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Purpose: The role of administrative databases for research on drug safety during pregnancy can be limited by their inaccurate assessment of the timing of exposure, as the gestational age at birth is typically unavailable. Therefore, we sought to develop and validate algorithms to estimate the gestational age at birth using information available in these databases., Methods: Using a population-based cohort of 286,432 mother-child pairs in British Columbia (1998-2007), we validated an ICD-9/10-based preterm-status indicator and developed algorithms to estimate the gestational age at birth on the basis of this indicator, maternal age, singleton/multiple status, and claims for routine prenatal care tests. We assessed the accuracy of the algorithm-based estimates relative to the gold standard of the clinical gestational age at birth recorded in the delivery discharge record., Results: The preterm-status indicator had specificity and sensitivity of 98% and 91%, respectively. Estimates from an algorithm that assigned 35 weeks of gestational age at birth to deliveries with the preterm-status indicator and 39 weeks to those without them were within 2 weeks of the clinical gestational age at birth in 75% of preterm and 99% of term deliveries., Conclusions: Subtracting 35 weeks (245 days) from the date of birth in deliveries with codes for preterm birth and 39 weeks (273 days) in those without them provided the optimal estimate of the beginning of pregnancy among the algorithms studied., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objective: An instrumental variable (IV) is an unconfounded proxy for a study exposure that can be used to estimate a causal effect in the presence of unmeasured confounding. To provide reliably consistent estimates of effect, IVs should be both valid and reasonably strong. Physician prescribing preference (PPP) is an IV that uses variation in doctors' prescribing to predict drug treatment. As reduction in covariate imbalance may suggest increased IV validity, we sought to examine the covariate balance and instrument strength in 25 formulations of the PPP IV in two cohort studies., Study Design and Setting: We applied the PPP IV to assess antipsychotic medication (APM) use and subsequent death among two cohorts of elderly patients. We varied the measurement of PPP, plus performed cohort restriction and stratification. We modeled risk differences with two-stage least square regression. First-stage partial r(2) values characterized the strength of the instrument. The Mahalanobis distance summarized balance across multiple covariates., Results: Partial r(2) ranged from 0.028 to 0.099. PPP generally alleviated imbalances in nonpsychiatry-related patient characteristics, and the overall imbalance was reduced by an average of 36% (+/-40%) over the two cohorts., Conclusion: In our study setting, most of the 25 formulations of the PPP IV were strong IVs and resulted in a strong reduction of imbalance in many variations. The association between strength and imbalance was mixed.

Background: Bias in studies of preventive medications can occur when healthier patients are more likely to initiate and adhere to therapy than less healthy patients. We sought evidence of this bias by examining associations between statin exposure and various outcomes that should not be causally affected by statin exposure, such as workplace and motor vehicle accidents., Methods and Results: We conducted a prospective cohort study of statin patients using data from British Columbia, Canada, a multiethnic society with a population of 4.3 million people. Study subjects were 141 086 patients who initiated statins for primary prevention. We examined the association between adherence and multiple outcomes such as accidents and screening procedures using multivariable-adjusted Cox proportional hazards models. The study population was 49% female and had an average age of 61 years. The results from our multivariable-adjusted models showed that more adherent patients were less likely to have accidents than less adherent patients. This effect was greatest for motor vehicle accidents (hazard ratio, 0.75; 95% confidence interval, 0.72 to 0.79) and workplace accidents (hazard ratio, 0.77; 95% confidence interval, 0.74 to 0.81). More adherent patients had a greater likelihood of using screening services (hazard ratio, 1.17; 95% confidence interval, 1.15 to 1.20) and a lower likelihood of developing other diseases likely to be unrelated to a biological affect of a statin (hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.89)., Conclusions: Our study contributes compelling evidence that patients who adhere to statins are systematically more health seeking than comparable patients who do not remain adherent. Caution is warranted when interpreting analyses that attribute surprising protective effects to preventive medications.

Instrumental variable analyses are increasingly used in epidemiologic studies. For dichotomous exposures and outcomes, the typical 2-stage least squares approach produces risk difference estimates rather than relative risk estimates and is criticized for assuming normally distributed errors. Using 2 example drug safety studies evaluated in 3 cohorts from Pennsylvania (1994-2003) and British Columbia, Canada (1996-2004), the authors compared instrumental variable techniques that yield relative risk and risk difference estimates and that are appropriate for dichotomous exposures and outcomes. Methods considered include probit structural equation models, 2-stage logistic models, and generalized method of moments estimators. Employing these methods, in the first study the authors observed relative risks ranging from 0.41 to 0.58 and risk differences ranging from -1.41 per 100 to -1.28 per 100; in the second, they observed relative risks of 1.38-2.07 and risk differences of 7.53-8.94; and in the third, they observed relative risks of 1.45-1.59 and risk differences of 3.88-4.84. The 2-stage logistic models showed standard errors up to 40% larger than those of the instrumental variable probit model. Generalized method of moments estimation produced substantially the same results as the 2-stage logistic method. Few substantive differences among the methods were observed, despite their reliance on distinct assumptions.

Objective: To evaluate the effects of patient copayment and coinsurance policies on adherence to therapy with beta-adrenergic blocking agents (beta-blockers) and on the rate of initiation of beta-blocker therapy after acute myocardial infarction (MI) in a population-based natural experiment., Study Design: Three sequential cohorts included British Columbia residents age 66 years and older who initiated beta-blocker therapy during time intervals with full drug coverage (2001), a $10 or $25 copayment (2002), and 25% coinsurance (2003-2004). We used linked data on all prescription drug dispensings, physician services, and hospitalizations. Follow-up of each cohort was 9 months after the policy changes., Methods: We measured the proportion of subjects in each cohort who were adherent to beta-blocker therapy over time, with adherence defined as having >80% of days covered. We also measured the proportion of patients initiating beta-blocker therapy after acute MI. Policy effects were evaluated using multivariable regression., Results: Adherence to beta-blocker therapy was marginally reduced as a consequence of the copayment policy (-1.3 percentage points, 95% confidence interval [CI] = -2.5 , -0.04) or the coinsurance policy (-0.8 percentage points, 95% CI = -2.0, 0.3). The proportion of patients initiating beta-blockers after hospitalization for acute MI remained steady at about 61% during the study period, similar to that observed in a control population of elderly Pennsylvania residents with full drug coverage., Conclusions: Fixed patient copayment and coinsurance policies had little negative effect on adherence to relatively inexpensive beta-blocker therapy, or initiation of beta-blockers after acute MI.

Background: As medication spending grows, Medicare Part D will need to adapt its coverage policies according to emerging evidence from a variety of insurance policies. We sought to evaluate the consequences of copayment and coinsurance policies on the initiation of statin therapy after acute myocardial infarction and adherence to therapy in statin initiators using a natural experiment of all British Columbia residents aged 66 years and older., Methods and Results: Three consecutive cohorts that included all patients who began statin therapy during full drug coverage (2001), coverage with a $10 or $25 copay (2002), and coverage with a 25% coinsurance benefit (2003-2004) were followed up with linked healthcare utilization data (n=51,561). Follow-up of cohorts was 9 months after each policy change. Adherence to statin therapy was defined as > or = 80% of days covered. Relative to full-coverage policies, adherence to new statin therapy was significantly reduced, from 55.8% to 50.5%, under a fixed copayment policy (-5.4% points; 95% CI, -6.4% to -4.4%) and the subsequent coinsurance policy (-5.4% points; 95% CI, -6.3% to -4.4%). An uninterrupted increase in the proportion of patients initiating statin therapy after an acute myocardial infarction (1.7% points per quarter) was observed over the study period, similar to a Pennsylvania control population with full coverage. Sudden changes to full out-of-pocket spending, similar to Medicare's Part D "doughnut hole," almost doubled the risk of stopping statins (adjusted odds ratio, 1.94, 95% CI, 1.82 to 2.08)., Conclusions: Fixed patient copayment and coinsurance policies have negative effects on adherence to statin lipid-lowering drug therapy but not on their initiation after myocardial infarction.

Background: Evaluations of drug cost-sharing policies within the same population are needed for a fair comparison of different options., Objective: The aim of this work was to analyze the impact of 2 changes in a public drug insurance plan on the use of inhaled medications in British Columbia (BC), Canada., Methods: Data for the period from 1997 to 2004 were used to assess whether changes in the use of steroid, beta2-agonist, and anticholinergic inhalers were associated with insurance-plan changes in a large, natural experiment involving all BC residents aged>or=65 years. The 3 sequential policies included full coverage, fixed copayments at the beginning of 2002, and 25% coinsurance with an income-based deductible beginning May 1, 2003. Linkable prescription, physician billing, hospitalization, and mortality records were obtained from the BC Ministry of Health Services. From the total population of residents aged>or=65 years, we extracted data for all patients to whom inhaled steroids, beta2-agonists, or anticholinergics were dispensed on or after January 1, 1997. Multivariable linear regression was used to estimate inhaler use during a 60-month baseline period and during implementation of the subsequent copayment and coinsurance plus deductible policies. We used logistic regression to identify predictors of initiation and cessation use of inhaled medications among older patients., Results: Use declined for inhaled steroids (-12.3%; P<0.001), inhaled anticholinergics (-12.2%; P<0.001), and inhaled beta2-agonists (-5.8%; P<0.001). Patients with new diagnoses of asthma or chronic obstructive pulmonary disease were 25% (95% CI, 14%-31%) less likely to initiate treatment with inhaled steroids when covered by the copayment or coinsurance plus deductible policies than when they had full coverage. Chronic users of inhaled steroids were 47% (95% CI, 40%-55%) more likely to cease treatment when they were covered by the copayment policy and 22% (95% CI, 15%-29%) more likely to cease when covered by the coinsurance plus deductible policy than when they had full coverage., Conclusions: The copayment and coinsurance plus deductible policies were associated with significant reductions in use of inhaled medications, mostly due to decreased initiation and increased cessation rates. However, the consequences of these policies on health outcomes have not yet been determined.

Objective: The performance of standard comorbidity scores to control confounding is poorly defined in health care utilization data across elderly populations. We sought to evaluate and rank the performance of comorbidity scores across selected U.S. and Canadian elderly populations using health care utilization databases., Design: Cross-population validation study., Participants: Study participants were residents age 65 years or older who had prescription drug coverage through state-funded programs selected from several large health care utilization databases available to the investigators: British Columbia, BC (N = 141,161), New Jersey, NJ (N = 235,881), and Pennsylvania, PA (N = 230,913)., Measurements: We calculated 6 commonly used comorbidity scores for all subjects during the baseline year (1994 for NJ and PA, and 1995 for BC). These included scores based on diagnoses (Romano, Deyo, D'Hoore, Ghali) and prescription drugs (CDS-1, CDS-2). The study outcome was 1-year mortality. The performance of scores was measured by c-statistics derived from multivariate logistic regression that included age and gender., Main Results: Across these 4 large elderly populations, we found the same rank order of performance in predicting 1-year mortality after including age and gender in each model: Romano (c-statistic 0.754 to 0.771), Deyo (c-statistic 0.753 to 0.768), D'Hoore (c-statistic 0.745 to 0.760), Ghali (c-statistic 0.733 to 0.745), CDS-1 (c-statistic 0.689 to 0.738), CDS-2 (c-statistic 0.677 to 0.718), and age and gender alone (c-statistic 0.664 to 0.681). Performance was improved by an average of 6% by adding the number of different prescription drugs received during the past year., Conclusions: Performance ranking of 6 frequently used comorbidity scores was consistent across selected elderly populations. We recommend that investigators use these performance data as one important factor when selecting a comorbidity score for epidemiologic analyses of health care utilization data.

Background: Gender-specific attitudes and communication styles are known to influence both the content and outcome of medical visits. Therefore, gender-specific differences in response to cost containment may also occur., Objective: The purpose of this study was to assess the effect of physician gender on changes in prescribing patterns of angiotensin-converting enzyme (ACE) inhibitors after the implementation of reference pricing for prescription drugs in British Columbia, Canada., Methods: Reference pricing is a cost-sharing policy by which use of high-priced medication requires out-of-pocket payment of the price difference between the cost-sharing drug and a lower-cost drug within the same class. In British Columbia, reference pricing for ACE inhibitors was introduced on January 1, 1997. Analysis was carried out on linked pharmacy and medical service claims data on 927 female and 2922 male physicians treating 47,680 Pharmacare Plan A enrollees who were aged >-65 years and were prescribed a high-priced ACE inhibitors before the implementation of reference pricing., Results: Female physicians (24.1% of all physicians) were younger, treated more female patients, had patients with fewer chronic illnesses, and worked more often as general practitioners than did male physicians. The patients of female physicians were more likely to receive a written physician-requested exemption from copayment, according to a multivariate logistic regression analysis (odds ratio [OR], 1.25; 95% CI, 1.04-1.50). Data suggested that patients of female physicians were more likely to stop antihypertensive drug therapy (OR, 1.43; 95% CI, 0.96-2.13); however, this was independent of the new copayment policy., Conclusions: The results provide empirical evidence that physician gender is associated with slightly different patient management strategies regarding physician-requested exemptions after the start of a new drug cost-sharing policy. However, these differences are unlikely to have meaningful clinical or economic consequences.

A causal relation between drug benefit policy change and the increase in adverse outcomes can be tested by comparing the experience of a group of patients affected by the policy vs. the (counterfactual) experience of the same patients if the policy had not been implemented. Because counterfactual experiences cannot be observed, it must be assumed that the counterfactual is correctly described by extrapolating from the same population's previous experience. The null hypothesis of no policy effect can be empirically tested using quasi-experimental longitudinal designs with repeated measures. If compliance to a policy is low, results may be biased towards the null, but a subgroup analysis of compliers may be biased by nonignorable treatment selection. Using the example of reference drug pricing in British Columbia we discuss assumptions for causal interpretations of such analyses, and provide supplementary analyses to assess and improve the validity of findings. Results from nonrandomized comparisons of subgroups defined by their compliance to a policy change should generally be interpreted cautiously, and several biases should be explored.

Background: Increasing copayments for higher-priced prescription medications has been suggested as a means to help finance drug coverage for elderly patients, but evaluations of the impact of such policies are rare. The objective of this study was to analyze the effect of reference-based pricing of angiotensin-converting enzyme (ACE) inhibitors on drug utilization, cost savings and potential substitution with other medication classes., Methods: We analyzed 36 months of claims data from British Columbia for 2 years before and 1 year after implementation of reference-based pricing (in January 1997). The 119,074 patients were community-living Pharmacare beneficiaries 65 years of age or older who used ACE inhibitors during the study period. The main outcomes were changes over time in use of ACE inhibitors, use of antihypertensive drugs and expenditures for antihypertensive drugs, as well as predictors of medication switching related to reference-based pricing., Results: We observed a sharp decline (29%) in the use of higher-priced cost-shared ACE inhibitors immediately after implementation of the policy (p < 0.001). After a transition period, the post-implementation utilization rate for all ACE inhibitors was 11% lower than projected from pre-implementation data. However, overall utilization of antihypertensives was unchanged (p = 0.40). The policy saved $6.7 million in pharmaceutical expenditures during its first 12 months. Patients with heart failure or diabetes mellitus who were taking a cost-shared ACE inhibitor were more likely to remain on the same medication after implementation of reference-based pricing (OR 1.12 [95% confidence interval, CI, 1.06-1.19] and 1.28 [95% CI 1.20-1.36] respectively). Patients with low-income status were more likely than those with high-income status to stop all antihypertensive therapy (OR 1.65 [95% CI 1.43-1.89]), which reflects a general trend toward discontinuation of therapy among these patients even before implementation of reference-based pricing., Interpretation: Reference-based pricing in British Columbia achieved a sustained reduction in drug expenditures, and no changes in overall use of antihypertensive therapy were observed. Further research is needed on the overall health and economic effects of such policies.