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1.  The Prevalence and Trends of Antiviral Medication Use during Pregnancy in the U.S. A population-based study of 664,297 deliveries in 2001-2007 
Maternal and child health journal  2014;18(1):10.1007/s10995-013-1234-9.
To evaluate the prevalence, trends, timing and duration of exposure to antiviral medications during pregnancy within a US cohort of pregnant women and to evaluate the proportion of deliveries with a viral infection diagnosis among women given antiviral medication during pregnancy.
Live-born deliveries between 2001 and 2007, to women aged 15 to 45 years, were included from the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP), a collaborative research program between the U.S. Food and Drug Administration and eleven health plans. They were evaluated for prevalence, timing, duration, and temporal trends of exposure to antiviral medications during pregnancy. We also calculated the proportion of deliveries with a viral infection diagnosis among those exposed to antiviral medications.
Among 664,297 live births, the overall prevalence of antiviral exposure during pregnancy was 4% (n=25,155). Between 2001 and 2007, antiviral medication exposure during pregnancy doubled from 2.5% to 5%. The most commonly used antiviral medication was acyclovir, with 3% of the deliveries being exposed and most of the exposure occurring after the 1st trimester. Most deliveries exposed to antiviral medications were exposed for less than 30 days (2% of all live births). Forty percent of the women delivering an infant exposed to antiviral medications had a herpes diagnosis.
Our findings highlight the increased prevalence of women delivering an infant exposed to antiviral medications over time. These findings support the need for large, well-designed studies to assess the safety and effectiveness of these medications during pregnancy.
PMCID: PMC3776000  PMID: 23420306
2.  A Critical Review of Methods to Evaluate the Impact of FDA Regulatory Actions 
Pharmacoepidemiology and drug safety  2013;22(9):10.1002/pds.3480.
To conduct a synthesis of the literature on methods to evaluate the impacts of FDA regulatory actions, and identify best practices for future evaluations.
We searched MEDLINE for manuscripts published between January 1948 and August 2011 that included terms related to FDA, regulatory actions, and empirical evaluation; the review additionally included FDA-identified literature. We used a modified Delphi method to identify preferred methodologies. We included studies with explicit methods to address threats to validity, and identified designs and analytic methods with strong internal validity that have been applied to other policy evaluations.
We included 18 studies out of 243 abstracts and papers screened. Overall, analytic rigor in prior evaluations of FDA regulatory actions varied considerably; less than a quarter of studies (22%) included control groups. Only 56% assessed changes in the use of substitute products/services, and 11% examined patient health outcomes. Among studies meeting minimal criteria of rigor, 50% found no impact or weak/modest impacts of FDA actions and 33% detected unintended consequences. Among those studies finding significant intended effects of FDA actions, all cited the importance of intensive communication efforts. There are preferred methods with strong internal validity that have yet to be applied to evaluations of FDA regulatory actions.
Rigorous evaluations of the impact of FDA regulatory actions have been limited and infrequent. Several methods with strong internal validity are available to improve trustworthiness of future evaluations of FDA policies.
PMCID: PMC3825208  PMID: 23847020
FDA; Regulatory Actions; Evaluation Methodology
3.  Methods of linking mothers and infants using health plan data for studies of pregnancy outcomes 
Research on medication safety in pregnancy often utilizes health plan and birth certificate records. This study discusses methods used to link mothers with infants, a crucial step in such research.
We describe how 8 sites participating in the Medication Exposure in Pregnancy Risk Evaluation Program created linkages between deliveries, infants and birth certificates for the 2001–2007 birth cohorts. We describe linkage rates across sites and, for two sites, we compare the characteristics of populations linked using different methods.
Of 299,260 deliveries, 256,563 (86%; range by site, 74–99%) could be linked to infants using a deterministic algorithm. At two sites, using birth certificate data to augment mother-infant linkage increased the representation of mothers who were Hispanic or non-white, younger, Medicaid recipients, or had low educational level. A total of 236,460 (92%; range by site, 82–100%) deliveries could be linked to a birth certificate.
Tailored approaches enabled linking most deliveries to infants and to birth certificates, even when data systems differed. The methods used may affect the composition of the population identified. Linkages established with such methods can support sound pharmacoepidemiology studies of maternal drug exposure outside the context of a formal registry.
PMCID: PMC3707923  PMID: 23596095
Birth Certificates; Medicaid; Pregnancy Outcome/epidemiology; Medical Record Linkage
4.  Validation of an Algorithm to Estimate Gestational Age in Electronic Health Plan Databases 
To validate an algorithm that uses delivery date and diagnosis codes to define gestational age at birth in electronic health plan databases.
Using data from 225,384 live born deliveries among women aged 15–45 years in 2001–2007 within 8 of the 11 health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program, we compared 1) the algorithm-derived gestational age versus the “gold-standard” gestational age obtained from the infant birth certificate files; and 2) the prenatal exposure status of two antidepressants (fluoxetine and sertraline) and two antibiotics (amoxicillin and azithromycin) as determined by the algorithm-derived versus the gold-standard gestational age.
The mean algorithm-derived gestational age at birth was lower than the mean obtained from the birth certificate files among singleton deliveries (267.9 versus 273.5 days) but not among multiple-gestation deliveries (253.9 versus 252.6 days). The algorithm-derived prenatal exposure to the antidepressants had a sensitivity and a positive predictive value (PPV) of ≥95%, and a specificity and a negative predictive value (NPV) of almost 100%. Sensitivity and PPV were both ≥90%, and specificity and NPV were both >99% for the antibiotics.
A gestational age algorithm based upon electronic health plan data correctly classified medication exposure status in most live born deliveries, but misclassification may be higher for drugs typically used for short durations.
PMCID: PMC3644383  PMID: 23335117
algorithm; database; gestational age; maternal exposure; pregnancy; validation studies
5.  Prevalence and trends in the use of antipsychotic medications during pregnancy in the U.S., 2001–2007: A population-based study of 585,615 deliveries 
Archives of women's mental health  2013;16(2):149-157.
To estimate the prevalence of and temporal trends in prenatal antipsychotic medication use within a cohort of pregnant women in the U.S.
We identified live born deliveries to women aged 15–45 years in 2001–2007 from 11 U.S. health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). We ascertained prenatal exposure to antipsychotics from health plan pharmacy dispensing files, gestational age from linked infant birth certificate files, and ICD-9-CM diagnosis codes from health plan claims files. We calculated the prevalence of prenatal use of atypical and typical antipsychotics according to year of delivery, trimester of pregnancy, and mental health diagnosis.
Among 585,615 qualifying deliveries, 4,223 (0.72%) were to women who received an atypical antipsychotic and 548 (0.09%) were to women receiving a typical antipsychotic any time from 60 days before pregnancy through delivery. There was a 2.5-fold increase in atypical antipsychotic use during the study period, from 0.33% (95% confidence interval: 0.29%, 0.37%) in 2001 to 0.82% (0.76%, 0.88%) in 2007, while the use of typical antipsychotics remained stable. Depression was the most common mental health diagnosis among deliveries to women with atypical antipsychotic use (63%), followed by bipolar disorder (43%) and schizophrenia (13%).
The number and proportion of pregnancies exposed to atypical antipsychotics has increased dramatically in recent years. Studies are needed to examine the comparative safety and effectiveness of these medications relative to other therapeutic options in pregnancy.
PMCID: PMC3715880  PMID: 23389622
Antipsychotics; database; pregnancy; prevalence
6.  Validity of Health Plan and Birth Certificate Data for Pregnancy Research 
To evaluate the validity of health plan and birth certificate data for pregnancy research.
A retrospective study was conducted using administrative and claims data from 11 U.S. health plans, and corresponding birth certificate data from state health departments. Diagnoses, drug dispensings, and procedure codes were used to identify infant outcomes (cardiac defects, anencephaly, preterm birth, and neonatal intensive care unit [NICU] admission) and maternal diagnoses (asthma and systemic lupus erythematosus [SLE]) recorded in the health plan data for live born deliveries between January 2001 and December 2007. A random sample of medical charts (n = 802) was abstracted for infants and mothers identified with the specified outcomes. Information on newborn, maternal, and paternal characteristics (gestational age at birth, birth weight, previous pregnancies and live births, race/ethnicity) was also abstracted and compared to birth certificate data. Positive predictive values (PPVs) were calculated with documentation in the medical chart serving as the gold standard.
PPVs were 71% for cardiac defects, 37% for anencephaly, 87% for preterm birth, and 92% for NICU admission. PPVs for algorithms to identify maternal diagnoses of asthma and SLE were ≥ 93%. Our findings indicated considerable agreement (PPVs > 90%) between birth certificate and medical record data for measures related to birth weight, gestational age, prior obstetrical history, and race/ethnicity.
Health plan and birth certificate data can be useful to accurately identify some infant outcomes, maternal diagnoses, and newborn, maternal, and paternal characteristics. Other outcomes and variables may require medical record review for validation.
PMCID: PMC3492503  PMID: 22753079
administrative databases; birth certificate; positive predictive value; pregnancy; validation
7.  Prevalence, Trends, and Patterns of Use of Antidiabetic Medications Among Pregnant Women, 2001–2007 
Obstetrics and gynecology  2013;121(1):http://10.1097/AOG.0b013e318278ce86.
To describe the prevalence, trends, and patterns in use of antidiabetic medications to treat hyperglycemia and insulin resistance prior to and during pregnancy in a large U.S. cohort of insured pregnant women.
Pregnancies resulting in livebirths were identified (N=437,950) from 2001–2007 among 372,543 women 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 infant birth certificates.
Just over one percent (1.21%) of deliveries were to women dispensed antidiabetic medication(s) 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<0.001) due to a rise in metformin use. Most women using metformin before pregnancy had a diagnosis code for polycystic ovaries or female infertility (67.2%) while 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 <0.001). Approximately two-thirds (68%) of women using metformin before pregnancy did not use any antidiabetic medications during pregnancy.
Antidiabetic medication use prior to and during pregnancy rose from 2001–2007, possibly due to increasing prevalence of gestational diabetes mellitus, type 1 and type 2 diabetes, and other conditions associated with insulin resistance.
PMCID: PMC3811068  PMID: 23262934
8.  Trends in the use of antiepileptic drugs (AEDs) among pregnant women in the U.S., 2001-2007: a Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) study 
Little is known about the extent of antiepileptic drug (AED) use in pregnancy, particularly for newer agents. Our objective was to assess whether AED use has increased among pregnant women in the U.S., 2001-2007.
We analyzed data from the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) database, 1 January 2001 to 31 December 2007. We identified live-born deliveries among women, aged 15-45 years on delivery date, who were members of MEPREP health plans (N = 585,615 deliveries). Pregnancy exposure to AEDs, determined through outpatient pharmacy dispensing files. Older AEDs were available for clinical use before 1993; other agents were considered newer AEDs. Information on sociodemographic and medical/reproductive factors was obtained from linked birth certificate files. Maternal diagnoses were identified based on ICD-9 codes.
Prevalence of AED use during pregnancy increased between 2001 (15.7 per 1,000 deliveries) and 2007 (21.9 per 1,000 deliveries), driven primarily by a five-fold increase in the use of newer AEDs. Thirteen percent of AED-exposed deliveries involved a combination of two or more AEDs. Psychiatric disorders were the most prevalent diagnoses, followed by epileptic and pain disorders, among AED users regardless of AED type, year of conception or gestational period.
AED use during pregnancy increased between 2001 and 2007, driven by a five-fold increase in the use of newer AEDs. Nearly one in eight AED-exposed deliveries involved the concomitant use of more than one AED. Additional investigations of the reproductive safety of newer AEDs may be needed.
PMCID: PMC3481178  PMID: 23061694
pregnancy; anticonvulsant; antiepileptic drugs; drug utilization; prescription practices
9.  Mini-Sentinel Systematic Evaluation of Health Outcome of Interest Definitions for Studies Using Administrative and Claims Data 
Pharmacoepidemiology and drug safety  2012;21(0 1):10.1002/pds.2313.
To identify and describe the validity of algorithms used to detect heart failure (HF) using administrative and claims data sources.
Systematic review of PubMed and Iowa Drug Information Service (IDIS) searches of the English language were performed to identify studies published between 1990 and 2010 that evaluated the validity of algorithms for the identification of patients with HF using and claims data. Abstracts and articles were reviewed by two study investigators to determine their relevance based on predetermined criteria.
The initial search strategy identified 887 abstracts. Of these, 499 full papers were reviewed and 35 studies included data to evaluate the validity of identifying patients with HF. Positive predictive values (PPVs) were in the acceptable to high range, with most being very high (>90%). Studies that included patients with a primary hospital discharge diagnosis of ICD-9 code 428.X had the highest PPV and specificity for HF. PPVs for this algorithm ranged from 84% - 100%. This algorithm, however, may compromise sensitivity since many HF patients are managed on an outpatient basis. The most common ‘gold standard’ for the validation of HF was the Framingham Heart Study criteria.
The algorithms and definitions employed to identify HF using administrative and claims data perform well, particularly when using a primary hospital discharge diagnosis. Attention should be paid to whether patients who are managed on an outpatient basis are included in the study sample. Including outpatient codes in the described algorithms would increase the sensitivity for identifying new cases of HF.
PMCID: PMC3808171  PMID: 22262599
congestive heart failure; validation; administrative data
10.  Medication Exposure in Pregnancy Risk Evaluation Program 
Maternal and child health journal  2012;16(7):1349-1354.
To describe a program to study medication safety in pregnancy, the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). MEPREP is a multi-site collaborative research program developed to enable the conduct of studies of medication use and outcomes in pregnancy. Collaborators include the U.S. Food and Drug Administration and researchers at the HMO Research Network, Kaiser Permanente Northern and Southern California, and Vanderbilt University. Datasets have been created at each site linking healthcare data for women delivering an infant between January 1, 2001 and December 31, 2008 and infants born to these women. Standardized data files include maternal and infant characteristics, medication use, and medical care at 11 health plans within 9 states; birth certificate data were obtained from the state departments of public health. MEPREP currently involves more than 20 medication safety researchers and includes data for 1,221,156 children delivered to 933,917 mothers. Current studies include evaluations of the prevalence and patterns of use of specific medications and a validation study of data elements in the administrative and birth certificate data files. MEPREP can support multiple studies by providing information on a large, ethnically and geographically diverse population. This partnership combines clinical and research expertise and data resources to enable the evaluation of outcomes associated with medication use during pregnancy.
PMCID: PMC3361624  PMID: 22002179
Pregnancy; Birth outcomes; Distributed data network
11.  Drug Adverse Event Detection in Health Plan Data Using the Gamma Poisson Shrinker and Comparison to the Tree-based Scan Statistic 
Pharmaceutics  2013;5(1):179-200.
Background: Drug adverse event (AE) signal detection using the Gamma Poisson Shrinker (GPS) is commonly applied in spontaneous reporting. AE signal detection using large observational health plan databases can expand medication safety surveillance. Methods: Using data from nine health plans, we conducted a pilot study to evaluate the implementation and findings of the GPS approach for two antifungal drugs, terbinafine and itraconazole, and two diabetes drugs, pioglitazone and rosiglitazone. We evaluated 1676 diagnosis codes grouped into 183 different clinical concepts and four levels of granularity. Several signaling thresholds were assessed. GPS results were compared to findings from a companion study using the identical analytic dataset but an alternative statistical method—the tree-based scan statistic (TreeScan). Results: We identified 71 statistical signals across two signaling thresholds and two methods, including closely-related signals of overlapping diagnosis definitions. Initial review found that most signals represented known adverse drug reactions or confounding. About 31% of signals met the highest signaling threshold. Conclusions: The GPS method was successfully applied to observational health plan data in a distributed data environment as a drug safety data mining method. There was substantial concordance between the GPS and TreeScan approaches. Key method implementation decisions relate to defining exposures and outcomes and informed choice of signaling thresholds.
PMCID: PMC3834945  PMID: 24300404
pharmacovigilance; drug safety surveillance; adverse events data mining; gamma Poisson shrinkage; tree-based scan statistic
12.  A Systematic Review of Validated Methods for Identifying Cerebrovascular Accident or Transient Ischemic Attack Using Administrative Data 
Pharmacoepidemiology and drug safety  2012;21(Suppl 1):100-128.
To perform a systematic review of the validity of algorithms for identifying cerebrovascular accidents (CVAs) or transient ischemic attacks (TIAs) using administrative and claims data.
PubMed and Iowa Drug Information Service (IDIS) searches of the English language literature were performed to identify studies published between 1990 and 2010 that evaluated the validity of algorithms for identifying CVAs (ischemic and hemorrhagic strokes, intracranial hemorrhage and subarachnoid hemorrhage) and/or TIAs in administrative data. Two study investigators independently reviewed the abstracts and articles to determine relevant studies according to pre-specified criteria.
A total of 35 articles met the criteria for evaluation. Of these, 26 articles provided data to evaluate the validity of stroke, 7 reported the validity of TIA, 5 reported the validity of intracranial bleeds (intracerebral hemorrhage and subarachnoid hemorrhage), and 10 studies reported the validity of algorithms to identify the composite endpoints of stroke/TIA or cerebrovascular disease. Positive predictive values (PPVs) varied depending on the specific outcomes and algorithms evaluated. Specific algorithms to evaluate the presence of stroke and intracranial bleeds were found to have high PPVs (80% or greater). Algorithms to evaluate TIAs in adult populations were generally found to have PPVs of 70% or greater.
The algorithms and definitions to identify CVAs and TIAs using administrative and claims data differ greatly in the published literature. The choice of the algorithm employed should be determined by the stroke subtype of interest.
PMCID: PMC3412674  PMID: 22262598
cerebrovascular accident; transient ischemic attack; validation; administrative data
13.  ADHD Medications and Risk of Serious Cardiovascular Events In Young and Middle-Aged Adults 
Jama  2011;306(24):2673-2683.
More than 1.5 million US adults use stimulants and other medications labeled for treatment of attention deficit hyperactivity disorder (ADHD). These agents can increase heart rate and blood pressure, raising concerns about their cardiovascular safety.
Examine whether current use of medications used primarily to treat ADHD is associated with increased risk of serious cardiovascular events in young and middle-aged adults.
Retrospective, population-based cohort study
Computerized health records from 4 study sites (OptumInsight Epidemiology, Tennessee Medicaid, Kaiser Permanente California, and the HMO Research Network), starting in 1986 at one site and ending in 2005 at all sites, with additional covariate assessment using 2007 survey data.
Adults aged 25–64 years with dispensed prescriptions for methylphenidate, amphetamine, or atomoxetine at baseline. Each medication user (n=150,359) was matched to two non-users on study site, birth year, sex, and calendar year (total users and non-users=443,198).
Main Outcome
Serious cardiovascular events, including myocardial infarction (MI), sudden cardiac death (SCD), or stroke. Comparison between current or new users and remote users to account for potential healthy user bias.
During 806,182 person-years of follow-up (median 1.3 years per person), 1357 cases of MI, 296 cases of SCD, and 575 cases of stroke occurred. There were 107,322 person-years of current use (median 0.33 years), with a crude incidence per 1000 person-years of 1.34 (95% CI, 1.14–1.57) for MI, 0.30 (95% CI, 0.20–0.42) for SCD, and 0.56 (95% CI, 0.43–0.72) for stroke. The multivariable adjusted rate ratio (RR) of serious cardiovascular events for current use vs non-use of ADHD medications was 0.83 (95% CI 0.72–0.96). Among new users of ADHD medications, the adjusted RR was 0.77 (95% CI 0.63–0.94). The adjusted RR was 1.03 (95% CI, 0.86–1.24) for current use vs remote use, and was 1.02 (95% CI, 0.82–1.28) for new use vs remote use.
Among young and middle-aged adults, current or new use of ADHD medications, compared with non-use or remote use, was not associated with an increased risk of serious cardiovascular events. Apparent protective associations likely represent healthy user bias.
PMCID: PMC3350308  PMID: 22161946
14.  Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta-blockers during pregnancy 
Calcium channel blockers and beta-blockers are widely used during pregnancy, but data on their safety for the developing infant is scarce. We used population-based data from 5 HMOs to study risks for perinatal complications and congenital defects among infants exposed in-utero.
We studied women older than 15 years delivering an infant between 1/1/96 to 12/31/00, who had been continuously enrolled with prescription drug coverage for >= one year prior to delivery. Information on prescription drug dispensings, inpatient and outpatient diagnoses and procedures was obtained from automated databases at each HMO.
There were 584 full-term infants exposed during pregnancy to beta-blockers and 804 full-term infants exposed to calcium-channel blockers, and over 75,000 unexposed mother-infant pairs with >= 30 days follow-up. Infants exposed to beta-blockers in the third trimester of pregnancy had over three-fold increased risk for hypoglycemia (RR 3.1; 95% CI 2.2, 4.2) and an approximately two-fold increased risk for feeding problems (RR 1.8; 95% CI 1.3, 2.5). Infants exposed to calcium-channel blockers in the third trimester had an increased risk for seizures (RR 3.6 95% CI 1.3, 10.4). Chart review confirmed the majority of the exposed seizure and hypoglycemia cases. There were no increased risks for congenital anomalies among either group of infants, except for the category of upper alimentary tract anomalies; this increased risk was based on only two exposed cases.
Infants whose mothers receive beta-blockers are at increased risk for neonatal hypoglycemia, while those whose mothers take calcium-channel blockers are at increased risk for neonatal seizures.
PMCID: PMC3232183  PMID: 21254284
calcium channel blockers; beta-blockers; pregnancy; perinatal; malformation; anomalies; prescription drug; drug safety
15.  Adherence and Occurrence of Fractures after Switching to Once-Monthly Oral Bisphophonates 
Pharmacoepidemiology and drug safety  2010;19(12):1233-1240.
Reducing dosing demands of medications generally increases adherence, although this relationship has not been demonstrated with the once-monthly oral bisphosphonates (BP). The study aim is to test whether switching from once-weekly BPs to once-monthly BPs improves adherence and fracture risk.
This is an interrupted times-series analysis of new users of once-weekly BPs in a nationwide administrative health database from 2003–2007. Participants include 1835 individuals who switched to once-monthly BPs and two propensity-matched comparator groups: 1835 individuals who switched to a different once-weekly BP, and 1835 who did not switch. We measured changes in adequate adherence pre- and post-switch as monthly medication possession ratio >0.80, and calculated incidence rate ratios [IRR] of osteoporotic fractures.
All study groups experienced major adherence failure in the first year of therapy: the proportion of adequate adherers was 42% among once-monthly switchers, 47% among once-weekly switchers, and 37% among nonswitchers. However, the once-monthly switch was associated with less adherence failure (4% fewer adherers per month pre-switch vs. 1% fewer adherers per month post-switch, p<.000). There was no statistically significant change in adherence rates for the other groups. We did not detect significantly reduced fracture risk with once-monthly switch: 1 year post-switch, the fracture incidence risk ratios for once-monthly switchers relative to once-weekly switchers were IRR 0.83, 95% CI: 0.50–1.36, and IRR 0.90, 95% CI: 0.54–1.49, relative to nonswitchers).
Reducing the dosing demands of oral bisphosphonates from once-weekly to once-monthly decreased adherence failure but had an uncertain impact on fracture risk.
PMCID: PMC3079953  PMID: 21108489
patient compliance; bisphosphonates; osteoporosis; osteoporotic fractures; medication adherence
16.  Adoption of Once-monthly Oral Bisphosphonates and the Impact on Adherence 
The American journal of medicine  2010;123(3):275-280.
The extent of the adoption of once-monthly bisphosphonates into general clinical practice is not known, nor is it known if the novel formulation improves adherence.
We analyzed administrative claims 2003-2006 from a large employer-based health insurance database for incident use of oral bisphosphonates and stratified users by daily, weekly and monthly dosing regimen. We measured adherence as the medication possession ratio (MPR) during the first year of therapy. We compared patient characteristics by dosing regimen and evaluated how the dosing regimen influenced the MPR.
We identified 61,125 incident users of bisphosphonates (n=1034 daily, n=56,925 weekly, n=3166 monthly). Monthly bisphosphonate users were, on average, slightly older than the other groups (mean age 66 years monthly vs. 65 weekly or 66 daily, p<.05.) and more often lived in the U.S. North Central or South (76% vs. 72% weekly or 69% daily users, p<.05). There were no detectable differences among the dosing groups in the history of serious GI risk, comorbidity burden, or prior osteoporotic fractures. During the first year of bisphosphonate therapy, 49% of monthly users had MPR ≥80% compared to 49% weekly users (N.S.) or 23% daily users (p<.0001).
We found little evidence of preferential prescribing of monthly bisphosphonates to certain types of patients. Furthermore, we found no evidence of improved bisphosphonate adherence with monthly dosing relative to weekly dosing, although adherence with either weekly or monthly dosing was significantly better than with daily dosing.
PMCID: PMC2831769  PMID: 20193837
patient compliance; bisphosphonates; novel formulation
17.  The Dynamics of Chronic Gout Treatment: medication gaps and return to therapy 
To identify gaps in therapy with urate-lowering drugs for the treatment of gout as well as factors associated with resuming therapy.
We identified persons from two integrated delivery systems 18 years or older with a diagnosis of gout who initiated use of a urate-lowering drug from January 1, 2000 through June 30, 2006 and who had a gap in therapy. A gap was defined as a period of over 60 days after the completion of one prescription in which no refill for a urate-lowering drug was obtained. Survival curves were used to assess return to therapy of urate-lowering drugs. Cox proportional hazards analysis estimated the association between covariates and return to therapy.
There were 4,166 new users of urate-lowering drugs (97% received allopurinol) of whom 2,929 (70%) had a gap in therapy. Among those with a gap, in 75% it occurred in the first year of therapy. Fifty percent of patients with a gap returned to therapy within 8 months, and by 4 years it was 75%. Age 45 to 74 (<45 referent) and greater duration of urate-lowering drug use prior to the gap was associated with resuming treatment within one year. In contrast, receipt of NSAIDs or glucocorticoids in the year prior to the gap was associated with a reduced likelihood of resuming therapy.
The majority of gout patients with gaps in urate-lowering drug use returned to treatment. More investigation is needed to better understand why patients may go for months without refilling prescriptions given the clinical consequences of nonadherence.
PMCID: PMC2813203  PMID: 20102992
persistence; adherence; compliance; gout; urate lowering drugs
18.  Medication Adherence and the Use of Generic Drug Therapies 
to assess if the lower copayments often charged for generic drugs explains the improved drug adherence associated with use of generic drugs.
We analyzed 2001–2004 healthcare claims data from 45 large employers. Study subjects were aged 18 years +, had 1 or more of 5 study conditions (hypercholesterolemia, hypertension, hypothyroidism, seizure disorders, and type 2 diabetes), and new use of generic-only or brand-only drug therapy for that condition. We measured adherence as the medication possession ratio (MPR), and adequate adherence as MPR >= 80%. Logistic regressions were conducted to assess adequate adherence adjusting for copayments.
We identified 327,629 new users of drug therapy for the study conditions. Proportion of individuals starting generic therapies ranged from 9% in hypothyroidism to 45% in hypertension. After 1 year of therapy, 66.2% of individuals with hypothyroidism achieved MPR >= 80% compared to 53.4% with hypertension, 53.2% with hypercholesterolemia, 52.0% with diabetes, and 42.2% with seizure disorders. Logistic regressions of adequate adherence showed generics were associated with higher adherence relative to brands in 2 conditions (hypercholesterolemia AOR 1.52, 95% CI: 1.44–1.60; diabetes AOR 1.06, 95% CI: 1.01–1.12, p<.05), with lower adherence in 2 conditions (hypertension AOR 0.75, 95% CI:.73-.77; hypothyroidism AOR 0.86, 95% CI:.78-.94, p<.05), and no difference in seizure disorders. In comparison, the likelihood of achieving MPR >= 80% with $0 copayments relative to $1-$9 ranged from AOR 1.32 for seizure disorders (95% CI: 1.41–1.43) to AOR 1.45 for hypothyroidism (95% CI: 1.43–1.48).
Generic prescribing was associated with improved medication adherence in 2 of 5 study conditions, and the effect was modest. Copayments of $0 were associated with improved adherence across all study conditions.
PMCID: PMC2918380  PMID: 19589012
adherence; type 2 diabetes; hypertension; hypercholesterolemia; hypothyroidism; and seizure disorders
19.  Medication Adherence of Patients with Selected Rheumatic Conditions: A Systematic Review of the Literature 
Nonadherence with medication treatment has been found to occur in large proportions of patients with a broad range of chronic conditions. Our aim was to perform a systematic review of the literature examining adherence with treatments for inflammatory rheumatic conditions to assess the magnitude of the problem in this patient population.
A MEDLINE search of English language literature was performed to identify studies published between January 1, 1985 and November 30, 2007 that evaluated adherence with chronic medications needed in the treatment of rheumatic conditions.
A total of 20 articles met the criteria for evaluation, the majority of which focused on the treatment of rheumatoid arthritis. Most of the studies examined the use of nonsteroidal anti-inflammatory medications and disease modifying anti-rheumatic drugs. Adherence was assessed based on self-report, pill counts, pharmacy dispensings, openings of pill containers using electronic devices, laboratory assays, and physician assessment. Adherence varied greatly based on the adherence measure used, arthritic condition evaluated and medication under study. Overall, the highest rates of adherence were based on self-reports for a wide variety of medications and conditions (range of persons reporting adherence was 30 to 99%), while the lowest adherence rates were for allopurinol based on pharmacy dispensings (18–26%).
Adherence has not been widely examined for most chronic inflammatory rheumatic conditions and the few studies that exist used different definitions and populations, thus limiting any conclusions. However, the current literature does suggest that nonadherence is a substantial problem.
PMCID: PMC2695137  PMID: 18336875
adherence; arthritis
20.  Patient Decision to Initiate Therapy for Osteoporosis: The Influence of Knowledge and Beliefs 
Journal of General Internal Medicine  2008;23(11):1815-1821.
There are effective treatments to prevent osteoporotic fractures, but these treatments are underutilized.
To evaluate the influence of patient characteristics, perceptions, knowledge and beliefs about osteoporosis on the decision to initiate osteoporotic treatment.
We identified female members of a managed care plan who had a dual energy x-ray absorptiometry (DXA) bone density test and fulfilled World Health Organization criteria for osteoporosis. Patients were excluded if they received osteoporotic medications in the prior 6 months.
Patients were sent a questionnaire that included items assessing satisfaction with physician–patient communication, trust in the physician, osteoporosis knowledge and beliefs, beliefs about prescription medications, and perceptions of barriers to medication use. Administrative electronic health records were used to identify prescription drug use and health care utilization.
Two hundred and thirty-six women returned surveys and research authorization forms out of 465 contacted for participation. One hundred and thirty-five (57.2%) filled a prescription for an osteoporotic drug in the first 3 months after the DXA exam. The largest differences between initiators and non-initiators were in beliefs in the benefits of medications, and distrust of medications, with initiators believing more strongly in the benefits and effectiveness of medications (p < .001), and non-initiators reporting more distrust of medications (p < .001). Osteoporosis knowledge and the belief that osteoporosis is a serious disease were also related to therapy initiation in bivariate analysis.
Only 57% of patients initiated osteoporotic medication within 3 months of diagnosis. The decision to start osteoporosis treatment appeared to be related to a patient’s beliefs in the effectiveness of osteoporosis medications and distrust of medications.
PMCID: PMC2585659  PMID: 18787907
medication adherence; patient preferences; osteoporosis; decision-making
21.  Comparison of Drug Adherence Rates Among Patients with Seven Different Medical Conditions 
Pharmacotherapy  2008;28(4):437-443.
Study Objective
To compare drug adherence rates among patients with gout, hypercholesterolemia, hypertension, hypothyroidism, osteoporosis, seizure disorders, and type 2 diabetes mellitus by using a standardized approach.
Longitudinal study.
Data Source
Health care claims data from 2001–2004.
A total of 706,032 adults aged 18 years or older with at least one of the seven medical conditions and with incident use of drug therapy for that condition.
Measurements and Main Results
Drug adherence was measured as the sum of the days’ supply of drug therapy over the first year observed. Covariates were age, sex, geographic residence, type of health plan, and a comorbidity score calculated by using the Hierarchical Condition Categories risk adjuster. Bivariate statistics and stratification analyses were used to assess unadjusted means and frequency distributions. Sample sizes ranged from 4984 subjects for seizure disorders to 457,395 for hypertension. During the first year of drug therapy, 72.3% of individuals with hypertension achieved adherence rates of 80% or better compared with 68.4%, 65.4%, 60.8%, 54.6%, 51.2%, or 36.8% for those with hypothyroidism, type 2 diabetes, seizure disorders, hypercholesterolemia, osteoporosis, or gout, respectively. Age younger than 60 years was associated with lower adherence across all diseases except seizure disorders. Comorbidity burden and adherence varied by disease. As comorbidity increased, adherence among subjects with osteoporosis decreased, whereas adherence among those with hypertension, hypercholesterolemia, or gout increased. Add-on drug therapies and previous experience with taking drugs for the condition increased adherence among subjects with hypertension, type 2 diabetes, hypothyroidism, or seizure disorders but not the other conditions.
This uniform comparison of drug adherence revealed modest variation across six of seven diseases, with the outlier condition being gout.
PMCID: PMC2737273  PMID: 18363527
drug adherence; comparative study; type 2 diabetes mellitus; hypertension; osteoporosis; hypercholesterolemia; gout; hypothyroidism; seizure disorders
22.  Adherence with urate-lowering therapies for the treatment of gout 
Adherence to urate-lowering drugs (ULDs) has not been well evaluated among those with gout. Our aim was to assess the level and determinants of non-adherence with ULDs prescribed for gout.
We identified persons using two integrated delivery systems aged 18 years or older with a diagnosis of gout who initiated use of allopurinol, probenecid or sulfinpyrazone from 1 January 2000 to 30 June 2006. Non-adherence was measured using the medication possession ratio (MPR) over the first year of therapy and defined as an MPR < 0.8. Descriptive statistics were calculated and logistic regression was used to estimate the strength of the association between patient characteristics and non-adherence.
A total of 4,166 gout patients initiated ULDs; 97% received allopurinol. Median MPR for any ULD use was 0.68 (interquartile range (IQR) 0.64). Over half of the patients (56%) were non-adherent (MPR < 0.8). In adjusted analyses, predictors of poor adherence included younger age (odds ratio (OR) 2.43, 95% confidence interval (CI) 1.86 to 3.18 for ages <45 and OR 1.44, 95% CI 1.08 to 1.93 for ages 45 to 49), fewer comorbid conditions (OR 1.46, 95% CI 1.20 to 1.77), no provider visits for gout prior to urate-lowering drug initiation (OR 1.28, 95% CI 1.05 to 1.55), and use of non-steroidal anti-inflammatory drugs in the year prior to urate-lowering drug initiation (OR 1.15, 95% CI 1.00 to 1.31).
Non-adherence amongst gout patients initiating ULDs is exceedingly common, particularly in younger patients with less comorbidity and no provider visits for gout prior to ULD initiation. Providers should be aware of the magnitude of non-adherence with ULDs.
PMCID: PMC2688196  PMID: 19327147
23.  Laboratory Monitoring of Drugs at Initiation of Therapy in Ambulatory Care 
Journal of General Internal Medicine  2005;20(12):1120-1126.
Background and Objectives
Product labeling and published guidelines reflect the importance of monitoring laboratory parameters for drugs with a risk of organ system toxicity or electrolyte imbalance. Limited information exists about adherence to laboratory monitoring recommendations. The objective of this study was to describe laboratory monitoring among ambulatory patients dispensed medications for which laboratory testing is recommended at therapy initiation.
Design and Subjects
We conducted a retrospective cross-sectional analysis of patients in 10 geographically distributed health maintenance organizations who were newly prescribed medications with recommended laboratory test monitoring. The main outcome measure was the proportion of initial drug dispensing without recommended baseline laboratory monitoring for 35 newly initiated drugs or drug classes.
One hundred seven thousand, seven hundred sixty-three of 279,354 (39%) initial drug dispensings occurred without recommended laboratory monitoring. Patients without monitoring were younger than patients who had monitoring (median 57 vs 61 years, P<.001). Thirty-two percent of dispensings where a serum creatinine was indicated did not have it evaluated (range across drugs, 12% to 61%); 39% did not have liver function testing (range 10% to 75%); 32% did not have hematologic monitoring (range 9% to 51%); and 34% did not have electrolyte monitoring (range 20% to 62%) (P<.001).
Substantial opportunity exists to improve laboratory monitoring of drugs for which such monitoring is recommended. This study emphasizes the need for research to identify the clinical implications of not conducting recommended laboratory monitoring, existing barriers to monitoring, and methods to improve practice.
PMCID: PMC1490279  PMID: 16423101
laboratory monitoring; ambulatory; drug therapy
24.  The Impact of Comorbidities on Hormone Use 
Determine the impact of fracture, coronary disease, and diabetes on changes in rates of discontinuation and initiation of estrogen therapy with (EPT) and without (ET) progestin, before (September 1, 1999 to June 30, 2002, baseline) versus 5 months after (follow-up) release of the Women's Health Initiative EPT trial results (WHI).
Observational cohort; 169,586 women 40 to 80 years old from 5 U.S. HMOs.
We used pharmacy data to identify ET and EPT users. A woman was a user any month she filled ≥1 estrogen prescription and in subsequent months based upon the number of pills/patches dispensed. We used inpatient and outpatient claims to identify fracture January 1, 1999 to June 30, 2002 and pharmacy data to identify disease-based groups of medications for diabetes and cardiovascular disease.
EPT/ET prevalence, initiation, and discontinuation rates.
Baseline to follow-up EPT and ET prevalence declined 45% and 22%, respectively, with no difference by comorbidity. Follow-up EPT initiation was half the baseline rate irrespective of comorbidity. Compared to baseline, follow-up EPT discontinuation rates increased among women with diabetes (relative risk [RR], 6.9; 95% confidence interval [CI], 5.6 to 8.4), cardiovascular disease (RR, 5.5; 95% CI, 4.9 to 6.2), fracture (RR, 3.8; 95% CI, 2.4 to 5.7), and no comorbidity (RR, 4.4; 95% CI, 3.9 to 4.9). The RRs for follow-up versus baseline EPT discontinuation were higher among women with diabetes (P <.01) and cardiovascular disease (P <.01) versus women without these comorbidities. ET discontinuation rates among these same groups were elevated 2- to 2.8-fold.
Diabetes and cardiovascular disease were associated with higher EPT discontinuation rates post-WHI compared to women without comorbidity; comorbidity had little impact on changes in prevalence or initiation of ET/EPT after release of the WHI.
PMCID: PMC1490092  PMID: 15857493
hormone therapy; women; menopause; estrogen; fracture

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