Factors Associated with Results and Conclusions of Trials of Thiazolidinediones

Background

When a sponsor funds a study of two competing drugs in a head-to-head comparison, the results and conclusions are likely to favor the sponsor’s drug. Thiazolidinediones, oral medications used for the treatment of type 2 diabetes, are one of the most costly choices of oral anti-diabetic medications, yet they do not demonstrate clinically relevant differences in achieving lower glycosylated hemoglobin levels compared to other oral antidiabetic drugs. Our aim is to examine associations between research funding source, study design characteristics aimed at reducing bias, and other factors with the results and conclusions of randomized controlled trials (RCTs) of thiazolidinediones compared to other oral hypoglycemic agents.

Methods and Findings

This is a cross-sectional study of 61 published RCTs comparing a thiazolidinedione (glitazone) to another anti-diabetic drug or placebo for treatment of type 2 diabetes. Data on study design characteristics, funding source, author’s financial ties, results for primary outcomes, and author conclusions were extracted. Univariate logistic regression identified associations between independent variables and results and conclusions that favored the glitazone. Of the RCTs, 59% (36/61) were funded by industry, 39% (24/61) did not disclose any funding. Common study design weaknesses included inadequate blinding and lack of concealment of allocation. Trials that reported favorable glycemic control results for the glitazone were more likely to have adequate blinding (OR (95% CI)  = 5.42 (1.46, 21.19), p = 0.008) and have a corresponding author with financial ties to the glitazone manufacturer (OR (95% CI)  = 4.12 (1.05, 19.53); p = 0.04). Trials with conclusions favoring the glitazone were less likely to be funded by a comparator drug company than a glitazone company (OR (95% CI)  = 0.026 (0, 0.40), p = 0.003) and less likely to be published in journals with higher impact factors (OR (95% CI)  = 0.79 (0.62, 0.97), p = 0.011). One limitation of our study is that we categorized studies as funded by industry based on each article’s disclosure which could underestimate the number of industry sponsored studies and personal ties of investigators. Additionally, our study did not include any head-to-head comparisons of one glitazone to another.

Conclusions

Published RCT comparisons of glitazones with other anti-diabetic drugs or placebo are predominantly industry supported and this support, as well as the financial ties of study authors, appears to be associated with favorable findings.     

Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium

BackgroundHypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals.MethodsUsing a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).ResultsAlthough drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (P_interaction > 5.0×10⁻⁸). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (P_interaction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.     

Antihypertensive medications and survival in patients with cancer: A population-based retrospective cohort study

Background: The association between antihypertensive medications and survival in cancer patients remains unclear. Objectives: To explore the association between classes of antihypertensive drugs and survival in cancer patients. Methods: Provincial Cancer Registry data was linked with a Provincial Drug Program Information Network (DPIN) for patients with lung (n = 4241), colorectal (n = 3967), breast (n = 4019) or prostate (n = 3355) cancer between the years of 2004 and 2008. Cox regression analyses were used to compare survival of patients using beta blockers (BBs), angiotensin-converting enzyme inhibitors/receptor blockers (ACEi/ARB), calcium channel blockers (CCBs) or thiazide diuretics (TDs) to survival of patients who did not use any of these antihypertensive drugs. Survival of patients using only one class of antihypertensive drugs were compared to each other, with BBs as the reference class. Results: Compared to the antihypertensive drug non-user cohort, BBs had no effect on survival for any of the cancers. ACEi/ARBs use was weakly associated with increased deaths for breast cancer (HR: 1.22, 95% CI: 1.04–1.44) and lung cancer (HR: 1.11, 95% CI: 1.03–1.21) patients. Deaths were also increased with CCB use in patients with breast cancer (HR: 1.22, 95% CI: 1.02–1.47) and with TD use in lung cancer patients (HR: 1.1, 95% CI: 1.01–1.19). There was strong evidence (p-value <0.0001) of an increase in deaths with TD use for colorectal (HR: 1.28, 95% CI: 1.15–1.42), and prostate (HR 1.41, 1.2–1.65) cancer patients. When including only antihypertensive drug users prescribed one drug class, lung cancer patients receiving CCBs had improved survival compared to BBs (HR 0.79, 95% CI: 0.64–0.98). Conclusions: Some classes of antihypertensive agents are associated with a decreased survival in certain cancers. The decrease could be due to more comorbidities in antihypertensive drug users. However, CCB use was associated with improved survival in lung cancer patients.     

Conflicts of Interest among Authors of Clinical Practice Guidelines for Glycemic Control in Type 2 Diabetes Mellitus

Background

Conflict of interest (COI) is an important potential source of bias in the development of clinical practice guidelines (CPGs).

Objectives

To examine rates of disclosure of COI, including financial interests in companies that manufacture drugs that are recommended in CPGs on glycemic control in type 2 diabetes mellitus, and to explore the relationship between recommendations for specific drugs in a guideline and author COI.

Methods

We identified a cohort of relevant guidelines from the National Guideline Clearinghouse (NGC) and abstracted COI disclosures from all guideline authors for this observational, cross-sectional study. We determined which hypoglycemic drugs were recommended in each guideline, and explored the relationship between specific disclosures and whether a drug was recommended.

Results

Among 13 included guidelines, the percentage of authors with one or more financial disclosures varied from 0 to 94% (mean 44.2%), and was particularly high for two US-based guidelines (91% and 94%). Three guidelines disclosed no author financial COI. The percentage of authors with disclosures of financial interests in manufacturers of recommended drugs was also high (mean 30%). On average, 56% of manufacturers of patented drugs recommended in each guideline had one or more authors with a financial interest in their company. We did not find a significant relationship between financial interests and whether a drug was recommended in our sample; US-based guidelines were more likely to make recommendations for a specific drug compared to non-US based guidelines.

Discussion

Authors of this cohort of guidelines have financial interests directly related to the drugs that they are recommending. Although we did not find an association between author COI and drugs recommended in these guidelines and we cannot draw conclusions about the validity of the recommendations, the credibility of many of these guidelines is in doubt.     

Determinants of Medication Adherence to Antihypertensive Medications among a Chinese Population Using Morisky Medication Adherence Scale

Background and Objectives

Poor adherence to medications is one of the major public health challenges. Only one-third of the population reported successful control of blood pressure, mostly caused by poor drug adherence. However, there are relatively few reports studying the adherence levels and their associated factors among Chinese patients. This study aimed to study the adherence profiles and the factors associated with antihypertensive drug adherence among Chinese patients.

Methods

A cross-sectional study was conducted in an outpatient clinic located in the New Territories Region of Hong Kong. Adult patients who were currently taking at least one antihypertensive drug were invited to complete a self-administered questionnaire, consisting of basic socio-demographic profile, self-perceived health status, and self-reported medication adherence. The outcome measure was the Morisky Medication Adherence Scale (MMAS-8). Good adherence was defined as MMAS scores greater than 6 points (out of a total score of 8 points).

Results

From 1114 patients, 725 (65.1%) had good adherence to antihypertensive agents. Binary logistic regression analysis was conducted. Younger age, shorter duration of antihypertensive agents used, job status being employed, and poor or very poor self-perceived health status were negatively associated with drug adherence.

Conclusion

This study reported a high proportion of poor medication adherence among hypertensive subjects. Patients with factors associated with poor adherence should be more closely monitored to optimize their drug taking behavior.     

A review of the positive and negative effects of cardiovascular drugs on sexual function: a proposed table for use in clinical practice

Several antihypertensive drugs, such as diuretics and β-blockers, can negatively affect sexual function, leading to diminished quality of life and often to noncompliance with the therapy. Other drug classes, however, such as angiotensin II receptor blockers (ARBs) are able to improve patients’ sexual function. Sufficient knowledge about the effects of these widely used antihypertensive drugs will make it possible for cardiologists and general practitioners to spare and even improve patients’ sexual health by switching to different classes of cardiac medication. Nevertheless, previous data (part I) indicate that most cardiologists lack knowledge about the effects cardiovascular agents can have on sexual function and will thus not be able to provide the necessary holistic patient care with regard to prescribing these drugs. To be able to improve healthcare on this point, we aimed to provide a practical overview, for use by cardiologists as well as other healthcare professionals, dealing with sexual dysfunction in their clinical practices. Therefore, a systematic review of the literature was performed. The eight most widely used classes of antihypertensive drugs have been categorised in a clear table, marking whether they have a positive, negative or no effect on sexual function.     

Drivers of Wetland Conversion: a Global Meta-Analysis

Meta-analysis of case studies has become an important tool for synthesizing case study findings in land change. Meta-analyses of deforestation, urbanization, desertification and change in shifting cultivation systems have been published. This present study adds to this literature, with an analysis of the proximate causes and underlying forces of wetland conversion at a global scale using two complementary approaches of systematic review. Firstly, a meta-analysis of 105 case-study papers describing wetland conversion was performed, showing that different combinations of multiple-factor proximate causes, and underlying forces, drive wetland conversion. Agricultural development has been the main proximate cause of wetland conversion, and economic growth and population density are the most frequently identified underlying forces. Secondly, to add a more quantitative component to the study, a logistic meta-regression analysis was performed to estimate the likelihood of wetland conversion worldwide, using globally-consistent biophysical and socioeconomic location factor maps. Significant factors explaining wetland conversion, in order of importance, are market influence, total wetland area (lower conversion probability), mean annual temperature and cropland or built-up area. The regression analyses results support the outcomes of the meta-analysis of the processes of conversion mentioned in the individual case studies. In other meta-analyses of land change, similar factors (e.g., agricultural development, population growth, market/economic factors) are also identified as important causes of various types of land change (e.g., deforestation, desertification). Meta-analysis helps to identify commonalities across the various local case studies and identify which variables may lead to individual cases to behave differently. The meta-regression provides maps indicating the likelihood of wetland conversion worldwide based on the location factors that have determined historic conversions.     

Debate: Does it matter how you lower blood pressure?

Whether it matters how pressure is lowered has been debated since antihypertensive drugs proved to prevent cardiovascular events. However, in clinical trials, while the stroke benefit predicted by a given difference in blood pressure was achieved, the results for myocardial infarction were roughly half that expected. This suggested that adverse drug effects of diuretics and β-blockers might have detracted from their hypotensive effects. Trials with newer antihypertensive classes have revealed superior effects on outcomes associated with converting enzyme inhibitor use, and that α-blockers are less cardioprotective than diuretics. These studies establish that simple blood pressure reduction is an inadequate guide to therapy. The challenge now will be to determine the optimal therapy for each hypertensive patient.     

Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study

Objective To examine whether the association of inadequate or unclear allocation concealment and lack of blinding with biased estimates of intervention effects varies with the nature of the intervention or outcome.Design Combined analysis of data from three meta-epidemiological studies based on collections of meta-analyses.Data sources 146 meta-analyses including 1346 trials examining a wide range of interventions and outcomes.Main outcome measures Ratios of odds ratios quantifying the degree of bias associated with inadequate or unclear allocation concealment, and lack of blinding, for trials with different types of intervention and outcome. A ratio of odds ratios <1 implies that inadequately concealed or non-blinded trials exaggerate intervention effect estimates.Results In trials with subjective outcomes effect estimates were exaggerated when there was inadequate or unclear allocation concealment (ratio of odds ratios 0.69 (95% CI 0.59 to 0.82)) or lack of blinding (0.75 (0.61 to 0.93)). In contrast, there was little evidence of bias in trials with objective outcomes: ratios of odds ratios 0.91 (0.80 to 1.03) for inadequate or unclear allocation concealment and 1.01 (0.92 to 1.10) for lack of blinding. There was little evidence for a difference between trials of drug and non-drug interventions. Except for trials with all cause mortality as the outcome, the magnitude of bias varied between meta-analyses.Conclusions The average bias associated with defects in the conduct of randomised trials varies with the type of outcome. Systematic reviewers should routinely assess the risk of bias in the results of trials, and should report meta-analyses restricted to trials at low risk of bias either as the primary analysis or in conjunction with less restrictive analyses.     

Breastfeeding and Childhood Obesity: Shift of the Entire BMI Distribution or Only the Upper Parts?

A protective effect of breastfeeding on overweight (binary) has been reported by meta-analyses using logistic regression, whereas studies using linear regression and BMI (continuous) detected no significant association. To assess the relationship of these differences with different outcome classification, we compared results for linear, logistic, and quantile regression models in a cross-sectional data set of considerable size. Height, weight, and questionnaire data on 9,368 preschool children were collected during school-entry examinations in 1999 and 2002 in Bavaria, Southern Germany. We calculated multivariable linear, logistic, and quantile regression models with outcomes BMI, overweight, obesity, and BMI quantiles (as appropriate). Models considered the covariates breastfeeding (breastfed vs. never breastfed), gender, age, smoking in pregnancy, TV watching, maternal BMI, parental education, and early infant weight gain. No significant association was found in the linear regression model. In the logistic model, a significant association was observed for obesity (odds ratio: 0.72 (95% confidence interval (CI) 0.55, 0.94)). In quantile regression no significant point estimates were observed for the percentiles of 0.4-0.8. However, breastfeeding reduced the BMI of children having values on the 90th and 97th percentiles by -0.23 (95% CI -0.39, -0.07) and -0.26 (95% CI -0.45, -0.07) kg/m(2), respectively, on average. In contrast, breastfeeding was significantly associated with a low shift toward higher BMI values for BMI quantiles of 0.03 and from 0.1 to 0.3. The detection of associations between breastfeeding and childhood body composition might be related to the coding of the response variable (continuous or binary) and the statistical method used (linear, logistic, or quantile regression). Quantile regression should additionally be applied in such studies.     

Oral status and its association with obesity in Southern Brazilian older people

Background and objective: The loss of a functional dentition imposes eating difficulties and food avoidance, which may be detrimental in terms of nutritional status and health. The objective of this study was to investigate whether tooth loss and edentulism that were not rehabilitated with dental prostheses were associated with obesity among elderly in Southern Brazil. Materials and methods: A random sample of 872 independently living elderly was evaluated by means of a cross‐sectional study. Socio‐demographic, medical history and behaviour data were assessed using a standardised questionnaire. Two trained dentists assessed the number of teeth and use of prostheses in accordance with the WHO criteria. Height and weight were assessed and used to generate body mass index (BMI = weight (kilos)/height (cm)²) data. Participants were categorised into non‐obese (BMI ≤ 30) or obese (BMI > 30). Multivariate logistic regression was used to model the relationship between number of teeth and use of dental prostheses with obesity adjusting for confounders. Results: Multivariate logistic regression revealed that edentulous persons wearing only upper dentures (OR = 2.34, 95% CI 1.18–4.27) and dentate participants with one to eight teeth wearing 0‐to‐1 prosthesis (OR = 2.96, 95% CI 1.68–5.19) were more likely to be obese. Conclusion: The results show that a poorer oral status, represented by having fewer teeth that were not replaced by dental prostheses, was associated with obesity in Southern Brazil older people, suggesting a close relationship between poor oral status and systemic conditions that may have important clinical implications.     

Outcomes of Adult In-Hospital Cardiac Arrest Treated with Targeted Temperature Management: A Retrospective Cohort Study

AimTargeted temperature management (TTM) for in-hospital cardiac arrest (IHCA) is given different recommendation levels within international resuscitation guidelines. We aimed to identify whether TTM would be associated with favourable outcomes following IHCA and to determine which factors would influence the decision to implement TTM.MethodsWe conducted a retrospective observational study in a single medical centre. We included adult patients suffering IHCA between 2006 and 2014. We used multivariable logistic regression analysis to evaluate associations between independent variables and outcomes.ResultsWe included a total of 678 patients in our analysis; only 22 (3.2%) patients received TTM. Most (81.1%) patients met at least one exclusion criteria for TTM. In all, 144 (21.2%) patients survived to hospital discharge; among them, 60 (8.8%) patients displayed favourable neurological status at discharge. TTM use was significantly associated with favourable neurological outcome (OR: 3.74, 95% confidence interval [CI]: 1.19–11.00; p-value = 0.02), but it was not associated with survival (OR: 1.41, 95% CI: 0.54–3.66; p-value = 0.48). Arrest in the emergency department was positively associated with TTM use (OR: 22.48, 95% CI: 8.40–67.64; p value < 0.001) and having vasopressors in place at the time of arrest was inversely associated with TTM use (OR: 0.08, 95% CI: 0.004–0.42; p-value = 0.02).ConclusionTTM might be associated with favourable neurological outcome of IHCA patients, irrespective of arrest rhythms. The prevalence of proposed exclusion criteria for TTM was high among IHCA patients, but these factors did not influence the use of TTM in clinical practice or neurological outcomes after IHCA.     

The Geometric Increase in Meta-Analyses from China in the Genomic Era

Meta-analyses are increasingly popular. It is unknown whether this popularity is driven by specific countries and specific meta-analyses types. PubMed was used to identify meta-analyses since 1995 (last update 9/1/2012) and catalogue their types and country of origin. We focused more on meta-analyses from China (the current top producer of meta-analyses) versus the USA (top producer until recently). The annual number of meta-analyses from China increased 40-fold between 2003 and 2011 versus 2.4-fold for the USA. The growth of Chinese meta-analyses was driven by genetics (110-fold increase in 2011 versus 2003). The HuGE Navigator identified 612 meta-analyses of genetic association studies published in 2012 from China versus only 109 from the USA. We compared in-depth 50 genetic association meta-analyses from China versus 50 from USA in 2012. Meta-analyses from China almost always used only literature-based data (92%), and focused on one or two genes (94%) and variants (78%) identified with candidate gene approaches (88%), while many USA meta-analyses used genome-wide approaches and raw data. Both groups usually concluded favorably for the presence of genetic associations (80% versus 74%), but nominal significance (P<0.05) typically sufficed in the China group. Meta-analyses from China typically neglected genome-wide data, and often included candidate gene studies published in Chinese-language journals. Overall, there is an impressive rise of meta-analyses from China, particularly on genetic associations. Since most claimed candidate gene associations are likely false-positives, there is an urgent global need to incorporate genome-wide data and state-of-the art statistical inferences to avoid a flood of false-positive genetic meta-analyses.     

Nonindustry-Sponsored Preclinical Studies on Statins Yield Greater Efficacy Estimates Than Industry-Sponsored Studies: A Meta-Analysis

Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966–April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I² statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (−1.99; 95% CI −2.68, −1.31) versus studies sponsored by industry (−0.73; 95% CI −1.00, −0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study.     

Bayesian multivariate logistic regression

Bayesian analyses of multivariate binary or categorical outcomes typically rely on probit or mixed effects logistic regression models that do not have a marginal logistic structure for the individual outcomes. In addition, difficulties arise when simple noninformative priors are chosen for the covariance parameters. Motivated by these problems, we propose a new type of multivariate logistic distribution that can be used to construct a likelihood for multivariate logistic regression analysis of binary and categorical data. The model for individual outcomes has a marginal logistic structure, simplifying interpretation. We follow a Bayesian approach to estimation and inference, developing an efficient data augmentation algorithm for posterior computation. The method is illustrated with application to a neurotoxicology study.     

Long-Term Use of Angiotensin Receptor Blockers and the Risk of Cancer

The association between angiotensin receptor blockers (ARBs) and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK) General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan) entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years). When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96–1.03) or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06–1.20 and RR: 1.19; 95% CI: 1.12–1.27, respectively). This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.     

Hospitalización Domiciliaria Integral para la atención a pacientes mayores con procesos agudos discapacitantes: factores predictivos de éxito terapéutico

IntroductionSeveral authors have demonstrated the efficacy of different hospital-at-home strategies in older patients. The identification of prognostic factors is key for improving the targeting process of candidates.MethodsWe performed an analysis of a cohort of older patients attended due to disabling health crises (medical, orthopaedics, or stroke) by a hospital-at-home scheme developed in an integrated care institution over a 5-year period. Main outcomes were: health crisis resolution (discharge to Primary Care); functional resolution (relative functional gain ≥ 35%), and their combined variable. A logistic regression analysis was performed, including clinical variables from Comprehensive Geriatric Assessment at admission to detect factors related to favourable outcomes.ResultsA total of 484 patients were included. The main characteristics were: age 84.4 (6.7), female gender 69%, baseline Barthel score 74.2 (22.6), family-private caregiver/nursing home 82%/18%, referral from hospital wards/emergency department-community in 55%/45%. The main results (for selected processes medical/orthopaedics/stroke) were: health crisis resolution 71.7/87.5/77.6%; functional resolution 72.1/84.9/73.5%; favourable crisis resolution (health crisis resolution with functional resolution) 67.1/81.6/67.3%. Favourable crisis resolution was associated with [OR (95% CI)]: orthopaedic as main diagnosis [2.00 (1.22-3.29)], Barthel score at admission higher than 40 points [2.00 (1.18-3.38)], and the absence of pressure ulcers at admission [2.80 (1.68-4.65)].ConclusionsPatients presenting with an orthopaedic diagnosis, not having severe disability at admission, and not having pressure ulcers at admission could obtain better results on favourable crisis resolution. Suffering cognitive impairment or delirium, or being institutionalised, was not found related with less favourable results.     

Characteristics and treatment outcomes of patients with MDR and XDR tuberculosis in a TB referral hospital in Beijing: a 13-year experience

Background

Information on treatment outcomes among hospitalized patients with multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are scarce in China.

Methodology/Principal Findings

We conducted this retrospective study to analyze the characteristics and treatment outcomes in MDR- and XDR-TB patients in the 309 Hospital in Beijing, China during 1996–2009. Socio-demographic and clinical data were retrieved from medical records and analyzed. Logistic regression analysis was performed to identify risk factors associated with poor treatment outcomes and Cox proportional hazards regression model was further used to determine risk factors associated with death in TB patients. Among the 3,551 non-repetitive hospitalized TB patients who had drug susceptibility testing (DST) results, 716 (20.2%) had MDR-TB and 51 (1.4%) had XDR-TB. A total of 3,270 patients who had medical records available were used for further analyses. Treatment success rates (cured and treatment completed) were 90.9%, 53.4% and 29.2% for patients with non-MDR-TB, patients with MDR-TB excluding XDR-TB and patients with XDR-TB, respectively. Independent risk factors associated with poor treatment outcomes in MDR-TB patients included being a migrant (adjusted OR = 1.77), smear-positivity at treatment onset (adjusted OR = 1.94) and not receiving 3 or more potentially effective drugs (adjusted OR = 3.87). Independent risk factors associated with poor treatment outcomes in XDR-TB patients were smear-positivity at treatment onset (adjusted OR = 10.42) and not receiving 3 or more potentially effective drugs (adjusted OR = 14.90). The independent risk factors associated with death in TB patients were having chronic obstructive pulmonary disease (adjusted HR = 5.25) and having hypertension (adjusted HR = 4.31).

Conclusions/Significance

While overall satisfactory treatment success for non-MDR-TB patients was achieved, more intensive efforts should be made to better manage MDR- and XDR-TB cases in order to improve their treatment outcomes and to minimize further emergence of so-called totally drug-resistant TB cases.     

A Case Study of Discordant Overlapping Meta-Analyses: Vitamin D Supplements and Fracture

Background

Overlapping meta-analyses on the same topic are now very common, and discordant results often occur. To explore why discordant results arise, we examined a common topic for overlapping meta-analyses- vitamin D supplements and fracture.

Methods and Findings

We identified 24 meta-analyses of vitamin D (with or without calcium) and fracture in a PubMed search in October 2013, and analysed a sample of 7 meta-analyses in the highest ranking general medicine journals. We used the AMSTAR tool to assess the quality of the meta-analyses, and compared their methodologies, analytic techniques and results. Applying the AMSTAR tool suggested the meta-analyses were generally of high quality. Despite this, there were important differences in trial selection, data extraction, and analytical methods that were only apparent after detailed assessment. 25 trials were included in at least one meta-analysis. Four meta-analyses included all eligible trials according to the stated inclusion and exclusion criteria, but the other 3 meta-analyses “missed” between 3 and 8 trials, and 2 meta-analyses included apparently ineligible trials. The relative risks used for individual trials differed between meta-analyses for total fracture in 10 of 15 trials, and for hip fracture in 6 of 12 trials, because of different outcome definitions and analytic approaches. The majority of differences (11/16) led to more favourable estimates of vitamin D efficacy compared to estimates derived from unadjusted intention-to-treat analyses using all randomised participants. The conclusions of the meta-analyses were discordant, ranging from strong statements that vitamin D prevents fractures to equally strong statements that vitamin D without calcium does not prevent fractures.

Conclusions

Substantial differences in trial selection, outcome definition and analytic methods between overlapping meta-analyses led to discordant estimates of the efficacy of vitamin D for fracture prevention. Strategies for conducting and reporting overlapping meta-analyses are required, to improve their accuracy and transparency.     

Meta-Analysis of Clinical Fracture Risk Reduction of Antiosteoporosis Drugs: Direct and Indirect Comparisons and Meta-Regressions

ObjectiveAntiosteoporotic drug (AOD) trials have variabilities in duration and fracture risks. This study evaluated AOD’s versus controls regarding reduction in relative rates and rate differences in vertebral and hip fractures and comparative costs.MethodsPrimary randomized controlled trials of antiosteoporotic drugs in postmenopausal women with documentation of vertebral fracture rates or hip fracture rates were extracted from meta-analyses and PubMed through February 2021. Direct and indirect meta-analyses and meta-regressions analyzed the fracture reductions.ResultsThere were 24 randomized controlled trials of drug versus placebo (73 862 women) and 10 randomized controlled trials of drug versus drug. The reductions in the relative rates of vertebral fractures were significant for antiresorptive (alendronate, risedronate, zoledronate, denosumab, and raloxifene) and anabolic (teriparatide, abaloparatide, and romosozumab) drugs. Denosumab, teriparatide, and abaloparatide were more effective in reducing vertebral fracture rates than oral bisphosphates (all P < .05) but were not more effective in reducing vertebral fracture rates than zoledronate. The reductions in hip fracture rates were significant for alendronate, denosumab, and zoledronate (all P < .05), without significant differences among drugs. Anabolic drugs did not show significant hip fracture rate reduction. Meta-regression of rate differences enabled the calculation of costs per vertebral fracture prevented, which were estimated at >$100 000 for anabolic drugs and between $2289 and $28 947 for antiresorptive drugs. Many direct drug versus drug trials were underpowered to demonstrate benefits of one drug over another.ConclusionThis study suggests goal-directed, cost-effective therapies relative to patient risk for vertebral and hip fractures. Anabolic drugs are better at preventing vertebral fractures than oral bisphosphonates. Anabolic drugs are not superior to zoledronate or denosumab and are substantially more expensive. When comparing drugs that prevented hip fractures, there was no statistical benefit of any drug.