Not-so-surprising findings.
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Epidemiologic Studies↗
Biomedical subjects
Sebastian Schneeweiss
Publications and source records attributed to Sebastian Schneeweiss.
Reference drug programs: effectiveness and policy implications.
In the current economic environment, health care systems are constantly struggling to contain rapidly rising costs. Drug costs are targeted by a wide variety of measures. Many jurisdictions have implemented reference drug programs (RDPs) or similar therapeutic substitution programs. This paper summarizes the mechanism and rationale of RDPs and presents evidence of their economic effectiveness and clinical safety. RDPs for pharmaceutical reimbursement are based on the assumption that drugs within specified medication groups are therapeutically equivalent and clinically interchangeable and that a common reimbursement level can thus be established. If the evidence documents that a higher price for a given drug does not buy greater effectiveness or reduced toxicity, then under RDP such extra costs are not covered. RDPs or therapeutic substitutions based on therapeutic equivalence are seen as logical extensions of generic substitution that is based on bioequivalence of drugs. If the goal is to achieve full drug coverage for as many patients as possible in the most efficient manner, then RDPs in combination with prior authorization programs are safer and more effective than simplistic fiscal drug policies, including fixed co-payments, co-insurances, or deductibles. RDPs will reduce spending in the less innovative but largest market, while fully covering all patients. Prior authorization will ensure that patients with a specified indication will benefit from the most innovative therapies with full coverage. In practice, however, not all patients and drugs will fit exactly into one of the two categories. Therefore, a process of medically indicated exemptions that will consider full coverage should accompany an RDP. In the current economic environment, health care systems are constantly struggling to contain rapidly rising costs. Drug costs are targeted by a wide variety of measures. Many jurisdictions have implemented reference drug programs, and others are considering them. This paper summarizes the mechanism and rationale of RDPs, presents evidence of their economic effectiveness and clinical safety, and concludes with some practical implications of implementing RDP policies.
Cost Control↗
Selective prescribing led to overestimation of the benefits of lipid-lowering drugs.
OBJECTIVE: Observational studies have found beneficial effects of lipid-lowering drugs on diverse outcomes, including venous thromboembolism, hip fracture, dementia, and all-cause mortality. Selective use of these drugs in frail people may confound these relationships. STUDY DESIGN AND SETTING: We measured 1-year mortality in two cohorts of New Jersey residents, aged 65-99 years, enrolled in state-sponsored drug benefits programs: 112,463 persons hospitalized during the years 1991-1994 and 106,838 nonhospitalized enrollees. Use of lipid-lowering drugs and other medications, as well as diagnoses, were evaluated before follow-up. RESULTS: In age- and sex-adjusted analyses, users of lipid-lowering drugs had a 43% reduced death rate relative to nonusers among hospitalized enrollees and a 56% reduction in the nonhospitalized sample. Available markers of frailty and comorbidity predicted decreased use of these drugs. Control for the propensity to use lipid-lowering drugs attenuated but did not eliminate these effects. After such adjustment, users had a 30% reduction in death rate (95% confidence interval [CI]: 25%-35%) among hospitalized enrollees and a 41% reduction (95% CI: 35%-47%) in the nonhospitalized sample. Unmeasured frailty associated with a 26%-33% reduced odds of receiving lipid-lowering therapy could explain this effect. CONCLUSION: Frailty and comorbidity that influence use of preventive therapies can substantially confound apparent benefits of lipid-lowering drugs on outcomes.
Age Factors↗
Variable selection for propensity score models.
Despite the growing popularity of propensity score (PS) methods in epidemiology, relatively little has been written in the epidemiologic literature about the problem of variable selection for PS models. The authors present the results of two simulation studies designed to help epidemiologists gain insight into the variable selection problem in a PS analysis. The simulation studies illustrate how the choice of variables that are included in a PS model can affect the bias, variance, and mean squared error of an estimated exposure effect. The results suggest that variables that are unrelated to the exposure but related to the outcome should always be included in a PS model. The inclusion of these variables will decrease the variance of an estimated exposure effect without increasing bias. In contrast, including variables that are related to the exposure but not to the outcome will increase the variance of the estimated exposure effect without decreasing bias. In very small studies, the inclusion of variables that are strongly related to the exposure but only weakly related to the outcome can be detrimental to an estimate in a mean squared error sense. The addition of these variables removes only a small amount of bias but can increase the variance of the estimated exposure effect. These simulation studies and other analytical results suggest that standard model-building tools designed to create good predictive models of the exposure will not always lead to optimal PS models, particularly in small studies.
Confounding Factors, Epidemiologic↗
The validity of a rheumatoid arthritis medical records-based index of severity compared with the DAS28.
The objective of this work was to assess the convergent validity of a previously developed rheumatoid arthritis medical records-based index of severity (RARBIS) by comparing it with the 28-joint Disease Activity Score (DAS28). This study was conducted in subjects within the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS). We selected 100 patients with rheumatoid arthritis (RA) from the BRASS with DAS28 scores equally distributed in four quartiles. The medical records were reviewed to calculate the RARBIS, which includes indicators from the following categories: prior surgical history, radiologic and laboratory findings, clinical and functional status, and extra-articular manifestations. The Spearman correlation between the RARBIS and the DAS28 was assessed in the total study population and in relevant subgroups. We re-weighted on subscales and recalculated the RARBIS score. This was performed based on findings of correlations between the DAS28 and subscales; and also the result from a multiple linear regression with the DAS28 (as a dependent variable) and five subscales (as independent variables). The mean RARBIS was 4.36 (range 0-11). Among the total study cohort, the RARBIS was moderately correlated with the DAS28 (r = 0.41, 95% confidence interval [CI] 0.23-0.56). In subgroup analyses, including age, gender, rheumatoid factor status, and disease duration, we found no statistically significant differences in the correlations. After re-weighting, the correlation between the RARBIS and the DAS28 was somewhat improved (r = 0.48, 95% CI 0.31-0.62). In conclusion, the RARBIS correlated moderately well with the DAS28 in this population. The RARBIS has both face and convergent validity for patients with RA and relevant subgroups and may have application for medical records studies in patients with RA.
Arthritis, Rheumatoid↗
Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk.
OBJECTIVE: Controversy persists regarding the cardiovascular risks of treatment with selective cyclooxygenase 2 inhibitors (coxibs) and nonselective nonsteroidal antiinflammatory drugs (NSAIDs). This study was undertaken to examine, in a large group of new users of coxibs and NSAIDs, the rate of cardiovascular events, their time course, and whether baseline cardiovascular risk modified the rate ratios (RRs) for future events. METHODS: This cohort study included Medicare beneficiaries who enrolled in a state-run prescription drug plan that fully covered NSAIDs and coxibs without restriction. All study patients started use of a coxib or NSAID after January 1, 1999. The primary composite end point was a hospital admission for either myocardial infarction or ischemic stroke. Predefined exposure groups included the 3 coxibs available in the US during the study period (celecoxib, rofecoxib, and valdecoxib), as well as oral formulations of diclofenac, ibuprofen, naproxen, and a composite of all other NSAIDs. We compared the rate of cardiovascular events associated with each of these agents with that in a reference group of patients who did not use NSAIDs or coxibs, but started other medications unrelated to cardiovascular risk. Daily exposure to all study drugs was assessed based on filled prescription data. A Cox proportional hazards model stratified on calendar year that included other baseline cardiovascular risk factors constituted the primary analysis. RESULTS: We identified 74,838 users of NSAIDs or coxibs, and 23,532 comparable users of other drugs comprised the reference group. Adjusted models demonstrated a significant elevation in the event rate for rofecoxib (RR 1.15, 95% confidence interval [95% CI] 1.06-1.25) and a significant reduction in the rate for naproxen (RR 0.75, 95% CI 0.62-0.92). No other coxib or NSAID was associated with a significant increase or decrease in cardiovascular event rate. The increased rate associated with rofecoxib was seen in the first 60 days of use (adjusted RR 1.14, 95% CI 1.01-1.29) and thereafter (adjusted RR 1.14, 95% CI 1.02-1.28). Kaplan-Meier event curves showed a similar pattern of risk (early and persistent separation of the event curves) among long-term rofecoxib users at low or high baseline cardiovascular risk. CONCLUSION: We found an increased cardiovascular event rate among users of rofecoxib, and a decreased rate with naproxen use. Other coxibs and NSAIDs did not appear to be associated with a difference in event rate compared with users of other drugs. The increase in rate associated with rofecoxib was seen within the first 60 days and persisted. There was no important modification of the event rate based on the patient's baseline cardiovascular risk.
Aged↗
Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthritis.
OBJECTIVE: Concerns persist about a possible association between tumor necrosis factor alpha (TNFalpha) antagonist treatment and development of cancers in patients with rheumatoid arthritis (RA). This study was undertaken to estimate the association between treatment with biologic disease-modifying antirheumatic drugs (DMARDs) and development of cancer in patients with RA. METHODS: We conducted a cohort study pooling administrative databases from 2 US states and 1 Canadian province. A cohort of patients who had received a diagnosis of RA on > or =1 occasion and had been prescribed DMARDs was identified. We categorized patients with a prescription for a biologic DMARD as biologic DMARD users, and those with a prescription for methotrexate (MTX) but no biologic DMARD as MTX users. We used time-varying propensity scores to adjust for the large number of possible confounders and stratified proportional hazards regression to estimate the effects of biologic DMARDs on cancer. The primary end points were hematologic malignancies (lymphoma, multiple myeloma, and leukemia) and common solid tumors (colorectal, lung, stomach, breast, prostate, uterine, ovarian, urinary tract/bladder, and melanoma). RESULTS: The pooled cohort included 1,152 biologic DMARD users and 7,306 MTX users. We identified 11 hematologic malignancies and 46 solid tumors during 2,940 person-years of biologic DMARD use, and 88 hematologic malignancies and 558 solid tumors during 30,300 person-years of MTX use. Comparing biologic DMARD users with MTX users, the propensity score-adjusted pooled hazard ratio was 1.37 (95% confidence interval 0.71-2.65) for hematologic malignancies and 0.91 (95% confidence interval 0.65-1.26) for solid tumors. CONCLUSION: Our results indicate that users of biologic agents are unlikely to have a substantial increase in the risk of hematologic malignancies and solid tumors as compared with MTX users. Despite the use of large combined data sets, studying the effect of an infrequent exposure (biologic DMARDs) on rare diseases (hematologic malignancies) remains a challenge.
Aged↗
Simultaneous assessment of short-term gastrointestinal benefits and cardiovascular risks of selective cyclooxygenase 2 inhibitors and nonselective nonsteroidal antiinflammatory drugs: an instrumental variable analysis.
OBJECTIVE: To simultaneously assess the short-term reduction in risk of gastrointestinal (GI) complications and increase in risk of acute myocardial infarction (MI) by celecoxib compared with rofecoxib and several nonselective nonsteroidal antiinflammatory drugs (NSAIDs) using instrumental variable analysis. METHODS: A population of 49,711 Medicare beneficiaries ages 65 years and older who initiated nonselective NSAID or selective cyclooxygenase 2 inhibitor therapy between January 1, 1999, and December 31, 2002, was identified. The increase in risk of GI complications and MI within 180 days after initiation of NSAID (rofecoxib, diclofenac, ibuprofen, and naproxen compared with celecoxib) therapy was assessed using instrumental variable analysis. RESULTS: Compared with nonselective NSAIDs, celecoxib reduced the risk of GI complications by 1.4 per 100 users but increased the risk of MI by 0.3 per 100 users. Rofecoxib decreased GI complications by 1.1 per 100 users and increased the risk of MI by 0.3 per 100 users. Using celecoxib as the reference exposure showed an increase in the MI risk for rofecoxib (risk difference [RD] 1.40, 95% confidence interval [95% CI] -0.20, 3.01) and diclofenac (RD 6.07, 95% CI -0.02, 12.15). The RD for naproxen as well as its upper 95% CI was the lowest of all NSAIDs (RD -0.30, 95% CI -2.74, 2.14) and there was no significant difference in GI complication rates among all NSAIDs. CONCLUSION: In this instrumental variable analysis, diclofenac and rofecoxib had the least favorable benefit-risk balance among NSAIDs in older adults.
Aged↗
Sensitivity analysis and external adjustment for unmeasured confounders in epidemiologic database studies of therapeutics.
BACKGROUND: Large health care utilization databases are frequently used to analyze unintended effects of prescription drugs and biologics. Confounders that require detailed information on clinical parameters, lifestyle, or over-the-counter medications are often not measured in such datasets, causing residual confounding bias. OBJECTIVE: This paper provides a systematic approach to sensitivity analyses to investigate the impact of residual confounding in pharmacoepidemiologic studies that use health care utilization databases. METHODS: Four basic approaches to sensitivity analysis were identified: (1) sensitivity analyses based on an array of informed assumptions; (2) analyses to identify the strength of residual confounding that would be necessary to explain an observed drug-outcome association; (3) external adjustment of a drug-outcome association given additional information on single binary confounders from survey data using algebraic solutions; (4) external adjustment considering the joint distribution of multiple confounders of any distribution from external sources of information using propensity score calibration. CONCLUSION: Sensitivity analyses and external adjustments can improve our understanding of the effects of drugs and biologics in epidemiologic database studies. With the availability of easy-to-apply techniques, sensitivity analyses should be used more frequently, substituting qualitative discussions of residual confounding.
Anti-Inflammatory Agents, Non-Steroidal↗
Methods in pharmacoepidemiology: time-varying drug effects revisited.
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Case-Control Studies↗
Psychotropic medication use for behavioral symptoms of dementia.
Behavioral disturbances associated with dementia are common and burdensome. Although no psychotropic medications are currently approved by the US Food and Drug Administration (FDA) to treat such behavioral symptoms, a variety of drug classes are commonly used for these purposes. Atypical antipsychotic medications may be somewhat effective and are generally considered the pharmacologic treatments of choice; however "black box" warnings have recently been added to their labels by the FDA, warning of significantly increased risks of short-term mortality. Older conventional antipsychotic medications may also be somewhat effective but appear to pose risks that can be at least as great as those of the newer atypical drugs. Although antidepressants, benzodiazepines, mood stabilizers, acetylcholinesterase inhibitors, and N-methyl-D-aspartate (NMDA) receptor antagonists may be considered, particularly in patients with specific types of symptomatology, even less is known about their effectiveness and safety. Also, although various psychotropic medications used for behavioral disturbances in dementia patients may be somewhat effective, they have been increasingly associated with important safety risks.
Behavioral Symptoms↗
Impact of two sequential drug cost-sharing policies on the use of inhaled medications in older patients with chronic obstructive pulmonary disease or asthma.
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.
Administration, Inhalation↗
A therapeutic substitution policy for proton pump inhibitors: clinical and economic consequences.
OBJECTIVE: With the growing need to provide prescription drug benefits to older patients and to contain costs, it will be necessary to direct that coverage so as to make expenditures as efficient as possible. We evaluated the clinical and economic consequences of coverage restriction for 3 leading proton pump inhibitors (PPIs) in a large-scale natural experiment. METHODS: The study design was a time-trend analysis in the setting of a provincial drug benefits program in British Columbia, Canada. We studied all British Columbia residents aged 66 or older (N = 501,104) using linked data on all prescription drug dispensings, physician services, and hospitalizations between January 2002 and June 2004. The new policy restricted coverage to rabeprazole and required treatment failure with a histamine H2 blocker. More widely used PPIs (omeprazole, pantoprazole, and lansoprazole) had to be paid for out of pocket, unless the physician requested an exemption. The main outcome measures were utilization of PPIs, drug discontinuation rates, gastrointestinal hemorrhage rates, and drug expenditures. RESULTS: Utilization of the restricted PPIs declined sharply after the policy change (-14,850 daily doses per month per 10,000 residents, P < .0001), whereas use of the covered PPI increased sharply (+19,300, P < .0001), with 45% of all PPI users switching to the covered agent within 6 months. We found no increased use of H2 blockers or stopping of gastroprotective drugs. There was no increase in the monthly rate of hospitalization for gastrointestinal hemorrhage after the PPI restriction (P = .35) even though the study had the power to detect increases of 24 events per 10,000 residents with 95% confidence. There was a slight increase in physician visits 3 months after the policy change (P = .01) for a 2-month period when 9% of new rabeprazole users were switched back to a restricted PPI. In the first 6 months of the policy change, the provincial health plan saved at least 2.9 million Canadian dollars as a result of the policy change. CONCLUSIONS: Coverage restriction of 3 leading PPIs led to substantial utilization changes and savings, without increased noncompliance or clinical complication.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Evaluating short-term drug effects using a physician-specific prescribing preference as an instrumental variable.
BACKGROUND: Postmarketing observational studies of the safety and effectiveness of prescription medications are critically important but fraught with methodological problems. The data sources available for such research often lack information on indications and other important confounders for the drug exposure under study. Instrumental variable methods have been proposed as a potential approach to control confounding by indication in nonexperimental studies of treatment effects; however, good instruments are hard to find. METHODS: We propose an instrument for use in pharmacoepidemiology that is based on a time-varying estimate of the prescribing physician's preference for one drug relative to a competing therapy. The use of this instrument is illustrated in a study comparing the effect of exposure to COX-2 inhibitors with nonselective, nonsteroidal antiinflammatory medications on gastrointestinal complications. RESULTS: Using conventional multivariable regression adjusting for 17 potential confounders, we found no protective effect due to COX-2 use within 120 days from the initial exposure (risk difference = -0.06 per 100 patients; 95% confidence interval = -0.26 to 0.14). However, the proposed instrumental variable method attributed a protective effect to COX-2 exposure (-1.31 per 100 patients; -2.42 to -0.20) compatible with randomized trial results (-0.65 per 100 patients; -1.08 to -0.22). CONCLUSIONS: The instrumental variable method that we have proposed appears to have substantially reduced the bias due to unobserved confounding. However, more work needs to be done to understand the sensitivity of this approach to possible violations of the instrumental variable assumptions.
Aged↗
Instrumental variable analysis of secondary pharmacoepidemiologic data.
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Anti-Inflammatory Agents, Non-Steroidal↗
Prior authorization policies for selective cyclooxygenase-2 inhibitors in Medicaid: a policy review.
BACKGROUND: Many state Medicaid programs use prior authorization programs to limit spending on cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs (coxibs). However, the evidence base for the prior authorization criteria has not been examined previously. METHODS: We determined whether prior authorization was required for coxibs in state Medicaid programs and collected data on what precise criteria needed to be met for a coxib prescription to be authorized. Prior authorization criteria were compared to clinical evidence regarding which patients are most likely to benefit from coxibs. RESULTS: By mid-2004, 35 states had implemented prior authorization requirements for coxibs. Of 5 major clinical factors that identify patients likely to benefit from coxibs, 18 states (51%) included all 5 factors and 9 states (26%) included 2 or fewer. Most states (33/35; 94%) required a previous trial of nonselective nonsteroidal anti-inflammatory drugs before a coxib would be authorized. Several prior authorization programs included factors that had no connection to the clinical evidence. CONCLUSIONS: State Medicaid prior authorization policies for coxibs are heterogeneous in terms both of the criteria required to obtain a coxib and of the relationship of those criteria to clinical evidence. Development of clinically rational prescription drug policies should be a goal for all health insurers and represents an important priority for Medicare's prescription drug benefit program.
Anti-Inflammatory Agents, Non-Steroidal↗
Angiotensin inhibition after myocardial infarction: does drug class matter?
BACKGROUND: Angiotensin converting enzyme-inhibitors (ACEI) and angiotensin-II-receptor blockers (ARB) are equally efficacious in reducing mortality after MI, although the latter are far more costly. Little is known about their relative use after MI in typical care settings, and about their relative effectiveness outside the clinical trial setting. OBJECTIVES: To assess temporal trends in the relative use of ACEI and ARB after myocardial infarction, and to test for differences in 1-year survival between users of these drug classes. DESIGN: Retrospective closed cohort study. PATIENTS: Medicare beneficiaries who survived >90 days after myocardial infarction, had full prescription drug coverage, and who filled a prescription for either ACEI or ARB within 90 days of myocardial infarction. MEASUREMENTS: Relative use of ACEI versus ARB over time. Adjusted relative 1-year mortality between ACEI and ARB users. RESULTS: Between 1995 and 2004, 14,190 patients met inclusion criteria. Mean age was 80 years, 75% were female, and 90% were white. Overall, 88% received an ACEI, and 12% an ARB, with the proportion receiving an ARB increasing from 2% (1995) to 25% (2004; P<.001). Multivariate-adjusted 1-year mortality did not differ between ARB and ACEI users (HR: 1.04; 95% confidence interval: 0.88 to 1.22). The findings were similar for new users of ACEI/ARB, and for those with preexisting heart failure. CONCLUSIONS: ARB users had the same 1-year mortality after myocardial infarction as ACEI users in routine care. Use of more costly ARB has increased dramatically over time, to a quarter of ACEI/ARB users, despite the lack of a therapeutic advantage for most patients.
Aged↗
Indications for propensity scores and review of their use in pharmacoepidemiology.
Use of propensity scores to identify and control for confounding in observational studies that relate medications to outcomes has increased substantially in recent years. However, it remains unclear whether, and if so when, use of propensity scores provides estimates of drug effects that are less biased than those obtained from conventional multivariate models. In the great majority of published studies that have used both approaches, estimated effects from propensity score and regression methods have been similar. Simulation studies further suggest comparable performance of the two approaches in many settings. We discuss five reasons that favour use of propensity scores: the value of focus on indications for drug use; optimal matching strategies from alternative designs; improved control of confounding with scarce outcomes; ability to identify interactions between propensity of treatment and drug effects on outcomes; and correction for unobserved confounders via propensity score calibration. We describe alternative approaches to estimate and implement propensity scores and the limitations of the C-statistic for evaluation. Use of propensity scores will not correct biases from unmeasured confounders, but can aid in understanding determinants of drug use and lead to improved estimates of drug effects in some settings.
Bias↗