Recommendations for outcome measurement for deprescribing intervention studies.

Interpreting results from deprescribing interventions to generate actionable evidence is challenging owing to inconsistent and heterogeneous outcome definitions between studies. We sought to characterize deprescribing intervention outcomes and recommend approaches to measure outcomes for future studies. A scoping literature review focused on deprescribing interventions for polypharmacy and informed a series of expert panel discussions and recommendations. Twelve experts in deprescribing research, policy, and clinical practice interventions participating in the Measures Workgroup of the US Deprescribing Research Network sought to characterize deprescribing outcomes and recommend approaches to measure outcomes for future studies. The scoping review identified 125 papers reflecting 107 deprescribing studies. Common outcomes included medication discontinuation, medication appropriateness, and a broad range of clinical outcomes potentially resulting from medication reduction. Panel recommendations included clearly defining clinically meaningful medication outcomes (e.g., number of chronic medications, dose reductions), ensuring adequate sample size and follow-up time to capture clinical outcomes resulting from medication discontinuation (e.g., quality of life [QOL]), and selecting appropriate and feasible data sources. A new conceptual model illustrates how downstream clinical outcomes (e.g., reduction in falls) should be interpreted in the context of initial changes in medication measures (e.g., reduction in mean total medications). Areas needing further development include implementation outcomes specific to deprescribing interventions and measures of adverse drug withdrawal events. Generating evidence to guide deprescribing is essential to address patient, caregiver, and clinician concerns about the benefits and harms of medication discontinuation. This article provides recommendations and an initial conceptual framework for selecting and applying appropriate intervention outcomes to support deprescribing research.

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

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

Methods to identify dementia in the electronic health record: Comparing cognitive test scores with dementia algorithms.

BACKGROUND: Epidemiologic studies often use diagnosis codes to identify dementia outcomes. It remains unknown to what extent cognitive screening test results add value in identifying dementia cases in big data studies leveraging electronic health record (EHR) data. We examined test scores from EHR data and compared results with dementia algorithms. METHODS: This retrospective cohort study included patients 60+ years of age from Kaiser Permanente Washington (KPWA) during 2013-2018 and the Veterans Health Affairs (VHA) during 2012-2015. Results from the Mini Mental State Examination (MMSE) and the Saint Louis University Mental Status Examination (SLUMS) cognitive screening exams, were classified as showing dementia or not. Multiple dementia algorithms were created using combinations of diagnosis codes, pharmacy records, and specialty care visits. Correlations between test scores and algorithms were assessed. RESULTS: 3,690 of 112,917 KPWA patients and 2,981 of 102,981 VHA patients had cognitive test results in the EHR. In KPWA, dementia prevalence ranged from 6.4%-8.1% depending on the algorithm used and in the VHA, 8.9%-12.1%. The algorithm which best agreed with test scores required ≥2 dementia diagnosis codes in 12 months; at KPWA, 14.8% of people meeting this algorithm had an MMSE score, of whom 65% had a score indicating dementia. Within VHA, those figures were 6.2% and 77% respectively. CONCLUSIONS: Although cognitive test results were rarely available, agreement was good with algorithms requiring ≥2 dementia diagnosis codes, supporting the accuracy of this algorithm. IMPLICATIONS: These scores may add value in identifying dementia cases for EHR-based research studies.

Systematic Multi-Domain Alzheimer's Risk Reduction Trial (SMARRT): Study Protocol.

This article describes the protocol for the Systematic Multi-domain Alzheimer's Risk Reduction Trial (SMARRT), a single-blind randomized pilot trial to test a personalized, pragmatic, multi-domain Alzheimer's disease (AD) risk reduction intervention in a US integrated healthcare delivery system. Study participants will be 200 higher-risk older adults (age 70-89 years with subjective cognitive complaints, low normal performance on cognitive screen, and ≥ two modifiable risk factors targeted by our intervention) who will be recruited from selected primary care clinics of Kaiser Permanente Washington, oversampling people with non-white race or Hispanic ethnicity. Study participants will be randomly assigned to a two-year Alzheimer's risk reduction intervention (SMARRT) or a Health Education (HE) control. Randomization will be stratified by clinic, race/ethnicity (non-Hispanic white versus non-white or Hispanic), and age (70-79, 80-89). Participants randomized to the SMARRT group will work with a behavioral coach and nurse to develop a personalized plan related to their risk factors (poorly controlled hypertension, diabetes with evidence of hyper or hypoglycemia, depressive symptoms, poor sleep quality, contraindicated medications, physical inactivity, low cognitive stimulation, social isolation, poor diet, smoking). Participants in the HE control group will be mailed general health education information about these risk factors for AD. The primary outcome is two-year cognitive change on a cognitive test composite score. Secondary outcomes include: 1) improvement in targeted risk factors, 2) individual cognitive domain composite scores, 3) physical performance, 4) functional ability, 5) quality of life, and 6) incidence of mild cognitive impairment, AD, and dementia. Primary and secondary outcomes will be assessed in both groups at baseline and 6, 12, 18, and 24 months.

Prevalence of prescription opioid use disorder among chronic opioid therapy patients after health plan opioid dose and risk reduction initiatives.

BACKGROUND: No studies have assessed the comparative effectiveness of guideline-recommended interventions to reduce risk of prescription opioid use disorder among chronic opioid therapy (COT) patients. We compared the prevalence of prescription opioid use disorder among COT patients from intervention clinics that had implemented opioid dose and risk reduction initiatives for more than 4 years relative to control clinics that had not. METHODS: After a healthcare system in Washington State implemented interventions to reduce opioid dose and risks, we surveyed 1588 adult primary care COT patients to compare the prevalence of prescription opioid use disorder among COT patients from the intervention and control clinics. Intervention clinics managed COT patients at lower COT doses and with more consistent use of risk reduction practices. Control clinics cared for similar COT patients but prescribed higher opioid doses and used COT risk reduction practices inconsistently. Prescription opioid use disorder was assessed with the Psychiatric Research Interview for Substance and Mental Disorders. RESULTS: The prevalence of prescription opioid use disorder was 21.5% (95% CI=18.9% to 24.4%) among COT patients in the intervention clinics and 23.9% (95% CI=20.5% to 27.6%) among COT patients in the control clinics. The adjusted relative risk of prescription opioid use disorder was 1.08 (95% CI=0.89, 1.32) among the control clinic patients relative to the intervention clinic patients. CONCLUSIONS: Long-term implementation of opioid dose and risk reduction initiatives was not associated with lower rates of prescription opioid use disorder among prevalent COT patients. Extreme caution should be exercised by clinicians considering COT for patients with chronic non-cancer pain until benefits of this treatment and attendant risks are clarified.

Risk of Alzheimer's disease or dementia following a cancer diagnosis.

OBJECTIVE: We evaluated dementia and Alzheimer's disease (AD) risks after a cancer diagnosis in a population-based prospective cohort, the Adult Changes in Thought (ACT) study. METHODS: We followed community-dwelling people aged ≥65 years without dementia at study entry for incident dementia and AD from 1994-2015. We linked study data with cancer registry data and categorized cancer diagnoses as prevalent (diagnosed before ACT study enrollment) or incident (diagnosed during follow-up). We used Cox regression to estimate cause-specific hazard ratios (HRs) with 95% confidence intervals (CIs) for dementia or AD risk comparing people with a cancer diagnosis to people without cancer. We conducted sensitivity analyses restricted to people surviving beyond age 80, and stratified by cancer stage, type, and whether the cancer was smoking-related. RESULTS: Among 4,357 people, 756 (17.4%) had prevalent cancer; 583 (13.4%) developed incident cancer, 1,091 (25.0%) developed dementia, and 877 (20.1%) developed AD over a median 6.4 years (34,482 total person-years) of follow-up. Among complete cases (no missing covariates) with at least one follow-up assessment, adjusted HRs for dementia following prevalent and incident cancer diagnoses were 0.92 (95%CI: 0.76, 1.11) and 0.87 (95%CI: 0.64, 1.04), compared to no cancer history. HRs for AD were 0.95 (95%CI: 0.77, 1.17) for prevalent cancer and 0.73 (95%CI: 0.55, 0.96) for incident cancer. In sensitivity analyses, prevalent late-stage cancers were associated with reduced risks of dementia (HR = 0.51, 95%CI: 0.30, 0.89) and AD (HR = 0.50, 95%CI: 0.27, 0.94). When limited to people who survived beyond age 80, incident cancers were still associated with reduced AD risk (HR = 0.69, 95%CI: 0.51, 0.92). CONCLUSIONS: Our results do not support an inverse association between prevalent cancer diagnoses, which were primarily early-stage, less aggressive cancers, and risk of dementia or AD. A reduced risk of AD following an incident cancer diagnosis is biologically plausible but may reflect selective mortality.

Predicting 2-Year Risk of Developing Pneumonia in Older Adults without Dementia.

OBJECTIVES: To develop three prognostic indices of varying degree of required detail for 2-year pneumonia risk in older adults. DESIGN: Retrospective cohort study. SETTING: Group Health (GH), an integrated healthcare delivery system. PARTICIPANTS: Community-dwelling dementia-free individuals aged 65 and older who had been GH members for at least 2 years before start of follow-up and were enrolled in the Adult Changes in Thought study (N = 3,375; development cohort, n = 2,250; validation cohort, n = 1,125. MEASUREMENTS: Potential pneumonia risk factors were identified from questionnaire data and interviewer assessments of functional status, medical history, smoking and alcohol use, cognitive function, personal care, and problem solving. Risk factors were also identified based on physical measures such as grip strength and gait speed and administrative database information on comorbid illnesses, laboratory tests, and prescriptions dispensed. Incident community-acquired pneumonia was defined presumptively from administrative data and validated using medical record review. RESULTS: Participants (59% female) contributed 12,998 visits at which risk factors were assessed; 642 pneumonia events were observed during follow-up. Age, sex, chronic obstructive pulmonary disease, congestive heart failure, body mass index, and use of inhaled or oral corticosteroids were critical predictors in all prognostic indices. A risk score based on these seven variables, information on which is commonly available in electronic medical records (EMRs), had equal or better performance (c-index = 0.69 in the validation cohort) than scores including more-detailed data such as functional status. CONCLUSION: Data commonly available in EMRs can stratify older adults into groups with varying subsequent 2-year pneumonia risk.

Anesthesia Exposure and Risk of Dementia and Alzheimer's Disease: A Prospective Study.

OBJECTIVES: To evaluate the associations between anesthesia and dementia or Alzheimer's disease (AD) risk using prospectively collected data. DESIGN: Cohort study. PARTICIPANTS: Community-dwelling members of the Adult Changes in Thought cohort aged 65 and older and free of dementia at baseline (N = 3,988). MEASUREMENTS: Participants self-reported all prior surgical procedures with general or neuraxial (spinal or epidural) anesthesia at baseline and reported new procedures every 2 years. People undergoing high-risk surgery with general anesthesia, other surgery with general anesthesia, and other surgery with neuraxial anesthesia exposures were compared with those with no surgery and no anesthesia. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for dementia and AD associated with time-varying lifetime and recent (past 5 years) anesthesia exposures. RESULTS: At baseline, 254 (6%) people reported never having anesthesia; 248 (6%) had had one or more high-risk surgeries with general anesthesia, 3,363 (84%) had had one or more other surgeries with general anesthesia, and 123 (3%) had had one or more surgeries with neuraxial anesthesia. High-risk surgery with general anesthesia was not associated with greater risk of dementia (HR = 0.86, 95% CI = 0.58-1.28) or AD (HR = 0.95, 95% CI = 0.61-1.49) than no history of anesthesia. People with any history of other surgery with general anesthesia had a lower risk of dementia (HR = 0.63, 95% CI = 0.46-0.85) and AD (HR = 0.65, 95% CI = 0.46-0.93) than people with no history of anesthesia. There was no association between recent anesthesia exposure and dementia or AD. CONCLUSION: Anesthesia exposure was not associated with of dementia or AD in older adults.

Hypertensive disorders first identified in pregnancy increase risk for incident prehypertension and hypertension in the year after delivery.

BACKGROUND: Hypertensive disorders in pregnancy, including preeclampsia/eclampsia (PE/E) are associated with long-term cardiovascular disease risk. However, little is known about the effect of these conditions on risk for prehypertension (preHTN) or hypertension (HTN) in the early years after delivery. METHODS: The cohort consisted of women who had prenatal care and delivered a live singleton neonate at Kaiser Permanente Bellflower Medical Center in 2005-2010. Women with prepregnancy HTN or preHTN were excluded from analysis. Multivariable robust Poisson regression models were used to assess associations between any hypertensive disorder or PE/E and development of preHTN/HTN in the year after delivery, adjusted for maternal age, race/ethnicity, parity, smoking, prepregnancy weight status, gestational weight gain, gestational diabetes, and gestational age. RESULTS: Among 5960 women who were normotensive prior to pregnancy, 358 (6.0%) developed a hypertensive disorder in pregnancy, of whom 215 (60.1%) had PE/E. Overall, 63 (1.1%) developed HTN and 902 (15.1%) preHTN in the year after delivery. After accounting for all potential confounders, women with a hypertensive disorder in pregnancy and those with PE/E were 2.36 (95% confidence interval: 1.97-2.83) and 2.48 (95% confidence interval: 1.99-3.11) times as likely, respectively, to develop preHTN/HTN in the year after delivery as those without pregnancy-related HTN. Results were similar with and without adjustment for gestational diabetes. CONCLUSION: Our findings highlight the need for prospective studies aimed at determining whether early postpartum screening and improved follow-up of women with hypertensive disorders first identified in pregnancy may prevent future cardiovascular disease.

Prevalence, trends, and patterns of use of antidiabetic medications among pregnant women, 2001-2007.

OBJECTIVE: To describe the prevalence, trends, and patterns in use of antidiabetic medications to treat hyperglycemia and insulin resistance before and during pregnancy in a large U.S. cohort of insured pregnant women. METHODS: Pregnancies resulting in live births were identified (N=437,950) from 2001 to 2007 among 372,543 females 12-50 years of age at delivery from 10 health maintenance organizations participating in the Medication Exposure in Pregnancy Risk Evaluation Program. Information for these descriptive analyses, including all antidiabetic medications dispensed during this period, was extracted from electronic health records and newborn birth certificates. RESULTS: A little more than 1% (1.21%) of deliveries were to women dispensed antidiabetic medication in the 120 days before pregnancy. Use of antidiabetic medications before pregnancy increased from 0.66% of deliveries in 2001 to 1.66% of deliveries in 2007 (P<.001) because of an increase in metformin use. Most women using metformin before pregnancy had a diagnosis code for polycystic ovaries or female infertility (67.2%), whereas only 13.6% had a diagnosis code for diabetes. The use of antidiabetic medications during the second or third trimester of pregnancy increased from 2.8% of deliveries in 2001 to 3.6% in 2007 (P<.001). Approximately two thirds (68%) of women using metformin before pregnancy did not use any antidiabetic medications during pregnancy. CONCLUSIONS: Antidiabetic medication use before and during pregnancy increased from 2001 to 2007, possibly because of increasing prevalence of gestational diabetes mellitus, type 1 and type 2 diabetes, and other conditions associated with insulin resistance. LEVEL OF EVIDENCE: III.

Amount of leisure-time physical activity and risk of nonfatal myocardial infarction.

PURPOSE: To investigate the shape of the relation between amount of leisure-time physical activity (LTPA) and myocardial infarction (MI) risk. METHODS: Data were from a case-control study in a Washington State health maintenance organization, 1986 to 2002. Participants had no prior cardiovascular disease and good self-reported health before selection. Telephone interviews asked 697 nonfatal MI cases and 3,397 control subjects about 26 types of LTPA. Models adjusted for age, sex, year, treated hypertension, family history of heart disease, smoking, alcohol, aspirin, race, retirement, income, and education. RESULTS: Some LTPA was reported by 90% of control subjects and 84% of cases. Compared with no LTPA, participation in LTPA was associated with lower risk of MI (adjusted odds ratio [OR] = 0.67, 95% confidence interval [CI]: 0.52, 0.86). Among active participants, LTPA time was associated with risk of MI (OR = 0.66 for high versus low quartile, 95% CI: 0.51, 0.86). Risk of MI decreased with increasing total or nonstrenuous LTPA time up to the median, beyond which we could not detect an association between LTPA time and MI risk. CONCLUSIONS: Time engaged in LTPA, even nonstrenuous LTPA, was associated with lower risk of MI, and the shape of this relationship was nonlinear.

Cimetidine use and the risk for prostate cancer: results from the VITAL cohort study.

PURPOSE: The histamine-2 (H(2)) blocker cimetidine may alter androgen, zinc, and prolactin levels, which could alter prostate cancer risk. Increased risk for men filling more than 20 cimetidine prescriptions was reported previously. We examined the association between cimetidine use and prostate cancer risk in a cohort in western Washington State. METHODS: Participants were 33,506 men, 50 to 76 years old, enrolled in the VITamins And Lifestyle cohort (VITAL). H(2)-blocker use during the prior 10 years was self-reported through baseline questionnaire between October 2000 and December 2002. Men were followed up for subsequent prostate cancer by linkage to the Surveillance, Epidemiology and End Results cancer registry. We identified 548 incident invasive prostate cancer cases diagnosed from baseline to December 31, 2003. RESULTS: Overall, no association between ever use of cimetidine or years of cimetidine use and prostate cancer risk was observed. However, daily cimetidine use for 10 years was associated with increased risk (relative risk, 2.35; 95% confidence interval, 1.05-5.26) compared with nonuse of any H(2) blockers. Use of other H(2) blockers was not associated with prostate cancer. CONCLUSIONS: Additional studies are needed to determine whether long-term daily cimetidine use is associated with increased prostate cancer risk in other populations, and if so, the reason for this association.

Risk of epithelial ovarian cancer in relation to use of antidepressants, benzodiazepines, and other centrally acting medications.

OBJECTIVE: An increased risk of ovarian cancer among users of antidepressants and benzodiazepines has been observed in some but not all prior studies. We examined these associations in a population-based case-control study. METHODS: We identified 314 members of a health maintenance organization (HMO) who were diagnosed with epithelial ovarian cancer between 1981 and 1997, were aged 35-79 years at diagnosis, and had at least 4 years of HMO membership. Up to four controls were selected for each case (n = 790), matched on age, calendar year, and length of HMO membership. Information concerning past medication use was obtained from the computerized pharmacy database, established in 1977. RESULTS: Cases were slightly less likely than controls to have filled two antidepressant prescriptions (primarily for doxepin, amitriptyline, or imipramine) in any 6-month period prior to a reference date set 1.5 years before diagnosis (conditional odds ratio (OR) 0.71, 95% confidence interval (CI) 0.47-1.1), or to have used an antidepressant continuously for 6 months or longer (OR 0.64, 95% CI 0.36-1.1). Cases were less likely than controls to have filled two benzodiazepine prescriptions in 6 months (OR 0.70, 95% CI 0.47-1.0) or to have used benzodiazepines continuously for 6 months or longer (OR 0.53, 95% Cl 0.15-1.9). CONCLUSIONS: Our findings suggest that there is not an increased risk of ovarian cancer in women who have taken some types of antidepressants or benzodiazepines.