Updating the Comparative Evidence on Second-Generation Antipsychotic Use With Schizophrenia.

Objective: The objective of this study was to conduct a systematic review of literature comparing second-generation antipsychotics (SGAs) with each other and with first-generation antipsychotics (FGAs) in treating schizophrenia. Methods: MEDLINE, the Cochrane Library, and PsycINFO databases were searched through January 2020. Following standard methods, recent high-quality systematic reviews of each drug comparison and subsequently published primary studies were included to update the meta-analyses with any new data. Two reviewers independently conducted study selection, abstraction, and quality assessment. Results: Two systematic reviews and 29 newer trials (total of 162 trials of SGAs, N=53,861; 116 trials of SGAs versus FGAs, N=119,558) were included. Most trials were of fair quality, industry-funded, and included older SGAs and a few recently approved SGAs (asenapine, lurasidone, iloperidone, cariprazine, brexpiprazole and long-acting injection [LAI] formulations of aripiprazole and paliperidone). Older SGAs had similar effects on function, quality of life, mortality, and adverse event incidence, although clozapine improved symptoms more than most other drugs and olanzapine and risperidone were superior to some other drugs. Olanzapine, risperidone, ziprasidone, and aripiprazole performed similarly on outcomes of benefit compared with haloperidol. Risperidone LAI and olanzapine resulted in fewer withdrawals due to adverse events, but risk of diabetes increased with olanzapine. Haloperidol had greater incidence of adverse events than did olanzapine and risperidone, but similar effects on other outcomes. Conclusions: Most comparative evidence favored older SGAs, with clozapine, olanzapine, and risperidone superior on more outcomes than other SGAs. Older SGAs had similar benefits as haloperidol but with fewer adverse events.

Preliminary validation of the Claudication Symptom Instrument (CSI).

This article describes the development of the Claudication Symptom Instrument (CSI) and its measurement properties for evaluating the symptom experience of patients diagnosed with intermittent claudication (IC). We conducted semi-structured qualitative interviews with IC patients for item development and cognitive interviews in which patient comprehension of items was tested. We evaluated measurement properties using data collected and analyzed in the context of an observational comparative effectiveness study of IC treatments. Items measuring five symptom important to patients were developed and cognitively tested: Pain, Numbness, Heaviness, Cramping, and Tingling. Item means (higher means worse) ranged from 1.1 (Tingling) to 2.3 (Pain) (range: 0 'none' to 4 'extreme'). Rasch analysis yielded support for an overall score (χ2=26.5, df=20, p=0.15). The total CSI score differed by clinician-rated severity of mild versus moderate ( p<0.05), but not moderate versus severe. Re-administration of the CSI 5-10 days after baseline yielded an intra-class correlation coefficient of 0.86. Changes in CSI total score and VASCUQOL total score between baseline and 6 months post-treatment were correlated at -0.52 ( p<0.05). The CSI preliminarily meets accepted measurement standards for content validity, internal consistency and test-retest reliability, construct validity, and sensitivity for detecting change. Because of its high test-retest reliability, it may also be useful in clinical care with individual patients. It takes approximately 3 minutes to complete.

Favorable and publicly funded studies are more likely to be published: a systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to identify and quantify the characteristics of studies associated with the likelihood of publication. STUDY DESIGN AND SETTING: We searched for manuscripts that tracked cohorts of clinical studies ("cohorts") that from launch to publication. We explored the association of study characteristics with the probability of publication via traditional meta-analyses and meta-regression using random effects models. RESULTS: The literature review identified 85 cohorts of studies that met our inclusion criteria. The probability of publication was significantly higher for studies whose characteristics were favorable (odds ratio [OR] = 2.04; 95% confidence interval [CI]: 1.62, 2.57) or statistically significant (OR = 2.07; 95% CI: 1.52, 2.81), had a multicenter design (OR = 1.32; 95% CI: 1.16, 1.45), and were of later regulatory phase (3/4 vs. 1/2, OR = 1.34; 95% CI: 1.14, 1.49). Industry funding was modestly associated with lower (OR = 0.81; 95% CI: 0.67, 0.99) probability of publication. An exploratory analysis of effect modification revealed that the effect of the study characteristic "favorable results" on likelihood for publication was stronger for industry-funded studies. CONCLUSION: The study characteristics of favorable and significant results were associated with greater probability of publication.

Design Recommendations for Pharmacogenomics Clinical Decision Support Systems.

The use of pharmacogenomics (PGx) in clinical practice still faces challenges to fully adopt genetic information in targeting drug therapy. To incorporate genetics into clinical practice, many support the use of Pharmacogenomics Clinical Decision Support Systems (PGx-CDS) for medication prescriptions. This support was fueled by new guidelines to incorporate genetics for optimizing drug dosage and reducing adverse events. In addition, the complexity of PGx led to exploring CDS outside the paradigm of the basic CDS tools embedded in commercial electronic health records. Therefore, designing the right CDS is key to unleashing the full potential of pharmacogenomics and making it a part of clinicians' daily workflow. In this work, we 1) identify challenges and barriers of the implementation of PGx-CDS in clinical settings, 2) develop a new design approach to CDS with functional characteristics that can improve the adoption of pharmacogenomics guidelines and thus patient safety, and 3) create design guidelines and recommendations for such PGx-CDS tools.

Effectiveness of a Medical vs Revascularization Intervention for Intermittent Leg Claudication Based on Patient-Reported Outcomes.

Importance: Intermittent claudication (IC) is the most common presentation of infrainguinal peripheral artery disease. Both medical and revascularization interventions for IC aim to increase walking comfort and distance, but there is inconclusive evidence of the comparative benefit of revascularization given the possible risk of limb loss. Objective: To compare the effectiveness of a medical (walking program, smoking cessation counseling, and medications) vs revascularization (endovascular or surgical) intervention for IC in the community, focusing on outcomes of greatest importance to patients. Design, Setting, and Participants: Longitudinal (12-month follow-up) prospective observational cohort study conducted between July 3, 2011, and November 5, 2014, at 15 clinics associated with 11 hospitals in Washington State. Participants were 21 years or older with newly diagnosed or established IC. Interventions: Medical or revascularization interventions. Main Outcomes and Measures: Primary end points were 12-month change scores on the distance, speed, and stair-climb domains of the Walking Impairment Questionnaire (score range, 0-100). Secondary outcomes were change scores on the Walking Impairment Questionnaire pain domain (score range, 0-100), Vascular Quality of Life Questionnaire (VascuQol) (score range, 1-7), European Quality of Life-5 Dimension Questionnaire (EQ-5D) (score range, 0-1), and Claudication Symptom Instrument (CSI) (score range, 0-4). Results: A total of 323 adults were enrolled, with 282 (87.3%) in the medical cohort. At baseline, the mean duration of disease was longer for participants in the medical cohort, while those in the revascularization cohort reported more severe disease. Other characteristics were well balanced. At 12 months, change scores in the medical cohort reached significance for the following 3 outcomes: speed (5.9; 95% CI, 0.5-11.3; P = .03), VascuQol (0.28; 95% CI, 0.08-0.49; P = .008), and EQ-5D (0.038; 95% CI, 0.011-0.066; P = .006). In the revascularization cohort, there were significant improvements in the following 7 outcomes: distance (19.5; 95% CI, 7.9-31.0; P = .001), speed (12.1; 95% CI, 1.4-22.8; P = .03), stair climb (11.4; 95% CI, 1.3-21.5; P = .03), pain (20.7; 95% CI, 11.0-30.4; P < .001), VascuQol (1.10; 95% CI, 0.80-1.41; P < .001), EQ-5D (0.113; 95% CI, 0.067-0.159; P < .001), and CSI (-0.63; 95% CI, -0.96 to -0.31; P < .001). Relative improvements (percentage changes) at 12 months in the revascularization cohort over the medical cohort were observed as follows: distance (39.1%), speed (15.6%), stair climb (9.7%), pain (116.9%), VascuQol (41%), EQ-5D (18%), and CSI (13.5%). Conclusions and Relevance: Among patients with IC, those in the revascularization cohort had significantly improved function (Walking Impairment Questionnaire), better health-related quality of life (VascuQol and EQ-5D), and fewer symptoms (CSI) at 12 months compared with those in the medical cohort, providing important information to inform treatment strategies in the community.

The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop.

BACKGROUND: Increases in prescriptions of opioid medications for chronic pain have been accompanied by increases in opioid overdoses, abuse, and other harms and uncertainty about long-term effectiveness. PURPOSE: To evaluate evidence on the effectiveness and harms of long-term (>3 months) opioid therapy for chronic pain in adults. DATA SOURCES: MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL (January 2008 through August 2014); relevant studies from a prior review; reference lists; and ClinicalTrials.gov. STUDY SELECTION: Randomized trials and observational studies that involved adults with chronic pain who were prescribed long-term opioid therapy and that evaluated opioid therapy versus placebo, no opioid, or nonopioid therapy; different opioid dosing strategies; or risk mitigation strategies. DATA EXTRACTION: Dual extraction and quality assessment. DATA SYNTHESIS: No study of opioid therapy versus no opioid therapy evaluated long-term (>1 year) outcomes related to pain, function, quality of life, opioid abuse, or addiction. Good- and fair-quality observational studies suggest that opioid therapy for chronic pain is associated with increased risk for overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction, although there are few studies for each of these outcomes; for some harms, higher doses are associated with increased risk. Evidence on the effectiveness and harms of different opioid dosing and risk mitigation strategies is limited. LIMITATIONS: Non-English-language articles were excluded, meta-analysis could not be done, and publication bias could not be assessed. No placebo-controlled trials met inclusion criteria, evidence was lacking for many comparisons and outcomes, and observational studies were limited in their ability to address potential confounding. CONCLUSION: Evidence is insufficient to determine the effectiveness of long-term opioid therapy for improving chronic pain and function. Evidence supports a dose-dependent risk for serious harms. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Adherence to oral migraine-preventive medications among patients with chronic migraine.

BACKGROUND: Chronic migraine (CM) is a disabling disorder characterized by ≥15 headache days per month that has been shown to significantly reduce quality of life. Migraine-prevention guidelines recommend preventive medications as the standard of care for patients with frequent migraine. The aim of this study was to assess adherence to 14 commonly prescribed oral migraine-preventive medications (OMPMs) among patients with CM. METHODS: Retrospective claims analysis of a US claim database (Truven MarketScan® Databases) was queried to identify patients who were at least 18 years old, diagnosed with CM, and initiated an OMPM (antidepressants, beta blockers, or anticonvulsants) between January 1, 2008 and September 30, 2012. Medication possession ratios (MPR) and proportion of days covered (PDC) were calculated for each patient. A cutoff of ≥80% was used to classify adherence. The odds of adherence between OMPMs were compared using logistic regression models. RESULTS: Of the 75,870 patients identified with CM, 8688 met the inclusion/exclusion criteria. Adherence ranged between 26% to 29% at six months and 17% to 20% at 12 months depending on the calculation used to classify adherence (PDC and MPR, respectively). Adherence among the 14 OMPMs was similar except for amitriptyline, nortriptyline, gabapentin, and divalproex, which had significantly lower odds of adherence when compared to topiramate. CONCLUSION: Adherence to OMPMs is low among the US CM population at six months and worsens by 12 months.

Using indirect comparisons to compare interventions within a Cochrane review: a tool for comparative effectiveness research.

AIM: Assessing relative performance among competing interventions is an important part of comparative effectiveness research. Bayesian indirect comparisons add information to existing Cochrane reviews, such as which intervention is likely to perform best. However, heterogeneity variance priors may influence results and, potentially, clinical guidance. METHODS: We highlight the features of Bayesian indirect comparisons using a case study of a Cochrane review update in asthma care. The probability that one self-management educational intervention outperforms others is estimated. Simulation studies investigate the effect of heterogeneity variance prior distributions. RESULTS: Results suggest a 55% probability that individual education is best, followed by combination (39%) and group (6%). The intervention with few trials was sensitive to prior distributions. CONCLUSION: Bayesian indirect comparisons updates of Cochrane reviews are valuable comparative effectiveness research tools.

Implementation of a "real-world" learning health care system: Washington State's Comparative Effectiveness Research Translation Network (CERTAIN).

BACKGROUND: Learning health care systems apply the experiences of prior patients to inform care and help to guide decision making for current patients. These systems should help to deliver more effective, efficient, and appropriate care. Most examples of learning systems derive from integrated care delivery systems and examples of such systems in the community at large have been lacking. METHODS: The comparative effectiveness research translation network (CERTAIN) is a learning system bringing together hospitals and outpatient clinics across Washington State. CERTAIN leverages existing medical record-based data collection taking place at nearly all statewide hospitals and links this data collection with patient-reported information about function and quality of life. RESULTS: We have described the components of the CERTAIN infrastructure, the elements of a pilot project evaluating treatments of claudication, and the opportunities and challenges of developing and implementing a "real world" learning system. Examples in the areas of vascular disease, spine care, gastrointestinal disease, and urology. CONCLUSION: Learning health care systems face many operational challenges but hold great promise for discovery and implementation of more effective clinical practices.

Headache-related health resource utilisation in chronic and episodic migraine across six countries.

OBJECTIVE: To describe headache-related health resource usage in chronic and episodic migraine across six countries. METHODS: A web-based questionnaire eliciting data on several topics, including health resource usage, was administered to panellists with migraine from the USA, Canada, UK, Germany, France and Australia. Respondents were grouped into episodic and chronic migraine, based on reported headache phenotype and headache-day frequency. ORs were calculated, comparing usage in each country to that in the US, controlling for chronic versus episodic migraine and other factors. RESULTS: Relative to the USA, the odds of visiting a provider for headache during the preceding 3 months were significantly higher in all countries, except Germany. Respondents in France were more likely to report having a provider they typically visited for headache-related care. The odds of visiting the emergency department for headache were significantly lower in France, the UK and Germany, and hospitalisation for headache was significantly more frequent in Canada and Australia. Respondents from all countries, except Canada, were more likely to report currently using a prescription-acute treatment, and those from France were more likely to report trying more than three acute treatments. Preventive treatment use did not differ significantly. CONCLUSIONS: Headache-related resource usage differed significantly between the USA and other countries. US respondents were generally less likely to report recent provider visits and use of prescription-acute treatments. They were more likely to report emergency department visits than in European countries, but less likely to report hospitalisation than in Canada and Australia.

Practical choices for infobutton customization: experience from four sites.

Context-aware links between electronic health records (EHRs) and online knowledge resources, commonly called "infobuttons" are being used increasingly as part of EHR "meaningful use" requirements. While an HL7 standard exists for specifying how the links should be constructed, there is no guidance on what links to construct. Collectively, the authors manage four infobutton systems that serve 16 institutions. The purpose of this paper is to publish our experience with linking various resources and specifying particular criteria that can be used by infobutton managers to select resources that are most relevant for a given situation. This experience can be used directly by those wishing to customize their own EHRs, for example by using the OpenInfobutton infobutton manager and its configuration tool, the Librarian Infobutton Tailoring Environment.

Adherence to guidelines for the management of excessive warfarin anticoagulation.

OBJECTIVES: The American College of Chest Physicians (ACCP) provides guidelines for the management of excessive anticoagulation in patients receiving warfarin. This multi-site prospective cohort study evaluated patient-level practice patterns and adherence to ACCP guidelines. METHODS: Patients presenting with an INR > or = 4.5 between January 3 and April 29, 2005 were observed and therapeutic management documented. Adherence was assessed retrospectively. RESULTS: Four hundred and seventeen patients from 22 centers were observed. The mean, initial INR was 7.7. At enrollment, 85% of the patients had an INR < 9 or were not bleeding; 15% were seriously bleeding. Treatment for 170 patients (41%) did not adhere to guidelines. Among those, 15% were undertreated, 48% overtreated. Lack of adherence was attributed primarily to excessive doses (mean initial dose = 6.9 mg) and inappropriate routes of administration (subcutaneous or intramuscular) of vitamin K1. CONCLUSION: Adherence to the ACCP guidelines is low. Inappropriate use of vitamin K1 is the primary reason.