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1.  Measures of vitamin K antagonist control reported in atrial fibrillation and venous thromboembolism studies: a systematic review 
BMJ Open  2014;4(6):e005379.
Objective
To aid trialists, systematic reviewers and others, we evaluated the degree of standardisation of control measure reporting that has occurred in atrial fibrillation (AF) and venous thromboembolism (VTE) studies since 2000; and attempted to determine whether the prior recommendation of reporting ≥2 measures per study has been employed.
Design
Systematic review.
Search strategy
We searched bibliographic databases (2000 to June 2013) to identify AF and VTE studies evaluating dose-adjusted vitamin K antagonists (VKAs) and reporting ≥1 control measure. The types of measures reported, proportion of studies reporting ≥2 measures and mean (±SD) number of measures per study were determined for all studies and compared between subgroups.
Data extraction
Through the use of a standardised data extraction tool, we independently extracted all data, with disagreements resolved by a separate investigator.
Results
148 studies were included, 57% of which reported ≥2 control measures (mean/study=2.13±1.36). The proportion of time spent in the target international normalised ratio range (TTR) was most commonly reported (79%), and was frequently accompanied by time above/below range (52%). AF studies more frequently reported ≥2 control measures compared with VTE studies (63% vs 37%; p=0.004), and reported a greater number of measures per study (mean=2.36 vs 1.53; p<0.001). Observational studies were more likely to provide ≥2 measures compared with randomised trials (76% vs 33%; p<0.001) and report a greater number of measures (mean=2.58 vs 1.63; p<0.001). More recent studies (2004–2013) reported ≥2 measures more often than older (2000–2003) studies (59% vs 35%; p=0.05) and reported more measures per study (mean=2.23 vs 1.48; p=0.02).
Conclusions
While TTR was often utilised, studies reported ≥2 measures of VKA control only about half of the time and lacked consistency in the types of measures reported. A trend towards studies reporting greater numbers of VKA control measures over time was observed over our review time horizon, particularly, with AF and observational studies.
doi:10.1136/bmjopen-2014-005379
PMCID: PMC4067815  PMID: 24951111
2.  Estimating a minimal clinically important difference for the EuroQol 5-dimension health status index in persons with multiple sclerosis 
Background
Limited data define what constitutes a minimal clinically important difference (MCID) on the EuroQol 5-Dimension (EQ-5D) health status index in persons with multiple sclerosis (PwMS). We sought to estimate the MCID for the EQ-5D health index in North American PwMS.
Methods
PwMS completing the Patient Determined Disease Steps (PDDS) scale, 12-Item Multiple Sclerosis Walking Scale (MSWS-12) and EQ-5D as part of the North American Research Committee on Multiple Sclerosis (NARCOMS) registry’s spring 2011 update and supplemental survey were included in this retrospective, cross-sectional study. Distribution-based (standard error of measurement [SEM], 0.50 standard deviation [SD] and 0.33 SD unit) approaches were used to estimate a range of MCIDs for the EQ-5D based upon disease severity groups determined by the PDDS and MSWS-12 tertiles.
Results
A total of 3,044 participants were included. Moderately strong correlations between the EQ-5D and the PDDS and MSWS-12 were observed (Spearman’s r = -0.56 and -0.59, respectively, p < 0.0001 for both). MCID estimates based on PDDS score categories ranged from 0.065-0.158 (SEMs), 0.059-0.142 (0.50 SDs) and 0.039-0.095 (0.33 SDs). MCID estimates as measured by MSWS-12 tertile categories ranged from 0.068-0.098 (SEMs), 0.061-0.088 (0.50 SDs), and 0.041-0.059 (0.33 SDs). Across both the PDDS and tertiles of MSWS-12, MCID estimates tended to be larger as disease severity worsened. Mean weighted MCID estimates ranged from 0.05-0.084 for both the PDDS and MSWS-12 tertiles.
Conclusion
MCID estimates for the EQ-5D in PwMS were within the range of estimates seen for other disease states and appeared to be larger in those reporting more severe disease.
doi:10.1186/1477-7525-12-66
PMCID: PMC4018196  PMID: 24886430
Multiple sclerosis; Quality of life; Health status; EuroQol 5-Dimension; Minimal clinically important difference
3.  Impact of angina frequency on health utility values of patients with chronic stable angina 
Background
Chronic angina is a profoundly symptomatic disease. We evaluated the relationship between angina frequency and health utility.
Methods
We used data from stable angina patients reporting ≥3 attacks/week enrolled in the Efficacy of Ranolazine in Chronic Angina (ERICA) trial. Angina frequency was classified using the Seattle Angina Questionnaire angina frequency (SAQAF) domain into no (100); monthly (61-99); weekly (31-60); and daily (0-30) angina. EuroQol (EQ)-5D health utility scores were derived from SAQ data using two mapping equations. Median EQ-5D utility scores for each SAQAF classification after the 6-week trial period were calculated (reported as: Equation 1/Equation 2). Changes in EQ-5D utility scores from baseline to end-of-trial for patients achieving and not achieving a ≥20-point improvement in SAQAF score and improving and not improving ≥1 SAQAF classification were compared.
Results
Median EQ-5D utility scores (n = 548) were 0.68/0.60. Compared to patients reporting no angina symptoms (n = 28; 0.89/0.87) patients reporting monthly (n = 188; 0.80/0.76), weekly (n = 283; 0.72/0.65) and daily (n = 49; 0.65/0.54) symptoms had poorer health utility (p < 0.001 for both equations). Patients improving ≥1SAQAF classification (n = 254/541, 47%) experienced a median 0.05/0.07 greater improvement in EQ-5D health utility compared to those not improving ≥1 classification (p < 0.001 for both equations). Patients improving ≥20-points on the SAQAF (n = 355/541, 66%) experienced a median 0.06/0.07 greater improvement in health utility compared to those not achieving a ≥20-point improvement (p < 0.001 for both).
Conclusions
Chronic angina patient health utility decreases as angina frequency increases. Patients reporting clinically important improvement in angina frequency experience a tangible improvement in health utility.
Clinical trial registration
NCT00091429
doi:10.1186/1477-7525-12-39
PMCID: PMC3995582  PMID: 24628859
Chronic angina; Ranolazine; Seattle Angina Questionnaire; EQ-5D; Health utility
4.  Short-Term Consequences of Angiographically-Confirmed Coronary Stent Thrombosis 
PLoS ONE  2013;8(10):e77330.
Objectives
To conduct a meta-analysis to quantify the real-world incidence of in-hospital or 30-day death or myocardial infarction (MI), and angiographically-confirmed ST-related treatment costs.
Background
The short-term clinical and economic consequences of coronary stent thrombosis (ST) are thought to be significant.
Methods
We searched MEDLINE, Embase and Scopus from January 2000-July 2012 to identify observational/registry studies that evaluated a cohort of ≥25 patients experiencing angiographically-confirmed thrombosis of a drug-eluting or bare-metal stent, required the use of dual-antiplatelet therapy for guideline-recommended durations, and reported incidences of in-hospital or 30-day death or MI and/or ST-related treatment costs. Incidences and costs from each study were pooled using random-effects meta-analysis.
Results
Twenty-three studies were included. Of the 13 studies reporting in-hospital outcomes, 12 (N=8,832 STs) reported mortality data, with the pooled incidence rate estimated to be 7.9%, 95%CI=5.4%-11.3%, I2=86%. Ten studies (N=1,294 STs) reported 30-day death, with a pooled incidence of 11.6%, 95%CI=8.8%-15.1%, I2=55%. Patients experiencing early ST (within 30-days of implant) had higher in-hospital and 30-day mortality than those experiencing very-late ST (interaction p<0.04 for both). Stent type had no significant effect on in-hospital or 30-day mortality. In the 5 studies (N=542 STs) and 3 studies (N=180 STs) reporting in-hospital and 30-day MI, respectively, the pooled incidence rates were 6.1%, 95%CI=2.1%-16.2%, I2=88% and 9.5%, 95%CI=3.8%-22.0%, I2=65%. One study reported costs associated with ST, estimating the median/patient cost of hospitalization to treat early ST at $11,134 (in 2000US$).
Conclusions
Regardless of stent type used, the short-term consequences of coronary ST appear significant.
doi:10.1371/journal.pone.0077330
PMCID: PMC3797034  PMID: 24143219
5.  Methods used to conduct and report Bayesian mixed treatment comparisons published in the medical literature: a systematic review 
BMJ Open  2013;3(7):e003111.
Objectives
To identify published closed-loop Bayesian mixed treatment comparisons (MTCs) and to summarise characteristics regarding their conduct and reporting.
Design
Systematic review.
Methods
We searched multiple bibliographic databases (January 2006–31 July 2011) for full-text, English language publications of Bayesian MTCs comparing the effectiveness or safety of ≥3 interventions based on randomised controlled trials and having at least one closed loop. Methodological and reporting characteristics of MTCs were extracted in duplicate and summarised descriptively.
Results
We identified 34 Bayesian MTCs spanning 13 clinical areas. Publication of MTCs increased over the 5-year period; with 76.5% published during or after 2009. MTCs included a mean (±SD) of 35.9±30.1 trials (n=33 459±71 233 participants) and 8.5±4.3 interventions (85.7% pharmacological). Non-informative and informative prior distributions were reported to be used in 44.1% and 8.8% of MTCs, respectively, with the remainder failing to specify the prior used. A random-effects model was used to analyse the networks of trials in 58.5% of MTCs, all using WinBUGS; however, code was infrequently provided (20.6%). More than two-thirds of MTCs (76.5%) also conducted traditional meta-analysis. Methods used to evaluate convergence, heterogeneity and inconsistency were infrequently reported, but from those providing detail, methods appeared varied. MTCs most often used a binary effect measure (85.3%) and ranking of interventions based on probability was common (61.8%), although rarely displayed in a figure (8.8% of MTCs). MTCs were published in 24 different journals with a mean impact factor of 9.20±8.71. While 70.8% of journals imposed limits on word counts and 45.8% limits on the number of tables/figures, online supplements/appendices were allowed in 79.2% of journals. Publication of closed-loop Bayesian MTCs is increasing in frequency, but details regarding their methodology are often poorly described. Efforts in clarifying the appropriate methods and reporting of Bayesian MTCs should be of priority.
doi:10.1136/bmjopen-2013-003111
PMCID: PMC3717466  PMID: 23878173
Statistics & Research Methods; mixed treatment comparison; network meta-analysis
6.  Estimation of the effect of dalfampridine-ER on health utility by mapping the MSWS-12 to the EQ-5D in multiple sclerosis patients 
Background
Trials have not assessed the effect of dalfampridine-extended release (dalfampridine-ER) on health utility. We sought to evaluate the effect of dalfampridine-ER tablets (prolonged-release fampridine in Europe) on health utility in patients with multiple sclerosis (MS) by mapping subjects’ individual item scores from the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) onto the Euroqol 5-Dimension (EQ-5D) health utility index.
Methods
Data from study MS-F203, a randomized trial of dalfampridine-ER tablets, 10 mg twice daily, in patients with MS, were used to calculate the health utility scores with two MSWS-12 to EQ-5D mapping equations (one derived in a North American [NA] registry, the other a United Kingdom [UK] registry). MS-F203 participants were categorized as dalfampridine-ER 20%-responders (achieving ≥20% improvement on the Timed 25-Foot Walk), dalfampridine-ER 20%-nonresponders (<20% improvement), or placebo patients. Mean change in health utility scores from baseline to each double-blind treatment evaluation (visits 3-6 occurring at post-randomization weeks 2, 6, 10, and 14) and each off-drug follow-up evaluation (visits 7-8 occurring at weeks 16 and 18) were calculated and reported as effect sizes (ESs).
Results
Using the NA-derived equation, dalfampridine-ER 20%-responders demonstrated improvement in health utility vs. placebo; starting at week 6 (mean difference in ES = 0.44, p = 0.002) and maintained at weeks 10 (ES = 0.41, p = 0.01) and 14 (ES = 0.71, p < 0.001). These improvements were no longer evident after dalfampridine-ER was discontinued (p > 0.05 at weeks 16 and 18). Dalfampridine-ER 20%-nonresponders did not show improvement vs. placebo at any visit (p > 0.05 for all). When using the UK-derived equation, improvement was seen in dalfampridine-ER 20%-responders vs. placebo at weeks 2, 6, 10, and 14 (ESs = 0.49, 0.55, 0.59, and 0.99; p < 0.03 for all), but not when dalfampridine-ER was discontinued (weeks 16 and 18; p > 0.05 for both). Dalfampridine-ER 20%-nonresponders showed no improvement at any visit (p > 0.05 for all).
Conclusion
Regardless of the equation used, dalfampridine-ER response was associated with an improvement in health utility.
doi:10.1186/1477-7525-11-105
PMCID: PMC3699372  PMID: 23799913
Dalfampridine; EQ-5D; MSWS-12; Multiple sclerosis
7.  Mapping the 12-item multiple sclerosis walking scale to the EuroQol 5-dimension index measure in North American multiple sclerosis patients 
BMJ Open  2013;3(5):e002798.
Objective
To map the 12-item Multiple Sclerosis Walking Scale (MSWS-12) onto the EuroQol 5-dimension (EQ-5D) health-utility index in multiple sclerosis (MS) patients participating in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry.
Design
Cross-sectional MSWS-12 to EQ-5D cross-walking analysis.
Setting
NARCOMS registry spring 2010 biannual update and supplemental survey.
Participants
North American patients completing both the MSWS-12 and the EQ-5D randomly split into derivation and validation cohorts.
Outcome measures
Ordinary least squares regression was performed within the derivation cohort, with participants’ EQ-5D as the dependent variable. Results of the MSWS-12 were input as independent variable(s) into six regression models. Model goodness-of-fit was subsequently assessed in the validation cohort using the mean absolute error (MAE), root mean square error (RMSE) and the adjusted R2. The best performing model was refined in the entire cohort and utilised for additional analyses.
Results
A total of 3505 NARCOMS participants were included. Their mean±SD EQ-5D and MSWS-12 scores were 0.74±0.18 and 50.8±33.5, respectively, and these assessments were found to be moderately correlated (r=–0.553, p<0.001). The model using all individual MSWS-12 item scores as independent variables was found to have the best fit (MAE=0.109±0.096, RMSE=0.145, adjusted R2=0.329). The percentage of EQ-5D estimates within 0.05 and 0.10 of the actual value were 30% and 61%, respectively. This mapping equation was more precise in patients with moderate mobility impairment (MAE=0.087±0.061 at patient-determined disease step (PDDS) of 3–6) and less precise in patients with no (MAE=0.141±0.128 at PDDS of 0–2) or severe mobility impairment (MAE=0.121±0.049 at PDDS ≥7).
Conclusions
The EQ-5D scores can be predicted using the MSWS-12 item scores with reasonable precision in North American patients with MS. Prediction estimates were more precise in patients with moderate mobility impairment.
doi:10.1136/bmjopen-2013-002798
PMCID: PMC3664349  PMID: 23793699
Health Economics; Neurology; Statistics & Research methods
8.  College and School of Pharmacy Characteristics Associated With US News and World Report Rankings 
Objective. To determine the association between characteristics of colleges and schools of pharmacy and their rankings according to US News and World Report.
Methods. The 2008 US News and World Report, mean ranking scores (ranging from 2.0 to 5.0) for 78 US colleges and schools of pharmacy were compared with college and school characteristics, including academic program, students, faculty, and scholarship. The adjusted difference in mean ranking score associated with each characteristic was determined using a multivariate mixed linear regression model.
Results. The most powerful identified predictors of mean ranking score included the amount of grant funding (National Institutes of Health [NIH] and non-NIH funding) a college or school of pharmacy received and the yearly publication rates of its department of pharmacy (p≤0.001 for both). The adjusted mean ranking scores for colleges and schools receiving >$5 million and $1 million to $5 million in scholarly grant funding were respectively 0.77 and 0.26 points higher than those receiving none. Adjusted mean ranking scores for colleges and schools whose departments of pharmacy practice had publishing rates of >20 papers and 11 to 20 papers were respectively 0.40 and 0.17 points higher than those publishing ≤10 (p<0.05 for both).
Conclusion. The characteristic of colleges and schools of pharmacy most associated with US News and World Report rankings appears to be their scholarly productivity.
doi:10.5688/ajpe77355
PMCID: PMC3631730  PMID: 23610473
pharmacy education; ranking; assessment; teaching; publications; scholarship
9.  Impact of Mobility Impairment on Indirect Costs and Health-Related Quality of Life in Multiple Sclerosis 
PLoS ONE  2013;8(1):e54756.
This study was conducted to estimate the indirect costs and health-related quality of life (HRQoL) (utilities) of multiple sclerosis (MS) patients in the United States (US), and to determine the impact of worsening mobility on these parameters. In collaboration with the North American Research Committee on Multiple Sclerosis (NARCOMS) registry we conducted a cross-sectional study of participants who completed the biannual update and supplemental spring 2010 survey. Demographic, employment status, income, mobility impairment, and health utility data were collected from a sample of registry participants who met the study criteria and agreed to participate in the supplemental Mobility Study. Mean annual indirect costs per participant in 2011US$ and mean utilities for the population and for cohorts reporting different levels of mobility impairment were estimated. Analyses included 3,484 to 3,611 participants, based on survey completeness. Thirty-seven percent of registrants were not working or attending school and 46.7% of these reported retiring early. Indirect costs per participant per year, not including informal caregiver cost, were estimated at $30,601±31,184. The largest relative increase in indirect costs occurred at earlier mobility impairment stages, regardless of the measure used. Participants’ mean utility score (0.73±0.18) was lower than that of a similarly aged sample from the general US population (0.87). As with indirect costs, larger decrements in utility were seen at earlier mobility impairment stages. These results suggest that mobility impairment may contribute to increases in indirect costs and declines in HRQoL in MS patients.
doi:10.1371/journal.pone.0054756
PMCID: PMC3552958  PMID: 23355896
10.  Cost-Effectiveness of Apixaban Compared with Warfarin for Stroke Prevention in Atrial Fibrillation 
PLoS ONE  2012;7(10):e47473.
Background
Apixaban was shown to be superior to adjusted-dose warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF) and at least one additional risk factor for stroke, and associated with reduced rates of hemorrhage. We sought to determine the cost-effectiveness of using apixaban for stroke prevention.
Methods
Based on the results from the Apixaban Versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial and other published studies, we constructed a Markov model to evaluate the cost-effectiveness of apixaban versus warfarin from the Medicare perspective. The base-case analysis assumed a cohort of 65-year-old patients with a CHADS2 score of 2.1 and no contraindication to oral anticoagulation. We utilized a 2-week cycle length and a lifetime time horizon. Outcome measures included costs in 2012 US$, quality-adjusted life-years (QALYs), life years saved and incremental cost-effectiveness ratios.
Results
Under base case conditions, quality adjusted life expectancy was 10.69 and 11.16 years for warfarin and apixaban, respectively. Total costs were $94,941 for warfarin and $86,007 for apixaban, demonstrating apixaban to be a dominant economic strategy. Upon one-way sensitivity analysis, these results were sensitive to variability in the drug cost of apixaban and various intracranial hemorrhage related variables. In Monte Carlo simulation, apixaban was a dominant strategy in 57% of 10,000 simulations and cost-effective in 98% at a willingness-to-pay threshold of $50,000 per QALY.
Conclusions
In patients with AF and at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%, treatment with apixaban may be a cost-effective alternative to warfarin.
doi:10.1371/journal.pone.0047473
PMCID: PMC3467203  PMID: 23056642
11.  Effect of Biologic Agents on Non-PASI Outcomes in Moderate-to-Severe Plaque Psoriasis: Systematic Review and Meta-Analyses 
Introduction
The objective of this review was to conduct a systematic review with meta-analysis and Bayesian mixed treatment comparisons (MTC) evaluating the impact of biologics on non-Psoriasis Area and Severity Index (PASI) health outcomes in patients with moderate-to-severe plaque psoriasis.
Methods
MEDLINE and Cochrane Central Register of Controlled Trials were searched from 1966 to May 2009. Citations were screened for randomized, controlled trials of biologics versus either placebo or each other in adults with moderate-to-severe plaque psoriasis and reported any of several outcomes. Traditional and Bayesian MTC meta-analyses were conducted for each endpoint using either a random- or fixed-effect model where appropriate.
Results
Thirty-eight studies met eligibility criteria. All biologics showed significant improvement in achieving a good response on the static physician’s global assessment (PGA) versus placebo while, in the MTC, differences were noted between individual drugs. In achieving a good response on the dynamic PGA, all biologics showed significant improvements over placebo, while the MTC showed significant improvements with the anti-interleukins versus anti-T cells. Relative to placebo, antitumor necrosis factor (TNF) agents and anti-interleukins showed significant improvements in the Dermatology Life Quality Index (DLQI). Compared with placebo, the anti-TNF agents showed significant improvements in both 36-item Medical Outcomes Study Short-Form General Health Survey (SF-36) mental and physical component scores, while anti-T cell agents showed no improvements. The MTC showed no differences between any biologics for either the DLQI or SF-36.
Conclusion
Individual biologics and classes showed consistent benefits across non-PASI health outcomes in patients with moderate-to-severe plaque psoriasis while MTC meta-analyses suggested that some differences exist.
doi:10.1007/s13555-012-0009-3
PMCID: PMC3510417  PMID: 23205332
Biologics; Meta-analysis; Plaque psoriasis
12.  Effect of Biologic Agents on Non-PASI Outcomes in Moderate-to-Severe Plaque Psoriasis: Systematic Review and Meta-Analyses 
Dermatology and Therapy  2012;2(1):9.
Introduction
The objective of this review was to conduct a systematic review with meta-analysis and Bayesian mixed treatment comparisons (MTC) evaluating the impact of biologics on non-Psoriasis Area and Severity Index (PASI) health outcomes in patients with moderate-to-severe plaque psoriasis.
Methods
MEDLINE and Cochrane Central Register of Controlled Trials were searched from 1966 to May 2009. Citations were screened for randomized, controlled trials of biologics versus either placebo or each other in adults with moderate-to-severe plaque psoriasis and reported any of several outcomes. Traditional and Bayesian MTC meta-analyses were conducted for each endpoint using either a random- or fixed-effect model where appropriate.
Results
Thirty-eight studies met eligibility criteria. All biologics showed significant improvement in achieving a good response on the static physician’s global assessment (PGA) versus placebo while, in the MTC, differences were noted between individual drugs. In achieving a good response on the dynamic PGA, all biologics showed significant improvements over placebo, while the MTC showed significant improvements with the anti-interleukins versus anti-T cells. Relative to placebo, antitumor necrosis factor (TNF) agents and anti-interleukins showed significant improvements in the Dermatology Life Quality Index (DLQI). Compared with placebo, the anti-TNF agents showed significant improvements in both 36-item Medical Outcomes Study Short-Form General Health Survey (SF-36) mental and physical component scores, while anti-T cell agents showed no improvements. The MTC showed no differences between any biologics for either the DLQI or SF-36.
Conclusion
Individual biologics and classes showed consistent benefits across non-PASI health outcomes in patients with moderate-to-severe plaque psoriasis while MTC meta-analyses suggested that some differences exist.
doi:10.1007/s13555-012-0009-3
PMCID: PMC3510417  PMID: 23205332
Biologics; Meta-analysis; Plaque psoriasis
13.  Chapter 8: Meta-analysis of Test Performance When There is a “Gold Standard” 
Journal of General Internal Medicine  2012;27(Suppl 1):56-66.
Synthesizing information on test performance metrics such as sensitivity, specificity, predictive values and likelihood ratios is often an important part of a systematic review of a medical test. Because many metrics of test performance are of interest, the meta-analysis of medical tests is more complex than the meta-analysis of interventions or associations. Sometimes, a helpful way to summarize medical test studies is to provide a “summary point”, a summary sensitivity and a summary specificity. Other times, when the sensitivity or specificity estimates vary widely or when the test threshold varies, it is more helpful to synthesize data using a “summary line” that describes how the average sensitivity changes with the average specificity. Choosing the most helpful summary is subjective, and in some cases both summaries provide meaningful and complementary information. Because sensitivity and specificity are not independent across studies, the meta-analysis of medical tests is fundamentaly a multivariate problem, and should be addressed with multivariate methods. More complex analyses are needed if studies report results at multiple thresholds for positive tests. At the same time, quantitative analyses are used to explore and explain any observed dissimilarity (heterogeneity) in the results of the examined studies. This can be performed in the context of proper (multivariate) meta-regressions.
doi:10.1007/s11606-012-2029-1
PMCID: PMC3364353  PMID: 22648676
gold standard; test performance; meta-analysis
14.  Predictors of warfarin use in atrial fibrillation in the United States: a systematic review and meta-analysis 
BMC Family Practice  2012;13:5.
Background
Despite warfarin's marked efficacy, not all eligible patients receive it for stroke prevention in AF. The aim of this meta-analysis was to evaluate the association between prescriber and/or patient characteristics and subsequent prescription of warfarin for stroke prevention in patients with atrial fibrillation (AF).
Methods
Observational studies conducted in the US using multivariate analysis to determine the relationship between characteristics and the odds of receiving warfarin for stroke prevention were identified in MEDLINE, EMBASE and a manual review of references. Effect estimates of prescriber and/or patient characteristics from individual studies were pooled to calculate odds ratios (ORs) with 95% confidence intervals.
Results
Twenty-eight studies reporting results of 33 unique multivariate analyses were identified. Warfarin use across studies ranged from 9.1%-79.8% (median = 49.1%). There was a moderately-strong correlation between warfarin use and year of study (r = 0.60, p = 0.002). Upon meta-analysis, characteristics associated with a statistically significant increase in the odds of warfarin use included history of cerebrovascular accident (OR = 1.59), heart failure (OR = 1.36), and male gender (OR = 1.12). Those associated with a significant reduction in the odds of warfarin use included alcohol/drug abuse (OR = 0.62), perceived barriers to compliance (OR = 0.87), contraindication(s) to warfarin (OR = 0.81), dementia (OR = 0.32), falls (OR = 0.60), gastrointestinal hemorrhage (OR = 0.47), intracranial hemorrhage (OR = 0.39), hepatic (OR = 0.59), and renal impairment (OR = 0.69). While age per 10-year increase (OR = 0.78) and advancing age as a dichotomized variable (cut-off varied by study) (OR = 0.57) were associated with significant reductions in warfarin use; qualitative review of results of studies evaluating age as a categorical variable did not confirm this relationship.
Conclusions
Warfarin use has increased somewhat over time. The decision to prescribe warfarin for stroke prevention in atrial fibrillation is based upon multiple prescriber and patient characteristics. These findings can be used by family practice prescribers and other healthcare decision-makers to target interventions or methods to improve utilization of warfarin when it is indicated for stroke prevention.
doi:10.1186/1471-2296-13-5
PMCID: PMC3395868  PMID: 22304704
15.  Association Between CHADS2 Risk Factors and Anticoagulation-Related Bleeding: A Systematic Literature Review 
Mayo Clinic Proceedings  2011;86(6):509-521.
OBJECTIVE: To determine the strength of evidence supporting an accentuated bleeding risk when patients with CHADS2 risk factors (chronic heart failure, hypertension, advanced age, diabetes, and prior stroke/transient ischemic attack) receive warfarin.
METHODS: A systematic literature search of MEDLINE (January 1, 1950, through December 22, 2009) and Cochrane CENTRAL (through December 22, 2009) was conducted to identify studies that reported multivariate results on the association between CHADS2 covariates and risk of bleeding in patients receiving warfarin. Each covariate was evaluated for its association with a specific type of bleeding. Individual evaluations were rated as good, fair, or poor using methods consistent with those recommended by the Agency for Healthcare Research and Quality. The strength of the associations between each CHADS2 covariate and a specific type of bleeding was determined using Grading of Recommendations Assessment, Development and Evaluation criteria as insufficient, very low, low, moderate, or high for the entire body of evidence.
RESULTS: Forty-one studies were identified, reporting 127 multivariate evaluations of the association between a CHADS2 covariate and bleeding risk. No CHADS2 covariate had a high strength of evidence for association with any bleeding type. For the vast majority of evaluations, the strength of evidence between covariates and bleeding was low. Advanced age was the only covariate that had a moderate strength of evidence for association; this was the strongest independent positive predictor for major bleeding. Similar findings were observed regardless of whether all included studies, or only those evaluating patients with atrial fibrillation, were assessed.
CONCLUSION: The associations between CHADS2 covariates and increased bleeding risk were weak, with the exception of age. Given the known association of the CHADS2 score and stroke risk, the decision to prescribe warfarin should be driven more by patients' risk of stroke than by the risk of bleeding.
The associations between CHADS2 covariates and increased bleeding risk were weak, with the exception of age; given the known association of CHADS2 score and stroke risk, the decision to prescribe warfarin should be driven more by the patient's risk of stroke than by risk of bleeding.
doi:10.4065/mcp.2010.0755
PMCID: PMC3104910  PMID: 21628615
16.  Number and Impact of Published Scholarly Works by Pharmacy Practice Faculty Members at Accredited US Colleges and Schools of Pharmacy (2001-2003) 
Objective
To evaluate the quantity and quality of published literature conducted by pharmacy practice faculty members in US colleges and schools of pharmacy for the years 2001-2003.
Methods
The Web of Science bibliographic database was used to identify publication citations for the years 2001-2003, which were then evaluated in a number of different ways. Faculty members were identified using American Association of Colleges of Pharmacy rosters for the 2000-2001, 2001-2002, and 2002-2003 academic years.
Results
Two thousand three hundred seventy-four pharmacy practice faculty members generated 1,896 publications in Web of Science searchable journals. A small number of faculty members (2.1%) were responsible for a large proportion of publications (30.6%), and only 4.9% of faculty members published 2 or more publications in these journals per year. The average impact factor for the top 200 publications was 7.6.
Conclusion
Pharmacy practice faculty members contributed substantially to the biomedical literature and their work has had an important impact. A substantial portion of this work has come from a small subset of faculty members.
PMCID: PMC1913293  PMID: 17619644
17.  Novel Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Systematic Review of Cost-Effectiveness Models 
PLoS ONE  2013;8(4):e62183.
Objective
To conduct a systematic review of economic models of newer anticoagulants for stroke prevention in atrial fibrillation (SPAF).
Patients and Methods
We searched Medline, Embase, NHSEED and HTA databases and the Tuft’s Registry from January 1, 2008 through October 10, 2012 to identify economic (Markov or discrete event simulation) models of newer agents for SPAF.
Results
Eighteen models were identified. Each was based on a lone randomized trial/new agent, and these trials were clinically and methodologically heterogeneous. Dabigatran 150 mg, 110 mg and sequentially-dosed were assessed in 9, 8, and 9 models, rivaroxaban in 4 and apixaban in 4. Warfarin was a first-line comparator in 94% of models. Models were conducted from United States (44%), European (39%) and Canadian (17%) perspectives. Models typically assumed patients between 65–73 years old at moderate-risk of stroke initiated anticoagulation for/near a lifetime. All models reported cost/quality-adjusted life-year, 22% reported using a societal perspective, but none included indirect costs. Four models reported an incremental cost-effectiveness ratio (ICER) for a newer anticoagulant (dabigatran 110 mg (n = 4)/150 mg (n = 2); rivaroxaban (n = 1)) vs. warfarin above commonly reported willingness-to-pay thresholds. ICERs vs. warfarin ranged from $3,547–$86,000 for dabigatran 150 mg, $20,713–$150,000 for dabigatran 110 mg, $4,084–$21,466 for sequentially-dosed dabigatran and $23,065–$57,470 for rivaroxaban. Apixaban was found economically-dominant to aspirin, and dominant or cost-effective ($11,400–$25,059) vs. warfarin. Indirect comparisons from 3 models suggested conflicting comparative cost-effectiveness results.
Conclusions
Cost-effectiveness models frequently found newer anticoagulants cost-effective, but the lack of head-to-head trials and the heterogeneous characteristics of underlying trials and modeling methods make it difficult to determine the most cost-effective agent.
doi:10.1371/journal.pone.0062183
PMCID: PMC3633898  PMID: 23626785
18.  Systematic review: comparative effectiveness of adjunctive devices in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention of native vessels 
Background
During percutaneous coronary intervention (PCI), dislodgement of atherothrombotic material from coronary lesions can result in distal embolization, and may lead to increased major adverse cardiovascular events (MACE) and mortality. We sought to systematically review the comparative effectiveness of adjunctive devices to remove thrombi or protect against distal embolization in patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI of native vessels.
Methods
We conducted a systematic literature search of Medline, the Cochrane Database, and Web of Science (January 1996-March 2011), http://www.clinicaltrials.gov, abstracts from major cardiology meetings, TCTMD, and CardioSource Plus. Two investigators independently screened citations and extracted data from randomized controlled trials (RCTs) that compared the use of adjunctive devices plus PCI to PCI alone, evaluated patients with STEMI, enrolled a population with 95% of target lesion(s) in native vessels, and reported data on at least one pre-specified outcome. Quality was graded as good, fair or poor and the strength of evidence was rated as high, moderate, low or insufficient. Disagreement was resolved through consensus.
Results
37 trials met inclusion criteria. At the maximal duration of follow-up, catheter aspiration devices plus PCI significantly decreased the risk of MACE by 27% compared to PCI alone. Catheter aspiration devices also significantly increased the achievement of ST-segment resolution by 49%, myocardial blush grade of 3 (MBG-3) by 39%, and thrombolysis in myocardial infarction (TIMI) 3 flow by 8%, while reducing the risk of distal embolization by 44%, no reflow by 48% and coronary dissection by 70% versus standard PCI alone. In a majority of trials, the use of catheter aspiration devices increased procedural time upon qualitative assessment.
Distal filter embolic protection devices significantly increased the risk of target revascularization by 39% although the use of mechanical thrombectomy or embolic protection devices did not significantly impact other final health outcomes. Distal balloon or any embolic protection device increased the achievement of MBG-3 by 61% and 20% and TIMI3 flow by 11% and 6% but did not significantly impact other intermediate outcomes versus control. Upon qualitative analysis, all device categories, with exception of catheter aspiration devices, appear to significantly prolong procedure time compared to PCI alone while none appear to significantly impact ejection fraction. Many of the final health outcome and adverse event evaluations were underpowered and the safety of devices overall is unclear due to insufficient amounts of data.
Conclusions
In patients with STEMI, for most devices, few RCTs evaluated final health outcomes over a long period of follow-up. Due to insufficient data, the safety of these devices is unclear.
doi:10.1186/1471-2261-11-74
PMCID: PMC3313863  PMID: 22185559

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