Vitamin D insufficiency is associated with many disorders, leading to calls for widespread supplementation. Some investigators suggest that more clinical trials to test the effect of vitamin D on ...disorders are needed.
We did a trial sequential meta-analysis of existing randomised controlled trials of vitamin D supplements, with or without calcium, to investigate the possible effect of future trials on current knowledge. We estimated the effects of vitamin D supplementation on myocardial infarction or ischaemic heart disease, stroke or cerebrovascular disease, cancer, total fracture, hip fracture, and mortality in trial sequential analyses using a risk reduction threshold of 5% for mortality and 15% for other endpoints.
The effect estimate for vitamin D supplementation with or without calcium for myocardial infarction or ischaemic heart disease (nine trials, 48 647 patients), stroke or cerebrovascular disease (eight trials 46 431 patients), cancer (seven trials, 48 167 patients), and total fracture (22 trials, 76 497 patients) lay within the futility boundary, indicating that vitamin D supplementation does not alter the relative risk of any of these endpoints by 15% or more. Vitamin D supplementation alone did not reduce hip fracture by 15% or more (12 trials, 27 834 patients). Vitamin D co-administered with calcium reduced hip fracture in institutionalised individuals (two trials, 3853 patients) but did not alter the relative risk of hip fracture by 15% or more in community-dwelling individuals (seven trials, 46 237 patients). There is uncertainty as to whether vitamin D with or without calcium reduces the risk of death (38 trials, 81 173).
Our findings suggest that vitamin D supplementation with or without calcium does not reduce skeletal or non-skeletal outcomes in unselected community-dwelling individuals by more than 15%. Future trials with similar designs are unlikely to alter these conclusions.
Health Research Council of New Zealand.
To determine postnatal changes in plasma and interstitial glucose concentrations of healthy infants receiving current recommended care and to compare the incidence of low concentrations with ...recommended thresholds for treatment of at-risk infants.
A prospective masked observational study in Hamilton, New Zealand. Healthy, term, appropriately grown singletons had continuous glucose monitoring and repeated heel-prick plasma glucose measurements (4 in the first 24 hours then twice daily using the glucose oxidase method) from birth to 120 hours.
The 67 infants had a mean birth weight of 3584 ± 349 g, and gestational age of 40.1 ± 1.2 weeks. The mean glucose concentrations increased over the first 18 hours, remained stable to 48 hours (59 ± 11 mg/dL; 3.3 ± 0.6 mmol/L) before increasing to a new plateau by the fourth day (89 ± 13 mg/dL; 4.6 ± 0.7 mmol/L). Plasma glucose concentrations of 47 mg/dL (2.6 mmol/L) approximated the 10th percentile in the first 48 hours, and 39% of infants had ≥1 episode below this threshold. Early term infants had lower mean glucose concentrations than those born at later gestational ages and were more likely to have episodes <47 mg/dL (<2.6 mmol/L) (19/32 59% vs 7/35 20%; relative risk, 3.0; 95% CI, 1.4-6.1; P = .001).
Healthy infants seem to complete their metabolic transition by day 4. Many have glucose concentrations below the accepted thresholds for treatment of hypoglycemia.
ACTRN: 12615000986572.
Objective To examine the evidence underpinning recommendations to increase calcium intake through dietary sources or calcium supplements to prevent fractures.Design Systematic review of randomised ...controlled trials and observational studies of calcium intake with fracture as an endpoint. Results from trials were pooled with random effects meta-analyses.Data sources Ovid Medline, Embase, PubMed, and references from relevant systematic reviews. Initial searches undertaken in July 2013 and updated in September 2014.Eligibility criteria for selecting studies Randomised controlled trials or cohort studies of dietary calcium, milk or dairy intake, or calcium supplements (with or without vitamin D) with fracture as an outcome and participants aged >50.Results There were only two eligible randomised controlled trials of dietary sources of calcium (n=262), but 50 reports from 44 cohort studies of relations between dietary calcium (n=37), milk (n=14), or dairy intake (n=8) and fracture outcomes. For dietary calcium, most studies reported no association between calcium intake and fracture (14/22 for total, 17/21 for hip, 7/8 for vertebral, and 5/7 for forearm fracture). For milk (25/28) and dairy intake (11/13), most studies also reported no associations. In 26 randomised controlled trials, calcium supplements reduced the risk of total fracture (20 studies, n=58 573; relative risk 0.89, 95% confidence interval 0.81 to 0.96) and vertebral fracture (12 studies, n=48 967. 0.86, 0.74 to 1.00) but not hip (13 studies, n=56 648; 0.95, 0.76 to 1.18) or forearm fracture (eight studies, n=51 775; 0.96, 0.85 to 1.09). Funnel plot inspection and Egger’s regression suggested bias toward calcium supplements in the published data. In randomised controlled trials at lowest risk of bias (four studies, n=44 505), there was no effect on risk of fracture at any site. Results were similar for trials of calcium monotherapy and co-administered calcium and vitamin D. Only one trial in frail elderly women in residential care with low dietary calcium intake and vitamin D concentrations showed significant reductions in risk of fracture.Conclusions Dietary calcium intake is not associated with risk of fracture, and there is no clinical trial evidence that increasing calcium intake from dietary sources prevents fractures. Evidence that calcium supplements prevent fractures is weak and inconsistent.
BACKGROUND:Statistical techniques can investigate data integrity in randomized controlled trials (RCTs). We systematically reviewed and analyzed all human RCTs undertaken by a group of researchers, ...about which concerns have been raised.
METHODS:We compared observed distributions of p values for between-groups differences in baseline variables, for standardized sample means for continuous baseline variables, and for differences in treatment group participant numbers with the expected distributions. We assessed productivity, recruitment rates, outcome data, textual consistency, and ethical oversight.
RESULTS:The researchers were remarkably productive, publishing 33 RCTs over 15 years involving large numbers of older patients with substantial comorbidity, recruited over very short periods. Treatment groups were improbably similar. The distribution of p values for differences in baseline characteristics differed markedly from the expected uniform distribution (p = 5.2 × 10). The distribution of standardized sample means for baseline continuous variables and the differences between participant numbers in randomized groups also differed markedly from the expected distributions (p = 4.3 × 10, p = 1.5 × 10, respectively). Outcomes were remarkably positive, with very low mortality and study withdrawals despite substantial comorbidity. There were very large reductions in hip fracture incidence, regardless of intervention (relative risk 0.22, 95% confidence interval 0.15–0.31, p < 0.0001, range of relative risk 0.10–0.33), that greatly exceed those reported in meta-analyses of other trials. There were multiple examples of inconsistencies between and within trials, errors in reported data, misleading text, duplicated data and text, and uncertainties about ethical oversight.
CONCLUSIONS:A systematic approach using statistical techniques to assess randomization outcomes can evaluate data integrity, in this case suggesting these RCT results may be unreliable.
Frequent use of personal, nonprotocol calcium supplements obscured an adverse effect of coadministered calcium and vitamin D (CaD) on cardiovascular risk in the Women's Health Initiative (WHI).
We ...investigated the effects of the use of personal calcium or vitamin D supplements on other outcomes in the WHI CaD Study (WHI CaD) by using the WHI limited-access clinical trials data set.
The WHI CaD was a 7-y, randomized, placebo-controlled trial of CaD (1 g Ca/400 IU vitamin D daily) in 36,282 community-dwelling, postmenopausal women. The incidence of total cancer (excluding nonmelanoma skin cancers), breast and colorectal cancers, hip and total fracture, and mortality was assessed by using Cox proportional hazards models.
In the WHI CaD, interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total, breast, and colorectal cancers but not for fracture or mortality. In 15,646 women (43%) who were not taking personal calcium or vitamin D supplements at randomization, CaD significantly decreased the risk of total, breast, and invasive breast cancers by 14-20% and nonsignificantly reduced the risk of colorectal cancer by 17%. In women taking personal calcium or vitamin D supplements, CaD did not alter cancer risk (HR: 1.06-1.26).
For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at randomization, CaD decreased the risk of total, breast, and colorectal cancers and did not change the risk of fractures or total mortality. The nonskeletal effects of CaD may be more important than the skeletal effects and should be considered when evaluating these supplements. The WHI CaD trial is registered at clinicaltrials.gov as NCT00000611.
Abstract
Aims
Whether prevalence and mortality of patients with heart failure with preserved or mid-range (40–49%) ejection fraction (HFpEF and HFmREF) are similar to those of heart failure with ...reduced ejection fraction (HFrEF), as reported in some epidemiologic studies, remains highly controversial. We determined and compared characteristics and outcomes for patients with HFpEF, HFmREF, and HFrEF in a prospective, international, multi-ethnic population.
Methods and results
Prospective multi-centre longitudinal study in New Zealand (NZ) and Singapore. Patients with HF were assessed at baseline and followed over 2 years. The primary outcome was death from any cause. Secondary outcome was death and HF hospitalization. Cox proportional hazards models were used to compare outcomes for patients with HFpEF, HFmrEF, and HFrEF. Of 2039 patients enrolled, 28% had HFpEF, 13% HFmrEF, and 59% HFrEF. Compared with HFrEF, patients with HFpEF were older (62 vs. 72 years), more commonly female (17% vs. 48%), and more likely to have a history of hypertension (61% vs. 78%) but less likely to have coronary artery disease (55% vs. 41%). During 2 years of follow-up, 343 (17%) patients died. Adjusting for age, sex, and clinical risk factors, patients with HFpEF had a lower risk of death compared with those with HFrEF (hazard ratio 0.62, 95% confidence interval 0.46–0.85). Plasma (NT-proBNP) was similarly related to mortality in both HFpEF, HFmrEF, and HFrEF independent of the co-variates listed and of ejection fraction. Results were similar for the composite endpoint of death or HF and were consistent between Singapore and NZ.
Conclusion
These prospective multinational data showed that the prevalence of HFpEF within the HF population was lower than HFrEF. Death rate was comparable in HFpEF and HFmrEF and lower than in HFrEF. Plasma levels of NT-proBNP were independently and similarly predictive of death in the three HF phenotypes.
Trial Registration
Australian New Zealand Clinical Trial Registry (ACTRN12610000374066).
Context: Fragility fractures cause significant morbidity and mortality. Effective osteoporosis treatment can reduce fracture incidence, but it is not known whether it reduces mortality.
Objective: ...The aim of the study was to determine whether effective osteoporosis treatment reduces mortality.
Data Sources: We searched Medline and the Cochrane Central Register of Trials prior to September 2008, as well as 2000–2008 American Society for Bone and Mineral Research conference abstracts.
Study Selection: Eligible studies were randomized placebo-controlled trials of approved doses of medications with proven efficacy in preventing both vertebral and nonvertebral fractures, in which the study duration was longer than 12 months and there were more than 10 deaths. Trials of estrogen and selective estrogen receptor modulators were specifically excluded.
Data Extraction: Data were extracted from the text of the retrieved articles, published meta-analyses, or the Food and Drug Administration web site.
Data Synthesis: Eight eligible studies of four agents (risedronate, strontium ranelate, zoledronic acid, and denosumab) were included in the primary analysis. During two alendronate studies, the treatment dose changed, and those studies were only included in secondary analyses. In the primary analysis, treatment was associated with an 11% reduction in mortality (relative risk, 0.89; 95% confidence interval, 0.80–0.99; P = 0.036). In the secondary analysis, the results were similar (relative risk, 0.90; 95% confidence interval, 0.81–1.0; P = 0.044). Mortality reduction was not related to age or incidence of hip or nonvertebral fracture, but was greatest in trials conducted in populations with higher mortality rates.
Conclusions: Treatments for osteoporosis with established vertebral and nonvertebral fracture efficacy reduce mortality in older, frailer individuals with osteoporosis who are at high risk of fracture.
In a meta-analysis of randomized placebo-controlled trials, effective osteoporosis treatments reduce mortality by approximately 10% in older, frailer individuals at high risk of fracture.
•In control datasets, the probability of both an identical mean and an identical SD for a baseline variable in separate randomized controlled trials or within an individual trial is low ...(<~3%)•Variables rounded to 1 significant figure or with small standard deviations have a higher proportion of identical summary statistics•We present an example of two randomized controlled trials with an improbably high proportion of identical summary statistics based on simulations and an example of an improbably high proportion of recurrent identical summary statistics in 34 independent cohort studies.•An unexpectedly high proportion of identical summary statistics may raise a “red flag” for concerns about publication integrity.
To examine the proposition that identical summary statistics (mean and/or SD) in different randomized controlled trials (RCT) or clinical cohorts can be explained by common or homogeneous source populations.
We estimated the probability of identical summary data in studies with high proportions of identical summary statistics, in simulations, and in control datasets.
The probability of both an identical mean and an identical SD for a variable in separate RCT is low (<~3%), unless the variable is rounded to 1 significant figure. In two RCT with identical summary statistics for 16 of 39 shared variables, simulations indicated the probability of the observed matches was <1 in 100,000. In 34 clinical cohorts with publication integrity concerns, the proportion of summary statistics from variables reported in ≥10 studies that were identical in ≥2 cohorts were high (42% for means, 52% for SD, and 29% for both), and improbable based on simulations and comparisons to control datasets.
The likelihood of multiple identical summary statistics within an individual RCT or across a body of RCT or cohort studies by the same research group is low, especially when both the mean, and the SD are identical, unless the variables are rounded to 1 significant figure.
Annual computed tomography (CT) is now widely recommended for lung cancer screening in the United States, although concerns remain regarding the potential harms, including those from overdiagnosis.
...To examine the effect of airflow limitation on overdiagnosis by comparing lung cancer incidence, histology, and stage shift in a subgroup of the National Lung Screening Trial (NLST).
In an NLST subgroup (n = 18,714), screening participants were randomized to annual computed tomography (CT, n = 9,357) or chest radiograph (n = 9,357) screening and monitored for a mean of 6.1 years. After baseline prebronchodilator spirometry, to identify the presence of airflow limitation, 18,475 subjects (99%) were assigned as having chronic obstructive pulmonary disease (COPD) or no COPD. Lung cancer prevalence, incidence, histology, and stage shift were compared after stratification by COPD.
For screening participants with spirometric COPD (n = 6,436), there was a twofold increase in lung cancer incidence (incident rate ratio, 2.15; P < 0.001) and, when compared according to screening arm, no excess lung cancers and comparable histology. Compared with chest radiography, there was also a trend favoring reduced late-stage and increased early-stage cancers in the CT arm (P = 0.054). For those with normal baseline spirometry (n = 12,039), we found an excess of lung cancers during screening in the CT arm, almost exclusively early-stage adenocarcinoma-related cancers (histology shift and overdiagnosis). After correction for these excess cancers, stage shift was marginal (P = 0.077).
In the CT arm of the NLST-ACRIN (American College of Radiology Imaging Network) cohort, COPD status was associated with a doubling of lung cancer incidence, no apparent overdiagnosis, and a more favorable stage shift.
Elevated serum urate is the most important causal risk factor for developing gout. However, in longitudinal cohort studies, a small proportion of people with normal urate levels develop gout and the ...majority of those with high urate levels do not. These observations may be due to subsequent variations in serum urate over time. Our analysis examined whether single or repeat testing of serum urate more accurately predicts incident gout over time. Individual participant data from three publicly-available cohorts were included. Data from paired serum urate measures 3-5 years apart, followed by an assessment of gout incidence 5-6 years from the second urate measure were used to calculate the predictive ability of four measures of serum urate on incident gout: the first measure, the second measure, the average of the two measures, and the highest of the two measures. Participants with prevalent gout prior to the second measure were excluded. Receiver operator characteristic (ROC) curves and area under the curve (AUC) statistics were computed to compare the four measures. A total of 16,017 participants were included across the three cohorts, with a mean follow-up from the first serum urate test of 9.3 years (range 8.9-10.1 years). Overall, there was a small increase in the mean serum urate between the first and second measures (322 μmol/L (5.42 mg/dL) vs. 340 μmol/L (5.71 mg/dL), P<0.001) which were a mean of 3.5 years apart, but the first and second measures were highly correlated (r = 0.81, P<0.001). No differences were observed in the predictive ability of incident gout between the four measures of serum urate measurement with ROC curve AUC statistics ranging between 0.81 (95% confidence intervals: 0.78-0.84) and 0.84 (95% confidence intervals: 0.81-0.87). These data show that repeat serum urate testing is not superior to a single measure of serum urate for prediction of incident gout over approximately one decade.
PDF
