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Confounding adjustment is required to estimate the effect of an exposure on an outcome in observational studies. However, variable selection and unmeasured confounding are particularly challenging when analyzing large healthcare data. Machine learning methods may help address these challenges. The objective was to evaluate the capacity of such methods to select confounders and reduce unmeasured confounding bias.A simulation study with known true effects was conducted. Completely synthetic and partially synthetic data incorporating real large healthcare data were generated. We compared Bayesian adjustment for confounding (BAC), generalized Bayesian causal effect estimation (GBCEE), Group Lasso and Doubly robust estimation, high-dimensional propensity score (hdPS), and scalable collaborative targeted maximum likelihood algorithms. For the hdPS, two adjustment approaches targeting the effect in the whole population were considered: Full matching and inverse probability weighting.In scenarios without hidden confounders, most methods were essentially unbiased. The bias and variance of the hdPS varied considerably according to the number of variables selected by the algorithm. In scenarios with hidden confounders, substantial bias reduction was achieved by using machine-learning methods to identify proxies as compared to adjusting only by observed confounders. hdPS and Group Lasso performed poorly in the partially synthetic simulation. BAC, GBCEE, and scalable collaborative-targeted maximum likelihood algorithms performed particularly well.Machine learning can help to identify measured confounders in large healthcare databases. They can also capitalize on proxies of unmeasured confounders to substantially reduce residual confounding bias.

Aims To identify and evaluate clinical pharmacology (CP) online curricular (e-Learning) resources that are internationally available for medical students. Methods Literature searches of Medline, EMBASE and ERIC databases and an online survey of faculty members of international English language medical schools, were used to identify CP e-Learning resources. Resources that were accessible online in English and aimed to improve the quality of prescribing specific medications were then evaluated using a summary percentage score for comprehensiveness, usability and quality, and for content suitability. Results Our literature searches and survey of 252 faculty (40.7% response rate) in 219 medical schools identified 22 and 59 resources respectively. After screening and removing duplicates, 8 eligible resources remained for evaluation. Mean total score was 53% (standard deviation = 13). The Australian National Prescribing Curriculum, ranked highest with a score of 77%, based primarily on very good ratings for usability, quality and suitable content. Conclusion Using a novel method and evaluation metric to identify, classify, and rate English language CP e-Learning resources, the National Prescribing Curriculum was the highest ranked open access resource. Future work is required to implement and evaluate its effectiveness on prescribing competence.

High-cost healthcare users (HCUs) are a small proportion of the population who use a disproportionate amount of healthcare resources. Although the phenomenon occurs across the entire age spectrum, older adults represent the majority of HCUs. HCUs have drawn increasing attention internationally from clinicians, health policy-makers, and government administrators. Many experts have suggested that the short- and long-term sustainability of the healthcare system is threatened unless current approaches to the care and healthcare costs of this population are modified. Complex case management and care coordination models are being implemented internationally to address HCUs despite a lack of strong evidence to support their effectiveness in improving clinical outcomes or savings in costs of care. We review what is known about HCUs and the available evidence for the effectiveness of interventions designed to manage their high and costly healthcare use.

Aims This study compares physicians' recall of the claims of benefits on cardiovascular disease and diabetes made by pharmaceutical sales representatives for drugs approved on the basis of a surrogate outcome, i.e., an off-label claim, compared with those approved on the basis of a serious morbidity or mortality (clinical) outcome. Methods Physicians in primary care practices in Montreal, Vancouver, Sacramento and Toulouse, who saw sales representatives as part of their usual practice and served a non-referral population, were contacted in blocks of 25 from a randomized list of all physicians practising in the relevant metropolitan area. We compared how frequently physicians reported that sales reps made claims of serious morbidity or mortality (clinically meaningful) benefits for drugs approved on the basis of surrogate outcomes vs. drugs approved on the basis of clinical outcomes. Results There were 448 promotions for 58 unique brand name cardiovascular and diabetes drugs. Claims of clinically meaningful benefit were reported in 156 (45%) of the 347 promotions for surrogate outcome drugs, constituting unwarranted efficacy claims, i.e., off-label promotion. Claims of clinical benefit were reported in 72 of the 101 promotions (71%) for drugs approved on the basis of clinical outcomes, adjusted OR = 0.3 (95% CI 0.2, 0.6), P

tudy Objectives Difficulties managing warfarin therapy have led to speculation that daily supplementation with a low dose of vitamin K might improve anticoagulation control and clinical outcomes. Thus we sought to review the available medical literature systematically examining the effectiveness of low-dose vitamin K supplementation for the reduction of clinically relevant adverse events due to vitamin K antagonist (VKA) use and for stabilization of the international normalized ratio (INR). Design We searched the Medline and Embase databases, the Cochrane Library, International Pharmaceutical Abstracts, and the U.S. National Institutes of Health clinical trials registry for randomized controlled trials of vitamin K supplementation versus placebo in patients receiving a VKA. We evaluated the outcomes of hemorrhage, thromboembolic events, and percentage of time in therapeutic range (TTR) of INRs by using the Grading of Recommendations Assessment, Development and Evaluation system for rating quality of evidence in the abstracted studies. Setting All randomized controlled trials studies published between 1970 and August 2012 which fitted our search strategy. Patients Patients over the age of 18 years on VKA therapy. Results Of the 624 studies we identified and screened, three studies (626 patients) were included in the meta-analysis. Most of the patients had a satisfactory TTR at baseline. We found low-quality evidence—downgraded for imprecision and risk of bias (i.e., limitation in study design and/or execution)—of no effect of vitamin K use (100 to 200 μg) on hemorrhagic events (relative risk [RR] 3.2, 95% confidence interval [CI] 0.2–64.2) and thromboembolic events (RR 2.2, 95% CI 0.1–47.5) and a significant but clinically unimportant effect on TTR with an absolute increase of 3.5% (95% CI 1.1–6.0). Conclusion This meta-analysis, despite the few studies and overall low quality, suggests no beneficial role of low-dose (100 to 200 μg) vitamin K supplementation on the reduction of clinically relevant adverse events in patients taking VKAs, despite a small improvement of the TTR. Data were insufficient, however, from patients with unstable INRs.

kaasalainen s, dolovich l, papaioannou a, holbrook a, lau e, ploeg j, levine m, cosby j & emily a (2011) Journal of Nursing and Healthcare of Chronic Illness 3, 407–418 The process of medication management for older adults with dementia Aim. The purpose of this study was to explore the personal experiences related to medication management of community-dwelling older adults diagnosed with dementia, their informal caregivers, as well as healthcare professionals who assist them. Background. Older adults who have dementia face many challenges in managing their medications while living in the community. Medication regimens used to treat a variety of conditions in older adults with dementia are usually overseen and coordinated by healthcare professionals such as community nurses, physicians and pharmacists, but often, more supports are needed. However, little research has been conducted to study the barriers and facilitators to medication adherence in this unique population. Methods. Using a grounded theory approach, 57 interviews were completed (10 nurses, 10 pharmacists, 6 physicians, 20 caregivers and 11 patients) in southern Ontario, Canada, in 2007. Findings. The findings indicate that the processes of medication management differ according to the level of dementia. A number of corresponding facilitators and barriers to medication management were identified. Medication management in early stage dementia is characterised by patients’ desire to maintain independence, denial of issues or disease, and a refusal to take medications owing to feeling angry. In late-stage dementia, older adults often refuse medications owing to delusional or suspicious thinking, which results in caregivers assuming responsibility for managing their medications. Conclusions. Older adults with dementia, their informal caregivers and the healthcare professionals who assist them are faced with the challenges of declining cognitive function and memory while trying to manage medications at home. However, a number of adherence strategies appear to be helpful and should be considered. Relevance to clinical practice. Healthcare professionals struggle with helping older adults who have dementia manage medications safely and therapeutically, often with little resources to draw from. Future work is needed to design, implement and evaluate supportive networks and interventions with the goal of helping older adults with dementia manage their medications better while living in the community.

Background The use of premedication to prevent acute transfusion reactions has been estimated to occur in 50% to 80% of transfusions. While this practice has some biologic rationale, few clinical studies have been performed to assess the efficacy of this practice, and the methodologic quality of these studies is variable. The primary objective of this study was to describe current practices regarding transfusion premedication to prevent febrile nonhemolytic transfusion reactions, mild allergic transfusion reactions, and transfusion-associated circulatory overload. Study design and methods We conducted an observational retrospective chart review of a stratified random sample of 324 transfusions that took place over a 6-month period. Data were abstracted from medical records and then scanned into a database for analysis. We calculated inter- and intraobserver agreement on key abstracted data to estimate assessment error. A two-phase adjudication process was used to determine whether or not medications given before the time of each transfusion were intended as premedications. Results Of the transfusions sampled, 1.6% (95% confidence interval, 0.4-3.9) were associated with premedication medications to prevent an acute transfusion reaction. Inter- and intraobserver reliability in the abstraction of key data points was good. Good agreement in adjudicator classification of outcomes was achieved only when adjudicators were provided with patient source documents. Conclusions Premedication use was infrequent and much less common than previously reported. Improved methods of capturing transfusion premedication, which likely require prospective assessments, are needed for future research studies.

Faced with growing drug expenditures, drug insurance plan executives have adopted various cost containment measures. One such policy, reference pricing (RP), limits drug plan reimbursement of interchangeable medicines to a reference price, which is typically equal to the price of the lowest cost interchangeable drug; any cost above that is borne by the patient. RP policies vary in the extent to which drugs are considered interchangeable by a particular plan (Lopez-Casasnovas and Puig-Junoy 2000). Under its most restrictive form—Type 1 RP—only chemically equivalent drugs (i.e., branded and “generic” versions of the same drug) are considered interchangeable. Under Type 2 RP, all drugs from the same therapeutic class are considered interchangeable. For instance, under such a system all nonsteroidal antiinflammatory drugs (NSAIDs), used for analgesia, would be reimbursed at the same rate. Under Type 3 RP, by contrast, all the different analgesic drugs, including opiates and NSAIDs, would be considered interchangeable. There have been calls to integrate RP into the Medicare prescription drug benefit (Huskamp et al. 2000; Morgan, Barer, and Agnew 2003). Unlike traditional patient cost sharing policies, RP fully subsidizes lower cost medicines, and, for those who meet exemption criteria, higher cost medicines as well. RP might therefore save money while avoiding the adverse impacts on patient health associated with patient cost sharing, which typically applies to all drugs (Tamblyn et al. 2001). While the debate on whether RP should be widely used in the U.S. has been heated, evidence on its outcomes is limited (Kanavos and Reinhardt 2003). In this paper, we use retrospective population-based claims data to compare the net drug program savings realized by the application of Type 1 and then Type 2 RP with the NSAIDs by Pharmacare, the publicly funded drug subsidy program for seniors and various other residents of British Columbia (BC), Canada. NSAIDs are among the most commonly used medications worldwide, with over 70 million prescriptions and more than 30 billion over-the-counter tablets sold each year in the U.S. (Wolfe, Lichtenstein, and Singh 1999). Over 15 percent of North Americans suffer from arthritis and/or musculoskeletal disease (Lawrence et al. 1998), and current guidelines endorse both NSAIDs and acetaminophen as first-line therapies for symptomatic osteoarthritis (ACR 2000). Potential program savings from RP depend on the vector of reimbursement prices of the drugs considered interchangeable as well as on the quantities dispensed. Potential savings are greatest when use is skewed toward higher priced drugs and the price spread—the difference between the highest and lowest drug prices—is large. The price spread can only increase (or at least not decrease) the greater the number of drugs that are deemed interchangeable; potential savings are therefore largest for Type 3 RP and lowest for Type 1 RP. There were considerable differences in the prices of the different NSAIDs in BC prior to the introduction of Type 2 RP. The cost of generic ibuprofen, for instance, varied between $0.11 and $0.16 per day (depending on the amount used), whereas the daily cost of a newer NSAID, etodolac, varied from $1.79 to $3.58 (Therapeutics Initiative 1995). Several factors can mitigate drug plan savings from RP. The first of these is the generosity of the criteria, if any, by which patients are exempted from RP. Pharmacare exempts patients who have failed or are likely to fail on a lower cost, fully reimbursed drug. Although the physician must submit a written petition for review by Pharmacare's pharmacist personnel, exemption requests are usually granted within 48 hours. Pharmacare also exempts all NSAID prescriptions written by rheumatologists from Type 2 RP. Second, physicians might “prescribe around” the RP restrictions. In other words, they might substitute relatively costly analgesic drugs, including various opiates, that are not subject to RP for those that are. Third, economic theory suggests that setting reimbursement rates according to the prices of a set of reference standard drugs might encourage the manufacturers of those drugs to raise retail prices (Zweifel and Crivelli 1996; Morton 1997; Anis and Wen 1998). On the other hand, experience from Type 2 RP introduced in European countries suggests that such price increases are offset by decreases in the retail prices of drugs that are only partially reimbursed by drug plans. Fourth, although the drug plan saves money on those beneficiaries who elect to pay extra for the higher cost drugs, these expenditures are merely shifted—overall drug costs do not decline. Finally, the health of patients who switch to lower quality drugs might suffer, resulting in an off-setting increase in drug and other treatment costs. While we do not have data on patient health outcomes and individual patients commonly report better efficacy and/or tolerability with particular NSAIDs (Walker, Chan, and Yood 1992; Langman et al. 2001), we note that there is no consistent evidence of clinically significant differences in the anti-inflammatory and analgesic effect of the numerous different NSAIDs (Brooks and Day 1991; Holbrook 2001). Retrospective analyses of observational data have suggested a hierarchy among conventional NSAIDs in their potential for gastrointestinal injury, but these differences can be attributed to variations in effective dose and channeling bias (Henry et al. 1996; Rodriguez 1998). Others have studied the effects of prior authorization programs targeting higher cost NSAIDs on the health-related quality of life (Momani, Madhavan, and Nau 2002) and medical services use (Kotzan et al. 1993; Smalley et al. 1995) of chronic NSAID users enrolled in various U.S. state Medicaid programs. None of these studies detected any deleterious effects among those who were denied Medicaid subsidies for the higher cost NSAIDs. To address the net effect of Type 1 and 2 RP on Pharmacare and patient analgesic expenditures, we used monthly Pharmacare claims data aggregated across its senior (age 65+ years) beneficiaries, over the period February 1993 to June 2001, to examine prescribing patterns, NSAID prices, Pharmacare expenditure, and patient out-of-pocket expenditure on individual NSAIDs and other analgesic drugs. A previous report indicated high accuracy and completeness of provincial government drug claims data (Williams and Young 1996a Williams and Young 1996b). We focused on seniors given that they are the highest per capita users of analgesics (Health Canada 2003), and the size and composition of the beneficiary population is relatively stable over time.

Aims To discuss the potential use of data mining and knowledge discovery in databases for detection of adverse drug events (ADE) in pharmacovigilance. Methods A literature search was conducted to identify articles, which contained details of data mining, signal generation or knowledge discovery in relation to adverse drug reactions or pharmacovigilance in medical databases. Results ADEs are common and result in significant mortality, and despite existing systems drugs have been withdrawn due to ADEs many years after licensing. Knowledge discovery in databases (KDD) is a technique which may be used to detect potential ADEs more efficiently. KDD involves the selection of data variables and databases, data preprocessing, data mining and data interpretation and utilization. Data mining encompasses a number of statistical techniques including cluster analysis, link analysis, deviation detection and disproportionality assessment which can be utilized to determine the presence of and to assess the strength of ADE signals. Currently the only data mining methods to be used in pharmacovigilance are those of disproportionality, such as the Proportional Reporting Ratio and Information Component, which have been used to analyse the UK Yellow Card Scheme spontaneous reporting database and the WHO Uppsala Monitoring Centre database. The association of pericarditis with practolol but not with other β-blockers, the association of captopril and other angiotensin-converting enzymes with cough, and the association of terfenadine with heart rate and rhythm disorders could be identified by mining the WHO database. Conclusion In view of the importance of ADEs and the development of massive data storage systems and powerful computer systems, the use of data mining techniques in knowledge discovery in medical databases is likely to be of increasing importance in the process of pharmacovigilance as they are likely to be able to detect signals earlier than using current methods.