BACKGROUND: Patients, physicians, and other decision makers make implicit but inevitable trade-offs among risks and benefits of treatments. Many methods have been proposed to promote transparent and rigorous benefit-risk analysis (BRA).
OBJECTIVE: To propose a framework for classifying BRA methods on the basis of key factors that matter most for patients by using a common mathematical notation and compare their results using a hypothetical example.
METHODS: We classified the available BRA methods into three categories: 1) unweighted metrics, which use only probabilities of benefits and risks; 2) metrics that incorporate preference weights and that account for the impact and duration of benefits and risks; and 3) metrics that incorporate weights based on decision makers' opinions. We used two hypothetical antiplatelet drugs (a and b) to compare the BRA methods within our proposed framework.
RESULTS: Unweighted metrics include the number needed to treat and the number needed to harm. Metrics that incorporate preference weights include those that use maximum acceptable risk, those that use relative-value-adjusted life-years, and those that use quality-adjusted life-years. Metrics that use decision makers' weights include the multicriteria decision analysis, the benefit-less-risk analysis, Boers' 3 by 3 table, the Gail/NCI method, and the transparent uniform risk benefit overview. Most BRA methods can be derived as a special case of a generalized formula in which some are mathematically identical. Numerical comparison of methods highlights potential differences in BRA results and their interpretation.
CONCLUSIONS: The proposed framework provides a unified, patient-centered approach to BRA methods classification based on the types of weights that are used across existing methods, a key differentiating feature.
BACKGROUND: While exercise has been shown to be beneficial for some musculoskeletal pain conditions, construction workers who are regularly burdened with musculoskeletal pain may engage less in leisure-time physical activity (LTPA) due to pain. In a small pilot study, we investigate how musculoskeletal pain may influence participation in LTPA among construction workers.
METHODS: A sequential explanatory mixed-methods design was employed using a jobsite-based survey (n = 43) among workers at two commercial construction sites and one focus group (n = 5).
RESULTS: Over 93% of these construction workers reported engaging in LTPA and 70% reported musculoskeletal pain. Fifty-seven percent of workers who met either moderate or vigorous LTPA guidelines reported lower extremity pain (i.e., ankle, knee) compared with 21% of those who did not engage in either LTPA (P = 0.04). Focus group analyses indicate that workers felt they already get significant physical activity out of their job because they are "moving all the time and not sitting behind a desk." Workers also felt they "have no choice but to work through pain and discomfort [as the worker] needs to do anything to get the job done."
CONCLUSION: Pilot study findings suggest that construction workers not only engage in either moderate or vigorous LTPA despite musculoskeletal pain but workers in pain engage in more LTPA than construction workers without pain.
BACKGROUND: Clinicians prescribe antibiotics to over 65% of adults with acute bronchitis despite guidelines stating that antibiotics are not indicated.
METHODS: To identify and understand primary care clinician perceptions about antibiotic prescribing for acute bronchitis, we conducted semi-structured interviews with 13 primary care clinicians in Boston, Massachusetts and used thematic content analysis.
RESULTS: All the participants agreed with guidelines that antibiotics are not indicated for acute bronchitis and felt that clinicians other than themselves were responsible for overprescribing. Barriers to guideline adherence included 6 themes: (1) perceived patient demand, which was the main barrier, although some clinicians perceived a recent decrease; (2) lack of accountability for antibiotic prescribing; (3) saving time and money; (4) other clinicians' misconceptions about acute bronchitis; (5) diagnostic uncertainty; and (6) clinician dissatisfaction in failing to meet patient expectations. Strategies to decrease inappropriate antibiotic prescribing included 5 themes: (1) patient educational materials; (2) quality reporting; (3) clinical decision support; (4) use of an over-the-counter prescription pad; and (5) pre-visit triage and education by nurses to prevent visits.
CONCLUSIONS: Clinicians continued to cite patient demand as the main reason for antibiotic prescribing for acute bronchitis, though some clinicians perceived a recent decrease. Clinicians felt that other clinicians were responsible for inappropriate antibiotic prescribing and that better pre-visit triage by nurses could prevent visits and change patients' expectations.
This study examined health belief model (HBM) relevant constructs in the context of indoor tanning cessation. Telephone interviews were conducted between December 2011 and April 2012 with participants drawn from the Growing Up Today Study (GUTS) population, specifically, former tanning bed users (N = 14, all females; mean age, 25.65 years) who reported frequent use in 2007, but had quit by 2010. Participants identified important motivations for quitting including health and financial reasons and the central role of family and friends in providing encouragement for indoor tanning cessation. However, participants also noted substantial barriers to maintaining indoor tanning quitting (e.g., social pressures to look good, tanning salon incentives). Participants' experience of withdrawal highlighted psychological factors more often than physical factors; some were open to resuming use in the future. The findings will be useful in intervention development to encourage cessation, the strengthening of policies to regulate the indoor tanning industry, as well as public health messaging to raise awareness of this prevalent, easily accessible cancer risk behavior.
BACKGROUND: Human papilloma virus (HPV) infection is highest among Black women and women of low socio economic position (SEP). These groups face inequities in access to health information on HPV.
OBJECTIVES: Our study sought to understand key information channels for delivering health information regarding HPV and the HPV vaccine to Black women of low SEP in Boston, Massachusetts. We anticipated that, owing to a legacy of experiences of discrimination, Black women of low SEP would prefer information from trusted and accessible sources, including friends, family, and community agencies, rather than clinical providers.
METHODS: We conducted a qualitative analysis using focus groups. We conducted five focus groups among 25 women in Boston, Massachusetts.
RESULTS: Contrary to what we anticipated, we found that women in all of the focus groups preferred to receive information from a physician or health center. Participants preferred to receive print materials they could triangulate with other sources. Notably, study participants had high access to care.
CONCLUSIONS: Our study suggests that physicians are trusted and preferred sources of information on HPV for Black women of low SEP in Boston. Our data underscore an important avenue for intervention: to improve dissemination of HPV-related information through physicians, including outreach in community settings.
OBJECTIVE: To examine methods for generating evidence on health outcomes in patients with rare diseases.
DESIGN: Methodological review of existing literature.
SETTING: PubMed, Embase, and Academic Search Premier searched for articles describing innovative approaches to randomized trial design and analysis methods and methods for conducting observational research in patients with rare diseases.
MAIN OUTCOME MEASURES: We assessed information related to the proposed methods, the specific rare disease being studied, and outcomes from the application of the methods. We summarize methods with respect to their advantages in studying health outcomes in rare diseases and provide examples of their application.
RESULTS: We identified 46 articles that proposed or described methods for studying patient health outcomes in rare diseases. Articles covered a wide range of rare diseases and most (72%) were published in 2008 or later. We identified 16 research strategies for studying rare disease. Innovative clinical trial methods minimize sample size requirements (n=4) and maximize the proportion of patients who receive active treatment (n=2), strategies crucial to studying small populations of patients with limited treatment choices. No studies describing unique methods for conducting observational studies in patients with rare diseases were identified.
CONCLUSIONS: Though numerous studies apply unique clinical trial designs and considerations to assess patient health outcomes in rare diseases, less attention has been paid to innovative methods for studying rare diseases using observational data.
BACKGROUND: With proliferating treatment options for anticoagulant therapy, physicians and patients must choose among them based on their benefits and risks. Using a Discrete Choice Experiment, we elicited patients' relative preferences for specific benefits and risks of anticoagulant therapy.
METHODS AND RESULTS: We selected a sample of US patients with cardiovascular disease from an online panel and elicited their preferences for benefits and risks of anticoagulant therapy: nonfatal stroke, nonfatal myocardial infarction, cardiovascular death, minor bleeding, major bleeding, bleeding death, and need for monitoring. These attributes were used to design scenarios describing hypothetical treatments that were labeled as new drug, old drug, or no drug. Latent class analysis was used to identify groups of patients with similar preferences. A total of 341 patients completed all Discrete Choice Experiment questions. On average, patients valued a 1% increased risk of a fatal bleeding event the same as a 2% increase in nonfatal myocardial infarction, a 3% increase in nonfatal stroke, a 3% increase in cardiovascular death, a 6% increase in major bleeding, and a 16% increase in minor bleeding. The odds of choosing no drug or old drug versus new drug were 0.72 (95% confidence interval, 0.61-0.84) and 0.86 (95% confidence interval, 0.81-0.93), respectively. Previous stroke or myocardial infarction was associated with membership in the class with larger negative preferences for these outcomes.
CONCLUSIONS: Patients' preferences for various outcomes of anticoagulant therapy vary and depend on their previous experiences with myocardial infarction or stroke. Incorporating these preferences into benefit risk calculation and treatment decisions can enhance patient-centered care.
BACKGROUND: Statins are effective in preventing cardiovascular events, but patients do not fully adhere to them.
OBJECTIVE: To determine whether patients are more adherent to generic statins versus brand-name statins (lovastatin, pravastatin, or simvastatin) and whether greater adherence improves health outcomes.
DESIGN: Observational, propensity score-matched, new-user cohort study.
SETTING: Linked electronic data from medical and pharmacy claims.
PARTICIPANTS: Medicare beneficiaries aged 65 years or older with prescription drug coverage between 2006 and 2008.
INTERVENTION: Initiation of a generic or brand-name statin.
MEASUREMENTS: Adherence to statin therapy (measured as the proportion of days covered [PDC] up to 1 year) and a composite outcome comprising hospitalization for an acute coronary syndrome or stroke and all-cause mortality. Hazard ratios (HRs) and absolute rate differences were estimated.
RESULTS: A total of 90,111 patients who initiated a statin during the study was identified; 83,731 (93%) initiated a generic drug, and 6380 (7%) initiated a brand-name drug. The mean age of patients was 75.6 years, and most (61%) were female. The average PDC was 77% for patients in the generic group and 71% for those in the brand-name group (P<0.001). An 8% reduction in the rate of the clinical outcome was observed among patients in the generic group versus those in the brand-name group (HR, 0.92 [95% CI, 0.86 to 0.99]). The absolute difference was -1.53 events per 100 person-years (CI, -2.69 to -0.19 events per 100 person-years).
LIMITATION: Results may not be generalizable to other populations with different incomes or drug benefit structures.
CONCLUSION: Compared with those initiating brand-name statins, patients initiating generic statins were more likely to adhere and had a lower rate of a composite clinical outcome.
PRIMARY FUNDING SOURCE: Teva Pharmaceuticals.
Large health care databases are used extensively for pharmacoepidemiologic studies. Unique methodological issues arise when applying self-controlled designs (i.e., using within-person comparisons) for active surveillance of newly marketed drugs. We use 3 examples to illustrate bias related to population-level exposure time trends when using outcome-indexed self-controlled (i.e., case-crossover) designs for active surveillance and evaluate the ability of the case-time-control design to adjust for bias from population-level exposure time trends. We mimicked active surveillance by conducting sequential analyses after market entry for 3 medications and outcomes (valdecoxib for myocardial infarction (MI), aripiprazole for MI, and telithromycin for acute liver failure) using Medicaid Analytic eXtracts (from all 50 US states, 2000-2006). The case-crossover exposure odds ratio (EOR) in the months immediately following valdecoxib market entry implausibly suggested a 12-fold higher risk of MI during exposed time relative to unexposed time; among age-, sex-, and time-matched controls, the corresponding EOR of 4.5 indicated strong population-level exposure time trends. Over subsequent monitoring periods, case-crossover EORs rapidly dropped to 1.4. Adjustment for bias from population-level exposure time trends with the case-time-control analysis resulted in more consistent associations between valdecoxib and MI across sequential monitoring periods. Similar results were observed in each example. Strong population-level exposure time trends can bias case-crossover studies conducted among "first-wave" users of newly marketed medications. Suggested strategies can help assess and adjust for population-level exposure time trends.
PURPOSE: We present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study.
METHODS: We used a self-controlled case series to estimate the incidence rate ratio (IRR) comparing the rate of INR measurements of ≥4.0 in concomitant tramadol and VKA-exposed periods to VKA-only-exposed periods. Secondary analyses considered specific subgroups, alternative exposure criteria, alternative outcome definitions, and other drugs.
RESULTS: We identified 513 VKA users with at least 1 INR measurement ≥4.0 and concomitant tramadol and VKA exposure during the observation period. The overall IRR was 1.80 (95% confidence interval [CI], 1.53-2.10), with a stronger association among users of phenprocoumon compared to warfarin (IRR, 3.37; 95%CI, 2.50-4.53 and IRR, 1.46; 95%CI, 1.20-1.76, respectively). We observed larger IRRs with stricter outcome definitions. Concomitant tramadol and VKA exposure was also associated with an increased rate of low INR measurements (i.e., <1.5; IRR, 1.70; 95%CI, 1.37-2.13). Morphine and, to some extent, oxycodone, penicillin, beta-blockers, and inhaled beta-agonists were associated with high INR.
CONCLUSIONS: The approach successfully identified an interaction between tramadol and VKA. However, associations observed for other drugs with no known VKA interaction suggest that the current approach may have too low specificity to be useful as a screening tool, at least for drugs for which time-varying confounding may be present.
Restrictive reimbursement policies-including those based on non-formulary drug status and prior authorizations-can create situations in which patients' use of prescription medications is not fully captured in administrative claims data. This can create bias in drug safety studies that depend solely on these data. An analysis in two Canadian provinces found that primary administrative databases captured only 61 % of dispensations of drugs for which restrictive reimbursement policies were in place. A subsequent simulation study found that, in certain circumstances bias due to exposure misclassification resulting from restrictive reimbursement policies can be quite large in analyses comparing outcomes between drug exposure groups. Investigators need to be knowledgeable about the data they analyze and know whether restrictive reimbursement policies are in place that might affect the capture of drugs of interest. It is also critical to understand the mechanisms by which restrictive reimbursement might cause bias in claims-based drug safety studies, the direction and magnitude of the potential bias, and strategies that could be used to mitigate such bias.
PURPOSE: The aim of this study was to develop and test a semi-automated process for conducting routine active safety monitoring for new drugs in a network of electronic healthcare databases.
METHODS: We built a modular program that semi-automatically performs cohort identification, confounding adjustment, diagnostic checks, aggregation and effect estimation across multiple databases, and application of a sequential alerting algorithm. During beta-testing, we applied the system to five databases to evaluate nine examples emulating prospective monitoring with retrospective data (five pairs for which we expected signals, two negative controls, and two examples for which it was uncertain whether a signal would be expected): cerivastatin versus atorvastatin and rhabdomyolysis; paroxetine versus tricyclic antidepressants and gastrointestinal bleed; lisinopril versus angiotensin receptor blockers and angioedema; ciprofloxacin versus macrolide antibiotics and Achilles tendon rupture; rofecoxib versus non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) and myocardial infarction; telithromycin versus azithromycin and hepatotoxicity; rosuvastatin versus atorvastatin and diabetes and rhabdomyolysis; and celecoxib versus ns-NSAIDs and myocardial infarction.
RESULTS: We describe the program, the necessary inputs, and the assumed data environment. In beta-testing, the system generated four alerts, all among positive control examples (i.e., lisinopril and angioedema; rofecoxib and myocardial infarction; ciprofloxacin and tendon rupture; and cerivastatin and rhabdomyolysis). Sequential effect estimates for each example were consistent in direction and magnitude with existing literature.
CONCLUSIONS: Beta-testing across nine drug-outcome examples demonstrated the feasibility of the proposed semi-automated prospective monitoring approach. In retrospective assessments, the system identified an increased risk of myocardial infarction with rofecoxib and an increased risk of rhabdomyolysis with cerivastatin years before these drugs were withdrawn from the market.
BACKGROUND: Methods for near-real-time monitoring of new drugs in electronic healthcare data are needed.
OBJECTIVE: In a novel application, we prospectively monitored ischemic, bleeding, and mortality outcomes among patients initiating prasugrel versus clopidogrel in routine care during the first 2 years following the approval of prasugrel.
METHODS: Using the HealthCore Integrated Research Database, we conducted a prospective cohort study comparing prasugrel and clopidogrel initiators in the 6 months following the introduction of prasugrel and every 2 months thereafter. We identified patients who initiated antiplatelets within 14 days following discharge from hospitalizations for myocardial infarction (MI) or acute coronary syndrome. We matched patients using high-dimensional propensity scores (hd-PSs) and followed them for ischemic (i.e., MI and ischemic stroke) events, bleed (i.e., hemorrhagic stroke and gastrointestinal bleed) events, and all-cause mortality. For each outcome, we applied sequential alerting algorithms.
RESULTS: We identified 1,282 eligible new users of prasugrel and 8,263 eligible new users of clopidogrel between September 2009 and August 2011. In hd-PS matched cohorts, the overall MI rate difference (RD) comparing prasugrel with clopidogrel was -23.1 (95 % confidence interval [CI] -62.8-16.7) events per 1,000 person-years and RDs were -0.5 (-12.9-11.9) and -2.8 (-13.2-7.6) for a composite bleed event outcome and death from any cause, respectively. No algorithms generated alerts for any outcomes.
CONCLUSIONS: Near-real-time monitoring was feasible and, in contrast to the key pre-marketing trial that demonstrated the efficacy of prasugrel, did not suggest that prasugrel compared with clopidogrel was associated with an increased risk of gastrointestinal and intracranial bleeding.
WHAT IS KNOWN AND OBJECTIVE: Since 2005, a mounting base of evidence has identified that conventional antipsychotic medications are associated with an increased risk of mortality among elderly patients when compared to atypical antipsychotics. This study sought to explore the feasibility of using the Emilia-Romagna Region (RER) database for comparative safety analyses by replicating and refining risk estimates of this well-known drug safety example through meta-analysis.
METHODS: We identified a cohort of 23 681 Italian RER patients (aged ≥65) who initiated treatment with a conventional or atypical antipsychotic between 1 July 2009 and 30 June 2011. We compared 180-day mortality using Cox proportional hazards models adjusted for risk factors for death, use of other medications and measures of health services utilization intensity, all measured before antipsychotic initiation. We conducted a meta-analysis of studies with similar methods against which to compare our results.
RESULTS: Among 14 462 and 9219 patients prescribed conventional and atypical antipsychotics, respectively, we observed 2402 (16·6%) and 821 (8·9%) deaths during follow-up. Conventional antipsychotic initiators were older and generally had higher prevalence of outcome risk factors and higher baseline health service use intensity. The crude hazard ratio (HR) was 1·95 [95% confidence interval (CI), 1·80-2·11], which decreased to 1·47 (95% CI, 1·35-1·60) after full adjustment. We identified seven published studies that examined this association using similar methods. The pooled HR from these studies was 1·34 (95% CI, 1·28-1·39). Including our study, the meta-analysis yielded a summary estimate of 1·35 (95% CI, 1·31-1·40) and did not introduce any heterogeneity (I(2) = 0%; P = 0·455).
WHAT IS NEW AND CONCLUSIONS: Our results support the use of the RER database for pharmacoepidemiological studies and provide an up-to-date and pooled estimate of the magnitude of the association between mortality and conventional vs. atypical antipsychotics.
Rare diseases are an important part of the public health, affecting 6-8% of the population, and drugs intended for rare diseases comprise the fastest growing subcategory of new drug approvals in the United States. However, clinical study of therapeutics in these populations is limited by the low prevalence of these diseases, and the natural history or pathogenesis of the disease may be poorly described. In addition, commonly used strategies for evaluation of postapproval safety and effectiveness, such as meta-analyses and review of spontaneous adverse event reports, may not be applicable. Alternative methodological approaches, including natural history studies, adaptive clinical trial designs, and epidemiological studies using patient-organized registries, show substantial promise for the study of rare disease therapeutics. Bayesian trials and distributed networks of large electronic databases are the most promising strategies for active and prospective monitoring of clinical interventions for rare diseases.