-up. Patients were urate-lowering therapy (ULT) naïve, aged 18 years or older, and had CKD Stages 2 to 4 at baseline. Health Plan enrollment with drug benefit was required. Exclusions included active cancer, dialysis, or other kidney disease., Main Outcome Measures: A 30% decrease or 30% improvement in eGFR from baseline., Results: A total of 12,751 patients met inclusion criteria; 2690 patients received ULT during follow-up and 10,061 did not. Target sUA was achieved in 1118 patients (42%) receiving ULT. A 30% improvement in eGFR was likelier in patients who achieved the target (odds ratio [OR] = 1.78, p < 0.001). Pairwise comparison of CKD stages showed a 30% improvement in eGFR in CKD Stage 2 (OR = 2.26, p = 0.017) and Stage 3 (OR = 2.23, p < 0.001) but not Stage 4 (OR = 1.50, p = 0.081)., Conclusion: Patients who achieve an American College of Rheumatology target sUA below 6 mg/dL during ULT have higher rates of eGFR improvement, especially in CKD Stages 2 and 3.

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 (1997–2012). Exposures included CCB or ACEi use of 1–12 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.

Context: Traditional hepatitis C virus treatment was limited by low cure rates, side effects, and stringent monitoring requirements. Sofosbuvir, a direct-acting antiviral agent with a cure rate of 96%, was introduced in 2013. However, trials frequently excluded patients with advanced liver disease and prior treatment experience. This study aims to elucidate the real-world cure rates and sofosbuvir safety profile., Methods: A retrospective cohort study was conducted at Kaiser Permanente Southern California involving patients with hepatitis C virus who received sofosbuvir treatment. Patients age 18 years and older were included, and pregnant patients were excluded. The primary end point was sustained virologic response at 12 weeks posttreatment. Secondary end points were safety and medication adherence. Multiple logistic regression analysis was used to compare patients with genotypes 1 and 2 infections., Results: Of the 213 study patients, 42.3% had cirrhosis, and 38% were treatment-experienced. Most patients (69.5%) received dual therapy (sofosbuvir + ribavirin), whereas the remainder (30.5%) received triple therapy (sofosbuvir + ribavirin + interferon). The overall rate of sustained virologic response at 12 weeks posttreatment rate was 72.9% for genotype 1 infection, 64.7% in the treatment-experienced subgroup, and 66.7% in the cirrhosis subgroup. Rates of sustained virologic response at 12 weeks posttreatment for genotypes 2 and 3 were 90.8% and 55%, respectively. Most patients experienced anemia and fatigue. Women and patients with a lower baseline viral load were statistically more likely to be cured., Conclusion: Real-world cure rates were similar to rates seen in clinical trials for genotype 2 infection and lower for genotype 1 infection. Patients with genotype 1 and 3 infection did better with triple therapy compared with dual therapy. Patients tolerated therapy well with side effects, serious adverse events, and discontinuation rates similar to clinical trials. Women and patients with lower baseline hepatitis C viral load were more likely to achieve sustained virological response at 12 weeks posttreatment.

The objective of this study was to evaluate the effectiveness of an automated telephone system reminding patients with hypertension and/or cardiovascular disease to obtain overdue medication refills. The authors compared the intervention with usual care among patients with an overdue prescription for a statin or lisinopril-hydrochlorothiazide (lisinopril-HCTZ). The primary outcome was refill rate at 2 weeks. Secondary outcomes included time to refill and change in low-density lipoprotein cholesterol and blood pressure. Significantly more patients who received a reminder call refilled their prescription compared with the usual-care group (statin cohort: 30.3% vs 24.9% [P<.0001]; lisinopril-HCTZ cohort: 30.7% vs 24.2% [P<.0001]). The median time to refill was shorter in patients receiving the reminder call (statin cohort: 29 vs 36 days [P<.0001]; lisinopril-HCTZ cohort: 24 vs 31 days [P<.0001]). There were no statistically significant differences in mean low-density lipoprotein cholesterol and blood pressure. These findings suggest the need for interventions that have a longer-term impact., (© 2015 Wiley Periodicals, Inc.)

Background and Aims: Previous studies have shown increased hepatic decompensation in patients with cirrhosis undergoing surgery. However, there are little data available in cirrhotics undergoing orthopedic surgery compared to cirrhotics who did not undergo surgery. The aim of this study was to examine the demographics, comorbid conditions, and clinical factors associated with hepatic decompensation within 90 days in cirrhotics who underwent orthopedic surgery., Methods: This is a retrospective matched cohort study. Inclusion criteria were cirrhosis diagnosis, age > 18 years, ≥ 6 months continuous health plan membership, and a procedure code for orthopedic surgery. Up to five cirrhotic controls without orthopedic surgery were matched on age, gender, and cirrhosis diagnosis date. Data abstraction was performed for demographics, socioeconomics, clinical, and decompensation data. Chart review was performed for validation. Multivariable analysis estimated relative risk of decompensation., Results: Eight hundred fifty-three orthopedic surgery cases in cirrhotics were matched with 4,263 cirrhotic controls. Among the cases and matched controls, the mean age was 60.5 years, and 52.2% were female. Within 90 days after surgery, cases had more decompensation compared to matched controls (12.8% vs 4.9%). Using multivariable analysis, orthopedic surgery, a 0.5 g/dL decrease in serum albumin, and a 1-unit increase in Charlson Comorbidity Index were associated with a significant increase in decompensation within 90 days of surgery. Diabetes, chronic obstructive pulmonary disease, and chronic kidney disease were seen with increased frequency in cases vs. matched controls., Conclusions: Cirrhotics who underwent orthopedic surgery had a significant increase in hepatic decompensation within 90 days of surgery compared to matched controls. An incremental decrease in serum albumin and an incremental increase in the Charlson Comorbidity Index were significantly associated with hepatic decompensation after surgery.

Objective: To compare traditional cardiovascular (CV) risk factor management among patients with rheumatoid arthritis (RA) to that of matched non-RA controls within a large US managed care setting., Methods: Adult patients with RA and age- and sex-matched general population (general controls) or osteoarthritis (OA) controls were identified between January 1, 2007 and December 31, 2011. We compared health care utilization, measurement, treatment, and treatment target achievement of traditional CV risk factors among subgroups of CV comorbidity during 1 year of followup between RA and controls., Results: A total of 9,440 RA patients, 31,009 general controls, and 10,352 OA controls were included. The proportions with measurements (blood pressure [BP], low-density lipoprotein [LDL] cholesterol, or hemoglobin A1c ), treatment (antihypertensive, statin, or anti-diabetes mellitus medications), and treatment target achievement were slightly higher in patients with RA compared with general controls. Controlling for other factors, RA patients were more likely to have a measurement of BP (odds ratio [OR] 16.77 [95% confidence interval (95% CI) 10.01-28.08]) or LDL cholesterol (OR 1.25 [95% CI 1.13-1.39]), and to receive antihypertensive (OR 1.84 [95% CI 1.47-2.30]) or anti-diabetic medications (OR 1.26 [95% CI 1.01-1.56]) compared to general controls. RA was not associated with receiving a statin (OR 1.01 [95% CI 0.92-1.12]); however, a target LDL level was more likely to be achieved in RA compared to general controls (OR 1.27 [95% CI 1.17-1.37]) as well as target levels of BP and hemoglobin A1c . These results were consistent with results for OA controls except for a lower probability of receiving a statin in RA compared to OA., Conclusion: Traditional CV risk factors in patients with RA were not less aggressively managed compared to non-RA controls., (© 2016, American College of Rheumatology.)

Background: Controversy persists about whether certain antidepressants reduce tamoxifen's effectiveness on lowering breast cancer recurrence. We investigated whether taking tamoxifen and antidepressants (in particular, paroxetine) concomitantly is associated with an increased risk of recurrence or contralateral breast cancer., Methods: We examined 16 887 breast cancer survivors (TNM stages 0-II) diagnosed between 1996 and 2007 and treated with tamoxifen in two California health plans. Women were followed-up through December 31, 2009, for subsequent breast cancer. The main exposure was the percent of days of overlap when both tamoxifen and an antidepressant (paroxetine, fluoxetine, other selective serotonin reuptake inhibitors, tricyclics, and other classes) were used. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models with time-varying medication variables., Results: Of the 16 887 women, half (n = 8099) used antidepressants and 2946 women developed subsequent breast cancer during the 14-year study period. We did not find a statistically significant increased risk of subsequent breast cancer in women who concurrently used paroxetine and tamoxifen. For 25%, 50%, and 75% increases in percent overlap days between paroxetine and tamoxifen, hazard ratios were 1.06 (95% CI = 0.98 to 1.14, P = .09), 1.13 (95% CI = 0.98 to 1.30, P = .09), and 1.20 (95% CI = 0.97 to 1.49, P = .09), respectively, in the first year of tamoxifen treatment but were not statistically significant. Hazard ratios decreased to 0.94 (95% CI = 0.81 to 1.10, P = .46), 0.89 (95% CI = 0.66 to 1.20, P = .46), and 0.85 (95% CI = 0.54 to 1.32, P = .46) by the fifth year (all non-statistically significantly). Absolute subsequent breast cancer rates were similar among women who used paroxetine concomitantly with tamoxifen vs tamoxifen-only users. For the other antidepressants, we again found no such associations., Conclusions: Using the comprehensive electronic health records of insured patients, we did not observe an increased risk of subsequent breast cancer in women who concurrently used tamoxifen and antidepressants, including paroxetine., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Achievement of sustained virologic response (SVR) and factors associated with treatment failure in hepatitis C virus (HCV) genotype 3 have been described in tertiary and referral care settings, with rates of SVR reported to range between 72% and 89%. Fewer data exist on SVR outside of these settings., Objective: To describe rates of SVR and characterize factors associated with achievement of SVR within an integrated health care delivery system., Methods: A retrospective cohort study of genotype 3 HCV patients treated with dual therapy (pegylated interferon-alpha plus ribavirin) was conducted at Kaiser Permanente Southern California. Adult patients diagnosed with HCV and testing positive for HCV-RNA genotype 3 were identified from electronic medical records. Data were collected on patient demographics, baseline health status, and comorbid conditions. A multivariate logistic regression model was used to determine the association between baseline patient factors and SVR., Results: A total of 484 HCV genotype 3 patients met the eligibility criteria. The median age was 49 years, and 65.7% were male. Overall, 252 (52.1%) achieved SVR. Aged ≥ 45 years and male gender were associated with lower rates of SVR; cirrhosis and chronic diseases (diabetes and chronic obstructive pulmonary disease) were also associated with lower rates of SVR., Conclusions: SVR was lower in patients within an integrated care delivery system than in those in tertiary and referral centers. Males and older patients had lower rates of SVR, as well as patients with cirrhosis, diabetes, and chronic obstructive pulmonary disease.

Objective: To determine the risks associated with zoster vaccine when administered to patients taking immunosuppressant medications., Patients and Methods: Patients enrolled in 1 of 7 managed care organizations affiliated with the Vaccine Safety Datalink between January 1, 2006, and December 31, 2009, were eligible. The exposure of interest was zoster vaccination in patients with current or remote immunosuppressant drug use. The primary outcomes were disseminated varicella zoster virus (VZV) and herpes zoster in the 42 days after vaccination. Automated data were collected on immunosuppressant drugs and baseline medical conditions. A logistic regression model using inverse probability treatment weights was used to estimate the odds of developing VZV or herpes zoster., Results: A total of 14,554 individuals had an immunosuppressant medication dispensed around the time of vaccination, including 4826 with current use and 9728 with remote use. Most patients were taking low-dose corticosteroids. No cases of disseminated VZV were found in the current or remote users. The risk of herpes zoster was elevated in the 42 days after vaccination in current vs remote users (adjusted odds ratio, 2.99; 95% CI, 1.58-5.70)., Conclusion: We found that patients taking immunosuppressant medications at the time of vaccination had a modest increased risk of herpes zoster in the 42 days after vaccination. The development of herpes zoster within 42 days after vaccination suggests that this is more likely due to reactivation of latent zoster virus than dissemination of the vaccine-derived varicella virus. These findings support the current zoster vaccination guidelines., (Copyright © 2015 Mayo Foundation for Medical Education and Research. All rights reserved.)

Background: The Biologics Price Competition and Innovation Act, introduced as part of the Affordable Care Act, directed the FDA to create an approval pathway for biologic products shown to be biosimilar or interchangeable with an FDA-approved innovator drug. These biosimilars will not be chemically identical to the reference agent. Investigational studies conducted with biosimilar agents will likely provide limited real-world evidence of their effectiveness and safety. How do we best monitor effectiveness and safety of biosimilar products once approved by the FDA and used more extensively by patients?, Objective: To determine the feasibility of developing a distributed research network that will use health insurance plan and health delivery system data to detect biosimilar safety and effectiveness signals early and be able to answer important managed care pharmacy questions from both the government and managed care organizations., Methods: Twenty-one members of the AMCP Task Force on Biosimilar Collective Intelligence Systems met November 12, 2013, to discuss issues involved in designing this consortium and to explore next steps., Results: The task force concluded that a managed care biosimilars research consortium would be of significant value. Task force members agreed that it is best to use a distributed research network structurally similar to existing DARTNet, HMO Research Network, and Mini-Sentinel consortia. However, for some surveillance projects that it undertakes, the task force recognizes it may need supplemental data from managed care and other sources (i.e., a "hybrid" structure model)., Conclusions: The task force believes that AMCP is well positioned to lead the biosimilar-monitoring effort and that the next step to developing a biosimilar-innovator collective intelligence system is to convene an advisory council to address organizational governance.

To examine the risks of genital herpes and antiherpes treatment during pregnancy in relation to preterm delivery (PTD), we conducted a multicenter, member-based cohort study within 4 Kaiser Permanente regions: northern and southern California, Colorado, and Georgia. The study included 662,913 mother-newborn pairs from 1997 to 2010. Pregnant women were classified into 3 groups based on genital herpes diagnosis and treatment: genital herpes without treatment, genital herpes with antiherpes treatment, and no herpes diagnosis or treatment (unexposed controls). After controlling for potential confounders, we found that compared with being unexposed, having untreated genital herpes during first or second trimester was associated with more than double the risk of PTD (odds ratio (OR) = 2.23, 95% confidence interval (CI): 1.80, 2.76). The association was stronger for PTD due to premature rupture of membrane (OR = 3.57, 95% CI: 2.53, 5.06) and for early PTD (≤35 weeks gestation) (OR = 2.87, 95% CI: 2.22, 3.71). In contrast, undergoing antiherpes treatment during pregnancy was associated with a lower risk of PTD compared with not being treated, and the PTD risk was similar to that observed in the unexposed controls (OR = 1.11, 95% CI: 0.89, 1.38). The present study revealed increased risk of PTD associated with genital herpes infection if left untreated and a potential benefit of antiherpes medications in mitigating the effect of genital herpes infection on the risk of PTD., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Gout flares are not well documented by diagnosis codes, making it difficult to conduct accurate database studies. We implemented a computer-based method to automatically identify gout flares using natural language processing (NLP) and machine learning (ML) from electronic clinical notes., Methods: Of 16,519 patients, 1,264 and 1,192 clinical notes from 2 separate sets of 100 patients were selected as the training and evaluation data sets, respectively, which were reviewed by rheumatologists. We created separate NLP searches to capture different aspects of gout flares. For each note, the NLP search outputs became the ML system inputs, which provided the final classification decisions. The note-level classifications were grouped into patient-level gout flares. Our NLP+ML results were validated using a gold standard data set and compared with the claims-based method used by prior literatures., Results: For 16,519 patients with a diagnosis of gout and a prescription for a urate-lowering therapy, we identified 18,869 clinical notes as gout flare positive (sensitivity 82.1%, specificity 91.5%): 1,402 patients with ≥3 flares (sensitivity 93.5%, specificity 84.6%), 5,954 with 1 or 2 flares, and 9,163 with no flare (sensitivity 98.5%, specificity 96.4%). Our method identified more flare cases (18,869 versus 7,861) and patients with ≥3 flares (1,402 versus 516) when compared to the claims-based method., Conclusion: We developed a computer-based method (NLP and ML) to identify gout flares from the clinical notes. Our method was validated as an accurate tool for identifying gout flares with higher sensitivity and specificity compared to previous studies., (Copyright © 2014 by the American College of Rheumatology.)

Objective: To assess the risk of adverse fetal outcomes following exposure to individual immunosuppressive drugs in pregnant women with chronic immune-mediated diseases., Methods: Health plan data were obtained from the Tennessee Medicaid and Kaiser Permanente Northern California and Southern California claims databases, with linkage to both vital records and medical records. Women with inflammatory arthropathies, those with systemic lupus erythematosus, and those with inflammatory bowel disease who filled prescriptions for immunosuppressive treatments during pregnancy were included. Major congenital malformations, fetal deaths, and life-threatening neonatal complications were identified from the electronic data and validated with medical record review., Results: The cohort included 608 infants, including 437 with exposure to immunosuppressive drugs during the mother's pregnancy (402 during the first trimester, and 35 during the second and third trimester only) and 171 whose mothers filled prescriptions for immunosuppressive treatments before, but not during, pregnancy. There were 25 pregnancies (4.1% of the cohort) with confirmed major congenital malformations, and 10 fetal deaths (1.6% of the cohort). Among 113 preterm infants with exposures during pregnancy, 23 (20.4%) had life-threatening neonatal complications, and among 485 term infants, 10 (2.1%) had life-threatening complications. Compared to the reference group (treatment before, but not during, pregnancy), the risk ratios (RRs) for adverse fetal outcomes associated with immunosuppressive treatments (by exposure category) during pregnancy included the following: methotrexate (RR 1.39, 95% confidence interval [95% CI] 0.43-4.53), tumor necrosis factor inhibitors (RR 0.98, 95% CI 0.38-2.55), hydroxychloroquine (RR 1.33, 95% CI 0.69-2.55), and other immunosuppressive medications (RR 0.98, 95% CI 0.48-1.98)., Conclusion: In this study, there was no evidence of a large increase in risk of adverse fetal outcomes from first-trimester exposure to immunosuppressive medications, although the confidence intervals for the risk ratios were wide. Further studies will be needed as use of these medications increases over time., (Copyright © 2014 by the American College of Rheumatology.)

Background: Primary nonadherence to a medication occurs when a drug is prescribed but the patient fails to pick the prescription up from the pharmacy. Managed care organizations that provide integrated care using electronic medical records (EMR) are an ideal setting to study primary nonadherence. , Objective: To identify patient and provider characteristics that are significantly associated with primary nonadherence to statin medications compared with a population of patients who picked up their first statin order.  , Methods: This was a retrospective cohort study of patients with a new statin prescription. Patients with a new order for a statin prescription between December 1, 2009, and February 28, 2010, were eligible. A statin order was considered new if the patient had no statin prescriptions in the previous 12 months. Study participants were 24 years and older with 12 months of continuous membership prior to the statin order. Patients were defined as primary nonadherent if they did not pick up their new prescription within 90 days. Descriptive and multivariate (conditional logistic regression) analyses of patients who did and did not pick up their new statin prescriptions were performed using demographic and socioeconomic information, health care utilization, health conditions, medical benefits, and prescriber characteristics.  , Results: A total of 19,826 patients with a new statin order that met all of the inclusion and exclusion criteria was identified. Of these, 3,049 patients (15.4%) did not pick up their statin prescriptions within 90 days of the order date. Primary nonadherent patients tended to be younger (55 vs. 57 years, P  less than  0.001) and healthier, with fewer comorbid conditions (Charlson Comorbidity Index ≥ 1, 42.2% vs. 52.3%, P  less than  0.001), lower rates of hospitalizations (7.2% vs. 12.0%, P  less than  0.001), fewer concurrent prescriptions (3 vs. 4, P  less than  0.001) and fewer clinic (4 vs. 5, P  less than  0.001) and emergency department visits (18.2% vs. 24.6%, P  less than  0.001) in the prior year than adherent patients. Although the multivariate model agreed well with the observed data, the characteristics included had a poor ability to predict primary nonadherence (c-statistic = 0.603).  , Conclusion: Primary nonadherence has been recognized as a significant problem for many years, and electronic health records are allowing researchers to investigate the extent of the problem. In this study, almost 1 in 6 patients (15.4%) failed to pick up their new statin order within 90 days. However, clinical and demographic information available in electronic health care data may not be useful in predicting primary nonadherence. New methods and interventions need to be developed to improve primary adherence.

Objectives: To identify self-reported reasons for not filling a new prescription for statin therapy., Study Design: A cross-sectional telephone survey., Methods: Potential participants were identified from a randomized, controlled trial among Kaiser Permanente Southern California (KPSC) members aged >24 years with no record of redeeming a new statin medication, defined as primary nonadherence. Among 1158 eligible patients, 98 were randomly selected and participated in a semi-structured telephone interview that included questions on whether the respondent redeemed their statin prescription, why the patient may have chosen not to use a KPSC pharmacy, reasons for not filling the prescription, use of non-prescription products for elevated cholesterol levels, and questions to assess health literacy., Results: At 12 weeks post-index prescription date, 75% of 98 respondents reported not filling their new statin prescription, 20% reported picking it up from a non-KPSC pharmacy, 4% had already picked up the prescription at a KPSC pharmacy, and 1% did not know if it had been filled. The 3 most commonly cited reasons for primary nonadherence were general concerns about taking the medication (63%), a decision to try lifestyle modifications (63%), and fear of side effects (53%). A substantial proportion (33%) of respondents reported inadequate health literacy., Conclusions: These data suggest the need for interventions that address patients' negative perceptions of statins while emphasizing the benefits of statin therapy for reducing cardiovascular morbidity and mortality in formats accessible to those with limited health literacy.

Objectives: To measure primary nonadherence (PNA) rates for 10 therapeutic drug groups and identify factors associated with PNA to chronic and acute medications., Study Design: Retrospective cohort study., Methods: New prescriptions written in an integrated healthcare system for study drugs were identified between December 1, 2009, and February 28, 2010. PNA was defined as the failure to fill a prescription within 14 days of when it was written. PNA rates were calculated by drug group and descriptive statistics were performed. Multivariable logistic regression was used to identify significant patient, provider, and prescription characteristics associated with PNA. Results were stratified by acute versus chronic treatment., Results: A total of 569,095 new prescriptions were written during the 3-month period. Across all drug groups, the PNA rate was 9.8%. PNA rates for individual drug groups varied and were highest for osteoporosis medications (22.4%) and antihyperlipidemics (22.3%). Patients who filled at least 1 prescription in the prior year (odds ratio [OR], 95% confidence interval [CI] for acute = 0.06 [0.06-0.07], for chronic = 0.11 [0.10-0.12]) or had a prescription for a symptomatic disease (OR = 0.51 [0.48-0.53]) were more likely to fill their prescription. Patients were more likely to be primary nonadherent if they were black (OR acute = 1.30 [1.25-1.36], chronic = 1.26 [1.18-1.33]) or treatment-naive to therapy (OR acute = 2.52 [2.36-2.7], chronic=1.07 [1.03-1.12])., Conclusions: Overall PNA was 9.8% but individual PNA rates varied by therapeutic drug group. Factors of PNA were mostly consistent across drug groups, but some depended on whether the treatment was acute or chronic.

Objective: An observational safety study of the quadrivalent human papillomavirus vaccine (HPV4) in women was conducted. This report presents findings from autoimmune surveillance. Design.  Subjects were followed for 180days after each HPV4 dose for new diagnoses of 16 prespecified autoimmune conditions., Setting: Two managed care organizations in California. Subjects.  Number of 189,629 women who received ≥1 dose of HPV4 between 08/2006 and 03/2008., Outcome: Potential new-onset autoimmune condition cases amongst HPV4 recipients were identified by electronic medical records. Medical records of those with ≥12-month health plan membership prior to vaccination were reviewed by clinicians to confirm the diagnosis and determine the date of disease onset. The incidence of each autoimmune condition was estimated for unvaccinated women at one study site using multiple imputations and compared with that observed in vaccinated women. Incidence rate ratios (IRR) were calculated. Findings were reviewed by an independent Safety Review Committee (SRC)., Results: Overall, 1014 potential new-onset cases were electronically identified; 719 were eligible for case review; 31-40% were confirmed as new onset. Of these, no cluster of disease onset in relation to vaccination timing, dose sequence or age was found for any autoimmune condition. None of the estimated IRR was significantly elevated except Hashimoto's disease [IRR=1.29, 95% confidence interval: 1.08-1.56]. Further investigation of temporal relationship and biological plausibility revealed no consistent evidence for a safety signal for autoimmune thyroid conditions. The SRC and the investigators identified no autoimmune safety concerns in this study., Conclusions: No autoimmune safety signal was found in women vaccinated with HPV4., (© 2011 The Association for the Publication of the Journal of Internal Medicine.)

Introduction: Black men have a higher incidence of advanced stage at diagnosis and mortality from prostate cancer than do men in other racial groups. Given that androgen-deprivation therapy (ADT) is one of the mainstays of treatment for advanced prostate cancer, we investigated the development of biochemical failure, or recurrence of elevated prostate-specific antigen (PSA) levels, among different races in men receiving ADT., Methods: Patients with prostate cancer who received ADT in the Kaiser Permanente Southern California Cancer Registry between January 2003 and December 2006 were eligible for inclusion in our study. Patients who had prior treatment for their cancer with surgery or radiation were excluded. Treatment failure was defined as an increase in PSA of >2 ng/mL from PSA nadir, with no subsequent decrease in PSA. We compared the biochemical failure rate in white patients to those in black, Hispanic, and Asian/other patients. The Cox proportional hazards regression model was used to estimate hazards ratios., Results: Our study population consisted of 681 patients: 416 (61%) were white; 107 (16%) were black; 107 (16%) were Hispanic; and 51 (7%) were Asian or another race. After we controlled for all demographic variables and for variables related to prostate cancer, blacks were the only group with a lower risk of treatment failure compared with whites. The hazard ratios for treatment failure were as follows: black versus white, 0.66 (p = 0.03); Hispanic versus white, 1.00 (p = 0.8); Asian/other race versus white, 1.5 (p = 0.1). In this multivariate analysis, pretreatment PSA level and cancer stage were the only other variables associated with a higher risk of treatment failure., Conclusion: Among patients receiving ADT as primary monotherapy for prostate cancer, blacks may have a lower rate of biochemical failure compared with whites. Although the etiology of this finding is unclear, it suggests the possibility that prostate cancer in black men may be more androgen sensitive than it is in white men.

Objective: In April 2005, the US Food and Drug Administration issued a public health advisory warning to health care clinicians about the cardiovascular (CV) safety of nonsteroidal anti-inflammatory drugs (NSAIDs). Although the warning about cyclooxygenase-2 selective NSAIDs was anticipated, little data exists about the CV safety of nonselective NSAIDs. We analyzed data from a group of NSAID users to determine if specific nonselective agents were associated with an increased risk of myocardial infarctions (MIs) and sudden cardiac death (SCD)., Design: A nested case-control design was used to study NSAID users ages 18 to 84 years. Cases were defined by a hospital admission for MI or an out-of-hospital SCD. Study control subjects were matched for age, sex, current Kaiser Permanente membership, and geographic location (Northern or Southern California). Odds ratios (OR) were estimated using conditional logistic regression., Results: Our base population included 1,394,764 NSAID users. From this population we identified 8143 cases and 31,496 matched study control subjects. The median time to event was <100 days for all NSAIDs. Two nonselective NSAIDs were associated with increased odds of adverse CV outcomes: indomethacin (OR, 1.27; 95% confidence interval, 1.04-1.56) and naproxen (OR, 1.14; 95% confidence interval, 1.00-1.30)., Conclusion: Our results suggest that some nonselective NSAIDs are associated with an increased risk of MI and SCD. We found the increased risk to be small compared with the risk associated with rofecoxib. Cardiovascular events occurred early in therapy. Caution is warranted with some nonselective NSAIDs, especially those for which other studies have found evidence of risk.

Objective: To evaluate the safety and effectiveness of a simvastatin-to-lovastatin therapeutic conversion program., Study Design: Observational database study of a therapeutic conversion in members of the Northern and Southern California regions of Kaiser Permanente, using a pretest/posttest design., Methods: All patients actively converted from simvastatin to lovastatin between April 1, 2002, and March 31, 2003, were identified for inclusion in the analysis. The conversion from simvastatin to lovastatin was based on an equipotent dose ratio of 1 mg of simvastatin to 2 mg of lovastatin. Electronic prescription record and laboratory data were collected for converted patients beginning 365 days before changing therapy through June 30, 2003. The primary effectiveness end point was a comparison of the preconversion and postconversion low-density lipoprotein cholesterol (LDL-C) levels. Safety end points included an analysis of preconversion and postconversion alanine aminotransferase (ALT) tests and creatine kinase values., Results: A total of 33,318 converted patients met criteria for inclusion in the analysis. The mean LDL-C was lowered from 110.9 to 108.4 mg/dL (P < .001) following the conversion to lovastatin. The percentage of patients with serum ALT levels greater than 3 times the upper limit of normal (ULN) was similar before (0.7%) and after (0.6%) conversion from simvastatin to lovastatin. Creatine kinase elevations greater then 10 times the ULN occurred at similar rates before and after the conversion., Conclusions: Overall, patients had an improvement in their lipid profile without evidence of hepatic or muscle enzyme elevations. Appropriately selected patients can be safely and effectively converted from simvastatin to lovastatin.